[Federal Register Volume 71, Number 167 (Tuesday, August 29, 2006)]
[Proposed Rules]
[Pages 51276-51357]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 06-7172]



[[Page 51275]]

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Part II





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Parts 20, 201, 207, et al.



Requirements for Foreign and Domestic Establishment Registration and 
Listing for Human Drugs, Including Drugs that are Regulated Under a 
Biologics License Application, and Animal Drugs; Proposed Rule

  Federal Register / Vol. 71, No. 167 / Tuesday, August 29, 2006 / 
Proposed Rules  

[[Page 51276]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 201, 207, 314, 330, 514, 515, 601, 607, 610, and 
1271

[Docket No. 2005N-0403]
RIN 0910-AA49


Requirements for Foreign and Domestic Establishment Registration 
and Listing for Human Drugs, Including Drugs that are Regulated Under a 
Biologics License Application, and Animal Drugs

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA) is proposing to amend 
its regulations governing drug establishment registration and drug 
listing. The proposed revisions would reorganize, consolidate, clarify, 
and modify current regulations concerning who must register 
establishments and list human drugs, human drugs that are also 
biological products (including vaccines and allergenic products), and/
or human cells, tissues, and cellular and tissue-based products (HCT/
Ps), and animal drugs. The proposal describes when and how to register 
and list and what information must be submitted for registration and 
listing. In addition, the proposal would make certain changes to the 
National Drug Code (NDC) system and would require the appropriate NDC 
number to appear on the labels for drugs subject to the listing 
requirements. The proposed regulations generally would require the 
electronic submission of all registration and most listing information. 
We (FDA) rely on establishment registration and drug listing 
information for administering many of our programs, such as 
postmarketing surveillance (including FDA inspections), bioterrorism, 
drug shortages and availability, and user fee assessments. We are 
taking this action to use the latest technology to improve our 
registration and listing system, which would further our goal of 
protecting the public health. We also believe that the conversion to an 
electronic system would make the registration and listing processes 
more efficient and effective for industry and us. We are also taking 
this action to support the implementation of, for example, the 
electronic prescribing provisions of the Medicare Prescription Drug, 
Improvement, and Modernization Act, our rulemaking requiring a bar code 
on certain drug products, and the DailyMed initiative.

DATES:  Submit written or electronic comments by November 27, 2006. 
Submit written comments on the information collection requirements by 
September 28, 2006 to OMB (see ADDRESSES). See section IX of this 
document for the proposed effective date and section X for the proposed 
compliance dates of a final rule based on this document.

ADDRESSES: You may submit comments, identified by Docket No. 2005N-0403 
and/RIN 0910-AA49, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm, including any personal information provided. For 
additional information on submitting comments, see the ``Comments'' 
heading of the SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.
    Information Collection Provisions: Submit written comments on the 
information collection provisions to the Office of Information and 
Regulatory Affairs, Office of Management and Budget (OMB).To ensure 
that comments on the information collection are received, OMB 
recommends that written comments be faxed to the Office of Information 
and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-6974.

FOR FURTHER INFORMATION CONTACT: For information concerning drugs 
regulated by the Center for Drug Evaluation and Research (CDER): 
Herbert Gerstenzang or John W. Gardner, Center for Drug Evaluation and 
Research (HFD-330), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-8920, [email protected] or 
[email protected].
    For information concerning products regulated by the Center for 
Biologics Evaluation and Research (CBER): Valerie A. Butler, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6210, [email protected].
    For information concerning animal drugs: Lowell Fried (HFV-212) or 
Isabel W. Pocurull (HFV-226), Center for Veterinary Medicine (CVM), 
Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855, 
301-827-7820 or 240-453-6853, [email protected] or 
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Summary of Current Registration and Listing Requirements
    A. Summary of Section 510 of the Act
    B. Summary of Current Registration and Listing Regulations
    1. Who Must Register and List Under Current Regulations?
    2. What Are the Current Registration Requirements?
    3. What Are the Current Listing Requirements?
    4. What Are the Current Requirements Associated With the Use of 
the NDC Number?
    5. Who Is Exempt from Registration and Listing Under Current 
Regulations and Who Is Not Covered by the Current Registration and 
Listing Requirements in 21 CFR part 207?
    6. Do Current Regulations Permit the Disclosure of Registration 
and Listing Information?
III. Highlights of the Proposed Rule
    A. Proposed Changes to the Current Registration and Listing 
Requirements

[[Page 51277]]

    B. Promotion of Department of Health and Human Services Federal 
Health Information Technology Initiatives
IV. Description of the Proposed Rule
    A. General
    1. What Is the Purpose of Proposed Part 207?
    2. Who Would Part 207 Cover?
    3. Who Would Not Be Subject to Part 207?
    4. Who Would Be Exempt from Registration and Listing?
    5. What Definitions and Interpretations of Terms Would Apply to 
Part 207?
    B. Registration
    1. Who Would Be Required to Register?
    2. When Would Initial Registration Information Be Provided?
    3. What Information Would Be Required for Registration?
    4. What Are the Proposed Requirements for Reviewing and Updating 
Registration Information?
    C. The National Drug Code (NDC) Number: What is It? How is It 
Used? What Changes Are We Proposing?
    1. What Is the NDC Number?
    2. How Did NDC Numbers Originate? How Are They Used?
    3. What Changes Are We Proposing?
    4. How Do We Intend to Implement the NDC Number Changes?
    D. Listing
    1. Who Would Be Required to List Drugs?
    2. When Would Initial Listing Information Be Provided?
    3. What Listing Information Would Be Required?
    4. What Listing Information Would Be Required for Manufacturers?
    5. What Listing Information Would Be Required for Repackers and 
Relabelers?
    6. What Listing Information Would Be Required for Drug Product 
Salvagers Who are Not Repackers or Relabelers?
    7. What Additional Drug Listing Information May Be Required?
    8. What Are the Proposed Requirements for Reviewing and Updating 
Listing Information?
    E. Electronic Format
    1. How Would Registration and Listing Information Be Provided to 
FDA?
    2. What Was the Electronic Submission Pilot Project?
    3. How Would the Electronic Registration and Listing System 
Work?
    4. What Are the Proposed Requirements for the Submission of 
Content of Labeling in Electronic Format?
    5. Would the Proposal Require Electronic Submission of 
Advertisements and Other Labeling?
    6. What Guidance Documents Do We Intend To Issue on Providing 
Registration and Listing Information Electronically?
    7. How Would 21 CFR Part 11 Apply to the Electronic Submission 
of Registration and Listing Information?
    8. What Language Would Be Used to Provide Registration and 
Listing Information?
    9. Could the Electronic Format Requirements Be Waived?
    F. Miscellaneous
    1. What Are the Proposed Requirements for an Official Contact 
and a United States Agent?
    2. What Legal Status Is Conferred by Registration and Listing?
    3. What Registration and Listing Information Would Be Made 
Available for Public Disclosure?
    G. Conforming Actions
    1. Withdrawal from Sale of Drugs with Approved Marketing 
Applications
    2. Proposed Revisions to Other Regulations
    3. Compliance Verification Reports
V. Legal Authority
VI. Analysis of Economic Impacts
VII. Paperwork Reduction Act of 1995
VIII. Environmental Impact
IX. Proposed Effective Date
X. Proposed Compliance Dates
XI. Federalism
XII. Request for Comments
XIII. References

I. Background

    We originally published establishment registration regulations for 
human drugs, certain biological products, and animal drugs in the 
Federal Register of February 14, 1963 (28 FR 1457) (proposed rule) and 
April 3, 1963 (28 FR 3195) (final rule), and listing regulations for 
these drugs in the Federal Register of December 12, 1972 (37 FR 26431) 
(proposed rule) and March 7, 1973 (38 FR 6258) (final rule).
    We currently maintain a database containing the establishment 
registration and drug listing information submitted on paper to us. We 
rely on complete and accurate registration and listing information to 
accomplish a number of our statutory and regulatory objectives. For 
example, we use registration and listing information to:
     Identify the manufacturers, repackers, relabelers, and 
drug product salvagers of marketed drugs;\1\
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    \1\ ``Drug'' or ``drugs'' refers to human drugs, including drugs 
that are regulated under a biologics license application, and animal 
drugs (including Type A medicated articles), unless otherwise 
specifically stated. ``Drugs'' is defined in proposed Sec.  207.1 
and discussed in section IV.A.5 of this document. Biological 
products subject to proposed part 207 are described in proposed 
Sec.  207.9(c).
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     Identify the manufacturers, repackers, or relabelers of a 
specific drug or ingredient when that drug or ingredient is in short 
supply or is needed for a national emergency. This information helps us 
facilitate prompt drug shipment to the place where it is needed. For 
example, during a bioterrorism incident, we could use drug listing 
information to identify manufacturers, repackers, and relabelers of 
drugs that would be helpful in preventing or counteracting the deadly 
effects of biological weapons. With this information, we could 
facilitate prompt shipment of the drugs as needed;
     Facilitate the recall of drugs marketed by manufacturers, 
repackers, and relabelers;
     Identify and catalogue marketed drugs;
     Administer our postmarketing surveillance programs for 
drugs, including the drug surveillance sampling program that monitors 
the quality of the national drug supply;
     Identify drugs marketed in violation of the law;
     Schedule and plan inspections of registered establishments 
pursuant to section 704 of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 374); and
     Determine which marketed drugs are identical, related, or 
similar to drugs reviewed for effectiveness under the Drug Efficacy 
Study Implementation (DESI) program.
    We also rely on registration and listing information to help us 
comply with several other statutory provisions. We use the information 
to:
     Determine which entities are subject to establishment and 
product user fees under the prescription drug user fee program and the 
animal drug user fee program (21 U.S.C.379h and 379).
     Generate accurate estimates of the number of 
manufacturers, repackers, relabelers, and drug product salvagers and 
drugs that are affected by our rulemaking. These estimates help us 
assess the impact of our regulations on the regulated industry, which 
we are required to do under the Regulatory Flexibility Act (5 U.S.C. 
601-612), as amended by the Small Business Regulatory Enforcement 
Fairness Act (Public Law 104-121), the Unfunded Mandates Reform Act of 
1995 (2 U.S.C. 1501 et seq.), the Paperwork Reduction Act of 1995 (44 
U.S.C. 3501-3520), Executive Order 12866 (September 30, 1993), and the 
Congressional Review Act (section 251 of Public Law 104-121).
    Registration and listing information will continue to be used for 
all of the important public health purposes outlined above. Moreover, 
recent technological advances would allow us to enhance the usefulness 
of registration and listing information. Specifically, we are proposing 
that registration and listing information be submitted to us by using 
the electronic drug registration and listing system that we intend to 
develop. In addition to making the registration and listing process 
more efficient for industry, the electronic submission of registration 
and listing information would allow us to review and use such 
information more quickly and effectively in carrying out all of the

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activities described above. Electronic submission of this information 
would also allow us to fully support the implementation of the 
provisions of the Medicare Prescription Drug, Improvement, and 
Modernization Act (Public Law 108-173) (Medicare Modernization Act), 
specifically the electronic prescribing provisions. In addition, 
electronic submission of registration and listing information would 
further the purpose of several statutes:
     The Public Health Security and Bioterrorism Preparedness 
and Response Act of 2002 (Public Law 107-188) (Bioterrorism Act) 
amended section 510(i) of the act (21 U.S.C. 360(i)) to require that 
foreign establishments submit, among other things, registration 
information electronically.
     The Medical Device User Fee and Modernization Act of 2002 
(Public Law 107-250) also amended section 510 of the act (at section 
510(p)) to explicitly give the Secretary of Health and Human Services 
(the Secretary) discretion to require the electronic submission of 
registration information, upon a finding that electronic receipt of 
such registration information is feasible, unless the Secretary grants 
a request for a waiver.
     The Government Paperwork Elimination Act of 1998 (Public 
Law 105-277, Title XVII) (GPEA) requires Federal agencies to give 
persons who are required to maintain, submit, or disclose information 
the option of doing so electronically when practicable as a substitute 
for paper, and to use electronic authentication (electronic signature) 
methods to verify the identity of the sender and the integrity of the 
electronic content.
    We believe that conversion to the electronic submission of 
registration and listing information will further the purpose of these 
laws and make the registration and listing processes more efficient and 
effective for industry and us.

II. Summary of Current Registration and Listing Requirements

A. Summary of Section 510 of the Act

    Section 510(c) of the act requires every person upon first engaging 
in the ``manufacture, preparation, propagation, compounding, or 
processing'' of a drug in any establishment that he owns or operates in 
any State to immediately register his name and place of business and 
such establishment. Under section 510(a)(1) of the act, the term 
``manufacture, preparation, propagation, compounding, or processing'' 
must include ``repackaging or otherwise changing the container, 
wrapper, or labeling of any drug package * * * in furtherance of the 
distribution of the drug * * * from the original place of manufacture 
to the person who makes final delivery or sale to the ultimate consumer 
or user.'' Section 510(a)(2) of the act mandates that the term ``name'' 
include, among other things, the name of each partner of a partnership, 
and the name of each corporate officer and director of a corporation. 
An owner or operator of a registered establishment must also 
immediately register any additional establishment that he owns or 
operates in any State and in which he begins the ``manufacture, 
preparation, propagation, compounding, or processing'' of a drug 
(section 510(d) of the act). An owner or operator of any establishment 
that engages in these activities must register its establishment on or 
before December 31 of each year (section 510(b) of the act). Section 
510(i) of the act contains certain registration requirements pertaining 
to foreign establishments (e.g., submission of the name of each 
importer of a drug in the United States that is known to the 
establishment, submission of the name of each person who imports or 
offers for import a drug into the United States for purposes of 
importation). Section 510(g) of the act provides for certain exemptions 
from the registration requirements. In addition, section 510(p) of the 
act gives the Secretary discretion to require the electronic submission 
of registration information, upon a finding that electronic receipt of 
such registration information is feasible, unless the Secretary grants 
a request for a waiver.
    Section 510(j)(1) of the act requires that every person, at the 
time of registration, submit a list of all drugs that are being 
manufactured, prepared, propagated, compounded, or processed by him for 
commercial distribution and that have not been previously listed by 
him. This information must be submitted in the form and manner 
prescribed by the Secretary (section 510(j)(1) of the act). This 
listing information must be accompanied by, among other things, a copy 
of certain labeling and, in some cases, advertising for certain 
categories of drugs. Section 510(j)(2) of the act requires certain 
changes in listing information to be reported every June and December, 
including any material changes in information previously submitted 
under the listing provisions.
    Section 510(e) of the act permits the Secretary to assign a 
registration number to any person or any establishments registered 
under section 510 and a listing number to each drug or class of drugs 
listed under section 510(j) as long as the listing number is the same 
as that assigned pursuant to the National Drug Code. The disclosure 
provision in section 510(f) of the act requires the Secretary to make 
available for inspection any registration filed under section 510. 
Section 510(f) also provides that certain listing information must be 
exempt from disclosure unless the Secretary finds that such exemption 
would be inconsistent with protection of the public health.

B. Summary of Current Registration and Listing Regulations

1. Who Must Register and List Under Current Regulations?
    Under current part 207 (21 CFR part 207), with certain exceptions, 
owners or operators of establishments that engage in the manufacturing 
or processing of a drug or drugs must, in addition to other 
requirements, register their establishments and submit listing 
information for each of their drugs in commercial distribution.\2\ 
Notwithstanding certain exceptions, foreign drug establishments that 
manufacture, repack, or relabel a drug that is imported or offered for 
import into the United States must also comply with the registration 
and listing requirements. As explained in section IV.E of this 
document, all registration and listing information must currently be 
submitted to us using paper forms specified by us.
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    \2\``Drug or drugs'' includes drugs regulated under a BLA. For a 
description of biological products covered under proposed part 207, 
see proposed Sec.  207.9(c).
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2. What Are the Current Registration Requirements?
    Current requirements for registration include, among other things, 
the following provisions:
     Owners or operators of establishments entering into the 
manufacturing or processing of a drug or drugs must register their 
establishments within 5 days after beginning the manufacturing or 
processing of drugs at the establishments (Sec.  207.21(a)).
     If owners or operators of the establishments have not 
previously entered into such operations, then those owners or operators 
must register within 5 days after the submission of a new drug 
application (NDA), abbreviated new drug application (ANDA), new animal 
drug application (NADA), abbreviated new animal drug application 
(ANADA), medicated feed mill license application, or biologics license 
application (BLA) (Sec.  207.21(a)).

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     Owners or operators of establishments that are required to 
register must renew their registration annually in accordance with the 
specified schedule (Sec.  207.21(a)). Changes in individual ownership, 
corporate or partnership structure, location, or drug-handling activity 
must be submitted as amendments to registration within 5 days of such 
changes (Sec.  207.26).
     We assign a permanent registration number to each 
registered establishment (Sec.  207.35).
     Private label distributors that do not otherwise 
manufacture or process drugs are not required to register; however, 
they must submit specified information to us to obtain a labeler code 
(Sec.  207.20(b)). Private label distributors are owners or operators 
of establishments not otherwise required to register under section 510 
of the act that distribute under their own label or trade name a drug 
manufactured or processed by a registered establishment.
3. What Are the Current Listing Requirements?
    Current requirements for listing include, among other things, the 
following provisions:
     Owners or operators of establishments must, at the time of 
registration, submit a list of every drug being manufactured or 
processed in commercial distribution at that time (Sec.  207.21(a)).
     Private label distributors that do not otherwise 
manufacture or process drugs are not required to list, but may elect to 
submit listing information directly to us (Sec.  207.20(b)). Currently, 
private label distributors that elect to submit listing information 
directly to us assume full responsibility for compliance with the 
requirements of part 207 (Sec.  207.20(b)). Owners or operators of 
establishments that are required to register and list must submit 
listing information to us on behalf of private label distributors that 
do not elect to submit listing information directly to us (Sec.  
207.20(b)).
     Drugs that may be subject to current listing requirements 
include bulk drug substances; finished dosage forms, whether 
prescription or over-the-counter (OTC) drugs; and Type A medicated 
articles (Sec.  207.25(b)).
     The required listing information submitted to us includes, 
but is not limited to:
    --The application number, if applicable,
    --Copies of current labeling as specified in current Sec.  
207.25(b) and, in some cases, a representative sampling of 
advertisements,
    --A quantitative listing of the active ingredient(s) (in some 
cases),
    --The NDC number, and
    --Any imprinting information (Sec.  207.25(b)).
     Owners or operators of establishments that are required to 
register must update their listing information every June and December 
or, at the discretion of the owner or operator, when the change occurs. 
Updated information must include, but is not limited to:
    --A list of each drug introduced by the registrant for commercial 
distribution that has not been included in any previously submitted 
list,
    --A list of all previously listed drugs for which commercial 
distribution has been discontinued,
    --A list of all drugs for which a notice of discontinuance was 
submitted and for which commercial distribution has resumed, and
    --Any material change, as defined under current Sec.  207.3(a)(3), 
in any information previously submitted (Sec.  207.30(a)).
4. What Are the Current Requirements Associated With the Use of the NDC 
Number?
    The NDC system is used, among other things, to assign a drug 
listing number to each drug or class of drugs.
     The NDC number currently consists of the labeler code, 
product code, and package code. We assign the labeler code, and, as 
stated in current regulations, ``establishments'' assign the product 
code and package code within certain parameters specified by us (Sec.  
207.35).
     Currently, we request, but not require, that the NDC 
number appear on all drug labels and labeling (Sec.  201.2 (21 CFR 
201.2), Sec.  207.35(b)(3)). However, drug products described in 
current Sec.  201.25(b) (21 CFR 201.25(b)) must have on the label a bar 
code that contains, at a minimum, the appropriate NDC number in a 
linear bar code that meets specified standards (Sec.  201.25).
     The current regulations specify both format and placement 
of the NDC number if the NDC number is included on drug labels and 
labeling (Sec.  207.35(b)(3)).
5. Who Is Exempt From Registration and Listing Under Current 
Regulations and Who Is Not Covered by the Current Registration and 
Listing Requirements in 21 CFR Part 207?
    Under current regulations, certain establishments are exempt from 
the registration and listing requirements. For example, practitioners 
who are licensed by law to prescribe or administer drugs and who 
manufacture or process drugs solely for use in their professional 
practice, and persons who manufacture or process drugs not for sale but 
solely for use in research, teaching, or chemical analysis are exempt 
from registration and listing requirements. Many of the exemptions in 
current Sec.  207.10 are also listed in section 510(g) of the act.
    The current regulations also describe those establishments that are 
not covered under part 207. Owners and operators of human blood and 
blood product establishments must register and list their products in 
accordance with part 607 (21 CFR part 607). However, such owners and 
operators who also manufacture or process other drug products at the 
same establishment must also register and list those drugs in 
accordance with part 207 (Sec.  207.7). Owners and operators of 
establishments that solely engage in the manufacture or processing of 
medical devices are not covered under part 207. However, such owners 
and operators must register and list their products in accordance with 
part 807.
6. Do Current Regulations Permit the Disclosure of Registration and 
Listing Information?
    The current regulations specify the registration and listing 
information submitted to us that is available for public disclosure 
(Sec.  207.37).

III. Highlights of the Proposed Rule

    This proposal would reorganize, consolidate, and modify the current 
registration and listing requirements. It would also assist us in 
promoting other important electronic health initiatives.

A. Proposed Changes to the Current Registration and Listing 
Requirements

    We are proposing many changes to the current registration and 
listing requirements. In section IV of this document, we discuss in 
detail these changes and the reasons for the changes. The most 
significant proposed changes to the current requirements are as 
follows:
     All registration information and most listing information 
would be provided to us electronically using the electronic drug 
registration and listing system that we intend to develop. (Currently, 
the information is submitted to us on paper forms.)
     The appropriate NDC number would be required, with certain 
exceptions, to appear on drug labels. The appropriate NDC number is the 
NDC number belonging to the manufacturer, repacker, or relabeler, that 
corresponds to the particular drug;

[[Page 51280]]

a repacker or relabeler would not be permitted to place an NDC number 
that corresponds to an original manufacturer on a repackaged or 
relabeled drug. Although the NDC number would not be required to appear 
on other drug labeling (that is, the prescription drug labeling or the 
package insert), the NDC number would need to accompany the submission 
of the other drug labeling. (Currently, we only request that the NDC 
number appear on drug labels and labeling. However, certain drug 
products must have on the label a bar code that contains, at a minimum, 
the appropriate NDC number (see Sec.  201.25).)
     All three sections of the NDC number--that is, the labeler 
code, product code, and package code--would be assigned prospectively 
by us to drugs that have not previously been assigned NDC numbers by a 
manufacturer, repacker, or relabeler. (Currently, we assign the labeler 
code, and the registered establishment or private label distributor 
assigns the product code and package code within certain parameters 
specified by us.) The labeler code assigned prospectively by us would 
be the same as the labeler code (or one of the labeler codes) used by 
the manufacturer, repacker, or relabeler on its currently marketed 
drugs.
     The NDC numbers currently assigned to drugs prior to the 
effective date of the rule would remain unchanged, provided those NDC 
numbers comply with the new regulations as finalized. FDA intends to 
validate that current NDC numbers comply with the new regulations as 
finalized. Manufacturers, repackers, and relabelers should review the 
information that they submitted to our registration and listing 
database to obtain an NDC number and update the information if 
necessary. They should complete their reviews and updates within 9 
months after a final rule's effective date. If, after the effective 
date of the final rule, there is a change in a drug (in accordance with 
proposed Sec.  207.33(f)), we would assign a new product code and 
package code to the newly changed drug, but the drug would keep the 
labeler code. If, after the effective date of the final rule, there is 
a change in a drug's packaging, we would assign a new package code to 
the drug, but the drug would keep the labeler code and the product 
code. (Currently, the registered establishment or private label 
distributor may assign the product and package codes within certain 
parameters specified by us.)
     Private label distributors would not be permitted to 
register or list under the proposed rule. (Currently, private label 
distributors submit certain information to request a labeler code and 
may list drugs. If the private label distributor elects not to submit 
drug listing information directly to us and to obtain a labeler code, 
the registered establishment must submit the drug listing information.) 
Manufacturers, repackers, relabelers, or drug product salvagers must 
submit drug listing information for those drugs they manufacture, 
repack, relabel, or salvage for a private label distributor.
     Drug product salvagers would, in addition to registering, 
be required to list the drugs they salvage, even if they do not repack 
or relabel the drugs. (Currently, drug product salvagers are required 
to register but not list.)
     The ``content of labeling'' as defined in proposed Sec.  
207.1 would be electronically submitted at the time of listing in a 
format that we can process, review, and archive. (Currently, all 
labeling required for listing is submitted in paper form.)

B. Promotion of the Department of Health and Human Services (DHHS) 
Federal Health Information Technology Initiatives

    The proposal would allow us to provide important support for the 
full implementation of the electronic prescription provisions of the 
Medicare Modernization Act. The proposal would also support other 
initiatives, described in section IV.C.2 of this document, including 
DHHS Federal Health Information Technology initiatives. The proposal 
would result in an up-to-date NDC number system, in which we assign the 
NDC number, providing for accurate, unique, and unambiguous NDC numbers 
for each drug. This would allow electronic systems to reliably and 
consistently link the NDC number to the appropriate drug labeling 
through another DHHS health information technology initiative, 
Structured Product Labeling (SPL). The drug labeling would supply the 
drug ingredient and other information necessary to support the 
development of the standards for medication terminology necessary for 
electronic prescribing. Other initiatives supported by this proposal, 
including bar coding for drugs, are discussed in section IV.C.2 of this 
document.

IV. Description of the Proposed Rule

    We are proposing to reorganize, consolidate, clarify, and modify 
the regulations in part 207. As a result, we have revised and 
recodified some provisions, added new provisions, and eliminated 
others. The following description of the proposed rule describes both 
new provisions and changes to existing regulations.

A. General

1. What Is the Purpose of Proposed Part 207?
    We are proposing to add new Sec.  207.5 to explicitly state the 
purpose of part 207, as set forth in the legislative history of the 
Drug Amendments of 1962 and the Drug Listing Act of 1972.
     Establishment registration information helps us to 
identify who is manufacturing, repacking, relabeling, or salvaging 
drugs and where those operations are being performed. As explained in 
Senate Report No. 1744, ``drugs should not be on the market unless 
[FDA] knows who is making them, and where they are being made. This 
will help stop illicit and substandard manufacturers who do not follow 
the methods or establish the controls called for by good manufacturing 
practice'' (1962 U.S.C.C.A.N. 2884, 2889). Knowing where drugs are 
being made is even more important today because it would increase the 
Nation's ability to prepare for and respond effectively to bioterrorism 
and other public health emergencies.
     Drug listing information gives us a current inventory of 
marketed drugs. As stated in Senate Report No. 92-924, ``[t]he 
effective enforcement of the drug provisions of the [a]ct requires the 
ready availability of a current inventory of all marketed drugs'' (1972 
U.S.C.C.A.N. 2963, 2964). Moreover, the intent of drug listing is to 
provide us ``with an effective means of surveillance'' (Id. at 2965). 
Both establishment registration and drug listing information facilitate 
our implementation and enforcement of the act and are used for many 
important public health purposes. In addition, this information will 
help us better respond to emergencies (for example, we will be in a 
better position to effectively facilitate recalls should there be such 
a need).
2. Who Would Part 207 Cover?
    We are proposing to add new Sec.  207.9 to explain that part 207 
would apply to the following.
     Domestic manufacturers, domestic repackers, domestic 
relabelers, and domestic drug product salvagers, unless they are exempt 
under section 510(g) of the act or proposed Sec.  207.13. The terms 
``domestic manufacturers,'' ``domestic repackers,'' ``domestic 
relabelers,'' and ``domestic drug product salvagers'' are defined in 
proposed Sec.  207.1 and are explained in section IV.A.5 of this 
document. Proposed Sec.  207.9 does not

[[Page 51281]]

change the scope of current part 207. Domestic manufacturers, domestic 
repackers, domestic relabelers, and domestic drug product salvagers 
would be covered under proposed part 207 whether or not the drugs they 
manufacture, repack, relabel, or salvage enter interstate commerce. 
Section 510(b) and (c) of the act refer to an establishment ``in any 
State.'' Congress's intention for section 510 of the act to apply to 
drugs both in interstate and intrastate commerce is stated in section 
301 of Public Law 82-781, in part, as follows: ``[T]he products of all 
[establishments in which drugs are manufactured, prepared, propagated, 
compounded, or processed] are likely to enter the channels of 
interstate commerce and directly affect such commerce; and * * * the 
regulation of interstate commerce in drugs without provision for 
registration and inspection of establishments that may be engaged only 
in intrastate commerce in such drugs would discriminate against and 
depress interstate commerce in such drugs, and adversely burden, 
obstruct, and affect such interstate commerce.''\3\ Accordingly, we are 
proposing to add to proposed Sec.  207.9 the clause ``regardless of 
whether their drugs enter interstate commerce'' to reflect this 
congressional finding. The phrase ``Drug products * * * must be listed 
whether or not the output of such establishments or any particular drug 
so listed enters interstate commerce'' is already included in current 
Sec.  207.20(a).
---------------------------------------------------------------------------

    \3\See footnote 1 of section 510 of the act.
---------------------------------------------------------------------------

     Foreign manufacturers, foreign repackers, foreign 
relabelers, and foreign drug product salvagers, unless they are exempt 
under proposed Sec.  207.13(c) through (h). Foreign manufacturers, 
foreign repackers, foreign relabelers, and foreign drug product 
salvagers are currently required to register, and foreign 
manufacturers, foreign repackers, and foreign relabelers are currently 
required to submit listing information in accordance with section 510 
of the act and Sec.  207.40. The terms ``foreign manufacturers,'' 
``foreign repackers,'' ``foreign relabelers,'' and ``foreign drug 
product salvagers'' are defined in proposed Sec.  207.1 and explained 
in section IV.A.5 of this document.
    An increased number of foreign manufacturers, foreign repackers, 
foreign relabelers, and foreign drug product salvagers may be required 
to comply with registration and/or listing requirements because we are 
proposing, as explained in section IV.A.4 of this document, to revoke 
certain provisions of current Sec.  207.40(a) and (b). We are proposing 
to revoke the exemption in current Sec.  207.40(a) relating to foreign 
establishments whose drugs enter a foreign trade zone and are re-
exported from the foreign trade zone without having entered U.S. 
commerce. We are also proposing to revoke, in part, current Sec.  
207.40(b), which allows for a component of a drug imported under 
section 801(d)(3) of the act (21 U.S.C. 381(d)(3)) to be imported or 
offered for import into the United States even if the component is not 
listed and manufactured, prepared, propagated, compounded, or processed 
at a registered foreign establishment. We are proposing to eliminate 
these two exemptions in current Sec.  207.40(a) and (b) from the 
registration and listing requirements in light of certain statutory 
changes that have occurred since the publication of the final rule on 
foreign establishment registration and listing. Those changes include 
enactment of the Bioterrorism Act, which reflects Congress' desire to 
increase the Nation's ability to prepare for and respond effectively to 
bioterrorism and other public health emergencies.
     Manufacturers of drugs regulated under a BLA, as follows:
    Manufacturers of drugs regulated under a BLA including, but not 
limited to: (1) Plasma derivatives such as albumin, Immune Globulin, 
Factor VIII and Factor IX, and recombinant versions of plasma 
derivatives or animal derived plasma derivatives; (2) vaccines; (3) 
allergenic products; (4) bulk product substances such as fractionation 
intermediates or pastes; and (5) therapeutic biological products.
    Establishments solely engaged in the manufacture, as defined in 
Sec.  1271.3(e) (21 CFR 1271.3(e)), of HCT/Ps, as defined in Sec.  
1271.3(d), that, under Sec.  1271.20, are also drugs regulated under 
section 351 of the Public Health Service Act (PHS Act) or section 505 
of the act. Proposed Sec.  207.9(c)(2) would direct these 
establishments to register and list those HCT/Ps with CBER by following 
the procedures described in subpart B of part 1271 (21 CFR part 1271) 
instead of the procedures for registration and listing described in 
part 207. Proposed Sec.  207.9(c)(2) is similar to current Sec.  
207.20(f), which we propose to revoke and replace with proposed Sec.  
207.9(c)(2).
    We are also explaining the relationship between the requirements 
for HCT/Ps in part 207 and part 1271 of this chapter. We have 
implemented, in part 1271, a comprehensive, risk-based regulatory 
approach for HCT/Ps. Under this approach, some HCT/Ps are regulated 
solely under section 361 of the PHS Act (42 U.S.C. 264) and the 
regulations in part 1271; other HCT/Ps are also subject to regulation 
as drugs or devices under the act and to premarket application or 
notification requirements (submissions may include BLAs, NDAs, or 
device PMAs, product development protocols, or 510(k) applications).
    Current Sec.  207.20(f) also states that the additional listing 
information requirements in current Sec.  207.31 are applicable to HCT/
Ps registered in accordance with the procedures in part 1271, subpart B 
if they are also drugs regulated under a BLA and/or the act. We are 
proposing to revoke current Sec.  207.31 and move several of its 
requirements to other sections of the proposed rule (see discussion in 
sections IV.C and IV.D of this document). Consistent with the 
provisions in current Sec.  207.20(f), the requirements will continue 
to apply to HCT/Ps that, under Sec.  1271.20, are also drugs regulated 
under a BLA or section 505 of the act.
    In addition, proposed Sec.  207.9(c)(2) would require the 
submission of information not currently required for HCT/Ps under part 
207, although the submission of such information has been required for 
drug products that are not HCT/Ps. For example, proposed Sec.  
207.9(c)(2) would require establishments to submit the NDC number, as 
described in proposed Sec. Sec.  207.49(a), 207.53(a), and 
207.54(b)(1), and the route of administration, as described in proposed 
Sec.  207.49(b). Under these provisions, such HCT/P establishments 
would not be required to register and list with both CBER and CDER. 
Rather, we envision that establishments will register with CBER, and 
then will be asked to provide additional information as required under 
part 207. We will manage our databases so that both CBER and CDER have 
use of the registration and listing information provided. The concept 
is that there will be a link in place when the establishment 
electronically accesses the electronic registration and listing system 
at http://www.fda.gov/cber/tissue/tisreg.htm for tissue registration. 
This will allow access to the drug database fields to fill in the 
additional information such as the NDC number. If the establishment 
enters that it manufactures a licensed biologic, this will trigger the 
link. At the current time, there is only one such product.
3. Who Would Not Be Subject to Part 207?
    Proposed Sec.  207.9 also describes two categories of 
establishments that would not be subject to part 207:
     Owners and operators of human blood and blood product

[[Page 51282]]

establishments. This proposed rule does not apply to owners and 
operators of human blood and blood product establishments unless they 
manufacture any of the products listed in proposed Sec.  207.9(c)(1)(i) 
and (c)(1)(iv). If the owners and operators of human blood and blood 
product establishments manufacture any of those products, then they 
must register and list under part 207. Establishments that collect or 
process whole blood and blood products as well as establishments 
involved in the testing of whole blood and blood products would 
register and list under part 607. For purposes of this proposal, blood 
and blood products consist of human whole blood, plasma, or serum or 
any product derived from human whole blood, plasma, or serum, and the 
term includes biological products regulated as licensed devices. 
Manufacturers of licensed devices and manufacturers of licensed 
biological components used in a licensed device would register and list 
under part 607. This exclusion is consistent with current Sec.  
207.7(a) and would not apply to owners and operators of human blood and 
blood product establishments who also manufacture other drugs.
     Establishments that solely manufacture, prepare, 
propagate, compound, assemble, or process medical devices. 
Establishment registration and device listing regulations for such 
establishments and initial importers of devices, including in vitro 
diagnostic products, are codified in part 807. Establishments that 
manufacture, prepare, propagate, compound, assemble, or process medical 
devices, and also manufacture, prepare, propagate, compound, or process 
drugs, are subject to part 207 for drugs and part 807 for devices.
    As a result of these proposed revisions clarifying the scope of 
part 207, proposed Sec.  207.9 includes the provisions in current Sec.  
207.7 that explain the applicability of part 207 to human blood and 
blood products and medical devices. We are also proposing to revoke 
related provisions that set forth addresses in the Center for Devices 
and Radiological Health (CDRH) and CBER for submitting registration and 
listing information, and provisions that specify the appropriate forms 
for submitting such information.
4. Who Would Be Exempt From Registration and Listing?
    Section 510(g) of the act and current Sec.  207.10 provide for 
exemptions from registration and drug listing requirements. Proposed 
Sec.  207.13 contains certain changes to some of the exemptions in 
current Sec.  207.10, as discussed in the first part of this section. 
Proposed Sec.  207.13 also incorporates without change some exemptions 
from current Sec.  207.10, as discussed at the end of this section.
    The introductory paragraph of proposed Sec.  207.13, largely 
consistent with current Sec.  207.10, states that, except as provided 
in proposed Sec.  207.13(i), the classes of persons listed in proposed 
Sec.  207.13 are exempt from registration and drug listing under 
section 510(g) of the act, or because we have found, under section 
510(g)(5) of the act, that their registration is not necessary for the 
protection of the public health. We are proposing to add the phrase 
``except as provided in proposed Sec.  207.13(i)'' to indicate that 
even though the classes of persons identified in paragraphs (a) through 
(h) are exempt from registration and drug listing, if such persons 
engage in activities as set forth in paragraph (i), the exemption does 
not apply and they are required nonetheless to register and list. We 
are also proposing to include in the introductory paragraph a sentence 
clarifying that the exemption under proposed Sec.  207.13 would not 
provide exemptions from other provisions of the act or regulations. For 
example, persons that do not have to register establishments and list 
drugs are still subject to the adulteration and misbranding provisions 
under sections 501 and 502 of the act (21 U.S.C. 351 and 352) and also 
may be subject to the new drug approval requirements under section 505 
of the act (21 U.S.C. 355) or new animal drug approval requirements 
under section 512 of the act (21 U.S.C. 360b). We may inspect their 
establishments in accordance with section 704 of the act and the 
current good manufacturing practice requirements. We are proposing to 
add the clarifying sentence because in the past some manufacturers, 
repackers, relabelers, and drug product salvagers that were exempt from 
registration and listing requirements incorrectly believed these 
provisions provided exemptions from other provisions of the act and 
regulations. Accordingly, we are proposing to add this sentence to 
remedy any confusion on this point.
    a. Pharmacies--The current exemption for pharmacies is codified at 
Sec.  207.10(a). The proposed rule would revise and clarify the 
exemption, and would move it to Sec.  207.13(a). Except as noted in the 
discussion below, proposed Sec.  207.13(a) is generally consistent with 
current Sec.  207.10(a).
    Under proposed Sec.  207.13(a), pharmacies would be exempt from the 
registration and listing requirements if they: Operate in conformance 
with all applicable local laws regulating the practice of pharmacy, 
including all applicable local laws regulating the dispensing of 
prescription drugs; regularly engage in dispensing prescription drugs 
upon prescription of practitioners licensed by law to administer these 
drugs to patients under their professional care; and do not manufacture 
(as defined in proposed Sec.  207.1), repack, or relabel drugs for sale 
other than in the regular course of the practice of pharmacy, including 
dispensing and selling drugs at retail.
    Additional language has been added to proposed Sec.  
207.13(a)(1)(i) and (a)(1)(ii) to more closely track the language in 
section 510(g)(1) of the act. In addition, proposed Sec.  207.13(a) 
does not include language that is in current Sec.  207.10(a) that 
provides that the supplying of prescription drugs to a practitioner 
licensed to administer the drugs for use in the course of the 
practitioner's professional practice or to other pharmacies to meet 
temporary inventory shortages are not acts that require pharmacies to 
register. We are deleting this language because it is not necessary. 
Pharmacies that engage in such activities would be exempt from 
registration if they fulfill the following requirements: Operate in 
conformance with all applicable local laws regulating the practice of 
pharmacy, including all applicable local laws regulating dispensing of 
prescription drugs (proposed Sec.  207.13(a)(1)(i)); regularly engage 
in dispensing prescription drugs upon prescription of practitioners 
licensed by law to administer these drugs to patients under their 
professional care (proposed Sec.  207.13(a)(1)(ii)); and do not 
manufacture (as defined in Sec.  207.1), repack, or relabel drugs for 
sale other than in the regular course of the practice of pharmacy, 
including dispensing and selling drugs at retail (proposed Sec.  
207.13(a)(1)(iii)).
    Proposed Sec.  207.13(a)(2) clarifies that pharmacies may 
potentially qualify for the exemption in proposed Sec.  207.13(a) only 
if they are located in any State as defined in section 201(a)(l) of the 
act (21 U.S.C. 321) (that is, any State or Territory of the United 
States, the District of Columbia, and the Commonwealth of Puerto Rico). 
This proposed provision is currently located in the introductory 
paragraph in current Sec.  207.10. We believe it would be more clear to 
place this provision in proposed Sec.  207.13(a)(2). This aspect of the 
proposed provision is consistent with current Sec. Sec.  207.10 and 
207.40.
    b. Hospitals, clinics, other health care entities, and public 
health agencies--The current exemption for hospitals, clinics, and 
public health agencies is

[[Page 51283]]

codified at Sec.  207.10(b). The proposed exemption is generally 
consistent with current Sec.  207.10(b), except for the addition of 
``other health care entities'' and other mostly minor revisions and 
clarifications, as described below. The proposed exemption would move 
to Sec.  207.13(b).
    Hospitals, clinics, other health care entities, and public health 
agencies are exempt, under proposed Sec.  207.13(b), from the 
registration and listing requirements if they: Operate establishments 
in conformance with all applicable local laws regulating the practice 
of pharmacy and medicine, including all applicable local laws 
regulating the dispensing of prescription drugs; regularly engage in 
dispensing prescription drugs, other than human blood or blood 
products, upon prescription of practitioners licensed by law to 
administer these drugs to patients under their professional care; and 
do not manufacture (as defined in proposed Sec.  207.1), repack, or 
relabel drugs other than in the regular course of the practice of 
pharmacy, including dispensing.
    The exemption in proposed Sec.  207.13(b) would be limited to 
hospitals, clinics, other health care entities, and public health 
agencies located in any State as defined in section 201(a)(1) of the 
act. The proposed provision requiring that such facilities be located 
in any State is currently located in the introductory paragraph in 
current Sec.  207.10. We believe it would be more clear to place this 
provision in proposed Sec.  207.13(b)(2). This proposed provision 
(except with respect to BLA holders and the clarification with respect 
to positron emission tomography (PET) drugs) is generally consistent 
with current Sec. Sec.  207.10 and 207.40.
    We are proposing to add ``other health care entities'' to this 
exemption because we are aware that other health care entities besides 
hospitals, clinics, and public health agencies (such as skilled nursing 
facilities) lawfully provide medical care and dispense drugs and 
logically are similarly situated to hospitals, clinics, and public 
health agencies for purposes of exempting them from registration and 
listing, if they meet the statutory and regulatory requirements.
    We are also proposing to add language to proposed Sec.  207.13(b) 
to make the exemption more consistent with the pharmacy exemption in 
proposed Sec.  207.13(a). For example, we are proposing to add language 
to proposed Sec.  207.13(b)(1)(i) so that this exemption also 
specifically requires compliance with all applicable laws regulating 
dispensing of prescription drugs, as is required by proposed Sec.  
207.13(a)(1)(i). We are similarly proposing to add Sec.  
207.13(b)(1)(iii) to be consistent with proposed Sec.  
207.13(a)(1)(iii), although in proposed Sec.  207.13(b)(1)(iii) we have 
not included the terms ``for sale'' or ``selling drugs at retail'' 
since this language is appropriate for retail pharmacies relying on the 
exemption provided by proposed Sec.  207.13(a), but not for hospitals, 
clinics, other health care entities, and public health agencies relying 
on the exemption provided by proposed Sec.  207.13(b).
    We believe that the exemption for hospitals, clinics, other health 
care entities, and public health agencies provided in proposed Sec.  
207.13(b)(2) should be relied upon by pharmacies within these health 
care entities that dispense drugs to patients receiving care in the 
health care entities and that meet the requirements of the exemption, 
but should not be relied upon by retail pharmacies located within these 
health care entities. Retail pharmacies should rely upon the exemption 
in proposed Sec.  207.13(a) if they meet the requirements of that 
proposed provision.
    c. Persons who manufacture, repack, relabel, or salvage certain 
medicated feeds--Although we are proposing to reorganize and clarify 
the exemption for persons who manufacture, repack, relabel, or salvage 
certain medicated feeds, we are not proposing to change the substance 
of the exemption. Under proposed Sec.  207.13(f), persons who 
manufacture, repack, relabel, or salvage Type B or Type C medicated 
feeds, except for manufacturers, repackers, relabelers, or drug product 
salvagers of Type B or Type C medicated feeds made from Category II, 
Type A medicated articles, are exempt from registration. This exemption 
would not apply to persons who would otherwise be required to register 
(such as manufacturers, repackers, relabelers, or drug product 
salvagers of certain free-choice feeds, as defined in 21 CFR 510.455, 
or certain liquid feeds, as defined in 21 CFR 558.5, where the 
specifications and/or formulas are not published and a feed mill 
license is required). Proposed Sec.  207.13(f) also clarifies that all 
manufacturers, repackers, relabelers, or drug product salvagers of Type 
B or Type C medicated feeds would be exempt from listing.
    d. The current exemptions for foreign trade zones and drugs 
imported under section 801(d)(3) of the act would be revoked--In 2001, 
we issued a final rule on foreign establishment registration and 
listing (66 FR 59138, November 27, 2001). The regulation created two 
exemptions in Sec.  207.40:
     Under current Sec.  207.40(a), a foreign establishment is 
not required to comply with the registration and listing requirements 
if its drug enters a foreign trade zone and is re-exported from that 
foreign trade zone without having entered U.S. commerce. We created 
this exemption as part of the final rule on foreign establishment 
registration and listing because registering such foreign 
establishments or listing drugs that were confined to a foreign trade 
zone--and were therefore not introduced into domestic commerce--was not 
considered necessary for the protection of the public health (see 66 FR 
59138 at 59139 and 59140).
     Current Sec.  207.40(b), which states that no drug may be 
imported or offered for import into the United States unless the drug 
is listed and manufactured, prepared, propagated, compounded, or 
processed at a registered foreign establishment, also states that this 
prohibition does not apply to components of drugs imported under 
section 801(d)(3) of the act. Section 801(d)(3) of the act, as it 
existed before June 2002, allowed persons to import unapproved or 
otherwise noncompliant articles (such as drug components) provided that 
the imported articles were further processed or incorporated into 
products and exported or, if not used, the imported articles were 
destroyed or exported. The provision in Sec.  207.40(b) reflected the 
fact that, at the time, section 801(d)(3) of the act imposed very few 
restrictions on the admission of drug components that are imported into 
the United States for further processing or incorporation into a 
product that will be exported from the United States (66 FR 59138 at 
59148).
    Given the additional level of import restrictions imposed by the 
Bioterrorism Act, and the underlying security concerns that led to the 
Bioterrorism Act's adoption, we are proposing to eliminate these two 
exemptions in current Sec.  207.40(a) and (b) from the registration and 
listing requirements. In particular, sections 321 and 322 of the 
Bioterrorism Act, which affected foreign establishment registration by 
amending sections 510 and 801 (among other provisions) of the act, 
suggest that Congress intended the information requirements for foreign 
establishments and imported products to be comprehensive, and that 
Congress regarded the information it was requiring to be important to 
its goal in increasing the Nation's ability to prepare for and respond 
effectively to bioterrorism and other public health emergencies. This, 
in turn, suggests to

[[Page 51284]]

FDA that the exceptions from the registration and listing requirements 
are therefore no longer appropriate.
    The Bioterrorism Act affected foreign establishment registration, 
in relevant part, by amending sections 510(i) and 801 of the act:
     To require, as part of an establishment's registration, 
the name of each importer of the drug that is known to the 
establishment and the name of each person who imports or offers to 
import the drug into the United States; and
     To provide that we may refuse admission of a product and, 
if the product is refused admission, that the product shall be held at 
the port of entry until a statement regarding the foreign 
establishment's registration is submitted to us.
    The amendment to section 510(i) of the act reflects a determination 
on the part of Congress that a foreign establishment shipping drugs to 
the United States should provide additional information in its 
registration (that is, information about importers and persons who 
import or offer for import). FDA is concerned that if a foreign 
establishment is not subject to this establishment registration 
requirement--either by virtue of importing into a foreign trade zone or 
by importing components under section 801(d)(3) of the act--it would 
allow some importers and persons who import or offer for import to go 
undetected, thereby creating an unnecessary vulnerability in Congress' 
system of requiring this information.
    The amendment to section 801(o) of the act reflects a determination 
that establishment registration and drug listing information is 
important enough that, if it is lacking at the time the article is 
offered for import, the article may be refused admission (and, if 
refused, shall be held at the port of entry). FDA is concerned that if 
a foreign establishment is exempt from the registration and listing 
requirements--either by virtue of importing into a foreign trade zone 
or by importing components under section 801(d)(3) of the act--FDA 
would be unable to rely on amended sections 510(i) and 801 of the act 
to require that imported products be held at the port of entry to the 
United States or to prevent such product's delivery to the importer or 
consignee. This situation would stand in the way of implementing 
Congress' apparent intent that this information be a prerequisite for 
entry of the imported product into the United States.
    We believe that removing the exception to the registration and 
listing requirements for products entering foreign trade zones and for 
products imported under section 801(d)(3) of the act is consistent with 
Congress' desire to increase the Nation's ability to prepare for and 
respond effectively to bioterrorism and other public health emergencies 
by requiring foreign establishments to provide more, rather than less, 
information for imported products.
    The Bioterrorism Act also revised section 801(d)(3) of the act, in 
part, by:
     Requiring importers to identify the manufacturers of the 
imported drug component, and each processor, packer, distributor, or 
other entity that had possession of the article from the manufacturer 
to the importer;
     Requiring certificates of analysis to accompany most 
imported articles; and
     Giving us the ability to refuse admission to the United 
States if we determine there is credible evidence or information 
indicating that the article is not intended to be further processed by 
the initial owner or consignee, or incorporated by the initial owner or 
consignee into a drug, biological product, or other product specified 
in section 801(d)(3) of the act that will be exported from the United 
States.
    These statutory changes also indicate a congressional desire to 
know more, rather than less, about the articles entering the United 
States under section 801(d)(3) of the act and to prevent potentially 
dangerous articles from entering the United States. The legislative 
history supports this belief, as the conference report for the 
Bioterrorism Act explained: ``Refusal of entry should not involve 
shipments between known shippers and known recipients unless the 
Secretary has received credible evidence or information that suggests 
such shipments may not be legitimate. The Managers intend to permit the 
Secretary to refuse admission of articles if the Secretary determines 
there is credible evidence or information that the articles may be used 
as instruments of terror. Such evidence might include highly toxic or 
otherwise exceptionally dangerous products going to recipients unknown 
to the Secretary or to recipients believed to lack the capability to 
further process such dangerous articles * * *.'' (See H. Rept. 107-481, 
l07th Cong. (2002), ``Joint Explanatory Statement of the Committee of 
Conference,'' ``Subtitle B--Protection of Drug Supply'' (discussing 
section 322).) The legislative history's references to ``known'' 
shippers, ``known'' recipients, and recipients who may lack the ability 
to further process an article, combined with the new statutory 
provision on refusing admission even if the article is imported under 
section 801(d)(3) of the act, strongly support our proposal to require 
that all drugs imported or offered for import into the United States be 
listed and manufactured at a registered foreign establishment. Failure 
to register such foreign establishments could compromise our ability to 
refuse admission of a dangerous article.
    Therefore, the proposed rule would eliminate the exemption from the 
establishment registration and drug listing requirements for foreign 
establishments whose drugs enter a foreign trade zone and are re-
exported from that foreign trade zone without having entered U.S. 
commerce. In addition, the proposal would require that all drugs 
imported or offered for import into the United States be listed and 
manufactured at a registered foreign drug establishment, even if the 
drug is imported under section 801(d)(3) of the act.
    e. Other exemptions--As described in current Sec.  207.10, the 
following remain exempt from registration and drug listing (proposed 
Sec.  207.13):
     Practitioners who are licensed by law to prescribe or 
administer drugs and who manufacture, repack, relabel, or salvage drugs 
solely for use in their professional practice (current Sec.  207.10(c); 
proposed Sec.  207.13(c)).
     Manufacturers, repackers, relabelers, or drug product 
salvagers of drugs solely for use in research, teaching, or chemical 
analysis and not for sale (current Sec.  207.10(d); proposed Sec.  
207.13(d)). Under proposed Sec.  207.13(d), manufacturers, repackers, 
relabelers, or drug product salvagers who manufacture, repack, relabel, 
or salvage drugs solely for use in research, teaching, or chemical 
analysis and not for sale are exempt from registration requirements. 
Proposed Sec.  207.13(d) would be consistent with the exemption in 
section 510(g)(3) of the act, except the language would be modified to 
take into account the proposed rule's uses of the terms 
``manufacturer,'' ``repacker,'' ``relabeler,'' ``drug product 
salvager,'' ``manufacture,'' ``repack,'' ``relabel,'' and ``salvage.'' 
We want to take the opportunity to remind interested persons that while 
the exemption from registration would apply to a sponsor that 
manufactures its own drug for use in its clinical trial of the drug, 
the exemption would not apply, for example, to a firm that manufactures 
a drug with the purpose of selling the drug to a sponsor for use in a 
clinical trial. In the latter situation, the manufacturer of the drug 
would be required to register.
     Manufacturers, repackers, relabelers, and drug product 
salvagers of

[[Page 51285]]

harmless inactive ingredients (current Sec.  207.10(e); proposed Sec.  
207.13(e)). We considered proposing to revoke this exemption because of 
concerns related to potential contamination of those inactive 
ingredients. However, we concluded that submitting and maintaining in 
the database all excipients, colorings, flavorings, emulsifiers, 
lubricants, preservatives, or solvents that become components of drugs 
could be burdensome for industry. In proposing to maintain this 
exemption, we note that current regulations governing the manufacture 
of finished drug products require all manufacturers to perform quality 
control testing to ensure that components meet established 
specifications (see generally, part 211 (21 CFR part 211)).
     Manufacturers, repackers, relabelers, and drug product 
salvagers of animal viruses, serums, toxins, or analogous products 
(current Sec.  207.10(g); proposed Sec.  207.13(g)).
     Carriers (current Sec.  207.10(h); proposed Sec.  
207.13(h)).
    f. Limits on exemptions--Proposed Sec.  207.13(i) would clarify 
that any of the persons who otherwise would qualify for an exemption 
under Sec.  207.13(a) through (h) are not exempt from registration or 
listing if they: (1) Manufacture (as defined in proposed Sec.  
207.1),\4\ repack, relabel, or salvage compounded positron emission 
tomography (PET) drugs as defined in section 201(ii) of the act; (2) 
manufacture (as defined in Sec.  600.3(u)) a biological product subject 
to licensing under section 351 of the Public Health Service (PHS) Act; 
(3) manufacture (as defined in Sec.  1271.3(e)) an HCT/P that, under 
Sec.  1271.20, are also drugs regulated under section 351 of the PHS 
Act or section 505 of the act; or (4) engage in activities that would 
otherwise require them to register under this part.
---------------------------------------------------------------------------

    \4\The term ``manufacture'' is defined in proposed Sec.  207.1 
and is used here for brevity to refer to the activities that trigger 
registration requirements (that is, ``manufacture, preparation, 
propagation, compounding, or processing'' of drugs). Although many 
PET facilities do not consider themselves to be ``manufacturing'' 
drugs, but rather preparing or compounding drugs, we are nonetheless 
using the term ``manufacture'' for brevity.
---------------------------------------------------------------------------

    Thus, any person identified in proposed Sec.  207.13(a) through 
(h), such as pharmacies, hospitals, clinics, other health care 
entities, public health agencies, or practitioners, if they 
manufacture, repack, relabel, or salvage compounded PET drugs, as 
defined in section 201(ii) of the act (21 U.S.C. 321(ii)), would fall 
outside the scope of the exemptions provided in proposed Sec.  
207.13(a) through (h). Manufacturers, repackers, relabelers, or drug 
product salvagers of compounded PET drugs are not included among the 
persons that are exempt from registration under proposed Sec.  207.13 
because exempting manufacturers of compounded PET drugs from 
registration would be inconsistent with section 121 of the Food and 
Drug Administration Modernization Act of 1997 (the Modernization Act) 
(Public Law 105-115), which addresses the regulation of PET drug 
products. Section 121 of the Modernization Act directs us to develop 
appropriate procedures for the approval of PET drugs under section 505 
of the act and appropriate CGMP requirements for such drugs. It also 
requires the submission of NDAs or ANDAs for PET drugs either 4 years 
after the date of enactment or 2 years after the date on which we 
establish approval procedures and CGMPs, whichever is longer. We 
published proposed CGMPs for PET drugs on September 20, 2005 (70 FR 
55038). If Congress had intended to exempt manufacturers, repackers, 
relabelers, or drug product salvagers of PET drugs from registration 
requirements, it would have done so. Given that PET manufacturers will 
be expected to comply with CGMP requirements and FDA will need to 
inspect them to determine compliance, it is reasonable to require PET 
manufacturers, repackers, relabelers, or drug product salvagers to 
register so we can identify PET manufacturers, repackers, relabelers, 
or drug product salvagers and the drugs they manufacture, repack, 
relabel, or salvage for inspection purposes. Therefore, the proposed 
rule would require compounded PET drug manufacturers, repackers, 
relabelers, or drug product salvagers to register with us and list 
their drugs in accordance with section 510(j) of the act and proposed 
part 207.
    Likewise, any person identified in Sec.  207.13(a) through (h) who 
would otherwise qualify for an exemption would not qualify for an 
exemption if it manufactures (as defined in Sec.  600.3(u)) a 
biological product subject to licensing under section 351 of the PHS 
Act.
    We note that to the extent a person manufactures, repacks, 
relabels, or salvages PET drugs as set forth in proposed Sec.  
207.13(i)(1) or manufactures a biological product subject to licensing 
as set forth in proposed Sec.  207.13(i)(2), the obligation to register 
and list would only apply to the extent that that person engages in the 
activities identified in proposed Sec.  207.13(i)(1) or (i)(2). For 
example, a hospital dispensing and administering drugs and that also 
manufactures compounded PET drugs would list only the PET drugs it 
manufactures, assuming none of its other activities would subject it to 
registration or listing requirements. Likewise, a public health agency 
dispensing and administering drugs that holds a biologics license 
application would list only the biological drugs it manufactures, 
assuming none of its other activities would subject it to registration 
or listing requirements.
    Proposed paragraph (i) also states that the exemptions provided in 
proposed Sec.  207.13(a) through (h) do not apply to such persons if 
they engage in activities that would otherwise require them to 
register. This concept appeared in current Sec.  207.10(e). We are 
proposing to apply this concept to all the exemptions in proposed Sec.  
207.13 to reiterate that if a person qualifies for an exemption from 
the activities stated in proposed Sec.  207.13(a) through (h), that 
person may still need to register if that person engaged in activities 
that would otherwise require registration.
5. What Definitions and Interpretations of Terms Would Apply to Part 
207?
    In proposed Sec.  207.1, we set forth new definitions and 
interpretations of terms for part 207 and revise or revoke certain 
definitions in current Sec.  207.3(a).
    Current Sec.  207.3(b) states that the definitions and 
interpretations of terms in sections 201, 502(e), and 510 of the act 
apply to the terms used in part 207. We are proposing to revoke this 
sentence because it is unnecessary and has caused confusion in the 
past. For purposes of proposed part 207, the following definitions and 
interpretations of terms would apply to proposed part 207:
    Act. This term, as used in proposed Sec.  207.1, remains the same 
as current Sec.  207.3(a)(1). ``Act'' means the Federal Food, Drug, and 
Cosmetic Act (52 Stat. 1040 et seq., as amended (21 U.S.C. 301 et 
seq.)), except as otherwise provided.
    Active pharmaceutical ingredient. We are proposing to replace the 
term ``bulk drug substance,'' as defined in current Sec.  207.3(a)(4), 
with the term ``active pharmaceutical ingredient.'' We believe that the 
term ``bulk drug substance'' may be confused with the term ``bulk 
drug.'' The term ``bulk drug,'' as commonly used in the pharmaceutical 
industry, means an active ingredient, inactive ingredient, or finished 
dosage form, packaged in a large container (for example, a drum). To 
prevent confusion, we are proposing to replace the term ``bulk drug 
substance'' with the more descriptive term ``active pharmaceutical 
ingredient.''
    We are also proposing to revise the definition of the current term 
``bulk

[[Page 51286]]

drug substance'' (changed to ``active pharmaceutical ingredient'' in 
the proposal) to make it consistent with the definition of ``drug 
substance'' in current Sec.  314.3 (21 CFR 314.3). Current Sec.  
207.3(a)(4) states, in part, that a ``bulk drug substance * * * becomes 
an active ingredient,'' but does not explain what it means for an 
ingredient to be ``active.'' We believe that the definition of ``drug 
substance'' in current Sec.  314.3 is more descriptive; that definition 
explains, in part, that ``drug substance means an active ingredient 
that is intended to furnish pharmacological activity or other direct 
effect in the diagnosis, cure, mitigation, treatment, or prevention of 
disease or to affect the structure or any function of the * * * body.'' 
Consistent with the language of current Sec.  314.3, we are proposing 
to define ``active pharmaceutical ingredient'' in proposed Sec.  207.1 
as any substance that is intended to furnish pharmacological activity 
or other direct effect in the diagnosis, cure, mitigation, treatment, 
or prevention of disease, or to affect the structure or any function of 
the body. Consistent with both current Sec.  314.3 and current Sec.  
207.3(a)(4), the term would not include intermediates used in the 
synthesis of the substance. As proposed, the term would include both an 
active pharmaceutical ingredient marketed alone and as part of a 
finished dosage form.
    Advertising and labeling. We are proposing to delete current Sec.  
207.3(a)(2), which explains that the terms ``advertising'' and 
``labeling,'' as used in current part 207, include the promotional 
material described in current Sec.  202.1(l)(1) and (l)(2) (21 CFR 
202.1(l)(1) and (l)(2)), respectively. We believe that this information 
is more appropriately included in the definitions of ``representative 
sampling of advertisements'' and ``representative sampling of any other 
labeling.'' As a result, we are proposing to revise the definitions of 
those terms accordingly and delete current Sec.  207.3(a)(2).
    Commercial distribution. We are not proposing to substantively 
change the definition of ``commercial distribution'' from that set 
forth in current Sec.  207.3(a)(5). The term would still mean any 
distribution of a human drug, except for investigational use under 21 
CFR part 312, and any distribution of an animal drug or an animal feed 
bearing or containing an animal drug for non-investigational uses. The 
term would not include internal or interplant transfer of an active 
pharmaceutical ingredient between registered establishments within the 
same parent, subsidiary, and/or affiliate company. For foreign 
manufacturers, foreign repackers, foreign relabelers, foreign drug 
product salvagers, foreign private label distributors, and foreign 
establishments, the term ``commercial distribution'' would have the 
same meaning except that it does not include distribution of any drug 
that is neither imported nor offered for import by it into the United 
States. We are proposing to change the term ``bulk drug substance'' in 
the current definition to ``active pharmaceutical ingredient'' because 
the proposal replaces the definition of ``bulk drug substance'' with 
the definition of ``active pharmaceutical ingredient.'' Defining 
``commercial distribution'' is important because, under proposed part 
207, listing information must be provided to us for any drug that is 
being manufactured, repacked, relabeled, or salvaged for commercial 
distribution.
    Content of labeling. We are proposing to add a new term, ``content 
of labeling,'' to part 207. The proposed definition of the term 
describes the labeling material that would be required to be 
electronically submitted at the time of listing under proposed 
Sec. Sec.  207.49(g) and 207.61(a)(2). The proposed requirement to 
electronically submit the ``content of labeling'' would be in addition 
to the current listing requirement that formatted copies of certain 
labeling be submitted. We are proposing to define ``content of 
labeling'' because, as explained in section IV.E.4 of this document, 
the electronic submission of the ``content of labeling'' would be 
required for drug listing to permit us to electronically review, 
compare, and extract data from the labeling.
     For human prescription drugs that the manufacturer regards 
as subject to section 505 of the act or section 351 of the PHS Act, we 
are proposing to define ``content of labeling'' as the content of the 
prescription drug labeling, as specified in Sec. Sec.  201.56, 201.57, 
and 201.80 (21 CFR 201.56, 201.57, and 201.80), including all text, 
tables, and figures.\5\
---------------------------------------------------------------------------

    \5\The use of the language ``that the manufacturer regards as 
subject to section 505 of the act or section 351 of the PHS Act,'' 
is explained in detail in section IV.D.7 of this document.
---------------------------------------------------------------------------

    This proposed definition is consistent with how the term ``content 
of labeling'' is used in the final rule entitled ``Requirements for 
Submission of Labeling for Human Prescription Drugs and Biologics in 
Electronic Format,'' (electronic labeling final rule), which published 
in the Federal Register of December 11, 2003 (68 FR 69009). Under the 
electronic labeling final rule, applicants are required to 
electronically submit, in a format that we can process, review, and 
archive, the ``content of labeling'' for human prescription drugs in 
NDAs, certain BLAs, ANDAs, supplements, and annual reports.\6\ The 
electronic labeling final rule, including the use of the term ``content 
of labeling,'' only applies to this subset of drugs. Under the 
proposal, however, as set forth in proposed Sec.  207.49(g), the 
``content of labeling'' would be provided for drugs subject to the 
listing requirements of proposed part 207.
---------------------------------------------------------------------------

    \6\For additional information, also see the guidance ``Providing 
Regulatory Submissions in Electronic Format--Content of Labeling'' 
(April 2005) (available at http://www.fda.gov/cder/guidance/index.htm), which discusses issues related to the submission of the 
content of labeling in electronic format in marketing applications 
for human drug and biological products. This guidance reflects our 
current thinking on providing in electronic format the content of 
labeling required in 21 CFR parts 314 and 601.
---------------------------------------------------------------------------

    Proposed part 207 would also differ in one other respect from the 
way ``content of labeling'' is used in the electronic labeling final 
rule. The electronic labeling final rule states that the ``content of 
labeling'' that must be submitted electronically is commonly referred 
to as the content of the package insert or professional labeling. We 
are proposing to use the term ``prescription drug labeling'' instead of 
the term package insert or professional labeling. ``Prescription drug 
labeling'' is used in the final rule entitled ``Requirements on Content 
and Format of Labeling for Human Prescription Drug and Biological 
Products,'' published in the Federal Register of January 24, 2006 (71 
FR 3922). In that final rule, ``prescription drug labeling'' is used to 
mean labeling for approved prescription drug products described in 
Sec. Sec.  201.56, 201.57, and 201.80, which is commonly described 
using a variety of terms including ``professional labeling,'' ``package 
insert,'' ``direction circular,'' or ``package circular.'' We are 
proposing that the term ``content of labeling'' for human prescription 
drugs, as defined in proposed Sec.  207.1 and required under proposed 
Sec.  207.49(g), would be the content of the ``prescription drug 
labeling.''
     For human prescription drugs that the manufacturer regards 
as not subject to section 505 of the act or section 351 of the PHS Act, 
we are proposing to define ``content of labeling'' as the labeling 
equivalent to the content of the prescription drug labeling, as 
specified in Sec. Sec.  201.56, 201.57, and 201.80, including all text, 
tables, and figures.
     For human OTC drugs, we are proposing to define ``content 
of labeling'' as the content of the drug facts labeling required by 
Sec.  201.66 (21 CFR

[[Page 51287]]

201.66) (format and content requirements for OTC drug product 
labeling), including all text, tables, and figures. Under Sec.  
201.66(b)(10), drug facts labeling means the title, headings, 
subheadings, and information required under or described in Sec.  
201.66(c) (content requirements).
     For animal drugs (including, but not limited to, drugs 
that the manufacturer regards as subject to section 512 of the act), we 
are proposing to define ``content of labeling'' as the content of the 
labeling that accompanies the drug that is necessary to enable safe and 
proper administration of the drug (for example, the labeling specified 
in Sec. Sec.  201.1 and 201.5 (21 CFR 201.1 and 201.5)), including all 
text, tables, and figures.
    Domestic. For the purposes of registration and listing under this 
proposal, and when used to modify the term ``manufacturer,'' 
``repacker,'' ``relabeler,'' ``drug product salvager,'' ``private label 
distributor,'' or ``establishment,'' we are proposing to use the term 
``domestic'' to refer to a manufacturer, repacker, relabeler, drug 
product salvager, private label distributor, or establishment within 
any State or Territory of the United States, the District of Columbia, 
or the Commonwealth of Puerto Rico. The terms ``manufacturer,'' 
``repacker,'' ``relabeler,'' ``drug product salvager,'' ``private label 
distributor,'' and ``establishment'' are defined in proposed Sec.  
207.1, and these definitions are discussed elsewhere in this section of 
the preamble. We are proposing to define the term ``domestic'' 
separately rather than repeat the meaning of the term under separate 
definitions for domestic manufacturer, domestic repacker, domestic 
relabeler, domestic drug product salvager, domestic private label 
distributor, and domestic establishment. The definition of ``foreign,'' 
as it would modify manufacturer, repacker, relabeler, drug product 
salvager, private label distributor, and establishment, is discussed 
elsewhere in this section of the preamble.
    Drug(s). We are proposing to use the term ``drug(s),'' for purposes 
of proposed part 207, to mean the same as the definition of ``drug'' in 
section 201(g)(1) of the act. Section 201(g)(1) of the act defines 
``drug'' to include, among other things, articles intended for use in 
the diagnosis, cure, mitigation, treatment, or prevention of disease in 
man or other animals, and articles (other than food) intended to affect 
the structure or any function of the body of man or other animals. 
``Drug(s)'' under proposed Sec.  207.1 would include drugs intended for 
use in humans, including the biologics described in proposed Sec.  
207.9(c), and animal drugs, including Type A medicated articles, and 
also includes articles ``intended for use as a component'' of any drug. 
The proposed term includes active pharmaceutical ingredients and 
finished dosage forms (prescription and OTC).
    Drug product salvager, drug product salvaging. We are proposing to 
use the term ``drug product salvaging'' to mean applying manufacturing 
controls such as those required by current good manufacturing practice 
in parts 210 (21 CFR part 210) and part 211 to drug products and 
segregating out those drug products that may have been subjected to 
improper storage conditions (such as extremes in temperature, humidity, 
smoke, fumes, pressure, age, or radiation) for the purpose of returning 
the products to the marketplace. We note, however, that drug product 
salvaging, like all manufacturing, must be conducted in accordance with 
current good manufacturing practice. We are proposing to use the term 
``drug product salvager'' to mean a person who owns or operates an 
establishment that engages in drug product salvaging. When not modified 
by ``domestic'' or ``foreign,'' as defined in proposed Sec.  207.1 and 
discussed in section IV.A.5 of this document, the term would include 
both domestic drug product salvagers and foreign drug product 
salvagers.
    Under current Sec.  207.3(a)(6), drug product salvaging means the 
act of segregating drug products that may have been subjected to 
improper storage conditions, such as extremes in temperature, humidity, 
smoke, fumes, pressure, age, or radiation, for the purpose of returning 
some or all of the products to the marketplace. We are proposing to 
revise the current definition of drug product salvaging to include 
``applying manufacturing controls such as those required by current 
good manufacturing practice in part 210 and part 211 to drug 
products.'' We are not proposing to change the meaning of drug product 
salvaging but to clarify the current definition by explaining that the 
term also includes applying manufacturing controls to drug products. 
Drug product salvagers apply manufacturing controls to drug products so 
that they can determine whether the drug products may have been 
subjected to improper storage conditions. As discussed further in 
sections IV.B.1 and IV.D.1 of this document, ``applying manufacturing 
controls to drug products and segregating drug products'' would be 
covered under the scope of manufacturing, preparing, propagating, 
compounding, or processing, and repackaging or otherwise changing the 
container, wrapper, or labeling of any drug package in furtherance of 
the distribution of the drug from the original place of manufacture to 
the person who makes the final delivery or sale to the ultimate 
consumer or user (section 510(a)(1) of the act). This activity would 
trigger the requirement to register under the act. In addition, under 
the proposal, drug product salvagers would also be subject to the drug 
listing requirements in section 510(j)(1) of the act because their 
activities involve conducting one of the aforementioned activities with 
respect to a given drug for the purpose of commercial distribution. As 
discussed in section IV.D.1 of this document, we are requesting 
comments specifically on whether drug product salvagers should be 
subject to the drug listing requirements because the drug products are 
being salvaged for commercial distribution.
    Establishment. We are proposing to revise the definition of 
``establishment'' at current Sec.  207.3(a)(7) to mean, for purposes of 
registration and drug listing, a place of business under one management 
at one geographic location. Under the proposed definition, one 
geographic location may include separate buildings within the same city 
if their activities are closely related to the same business enterprise 
and are under the supervision of the same local management. When not 
modified by ``domestic'' or ``foreign,'' as defined in proposed Sec.  
207.1 and discussed in section IV.A.5 of this document, the term would 
include both domestic establishments and foreign establishments. We are 
proposing to define the term ``establishment'' because, under proposed 
part 207, manufacturers, repackers, relabelers, and drug product 
salvagers must register each establishment, providing to us such 
information as the name and address of the establishment and type of 
operation performed at the establishment.
    The proposed definition of ``establishment'' would clarify the 
phrase ``at one general physical location'' in the current definition 
by revising the phrase to read ``one geographic location'' and stating 
that this may include separate buildings within the same city if their 
activities are closely related to the same business enterprise and are 
under the supervision of the same local management.
    The proposed definition of ``establishment'' is intended to 
simplify the current definition. The current definition defines 
establishment as a

[[Page 51288]]

place of business under one management at one general physical 
location, and includes, among others, independent laboratories that 
engage in control activities for a registered drug establishment (for 
example, consulting laboratories), manufacturers of medicated feeds and 
vitamin products that are drugs in accordance with section 201(g) of 
the act, human blood donor centers, animal facilities used for the 
production or control testing of licensed biologics, and establishments 
engaged in drug product salvaging. For brevity, the proposed definition 
of establishment does not restate the examples of establishments stated 
in the current definition. Some of these establishments would be 
covered under other definitions set forth in proposed Sec.  207.1 and 
explained in section IV.A.5 of this document. For example, 
``independent laboratories that engage in control activities for a 
registered drug establishment'' would be covered under the proposed 
definition of ``manufacturer.'' ``Establishments engaged in drug 
product salvaging'' would be covered under the proposed definition of 
``drug product salvager.''
    Establishment registration number. We are proposing to define 
``establishment registration number'' as the number assigned by FDA to 
the establishment during the establishment registration process 
required in this part. The establishment registration number is 
assigned to each establishment of each manufacturer, repacker, 
relabeler, or drug product salvager inspected by our district office. 
The establishment registration number is assigned when the 
manufacturer, repacker, relabeler, or drug product salvager begins 
manufacturing, repacking, relabeling, or salvaging drugs subject to 
part 207. The establishment registration number would identify, among 
other things, where the drug is manufactured, repacked, relabeled, or 
salvaged. Currently, the FDA Establishment Identifier (FEI) will be the 
number we assign as the establishment registration number. In the 
future, however, we may use a different number as the establishment 
registration number.
    Foreign. For the purposes of registration and listing under this 
proposal, and when used to modify the term ``manufacturer,'' 
``repacker,'' ``relabeler,'' ``drug product salvager,'' or ``private 
label distributor,'' we are proposing to use the term ``foreign'' to 
refer to a manufacturer, repacker, relabeler, drug product salvager, or 
private label distributor who is located in a foreign country and who 
manufactures, repacks, relabels, salvages, or distributes a drug that 
is imported or offered for import into the United States. When used to 
modify the term ``establishment,'' we are proposing to use the term 
``foreign'' to refer to an establishment that is located in a foreign 
country and is the site where a drug that is imported or offered for 
import into the United States was manufactured, repacked, relabeled, 
salvaged or distributed. The terms ``manufacturer,'' ``repacker,'' 
``relabeler,'' ``drug product salvager,'' ``private label 
distributor,'' and ``establishment'' are defined in proposed Sec.  
207.1, and these definitions are discussed elsewhere in this section of 
the preamble. We are proposing to define the term ``foreign'' 
separately rather than repeat the meaning of the term under separate 
definitions for foreign manufacturer, foreign repacker, foreign 
relabeler, foreign drug product salvager, foreign private label 
distributor, and foreign establishment. The definition of ``domestic,'' 
as it would modify manufacturer, repacker, relabeler, drug product 
salvager, private label distributor, and establishment, is discussed 
elsewhere in this section of the preamble.
    Importer. We are proposing to define ``importer'' to mean a company 
or individual in the United States that is an owner, consignee, or 
recipient of the foreign establishment's drug that is imported into the 
United States. We recognize that a foreign establishment may have more 
than one ``importer'' and we are proposing to include in this term any 
owner, consignee, or recipient, even if not the initial owner, 
consignee, or recipient, of the foreign establishment's drug that is 
imported into the United States. Under this proposal, the recipient of 
the drug would not include the consumer or patient who ultimately 
purchases, receives, or is administered the drug, unless the foreign 
establishment ships the drug directly to the consumer or patient. As 
described in section IV.B.3 of this document, this proposal would 
require foreign establishments to provide, for drugs manufactured, 
repacked, relabeled, or salvaged at the establishment, the name of each 
importer known to the establishment of such drug into the United 
States. Therefore, the establishment would need to provide the name of 
each owner, consignee, or recipient of the foreign establishment's drug 
imported into the United States that was known to the establishment. We 
describe more fully what we mean by ``known to the establishment'' in 
section IV.B.3 of this document. We invite comments on our definition 
of importer, including the scope of the entities included in the 
definition.
    Manufacture, manufacturer. We are proposing to use the term 
``manufacture'' for purposes of this part to mean each step in the 
manufacture, preparation, propagation, compounding, or processing of a 
drug. Manufacture includes the making by chemical, physical, 
biological, or other procedures or manipulations of a drug, including 
control procedures applied to the final product or to any part of the 
process. Manufacture includes manipulation, sampling, testing, or 
control procedures applied to the final product or to any part of the 
process, including, for example, analytical testing of drugs, for 
another registered establishment's drug.
    We are proposing to use the term ``manufacturer'' for purposes of 
this part to mean a person who owns or operates an establishment that 
manufactures a drug. When not modified by ``domestic'' or ``foreign,'' 
as defined in proposed Sec.  207.1 and discussed in section IV.A.5 of 
this document, ``manufacturer'' would include both domestic 
manufacturers and foreign manufacturers.
    Under section 510(a)(1) of the act, the term ``manufacture, 
preparation, propagation, compounding, or processing'' includes 
repackaging or otherwise changing the container, wrapper, or labeling 
of any drug package in furtherance of the distribution of the drug from 
the original place of manufacture to the person who makes final 
delivery or sale to the ultimate consumer or user. Accordingly, section 
510(a)(1) of the act sets up a shorthand way of referring to all the 
activities that trigger registration requirements by using the 
specified phrase ``manufacture, preparation, propagation, compounding, 
or processing'' throughout section 510 of the act. However, for 
purposes of proposed part 207, the term ``manufacture'' would refer to 
the manufacture, preparation, propagation, compounding, or processing 
of a drug, as set forth in the proposed definition.
    The term ``manufacturer'' would include, among others, control 
laboratories, contract laboratories, contract manufacturers, contract 
packers, contract labelers, and other entities that manufacture a drug, 
as defined in proposed Sec.  207.1 and discussed in section IV.A.5 of 
this document. A ``control laboratory'' and a ``contract laboratory'' 
include independent establishments that manipulate, sample, test, or 
perform other quality control functions for another registered 
establishment's drug, including, for example, analytical

[[Page 51289]]

testing of drugs. A ``contract manufacturer'' is sometimes employed by 
other manufacturers to manufacture the drug. Similarly, a manufacturer 
may sometimes subcontract part of the manufacturing process such as 
packing or labeling to a ``contract packer'' or a ``contract labeler.'' 
The term ``manufacturer'' would include control laboratories, contract 
laboratories, contract manufacturers, and other entities that 
manufacture a drug because their activities include the making of drugs 
by chemical, physical, biological, or other procedures, including the 
manipulation, sampling, testing, or control procedures applied to the 
final drug product or to a part of the process. Such activities would 
fall under the scope of activities (that is, manufacture, prepare, 
propagate, compound, or process) in section 510(a)(1) of the act that 
trigger registration requirements.
    The proposed definition of ``manufacture'' also explains that, for 
purposes of proposed part 207, the term manufacture is defined and used 
separately from the terms relabel, repack, and drug product salvage. 
Although we explain that repacking, relabeling, and drug product 
salvaging are activities that trigger registration (because the term 
``manufacture, preparation, propagation, compounding, or processing,'' 
under section 510 of the act includes repackaging or otherwise changing 
the container, wrapper, or labeling of any drug package in furtherance 
of the distribution of the drug from the original place of manufacture 
to the person who makes the final delivery or sale to the ultimate 
consumer or user), we believe that it is clearer to use four separate 
terms for the different activities for purposes of proposed part 207. 
We use separate terms so that we can clarify and differentiate the 
responsibilities of the four types of parties engaged in the separate 
activities of: ((1) Manufacturing that does not include repacking, 
relabeling, or drug product salvaging; (2) repacking; (3) relabeling; 
and (4) drug product salvaging).
    Similarly, the proposed definition of ``manufacturer'' explains 
that the term manufacturer is defined and used separately from the 
terms relabeler, repacker, and drug product salvager. We explain that 
repackers, relabelers, and drug product salvagers are ``manufacturers'' 
(as that entity is contemplated in section 510 of the act), but we 
believe that, for purposes of proposed part 207, it is clearer to use 
four separate terms for the different entities: (1) Manufacturers (that 
are not also repackers, relabelers, or drug product salvagers); (2) 
repackers; (3) relabelers; and (4) drug product salvagers. Repackers, 
relabelers, and drug product salvagers would be subject to the 
provisions of part 207 that are applicable to repackers, relabelers, 
and drug product salvagers, respectively, but would not be subject to 
the provisions of part 207 that are applicable to ``manufacturers,'' as 
that term is defined in this proposal. For example, if a repacker, 
relabeler, or a drug product salvager supplies us with the 
manufacturer's NDC number, we would not require the repacker, 
relabeler, or drug product salvager to provide all of the information 
that the manufacturer provides to list a drug or, for the repacker or 
relabeler, to obtain an NDC number. We would already have much of the 
information in the database linked to the manufacturer's NDC number, 
and it would be an unnecessary burden to require that the information 
be provided again.
    We are proposing to delete the definition of ``manufacturing or 
processing'' at current Sec.  207.3(a)(8) and incorporate parts of the 
definition elsewhere in the proposed definitions. For example, the 
phrase ``control procedures applied to the final product or to any part 
of the process'' in the proposed definition of ``manufacture'' is part 
of the current definition of ``manufacturing or processing.''
    Material change. We are proposing to revise the definition of ``any 
material change'' in current Sec.  207.3(a)(3). The current definition 
includes, but is not limited to: (1) Any change in the name of the 
drug; (2) any change in the identity or quantity of the active 
ingredient(s); (3) any change in the identity or quantity of the 
inactive ingredient(s) where quantitative listing of all ingredients is 
required by current Sec.  207.31(a)(2); (4) any significant change in 
the labeling of a prescription drug; and (5) any significant change in 
the label or package insert of an OTC drug. Changes that are not 
significant currently include changes in arrangement or printing or 
changes of an editorial nature. The proposed definition would continue 
to exclude labeling changes in arrangement or printing or labeling 
changes of an editorial nature. The inclusion of a bar code or NDC 
number on the label would not be considered a material change because 
it would be too burdensome to require the resubmission of labeling if 
the only change was to include a bar code or an NDC number. We are, 
however, proposing to rename the term ``material change'' and to more 
precisely identify all of the changes that would be considered 
``material'' in the current definition. With respect to manufacturers, 
repackers, and relabelers, and drug product salvagers, a change in any 
information provided under proposed Sec. Sec.  207.49, 207.53, 207.54, 
207.55, or 207.57 would be considered a material change.
    All listing information required under the proposal is needed to 
identify the drug. Under the broader definition of material change, as 
proposed, we would be better informed of changes to marketed drugs. 
This would result in more accurate and up-to-date drug listing 
information. Under proposed Sec.  207.57 and section 510(j)(2)(D) of 
the act, the June and December updates of listing information must 
include reports of ``material changes'' in listing information 
previously submitted. The proposed definition of ``material change'' 
has been revised to more precisely identify which changes must be 
reported under proposed Sec.  207.57.
    Person who imports or offers for import. We are proposing to define 
a ``person who imports or offers for import'' as an agent, broker, or 
other entity that the foreign establishment uses to facilitate the 
import of its drug into the United States. As described in section 
IV.B.3 of this document, this proposal would require foreign 
establishments to provide, for drugs manufactured, repacked, relabeled, 
or salvaged at the establishment, the name of each person known to the 
establishment who imports or offers for import such drug into the 
United States. Therefore, the establishment would need to provide the 
name of each agent, broker, or other entity that the foreign registrant 
uses to facilitate the import of its drug into the United States. We 
describe more fully what we mean by ``known to the establishment'' in 
section IV.B.3 of this document. The term ``person who imports or 
offers to import'' would not include carriers, consistent with the 
legislative history of the Bioterrorism Act. The legislative history 
shows that although the House provision originally would have required 
registration information for importers and carriers, the conference 
substitute changed the language. The conference substitute deleted the 
term ``carriers,'' replacing it with ``persons who import or offer for 
import,'' clarifying that foreign manufacturers are not required to 
include information on carriers with annual registration. (See H. Rept. 
107-481, 107th Cong., 2d sess., p. 140, 2002, Conf. Rept. to accompany 
H.R. 3448) We invite comments on our proposed definition of ``persons 
who import or offer for import.''
    We also invite comment on our use of the word ``facilitate'' in the 
proposed definition. We recognize that the term

[[Page 51290]]

could be interpreted to include middlemen or other entities that may be 
viewed as assisting with or promoting the importation of a drug into 
the United States. For example, we are aware that ``buyer's clubs'' 
could be captured in the definition if ``facilitate'' were to be 
interpreted broadly. Buyer's clubs are groups that consolidate orders 
for drugs purchased from foreign establishments and then, once those 
drugs are imported into the United States, send them to the individuals 
or other entities who ordered the drugs through the clubs. It is also 
possible that ``facilitate'' could be interpreted to include 
organizations that may promote the awareness and sale of products 
through advertisements on the internet, for example. We recognize that, 
under this proposal, foreign establishments would only be required to 
give us information for persons who import or offer for import that are 
known to the establishments. Although the knowledge requirement in this 
proposed rule would include information that the foreign establishment, 
and persons in the foreign establishment, has reason to know of, we 
believe it is likely that foreign establishments generally would not 
know about most of the ``middlemen'' described previously. Therefore, 
even though the term ``facilitate'' in the proposed definition would be 
interpreted broadly to include middlemen, if the foreign establishment 
did not know of, or have reason to know of, the middlemen, the foreign 
establishment would not be required to report information about the 
middlemen under this proposal.
    We also note that the terms ``broker'' or ``agent'' include 
``customhouse brokers'' who facilitate importation by filing documents 
with the U.S. Customs Service, as well as FDA and other Federal 
agencies responsible for the regulation of imported products. We 
specifically invite comment on our use of the term ``facilitate'' in 
this proposal. We invite comment on whether we should interpret the 
term ``facilitate'' broadly to include middlemen as described 
previously. We also invite comment on whether foreign establishments 
would know about such middlemen and, if so, what effect a requirement 
to report information about those middlemen would have on foreign 
establishments. We also invite comment on whether there are benefits 
associated with such a reporting requirement, and, if so, what they 
are.
    Private label distributor. We are proposing to define ``private 
label distributor'' to mean a person who owns or operates an 
establishment that commercially distributes, under its own label or 
trade name, any drug manufactured, repacked, relabeled, or salvaged by 
a registered establishment. When not modified by ``domestic'' or 
``foreign,'' as defined in proposed Sec.  207.1 and discussed in 
section IV.A.5 of this document, the term would include both domestic 
private label distributors and foreign private label distributors.
    Private label distributors are not considered to be manufacturers, 
repackers, relabelers, or drug product salvagers because they do not 
conduct any of the activities covered in section 510(a)(1) of the act 
with respect to the products they commercially distribute. Private 
label distributors only distribute drugs under their own label or trade 
name. The proposed definition is consistent with current Sec.  
207.20(b) and the description of private label distributors set forth 
in the 1973 final rule on drug listing requirements (38 FR 6258 at 
6259). We are proposing to define this term to clarify its meaning and 
to distinguish private label distributors from manufacturers, 
repackers, relabelers, and drug product salvagers. Under the proposed 
definition, a private label distributor does not engage in any 
activities performed by a manufacturer, repacker, relabeler, or drug 
product salvager for the drug it distributes. As discussed in section 
IV.D.1 of this document, private label distributors currently may elect 
to submit listing information to us for the drugs they distribute. 
Under the proposal, private label distributors would not be permitted 
to list, and manufacturers, repackers, relabelers, and drug product 
salvagers would be required to provide listing information to us for 
drugs being manufactured, repacked, relabeled, or salvaged for private 
label distributors. However, if a private label distributor is a 
manufacturer with respect to a particular drug or drugs, for example, 
the private label distributor is subject to the registration and 
listing requirements for manufacturers in proposed part 207 with 
respect to that drug or drugs.
    Relabel, relabeler. We are proposing to use the term ``relabel'' to 
mean changing the label or labels on a drug or drug package, or adding 
to the labeling for a drug or drug package, without repacking the drug 
or drug package. We remind interested persons that those activities 
must be conducted in accordance with the act and FDA regulations. We 
are proposing to use the term ``relabeler'' to mean a person who owns 
or operates an establishment that relabels a drug. When not modified by 
``domestic'' or ``foreign,'' as defined in proposed Sec.  207.1 and 
discussed in section IV.A.5 of this document, the term would include 
both domestic relabelers and foreign relabelers.
    Under the proposal, relabelers must provide registration and 
listing information. Under section 510(a)(1) of the act, the term 
``manufacture, preparation, propagation, compounding, or processing'' 
includes repackaging or otherwise changing the container, wrapper, or 
labeling of any drug package in furtherance of the distribution of the 
drug from the original place of manufacture to the person who makes 
final delivery or sale to the ultimate consumer or user. As discussed 
previously, we use the term ``relabeler'' separately from the term 
``manufacturer'' because, although the relabeler's registration and 
listing responsibilities in general are the same as those for 
manufacturers under the act, the proposal would modify some of these 
requirements. For example, as described under the definition of 
``manufacturer'' in section IV.A.5 of this document, if a relabeler 
supplies us with the manufacturer's NDC number, we would not require 
the relabeler to provide all of the information that the manufacturer 
provides to obtain an NDC number and to list a drug. We would already 
have much of the information in the database linked to the 
manufacturer's NDC number, and it would be an unnecessary burden to 
require that the information be provided again. Under the proposed 
definition, a relabeler does not engage in any other activity performed 
by a manufacturer for the drugs they relabel.
    Repack, repacker. We are proposing to use the term ``repack'' to 
mean repack or repackage or otherwise change the container or wrapper 
of a drug or drug package. We are proposing to use both the terms 
``repack'' and ``repackage'' in the definition because these terms are 
often used interchangeably with respect to drugs and, whether such 
activities are characterized as repacking or repackaging, they are 
subject to the requirements of this part. Although the term 
``repackaging'' is used in section 510(a)(1) of the act, the terms 
``repacking,'' ``repack,'' and ``repacker'' are more commonly used by 
industry when referring to this activity, and, therefore, we are using 
these terms throughout the proposal. We are proposing to use the term 
``repacker'' to mean a person who owns or operates an establishment 
that repacks a drug or drug package. When not modified by ``domestic'' 
or ``foreign,'' as defined in proposed Sec.  207.1 and discussed in 
section IV.A.5 of this document, the term would include both domestic 
repackers and foreign repackers.

[[Page 51291]]

    Under the proposal, repackers must provide registration and listing 
information. Under section 510(a)(1) of the act, the term 
``manufacture, preparation, propagation, compounding, or processing'' 
includes repackaging or otherwise changing the container, wrapper, or 
labeling of any drug package in furtherance of the distribution of the 
drug from the original place of manufacture to the person who makes 
final delivery or sale to the ultimate consumer or user. We use the 
term ``repacker'' separately from the term ``manufacturer'' because, 
although the repacker's registration and listing responsibilities in 
general are the same as those for manufacturers under the act, the 
proposal would modify some of these requirements. For example, as 
described under the definition of ``manufacturer'' in section IV.A.5 of 
this document, if a repacker supplies us with the manufacturer's NDC 
number, we would not require the repacker to provide all of the 
information that the manufacturer provides to obtain an NDC number and 
to list a drug. We would already have much of the information in the 
database linked to the manufacturer's NDC number, and it would be an 
unnecessary burden to require that the information be provided again. 
Under the proposed definition, a repacker does not engage in any other 
activity performed by a manufacturer for the drugs they repack.
    Representative sampling of advertisements. We are proposing to 
revise the definition of ``representative sampling of advertisements.'' 
Currently, Sec.  207.3(a)(2) explains that the term ``advertising'' as 
used in part 207 includes the promotional material described in Sec.  
202.1(l). However, current Sec.  207.3(a)(9) expressly excludes such 
material from the definition of ``representative sampling of 
advertisements.'' We believe that the inconsistency between the two 
provisions was an unintended result of certain editorial amendments 
made to part 207. We are proposing to revise the definition of 
``representative sampling of advertisements'' to resolve the 
inconsistency. Specifically, we believe that the content of current 
Sec.  207.3(a)(2) should be incorporated into the definition of 
``representative sampling of advertisements'' to clarify that the term 
includes the promotional material described in Sec.  202.1(l)(1).
    We are proposing to define ``representative sampling of 
advertisements'' as typical advertising material (including the 
promotional material described in Sec.  202.1(l)(1), but excluding 
labeling as determined in Sec.  202.1(l)(2)), that gives a balanced 
picture of the promotional claims used for the drug. In addition to 
resolving the inconsistency described previously, the proposed 
definition would delete the example currently provided in Sec.  
207.3(a)(9) (that is, if more than one medical journal advertisement is 
used but the promotional content is essentially identical, only one 
needs to be submitted). We believe that this example is unnecessary and 
are proposing to simplify the definition by deleting it.
    Representative sampling of any other labeling. We are proposing to 
revise the definition of ``representative sampling of any other 
labeling.'' We are proposing to delete current Sec.  207.3(a)(2), which 
explains that the term ``labeling'' as used in part 207 includes the 
promotional material described in Sec.  202.1(l)(2). We believe that 
this information would be more appropriately included in the definition 
of ``representative sampling of any other labeling.''
    We are proposing to define ``representative sampling of any other 
labeling'' as typical labeling material (including the promotional 
material described in Sec.  202.1(l)(2), but excluding labels and 
package inserts) that gives a balanced picture of the promotional 
claims used for the drug. In addition to incorporating the relevant 
content of current Sec.  207.3(a)(2), the proposed definition would 
delete the example currently provided in current Sec.  207.3(a)(10) 
(that is, if more than one brochure is used but the promotional content 
is essentially identical, only one needs to be submitted). We believe 
that this example is unnecessary and are proposing to simplify the 
definition by deleting it.
    United States agent. We are proposing to remove the definition of 
``United States agent'' in current Sec.  207.3(a)(11). Proposed Sec.  
207.69 would incorporate many of the provisions of the current 
definition of United States agent and current Sec.  207.40 
(registration and listing requirements for foreign establishments). The 
same requirements in the current definition appear at proposed Sec.  
207.69(b)(1), (b)(2), and (b)(3).

B. Registration

1. Who Would Be Required to Register?
    Proposed Sec.  207.17(a) would require manufacturers, repackers, 
relabelers, and drug product salvagers to register each establishment. 
This provision would replace the requirement at current Sec.  207.20(a) 
that owners or operators of all drug establishments that engage in the 
manufacture, preparation, propagation, compounding, or processing of a 
drug must register. The terms ``manufacturer,'' ``repacker,'' 
``relabeler,'' and ``drug product salvager,'' as defined in proposed 
Sec.  207.1 and discussed in section IV.A.5 of this document, more 
clearly indicate who must register.
    Manufacturers, repackers, relabelers, and drug product salvagers 
would be required to register because the activities they perform fall 
within the scope of activities that trigger registration requirements 
in section 510(a)(1) of the act. Section 510(a)(1) states that the 
phrase ``manufacture, preparation, propagation, compounding, or 
processing'' includes repacking or otherwise changing the container, 
wrapper, or labeling of any drug package in furtherance of the 
distribution of the drug from the original place of manufacture to the 
person who makes final delivery or sale to the ultimate consumer or 
user.
    We are proposing to use the terms ``repacker,'' ``relabeler,'' and 
``drug product salvager'' separately from the term ``manufacturer'' in 
the proposal because, although the repacker, relabeler, and drug 
product salvager's listing responsibilities in general are similar to 
those for manufacturers under the act, the proposal would modify some 
of these requirements. In particular, if a repacker, relabeler, or drug 
product salvager supplies us with the manufacturer's NDC number, we 
would not require the repacker, relabeler, or drug product salvager to 
provide all of the information that the manufacturer provides to list a 
drug. Similarly, we would not require repackers and relabelers to 
submit all of the information that the manufacturer submits to obtain 
an NDC number.
    Proposed Sec.  207.17(a) would enable us to identify who is making 
drugs and where they are being made. Being able to accurately identify 
who makes drugs and where they are made is very important. Certain 
marketed drugs may need to be quickly identified and used to help 
counteract the effects of a bioterrorism attack. Registration 
information also assists us in scheduling and planning inspections of 
registered establishments pursuant to section 704 of the act.
    Proposed Sec.  207.17(a) also provides that registration 
information may be submitted by the parent, subsidiary, and/or 
affiliate company for all establishments when operations are conducted 
at more than one establishment and there exists joint ownership and 
control among all the establishments. This provision would also apply 
when operations are

[[Page 51292]]

conducted at both domestic and foreign establishments and there exists 
joint ownership and control among all the establishments. This 
provision is consistent with current Sec.  207.20(a).
    We are proposing to revoke the requirement in current Sec.  
207.20(a) that no owner or operator may register an establishment if 
any part of that establishment is registered by another owner or 
operator. The requirement has caused uncertainty about who must 
register and which establishment must be registered. Under proposed 
Sec.  207.17(a), manufacturers, repackers, relabelers, and drug product 
salvagers must register each establishment unless they are otherwise 
exempt under section 510(g) of the act or proposed Sec.  207.13.
    Under proposed Sec.  207.17(b), private label distributors would 
not register with us unless they also manufacture, repack, relabel, or 
salvage drugs and are required to register under the act or proposed 
Sec.  207.17(a). Private label distributors are not considered to be 
manufacturers, repackers, relabelers, or drug product salvagers because 
they do not conduct any of the activities covered under section 
510(a)(1) of the act with respect to the drugs they commercially 
distribute. Private label distributors only distribute drugs under 
their own label or trade name. Proposed Sec.  207.17(b) would revise 
the provision in current Sec.  207.20(b) that owners or operators of 
establishments that distribute under their own label or trade name a 
drug manufactured or processed (as defined in current Sec.  
207.3(a)(8)) by a registered establishment may elect to obtain a 
labeler code from us and submit listing information directly to us. 
Under current regulations, if a private label distributor does not 
elect to submit drug listing information to us, the registered 
establishment must submit the drug listing information. As explained in 
section IV.D.1 of this document, we are proposing to revise current 
Sec.  207.20(b) and not permit private label distributors to register 
or list. Manufacturers, repackers, relabelers, and drug product 
salvagers must submit drug listing information for those drugs they 
manufacture, repack, relabel, or salvage for commercial distribution 
for a private label distributor.
2. When Would Initial Registration Information Be Provided?
    Under proposed Sec.  207.21, a domestic manufacturer, domestic 
repacker, domestic relabeler, and domestic drug product salvager must 
register each establishment no later than 5 calendar days after 
beginning to manufacture, repack, relabel, or salvage a drug. The 
proposed timeframe ``no later than 5 calendar days'' is consistent with 
current Sec.  207.21(a) in that the current registration requirement 
also provides for a 5-day registration timeframe for owners or 
operators of establishments entering into the ``manufacturing or 
processing'' of a drug (as defined in current Sec.  207.3(a)(8)). The 
proposed timeframe is also consistent with the requirement in section 
510(c) of the act to register each establishment ``immediately'' and 
``upon first engaging in the manufacture, preparation, propagation, 
compounding, or processing'' of a drug.
    Under proposed Sec.  207.21, a foreign manufacturer, foreign 
repacker, foreign relabeler, and foreign drug product salvager must 
register each establishment before a drug manufactured, repacked, 
relabeled, or salvaged at the establishment is imported or offered for 
import into the United States. This is consistent with current Sec.  
207.40(b), which states that no drug may be imported or offered for 
import into the United States unless it is listed and manufactured, 
prepared, propagated, compounded, or processed at a registered foreign 
drug establishment. In addition, section 510(i) of the act states that 
any establishment within any foreign country engaged in the 
manufacture, preparation, propagation, compounding, or processing of a 
drug or device that is imported or offered for import into the United 
States shall register with the Secretary.
    Proposed Sec.  207.21 uses the term ``each establishment'' to 
emphasize that the requirement to register would apply even if the 
manufacturer, repacker, relabeler, or drug product salvager has 
previously registered one or more other establishments. This proposed 
requirement is consistent with two provisions of section 510 of the 
act. Section 510(d) of the act requires registration of any additional 
establishment immediately upon beginning the manufacture, preparation, 
propagation, compounding, or processing of a drug at that 
establishment. Section 510(i)(1) of the act states that any 
establishment within any foreign country engaged in the manufacture, 
preparation, propagation, compounding, or processing of a drug or a 
device that is imported or offered for import into the United States 
must register with the Secretary.
    We are proposing to specify ``calendar'' days to be consistent with 
the terminology and timeframes used in the international pharmaceutical 
regulatory guidances of the International Conference on the 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) (http://www.ich.org) and the World 
Health Organization's Council for International Organizations of 
Medical Sciences (CIOMS) (http://www.cioms.ch).
    We are proposing to revoke the requirement in current Sec.  
207.21(a) to register within 5 days after submitting certain marketing 
applications if the owner or operator has not previously entered into 
the manufacture or processing of a drug (as defined in current Sec.  
207.3(a)(8)). We are also proposing to revoke the requirement in 
current Sec.  207.20(c) that, before beginning the manufacture or 
processing of a drug subject to certain marketing applications, an 
owner or operator of an establishment must register before the 
application is approved. We are proposing to revoke these requirements 
because, under proposed Sec.  207.21 and consistent with section 510(c) 
and (d) of the act, registration of each establishment must occur no 
later than 5 calendar days after beginning to manufacture, repack, 
relabel, or salvage a drug at the establishment. This provision would 
govern when to register an establishment rather than the date a 
marketing application is submitted or approved. We believe that this 
proposed requirement would provide us with sufficient notice as to who 
is manufacturing, repacking, relabeling, or salvaging drugs and where 
those activities are taking place. In addition, marketing application 
approval is linked to registration elsewhere in our regulations. Under 
current Sec.  314.125(b)(11) (21 CFR 314.125(b)(11)), we may refuse to 
approve an application if the drug will be manufactured or processed in 
an establishment that is not registered. For consistency with current 
Sec.  314.125(b)(11), we are proposing to revise Sec.  514.111(a)(12) 
(21 CFR 514.111(a)(12)) for NADAs to state that we will refuse to 
approve an application if ``the drug will be manufactured in whole or 
in part in an establishment that is not registered and not exempt from 
registration under section 510 of the act and part 207.'' For licensed 
human biological products, current 21 CFR 601.4(b) includes a provision 
that we must deny a BLA if the establishment or product does not meet 
``requirements established in Title 21, Chapter I'' (this would include 
the registration and listing provisions).
3. What Information Would Be Required for Registration?
    Under proposed Sec.  207.25, all manufacturers, repackers, 
relabelers,

[[Page 51293]]

and drug product salvagers must provide the following information to 
register each of their establishments:
     Name of the owner or operator of each establishment; if a 
partnership, the name of each partner would be submitted; if a 
corporation, the name of each corporate officer and director and the 
place of incorporation would be submitted (proposed Sec.  207.25(a)). 
This provision is consistent with section 510(a)(2) of the act, which 
states that ``the term 'name' shall include in the case of a 
partnership the name of each partner and, in the case of a corporation, 
the name of each corporate officer and director, and the State of 
incorporation.'' The proposal would replace ``State of incorporation'' 
with ``place of incorporation'' to include foreign corporations. 
Proposed Sec.  207.25(a) is also consistent with section 510(c) of the 
act, which states that ``Every person * * * shall immediately register 
with the Secretary his name, place of business, and such 
establishment.'' The proposal would use ``owner or operator'' for 
consistency with current Sec.  207.25(a), which provides that the 
information required for registration includes the name of the owner or 
operator of the establishment. Current Sec.  207.25(a) provides that 
the term ``name of the owner or operator'' includes, in the case of a 
partnership, the name of each partner and, in the case of a 
corporation, the name and title of each corporate officer and director 
and the name of the State of incorporation. The proposal would revoke 
the requirement to include the title of each corporate officer and 
director because we have determined that it is not necessary for 
registration purposes. Current Sec.  207.25(a) also requires the 
submission of the ``kind of ownership or operation (that is, 
individually owned, partnership, or corporation).'' The proposal would 
replace this requirement because the kind of ownership or operation 
would be captured under the requirement to provide, if applicable, the 
name of each partner, and corporate officer and director, and the place 
of incorporation in proposed Sec.  207.25(a).
     Name, trade name(s), and address of each establishment 
(proposed Sec.  207.25(b), (c), and (d)). This provision is consistent 
with section 510(c) of the act and current Sec.  207.25(a). The 
proposal would continue the requirement in current Sec.  207.25(a) to 
submit all trade names used by the establishment, but rephrase current 
Sec.  207.25(a) to clarify that, for purposes of this subsection, we 
want the trade name(s) of the establishment, names under which the 
establishment conducts business, and additional names by which the 
establishment is known. We are not seeking under this section the trade 
name(s) of the drugs of the establishment. Although we are interested 
in the trade names of the drugs, we can obtain that information through 
the drug listing requirements.
     Registration number of each establishment, if previously 
assigned to the establishment by us (proposed Sec.  207.25(e)). If not 
previously assigned by us, we would assign a registration number after 
we receive the registration information (proposed Sec.  207.25(e)). 
Under section 510(e) of the act, we may assign a registration number to 
any person or establishment registered and, under current Sec.  
207.35(a), we will assign a permanent registration number to each 
establishment that registers. The ``establishment registration number'' 
is defined in proposed Sec.  207.1 to mean the number assigned by FDA 
to the establishment during the establishment registration process. 
(Currently, the FEI will be the number we assign as the establishment 
registration number.) We are proposing to require the submission of the 
registration number because each establishment is identified by its 
registration number for registration and inspection purposes and to 
enable us to identify all registered establishments. The registration 
number is currently submitted on Form FDA 2656.
     Type of operations(s) performed at each establishment--for 
example, manufacturing, repacking, relabeling, or salvaging (proposed 
Sec. 207.25(f)). We are proposing to require this information because 
it is important for identifying, prior to an inspection, which 
operation the establishment engages in so that our investigators can be 
better prepared before inspection. Currently, the ``business type'' 
(for example, manufacturer, repacker, relabeler) must be submitted on 
Form FDA 2656.
     Name, address, telephone and fax numbers, and e-mail 
address of the official contact, as provided in proposed Sec.  
207.69(a), for each establishment (proposed Sec.  207.25(g)). We are 
proposing to require this information because we need a contact person 
to facilitate discussion with the manufacturer, repacker, relabeler, 
and drug product salvager. This information needs to be current and, 
under proposed Sec.  207.29(a)(3), any change in this information must 
be provided to us within 30 calendar days. This information is not 
required under current part 207. The requirements for the official 
contact are discussed in section IV.F.1 of this document.
     Information for foreign establishments only (proposed 
Sec.  207.25(h)). With respect to foreign establishments only, for 
drugs manufactured, repacked, relabeled, or salvaged at the 
establishment, the name, address, telephone and fax numbers, and e-mail 
address must also be provided for: (1) The United States agent, as 
provided in proposed Sec.  207.69(b), (2) each importer of such drug in 
the United States that is known to the establishment, and (3) each 
person who imports or offers for import such drug to the United States. 
The requirements for the United States agent are discussed in section 
IV.F.1 of this document. The name, address, and phone number of the 
United States agent is required to be submitted under current Sec.  
207.40(c). The information on importers and persons who import is not 
required to be submitted under current part 207. We are proposing to 
require the submission of the information on importers and persons who 
import because the Bioterrorism Act requires foreign establishments to 
submit, among other things, the name of each importer of each drug that 
is known to the manufacturer, repacker, relabeler, and drug product 
salvager and the name of each person who imports or offers for import 
each drug to the United States for purposes of importation. We want to 
make clear that the term ``known to'' would include any importer that 
is known to the foreign establishment as well as any importer that the 
foreign establishment has reason to know of. We therefore expect that 
the person responsible for completing the required registration forms 
on behalf of the foreign establishment would undertake appropriate due 
diligence in completing those forms, including to find out and report 
importers that others in his or her establishment know of or have 
reason to know of. In addition to the name, the proposal would require 
that the address, telephone and fax numbers, and e-mail address of each 
importer and of each person who imports or offers for import be 
provided to enable us to contact these persons.
    All information required under proposed Sec.  207.25 must be 
submitted for the establishment to be considered registered. As 
explained in section IV.B.l of this document, establishment 
registration would enable us to identify who is making drugs and where 
they are being made. Being able to accurately identify who makes drugs 
and where they are made is very important for protecting the public 
health. Among other things, registration information would enable us to 
become aware of and take action to stop manufacturers,

[[Page 51294]]

repackers, relabelers, and drug product salvagers who do not follow the 
requirements set forth in the act and in our regulations.
4. What Are the Proposed Requirements for Reviewing and Updating 
Registration Information?
    The proposal would modify and streamline the requirements 
associated with updating registration information. Currently, 
manufacturers, repackers, relabelers, and drug product salvagers must 
enter new or revised registration information on Form FDA 2656 and 
return the form to us annually. Under the proposal, manufacturers, 
repackers, relabelers, and drug product salvagers would access the 
electronic drug registration and listing system and review their 
current registration information online, making any changes where 
needed. Updating registration information would be less time consuming 
under the proposal because the manufacturer's, repacker's, relabeler's, 
and drug product salvager's information would be easily accessible at 
any time and only changes to the information already in the system 
would need to be entered in the fields provided.
    The following sections provide a description of the proposed 
requirements for reviewing and updating registration information and 
how they modify or reduce the burden of the current requirements.
    a. Expedited updates of registration information. Manufacturers, 
repackers, relabelers, and drug product salvagers would report, under 
proposed Sec.  207.29(a), the following changes as expedited updates no 
later than 30 calendar days after the change:
     The close or sale of an establishment;
     Any change in the name or address of an establishment; and
     Any change in the name, address, telephone and fax 
numbers, or e-mail address of the official contact or the United States 
agent.
    We are proposing to require that these changes be reported as 
expedited updates because we need to know as soon as possible when a 
business has closed or has been sold and when the establishment's name 
or address has changed. This information is especially important for 
scheduling inspections. We also need current information for contacting 
the official contact or United States agent. As previously mentioned, 
it is increasingly important for us to be able to identify where drugs 
are being made and when drugs are no longer available. The expedited 
receipt of this information will help promote the efficient enforcement 
of the act.
    Manufacturers, repackers, relabelers, and drug product salvagers 
are encouraged to provide expedited updates as soon as possible but no 
later than 30 calendar days after the change occurs. Our electronic 
drug registration and listing system will be easily accessible all the 
time to make changes.
    The close or sale of an establishment, and a change in the name or 
address of an establishment, are currently reported annually on Form 
FDA 2656.
    Proposed Sec.  207.29(a) would revise current Sec. Sec.  207.26 and 
207.40(c)(3). Current Sec.  207.26 requires the submission of certain 
amendments to registration information within 5 days of the change, and 
as noted previously, Sec.  207.40(c)(3) requires the submission of any 
changes to the United States agent's name, address, or phone number 
within 10 business days of the change. As explained below, the proposal 
would lengthen the time period for reporting the changes in current 
Sec.  207.40(c)(3). The proposal also would lengthen the time period 
for reporting some of the changes in current Sec.  207.26 and revoke 
some of the reporting requirements in current Sec.  207.26:
     A change in location would no longer be submitted as an 
amendment to registration within 5 days of the change, but would be 
reported under proposed Sec.  207.29(a)(2) as an expedited update no 
later than 30 calendar days after the change (``address'' of an 
establishment is used in the proposal instead of location). We have 
determined that notification no later than 30 calendar days would be 
sufficient and would be consistent with the proposed timeframe for the 
other expedited updates.
     A change in ``drug-handling activity'' would no longer be 
submitted as an amendment to registration within 5 days of the change. 
A change in this information would only be reported during the annual 
review and update under proposed Sec.  207.29(b). (The term ``type of 
operations'' is used in proposed Sec.  207.25(f) instead of ``drug-
handling activity.'') We have determined that annual notification of 
this change would be sufficient.
     Changes in ``individual ownership'' and ``corporate or 
partnership structure,'' in current Sec.  207.26, would no longer be 
reported as amendments to registration because the proposal would 
revoke the corresponding provision for registration in current Sec.  
207.25(a) (the ``kind of ownership or operation (that is, individually 
owned, partnership or corporation)''). As explained in section IV.B.3 
of this document, the kind of ownership or operation would no longer be 
submitted for registration because the information would be captured 
under the requirement to provide, if applicable, the name of the 
partner, corporate officer and director, and the place of incorporation 
in proposed Sec.  207.25(a). This information would be reviewed and 
updated annually under proposed Sec.  207.29(b). This proposed 
requirement is consistent with current Sec.  207.26, which specifies 
that changes in the names of officers and directors of the corporation 
do not require an amendment and must be submitted at the time of annual 
registration.
     Under current Sec.  207.26, a change in a registered 
establishment's firm name within 6 months of the registration of the 
establishment must be supported by a signed statement of the 
establishment's owner or operator that the change was not made for the 
purpose of changing the name of the manufacturer of a drug product 
under current Sec.  201.1. This verification would no longer be 
required to be submitted as an amendment to registration. A change in 
the name of an establishment would be reported under proposed Sec.  
207.29(a)(2) no later than 30 calendar days after the change.
    Proposed Sec.  207.29(a)(3) would revise current Sec.  
207.40(c)(3), which provides that a foreign drug establishment or 
United States agent must report to us, within 10 business days, any 
changes to the United States agent's name, address, or phone number. 
The proposal would make the following revisions:
     The changes to the information about the United States 
agent would be revised to include not only the name, address, and 
telephone number, but also the fax number and e-mail address. This 
provision would be consistent with the information required to be 
submitted for the United States agent for registration under proposed 
Sec.  207.25(h).
     The time period for reporting the changes would be 
lengthened to no later than 30 calendar days for consistency with the 
time period for the other expedited reports in proposed Sec.  
207.29(a).
     Changes in the name, address, telephone and fax numbers, 
and e-mail address of the official contact would also be reported under 
proposed Sec.  207.29(a)(3) within 30 calendar days. This provision 
would be consistent with the information required to be submitted for 
the official contact for registration under proposed Sec.  207.25(g).
     Under proposed Sec.  207.29(a)(3), the manufacturer, 
repacker, relabeler, and drug product salvager, official contact, or 
United States agent may notify us about a change of information for the 
designated official contact or United

[[Page 51295]]

States agent. This provision would make the updates easier than the 
requirement in current Sec.  207.40(c)(3) because it would enable the 
official contact and the United States agent (in addition to the 
manufacturer, repacker, relabeler, and drug product salvager) to update 
their own or each other's registration information.
     Under proposed Sec.  207.29(a)(3), only a manufacturer, 
repacker, relabeler, or drug product salvager may designate a new 
official contact or United States agent. This proposed requirement is 
necessary because the manufacturer, repacker, relabeler, and drug 
product salvager is ultimately responsible for the actions of the 
official contact and the United States agent.
    The requirements for the official contact and the United States 
agent are discussed in section IV.F.1 of this document.
    b. Annual review and update of registration information. Proposed 
Sec.  207.29(b) would require that the registration information 
provided under proposed Sec.  207.25 be reviewed and updated annually. 
This timeframe is consistent with the requirement in section 510(b) of 
the act that owners or operators register on or before December 31 of 
each year and with the requirement in current Sec.  207.21(a) that 
owners or operators renew their registration information annually. 
Proposed Sec.  207.29(b) uses the term ``review and update'' to stress 
the importance of first reviewing all registration information to 
determine if any changes have occurred and then updating the 
information where needed. Proposed Sec.  207.29(b)(1) specifies that 
the first review and update must occur no later than 1 year after the 
date of the initial registration of each establishment and that 
subsequent reviews and updates must occur no later than annually 
thereafter from the date of initial registration. Proposed Sec.  
207.29(b)(2) provides that the updates must reflect all changes that 
have occurred since the last annual review and update.
    The proposal would add a new requirement for updating registration 
information. Under proposed Sec.  207.29(b)(3), if none of the 
registration information has changed since the last annual registration 
(accomplished through the review and update of registration 
information), manufacturers, repackers, relabelers, and drug product 
salvagers must certify electronically that no changes have occurred. 
This is consistent with section 510(b) of the act, which requires 
manufacturers to register on or before December 31 of each year. If 
manufacturers, repackers, relabelers, and drug product salvagers 
certify that no changes have occurred, this certification would be the 
equivalent of resubmitting registration information, thereby satisfying 
the annual registration requirement. We are proposing to require that 
manufacturers, repackers, relabelers, and drug product salvagers 
certify annually that no changes have occurred because many 
manufacturers, repackers, relabelers, and drug product salvagers have 
not reviewed or updated this information on a regular basis. It has 
been difficult for us to determine whether failure to register annually 
is the result of no changes in information or noncompliance. The 
proposed requirement is intended to reduce these instances and improve 
the accuracy of our registration database. To increase the nation's 
ability to prepare for and respond effectively to bioterrorism and 
other public health emergencies, it is increasingly important for 
manufacturers, repackers, relabelers, and drug product salvagers to 
comply with registration requirements. With accurate information, we 
can identify where drugs are being made and better ensure that drugs 
are promptly available when needed. Furthermore, taking steps to 
increase compliance is consistent with section 301(p) of the act (21 
U.S.C 331(p)), which makes it a prohibited act to fail to register 
under section 510 of act.

C. The National Drug Code (NDC) Number: What is It? How is It Used? 
What Changes Are We Proposing?

1. What Is the NDC Number?
    The NDC number is a widely used identifier for drugs. It is a 
unique 10-digit number consisting of 3 segments: The labeler code, the 
product code, and the package code. Currently, the labeler code 
consists of four or five digits, the product code consists of either 
three or four digits, and the package code consists of either one or 
two digits. We assign the labeler code to the manufacturer, repacker, 
or relabeler after it has registered with us. For private label 
distributors, currently we provide a labeler code to the private label 
distributor if the private label distributor submits the required 
information to us. Alternatively, we provide a labeler code for a 
private label distributor to the manufacturer, repacker, or relabeler 
who is manufacturing, repacking, or relabeling the drug for the private 
label distributor after the manufacturer, repacker, or relabeler 
provides the required registration information pertaining to the 
private label distributor. The manufacturer, repacker, relabeler, or 
private label distributor then assigns the product code and package 
code to each drug within certain parameters that we have established.
2. How Did NDC Numbers Originate? How Are They Used?
    Created in 1969, NDC numbers were originally intended to ``provide 
an identification system in computer language to permit automated 
processing of drug data by Government agencies, drug manufacturers and 
distributors, hospitals, and insurance companies'' (see 34 FR 11157, 
July 2, 1969). Participation in the NDC system was voluntary initially, 
and the program covered ``firms which manufacture and label or which 
repackage and label drugs'' (id.). In 1971, the NDC system expanded to 
include ``distributors who are marketing drug products in interstate 
commerce, under their own name (label), and through multiple wholesale 
outlets and/or five or more retail outlets'' (see 36 FR 27, January 1, 
1971).
    The enactment of the Drug Listing Act of 1972 (Public Law 92-387, 
86 Stat. 559) changed the NDC number system even further. The Drug 
Listing Act required registered establishments to list all drugs that 
the establishment manufactures, prepares, propagates, compounds, or 
processes for commercial distribution and authorized us to assign a 
``listing number'' to each drug or class of drugs that was listed. The 
Drug Listing Act declared that, ``Any number assigned * * * shall be 
the same as that assigned pursuant to the National Drug Code.'' Thus, 
by linking drug listings to the NDC numbers, the Drug Listing Act, in 
essence, authorized us to make participation in the NDC number system 
mandatory. In addition, by referring to the word, ``drug,'' the Drug 
Listing Act extended the NDC number system to over-the-counter drugs 
and animal drugs (because both are ``drugs'' under the act and are 
listed under section 510(j) of the act).
    Today, NDC numbers continue to be an important, standardized, 
identification system for drug products used in data or claims 
processing, as well as in applications other than data or claims 
processing. For example, consumers may use NDC numbers to identify 
drugs that are the subject of a recall. Health care professionals 
submitting MedWatch reports (concerning possible adverse drug events) 
use NDC numbers to identify the drug at issue. Our investigators 
sometimes use NDC numbers to

[[Page 51296]]

determine a drug's compliance status by linking the NDC number to our 
registration and listing database to verify whether the manufacturer 
has registered and listed a particular drug. We compile the NDC numbers 
in the National Drug Code Directory, and the directory is accessible 
online at http://www.fda.gov/cder/ndc/database.
    In addition, several new or future public health programs or 
initiatives rely or will rely on NDC numbers. For example:
     On February 26, 2004 (69 FR 9120), we published in the 
Federal Register a final rule to require certain human drug and 
biological products to have bar codes (see 69 FR 9120). The bar code 
must contain, at a minimum, the drug's NDC number. This rule is 
designed to reduce the number of medication errors in hospitals and 
other health care settings by allowing health care professionals to use 
bar code scanning equipment to verify that the right drug (in the right 
dose and right route of administration) is being administered to the 
right patient at the right time.
     The electronic prescription drug program established by 
the Medicare Modernization Act promotes uniform standards that permit 
(among other things) electronic exchange of drug labeling and drug 
listing information maintained by us and by the National Library of 
Medicine (see 42 U.S.C. 1860D-4(e)(3)(C)(iii)). The goal behind the 
program is to reduce transcription and dispensing errors (which, in 
turn, lead to medication errors) and to prevent adverse drug 
interactions. As we stated previously in this document, drug listing 
numbers are, under the Drug Listing Act of 1972, to be the same as NDC 
numbers.
     The Health Insurance Portability and Accountability Act 
(Public Law 104-191) required, among other things, adoption of code set 
standards to facilitate electronic transactions. The standard code set 
for drugs is the NDC (see final rule on ``Health Insurance Reform: 
Standards for Electronic Transactions'' (65 FR 50312, August 17, 2000), 
45 CFR 162.1002(c); amended February 20, 2003: ``Health Insurance 
Reform: Modifications to Electronic Data Transaction Standards and Code 
Sets'' (68 FR 8381), 45 CFR 162.1002(a)(3) and (b)(2)).
     We are working with the National Library of Medicine, 
manufacturers, repackers, relabelers, and health care information 
suppliers to improve patient safety by better access to medication 
information through the DailyMed initiative. The DailyMed is an up-to-
date, computerized repository of medication information including 
product labeling. The changes we are proposing to the NDC number would 
complement the DailyMed initiative by providing a link to product 
labeling made available through the DailyMed. The product labeling in 
this repository would be in the form of SPL. SPL is a standardized 
computer readable product labeling that links the NDC number to the 
product information.
    To illustrate how this would work, someone could simply scan a bar 
code encoded with the NDC number or type into the DailyMed search 
program the NDC number on the carton label to access the most current 
information in the product labeling available from the DailyMed. This 
capability would enable DailyMed users to have the most up-to-date 
information for a drug, which could be an important public health 
benefit for consumers and health care professionals. For example, 
assume that a manufacturer modified its labeling to reflect a new 
adverse drug experience. If a consumer, pharmacist, or health care 
provider received a drug whose labeling had been printed earlier, the 
consumer, pharmacist, or health care provider would not be alerted to 
the new adverse drug experience. By using the DailyMed, the consumer, 
pharmacist, or health care provider would be able to access the new 
drug labeling and would, therefore, learn about the new adverse drug 
experience and possibly be able to avoid it. The consumer, pharmacist, 
or health care provider would also be better able to assess the risks 
and benefits of the drug and, therefore, would be able to make more 
informed decisions about using the drug. The DailyMed would be a 
publicly accessible repository of drug information that could be used 
in many ways by various parties, such as by those who could add value 
to the information, such as pricing information, and make it available 
to other parties.
    Unfortunately, despite the widespread and growing use and reliance 
on NDC numbers, the existing NDC number system has several 
shortcomings. For example, manufacturers, repackers, and relabelers can 
assign NDC numbers, and the current regulations at Sec.  
207.35(b)(4)(ii) permit them to re-use the product codes under certain 
circumstances (such as taking the NDC number assigned to drug X and 
then, after drug X has been discontinued, later assign the same NDC 
number to drug Z). Also, under current regulations, it is difficult for 
FDA to control the practice of a manufacturer, repacker, or relabeler 
making changes to a drug but continuing to use the same NDC number 
despite those changes.
    The manufacturer, repacker, and relabeler's ability to assign the 
product code and package code themselves has also resulted in problems 
that affect the National Drug Code Directory and its reliability. 
Product and package codes are not always assigned appropriately, and 
industry practices for assigning codes are inconsistent. In addition, 
manufacturers, repackers, and relabelers currently do not tell us what 
codes they have assigned until they list drugs with us; this means that 
the National Drug Code Directory is not always complete or 
comprehensive. Moreover, manufacturers, repackers, and relabelers may 
never list a product or may sometimes omit information or submit 
incorrect information to us; this often prevents us from including the 
correct information in the National Drug Code Directory and forces us 
to devote resources to obtaining, sometimes unsuccessfully, the correct 
information.
    Furthermore, because NDC code segments can vary in length (such as 
a NDC having a four-digit labeler code, a four-digit product code, and 
a two-digit package code while another NDC has a five-digit labeler 
code, a three-digit product code, and a two-digit package code), 
electronic systems that view the NDC as a single number might interpret 
two different NDC numbers as being the same number. For example, one 
manufacturer, repacker, or relabeler's drug might have a NDC number 
that reads as 12345-678-90 while another could have a drug whose NDC 
number reads as 1234-5678-90. If a database omits the hyphens, the 
result would be a misleading impression that both drugs have identical 
NDC numbers (i.e., 1234567890), although they are made by different 
manufacturers and may be entirely different products.
    We have also found that some manufacturers, repackers, and 
relabelers have assigned NDC numbers to products that are not drugs, 
such as dietary supplements and medical devices; such actions can 
confuse drug databases or lead to inappropriate reimbursements.
    Consequently, to address these shortcomings and to create an 
accurate, up-to-date NDC number system, we propose to revise the NDC 
number system. In brief, we believe that to ensure that the numbers are 
unique and unambiguous, we need to take on the responsibility of 
assigning the NDC numbers prospectively to drugs that have not 
previously been assigned NDC numbers by a manufacturer, repacker, or 
relabeler. The NDC numbers currently assigned to drugs prior to the 
effective date of the rule would remain unchanged, provided those NDC 
numbers comply with the new

[[Page 51297]]

regulations as finalized. FDA intends to validate that current NDC 
numbers comply with the new regulations as finalized. We believe that 
the NDC number structure can remain very similar to what exists today, 
as we describe below, and still allow for unique and unambiguous NDC 
numbers if we assign the NDC numbers.
    The proposal would also delete obsolete or unnecessary 
requirements. For example, current Sec.  207.35 refers to the National 
Health Related Items Code (NHRIC) system as another code system; the 
proposal would omit references to the NHRIC system because we no longer 
maintain the NHRIC database (see 42 FR 52808 at 52810, September 30, 
1977)).
    We describe the proposed changes in more detail in the next 
section.
3. What Changes Are We Proposing?
    a. Proposed Sec.  201.2--Drugs; National Drug Code (NDC) Number. 
Currently, Sec.  201.2 states that NDC numbers are requested, but not 
required, to appear on all drug labels and in all drug labeling, 
``including the label of any prescription drug container furnished to a 
consumer.'' Section 201.2 also states that if the NDC number appears on 
the drug label, it must be displayed as required by current Sec.  
207.35(b)(3).
    The proposal would revise Sec.  201.2 to explain:
     What drugs must have an NDC number, in human-readable 
form, on the label;
     What an appropriate NDC number is;
     Whether any other NDC number may appear on a label;
     What prefix must be used to identify the NDC number on the 
label; and
     Where the NDC number goes on the label.
    Specifically, proposed Sec.  201.2(a) would require the appropriate 
NDC number, in human-readable form, to appear on the labels of drugs 
subject to the drug listing requirements. In this case, the word 
``drugs'' should be interpreted in light of proposed Sec.  207.1 and 
encompasses human drugs, including the drugs regulated under a BLA, as 
described in proposed Sec.  207.9(c), and animal drugs, including Type 
A medicated articles. These drugs may be active pharmaceutical 
ingredients or finished dosage forms, whether prescription or OTC. The 
drugs regulated under a BLA, as described in proposed Sec.  207.9(c) 
include, but are not limited to: (1) Plasma derivatives such as 
albumin, Immune Globulin, Factor VIII and Factor IX, and recombinant 
versions of plasma derivatives or animal derived plasma derivatives; 
(2) Vaccines; (3) Allergenic products; (4) Bulk product substances such 
as fractionation intermediates or pastes; and (5) Therapeutic 
biological products.
    We propose to require human-readable NDC numbers to appear on drug 
labels because various individuals and databases use and rely on NDC 
numbers, and those individuals or databases might not have the 
technology or means to read an automatic identification technology such 
as a bar code that is required under Sec.  201.25. In addition, for 
those who are able to read bar codes, a human-readable NDC number may 
serve as a ``backup'' in case the bar code is damaged, cannot be read, 
or is otherwise illegible.
    Proposed Sec.  201.2(b) would explain that an ``appropriate NDC 
number'' is the NDC number that we have assigned (under proposed 
Sec. Sec.  207.33 or 207.37, which we discuss later in this part) to 
the last manufacturer, repacker or relabeler (including a drug product 
salvager who repacks or relabels the drug), or private label 
distributor responsible for the drug immediately before it is received 
by the wholesaler or retailer. For example, assume that a manufacturer 
makes a drug and sells that drug to a wholesaler or retailer. Under 
proposed Sec.  201.2(b), the manufacturer is the last person 
responsible for the drug immediately before it reached the wholesaler 
or retailer, so the appropriate NDC number would be the manufacturer's 
NDC number that we have assigned to that drug. If, however, the 
manufacturer sold the drug to a repacker, who then repackages the drug 
and sells the repackaged drug to a retailer, the repacker is the last 
person responsible for the drug immediately before it reached the 
retailer, so the appropriate NDC number would be the repacker's NDC 
number that we have assigned and not the manufacturer's NDC number.
    Identifying the last person responsible for a drug may be important 
in situations where the drug's quality, purity, labeling, or packaging 
may be at issue; for example, if a drug appeared to be contaminated, 
knowing who the last person was who manufactured, repacked, or 
relabeled the drug could help focus an investigation to determine how 
the contamination occurred. It also allows linking to the correct 
product information in the DailyMed. In addition, requiring the NDC 
number of the last manufacturer, repacker, relabeler, or private label 
distributor responsible for the drug immediately before it is received 
by the wholesaler or retailer would enable us to accurately and quickly 
identify the original manufacturer by connecting the NDC number on the 
label to the information in the electronic drug registration and 
listing system.
    The proposed approach of assigning NDC numbers would mean that 
repackers, for example, would have to use their own NDC number, rather 
than using the manufacturer's NDC number on drug labels. We recognize 
that some, but not all, repackers have been using the manufacturer's 
NDC number rather than their own on drug labels. We are aware that some 
repackers' practice of using the manufacturers' NDC numbers has led to 
some confusion among FDA, the Centers for Medicare & Medicaid Services 
(CMS), other Federal agencies, State agencies, and private insurance 
organizations that rely on NDC numbers for many purposes, including to 
identify a drug and a drug's source and for purposes of reimbursement 
and dispensing systems. It also has led to some confusion by 
practitioners and patients. There may be other reasons that this 
practice has posed difficulties or is cause for concern.
    We are aware that the use of manufacturer's NDC numbers by some 
repackers may lead to inaccurate or improper reimbursement by Medicaid, 
Medicare, and private insurers. It also may result in misunderstanding 
as to which rebate agreement a particular drug is covered by or whether 
a particular drug is covered by any rebate agreement at all.
    We are also aware that the use of manufacturer's NDC numbers by 
repackers may not always be accurate or consistent. For example, a 
repacker might use a manufacturer's NDC number for a particular drug 
and then continue to use that manufacturer's NDC number for generic 
equivalents to that drug. This may lead to confusion for caregivers and 
patients who may be dispensed medication based on the original 
manufacturer's NDC number, but receive a drug that is different in 
size, shape and/or color than the drug they are accustomed to using. 
Additionally, there could be reimbursement differences between one 
firm's product and another firm's product. Further, the NDC number of 
the wrong manufacturer on the drug's label (even if the drugs of both 
manufacturers are generic equivalents) may also be a problem when 
pharmacies rely on verification systems that include exact color images 
of drugs based on NDC numbers.
    Recently, the National Association of Chain Drug Stores (NACDS) and 
the Healthcare Distribution Management Association (HDMA) asked us to 
exercise enforcement discretion concerning our recent bar code rule 
(see

[[Page 51298]]

21 CFR 201.25 (69 FR 9170, February 26, 2004)) so that repackers could 
continue using manufacturers' NDC numbers on retail-based repackaged 
drug products (Ref. 1). In brief, NACDS and HDMA assert that FDA has 
``historically allowed the use of original manufacturer NDC numbers by 
repackagers on the product labels of retail-based repackaged drug 
products'' and that this practice is standard among repackers (Ref. 1, 
p. 2). NACDS and HDMA also stated that use of the repackers' NDC 
numbers ``is not necessary or desirable'' because repackers identify 
themselves on the drug labels and that procedures exist to allow recall 
of particular lots of repacked drugs (rather than all drugs made by a 
manufacturer). They also stated that mandatory use of the repackers' 
NDC numbers might affect patient safety adversely and create 
additional, excessive costs to patients, health care providers, and 
payers because databases use the manufacturers' NDC numbers and cannot 
be modified to accommodate repackers' NDC numbers (Ref. 1, pp. 4 
through 9). For example, NACDS and HDMA said that requiring repackers 
to use their own NDC numbers could ``greatly increase the potential for 
medication errors'' because pharmacists would: ``be required to 
inefficiently and manually choose between multiple options of the same 
product, e.g., Motrin 800mg by [one manufacturer] or Motrin 800mg 
repackaged by 5 different repackagers. The more NDC numbers in use for 
the same product across the country, the greater the chance that data 
entry errors will occur across the many pharmacies that use repackaged 
products.'' (Ref. 1, p. 7.) In addition, NACDS and HDMA said that 
requiring repackers to use their own NDC numbers would oblige them to 
pay substantial rebate fees under Medicaid when Congress intended drug 
manufacturers, not repackers, to pay those rebates and would complicate 
Medicaid billing; they further stated that requiring repackers to use 
their own NDC numbers would lead to a ``sharp reduction or elimination 
of this type of repackaging'' (Ref. 1, p. 8).
    On March 28, 2005, we issued a response to the letter from NACDS 
and HDMA. The response stated, among other things, that we intend to 
temporarily exercise our enforcement discretion and permit repackers to 
use manufacturers' NDC numbers in bar codes placed on their products. 
We said that there will be an opportunity to directly consider this 
issue when we issue our proposed rule on establishment registration and 
drug listing. The response stated that we will consider all information 
provided that documents the impact on repackers.
    We lack sufficient information to assess whether requiring 
repackers to use their own NDC numbers would be as problematic and 
expensive as NACDS and HDMA suggest. We also do not know the extent to 
which databases that use NDC numbers cannot be modified to accommodate 
repackers' NDC numbers or to associate more than one NDC number with 
drugs made by the same manufacturer. Moreover, although repackers 
currently assign their own NDC numbers and report those numbers to us, 
we do not know whether databases ignore or omit repackers' NDC numbers 
that we make available through the National Drug Code Directory.
    We believe that allowing repackers to use the manufacturers' NDC 
numbers would be contrary to the proposal's goal of making the NDC 
number unique and the system more accurate and reliable.
    We are requesting additional information on this issue. We 
specifically invite comments on the proposed approach of requiring on 
the drug's label the NDC number of the last manufacturer, repacker or 
relabeler (including the drug product salvager who repacks or relabels 
the drug), or private label distributor responsible for the drug 
immediately before it is received by the wholesaler or retailer, which 
would result in prohibiting the use of manufacturer's NDC numbers by 
repackers. We are especially interested in: (1) Examples and 
discussions of dispensing errors or difficulties, confusion, 
reimbursement problems, or other difficulties that may have been caused 
or contributed to by the practice of some repackers using the 
manufacturer's NDC number; (2) The magnitude of the problems that may 
be attributed to the use of manufacturer's NDC numbers by repackers and 
of the problems that NACDS and HDMA have articulated that may result 
from mandating the use of repacker's NDC numbers by repackers; (3) the 
extent to which such problems do or are likely to occur; and (4) 
whether there are technological (that is, software) solutions or 
alternatives that could address the issues presented in the NACDS and 
HDMA letter, other issues identified in this preamble, or those raised 
in comments to this proposed rule.
    By inviting comment, we are specifically giving NACDS and HDMA, and 
any other interested parties, the opportunity to comment on whether 
repackers should be able to use the manufacturers' NDC numbers on the 
repacked drugs' label.
    Proposed Sec.  201.2(c) states that only the appropriate NDC number 
required by proposed Sec.  201.2(b) may appear on the label. This 
provision would complement proposed Sec.  201.2(b) by requiring the 
drug's label to bear the appropriate NDC number.
    Proposed Sec.  201.2(d) would require the human-readable NDC number 
to be immediately preceded by the letters ``NDC.'' This provision would 
modify the current requirement at Sec.  207.35(b)(3)(ii), which states 
that the NDC number must be preceded by the prefix ``NDC'' or ``N'' 
when used on a label or labeling. We decided to limit the prefix to 
``NDC'' because, when compared to ``N'' alone, ``NDC'' is a clearer 
signal that the number following ``NDC'' is the NDC number.
    Proposed Sec.  201.2(e) would require that the appropriate NDC 
number appear clearly on the drug's label as defined by section 201(k) 
of the act. Section 201(k) of the act defines ``label'' as ``a display 
of written, printed, or graphic matter upon the immediate container of 
any article.'' Section 201(k) also states that ``a requirement made by 
or under authority of this Act that any word, statement, or other 
information appear on the label shall not be considered to be complied 
with unless such word, statement, or other information also appears on 
the outside container or wrapper, if any there be, of the retail 
package of such article, or is easily legible through the outside 
container or wrapper.'' This proposed requirement would be a change 
from current Sec.  207.35(b)(3)(i), which requires the NDC number to 
appear ``prominently in the top third of the principal display panel.'' 
We decided to remove the restriction on the NDC number's location 
because our bar code rule, which requires the bar code to encode the 
drug's NDC number, allows the bar code to appear anywhere on the drug's 
label. Consequently, some establishments may wish to place the human-
readable NDC number next to the bar code, so we have decided against 
specifying the location of the human-readable NDC number.
    We are also proposing to revise current Sec.  201.25 because, as 
discussed in section IV.A.5 of this document (definition of 
``drug(s)'') and in the February 26, 2004, bar code final rule, certain 
drugs that would be subject to proposed part 207 are not subject to 
current Sec.  201.25. Under proposed Sec.  201.25(e), a drug product 
that is subject to the drug listing requirements of proposed part 207 
but is not subject to current Sec.  201.25 may display a bar

[[Page 51299]]

code on the label only if the bar code meets the requirements of Sec.  
201.25(c). We are proposing this revision to help ensure consistency in 
the appearance, content, and placement of bar codes on drug labels. We 
are also proposing to revise current Sec.  201.25 to further clarify 
what ``appropriate'' NDC number must appear in the bar code. Current 
Sec.  201.25(c)(1) states that each drug product subject to current 
Sec.  201.25 must have a bar code that contains, at a minimum, the 
appropriate NDC number. To clarify this requirement, we are proposing 
to amend current Sec.  201.25(c)(1) to state that the ``appropriate NDC 
number,'' as used in current Sec.  201.25(c)(1), is described in 
proposed Sec.  201.2(b).
    We note that when there is a change in the NDC number on a drug 
product label, or when an NDC number is added to a label, application 
holders must submit revised labeling to us with their annual reports 
under Sec.  314.81(b)(2) for human drugs, Sec.  514.80(b)(4) for animal 
drugs (``periodic reports'' are required instead of ``annual 
reports''), and Sec.  601.12(f)(3) for biological drugs.
    b. Proposed Sec.  207.33--What is the National Drug Code Number, 
who must obtain it, and what information must be submitted? Proposed 
Sec.  207.33 would describe the NDC number and the process for 
obtaining NDC numbers. The proposal would differ from the pre-existing 
NDC number system by having us assign the NDC number for newly listed 
drugs, by describing the changes that would require a manufacturer, 
repacker, or relabeler to obtain a new NDC number, and by describing 
when information must be submitted to us to obtain an NDC number. Under 
the proposal, all three sections of the NDC number would be assigned 
prospectively by us to drugs that have not previously been assigned NDC 
numbers by a manufacturer, repacker, or relabeler. The NDC numbers 
currently assigned to drugs prior to the effective date of the rule 
would remain unchanged, provided those NDC numbers comply with the new 
regulations as finalized. FDA intends to validate that current NDC 
numbers comply with the new regulations as finalized.
    Currently, Sec.  207.35(a) states that we will provide a validated 
copy of an establishment's registration form and assign a permanent 
registration number to each drug establishment in accordance with our 
regulations. Current Sec.  207.35(b)(1) and (b)(2) state that we will 
assign a drug listing number to each drug or class of drugs and that 
the number of characters in that number may differ depending on whether 
the drug is already listed in the NDC system or the NHRIC system. For 
example, current Sec.  207.35(b)(1) states that if a drug is already 
listed in the NDC system or NHRIC system, the drug listing number is 
the same as that assigned under those codes and that we will add a lead 
zero to the first three characters to create a four-character labeler 
code. Current Sec.  207.35(b)(1) also states that manufacturers or 
distributors may retain alphanumeric characters that they already use 
in the product and package code segments and must inform us if they 
convert those code segments into numeric digits. Current Sec.  
207.35(b)(2) also explains how many characters may be in a labeler 
code, product code, and package code.
    Given that this proposal would designate the responsibility of 
assigning the NDC number to FDA, the proposal would eliminate many of 
the provisions in current Sec.  207.35, such as our need to provide to 
sponsors validated copies of registration forms as well as information 
on how to assign the product code and package code. Proposed Sec.  
207.33(a) explains that the NDC number is a unique 10-digit number 
composed of a labeler code, product code, and package code. Proposed 
Sec.  207.33(a) also states that we would assign the complete NDC 
number (that would include the existing labeler code, if any) to each 
drug that is subject to the listing requirements in part 207. We would 
use the same configuration when assigning each segment of the NDC 
number: The labeler code would be either five or four digits, the 
product code would be either four or three digits, and the package code 
would be either two digits or one digit. When we assign a NDC number to 
a drug, we intend to leave a space between the segments of the NDC 
number so that the separate codes are distinguishable. Manufacturers, 
repackers, and relabelers may add symbols, such as hyphens or 
asterisks, between the segments of the human-readable NDC number if 
they want to visually distinguish the codes in such a manner. Under the 
proposal, manufacturers, repackers, and relabelers would keep the same 
labeler code that they use for currently marketed drugs. However, if 
more than one labeler code is currently used by a manufacturer, 
repacker, or relabeler, only one labeler code would be used for any new 
NDC numbers that we would assign under this rule prospectively. Also, 
as described below, the proposal would allow currently marketed drugs 
to keep the same NDC numbers in most cases.
    Proposed Sec.  207.33(b)(1) and (b)(2) would require that 
manufacturers, repackers, relabelers, and, in certain circumstances, 
drug product salvagers, obtain NDC numbers from us for each drug that 
is subject to the drug listing requirements. In the case of drug 
product salvagers, they would obtain an NDC number for each drug that 
is subject to the drug listing requirements only if they repack or 
relabel the salvaged drug. For private label distributors, proposed 
Sec.  207.33(b)(3) states that the manufacturer, repacker, or relabeler 
who manufactures, repacks, or relabels the drug for the private label 
distributor is responsible for obtaining the NDC number from us for 
each drug that is subject to the drug listing requirements.
    Proposed Sec.  207.33(b) is intended to clarify who must obtain NDC 
numbers. For example, drug product salvagers ordinarily would not need 
to obtain NDC numbers because they merely salvage drugs. If a drug 
product salvager simply recovers the drug and sells it without 
repacking or relabeling the product, the drug product salvager would 
not need to obtain an NDC number for the salvaged drug. However, if the 
drug product salvager repacks or relabels the salvaged drug, then the 
drug product salvager is similar to a repacker or relabeler, and 
proposed Sec.  207.33(b) would require the drug product salvager to 
obtain an NDC number from us for the repacked or relabeled drug. As 
another example, under the proposal, private label distributors would 
not be permitted to register or list and, consequently, they would not 
obtain NDC numbers for the drugs they distribute. Instead, the 
manufacturer, repacker, or relabeler who manufactures, repacks, or 
relabels the drug for the private label distributor would be 
responsible for obtaining the NDC number, including a labeler code 
appropriate for the private label distributor. This change ensures that 
more accurate information is provided to FDA about the drug distributed 
by the private label distributor because the manufacturer supplies the 
necessary drug information to FDA.
    Under current Sec.  207.35, manufacturers, repackers, and 
relabelers assign NDC numbers to the drugs they manufacture, repack, or 
relabel, and private label distributors assign NDC numbers to the drugs 
they distribute if they opt to list the drugs themselves. Drug product 
salvagers currently do not receive NDC numbers for the drugs they 
salvage, and under current Sec.  207.20(a), they are not required to 
list the drugs they salvage.
    As noted previously, even though we would assign NDC numbers under 
the proposal, an establishment's labeler code would remain the same in 
most

[[Page 51300]]

cases. For example, if a manufacturer's labeler code were 12345, we 
would assign NDC numbers for the manufacturer's drugs and still use 
12345 as the manufacturer's labeler code. However, under the proposal, 
if a manufacturer, repacker, or relabeler uses more than one labeler 
code, we would prospectively assign NDC numbers that use only one 
labeler code for that manufacturer, repacker, or relabeler.
    Note, too, that other components in an NDC number may remain 
unchanged under the proposal. For example, assume that a drug is 
already listed in the National Drug Code Directory and its manufacturer 
later decides to change its package size. In this situation, the 
labeler code and the product code would ordinarily remain the same, 
and, generally, we would assign a new package code for the changed 
drug.
    Furthermore, if a drug already has an NDC number at the time of the 
effective date of a final rule, the drug would retain that NDC number 
provided that the manufacturer, repacker, or relabeler, within 9 months 
after the effective date of a final rule, reviews and updates, in 
accordance with proposed Sec. Sec.  201.2, 207.33, 207.37, 610.60, and 
610.61, the information in our database for the NDC number (see 
sections IV.C.4, IX, and X of this document for information on the 
proposed implementation and effective and compliance dates of this 
rulemaking). We also will work with manufacturers, repackers, and 
relabelers to address any problems with existing NDC numbers (such as 
duplicate or potentially duplicate NDC numbers) that might arise after 
a final rule becomes effective.
    Using a 5-digit labeler code, we estimate that we have the capacity 
for NDC numbers for up to 100,000 registered establishments, each 
having a capacity for up to 100,000 product/package size combinations 
(using the 5 remaining digits). If a registered establishment requires 
more than 100,000 product/package size codes, we could issue that 
establishment an additional labeler code. We currently have about 
25,000 active establishments in our registration database, utilizing 
less than half of the 5-digit labeler code capacity. We currently issue 
about 1,000 new labeler codes annually. If we reach NDC number capacity 
(possibly in 30 to 50 years), we could propose to either add 
alphanumeric capability or expand the number of numeric digits to 11 or 
12 (current Sec.  207.35(b)(2)(i) states that FDA will go from a 5- to 
6-digit labeler code if needed). This change in NDC numbers will 
necessitate advances in current UPC technology (due to the need for bar 
code reading), which we anticipate will likely occur prior to our 
reaching the 10-digit NDC numeric capacity.
    The proposal would also omit the references to Form FDA-2656 in 
current Sec.  207.35(a) and (b)(2) because the proposal's electronic 
submission of registration and listing information would make it 
unnecessary for us to provide validated copies of forms. In addition, 
because we would assign NDC numbers, the proposal would eliminate the 
provision in current Sec.  207.35(b)(1) that allows manufacturers and 
distributors to convert alphanumeric product codes and package codes 
they may have and report such changes to us. (If any establishment 
still has alphanumeric product or package codes for a drug, we will 
work with them to assign new NDC numbers.) The proposal would also omit 
references in current Sec.  207.35(b)(1) and (b)(2) to the NHRIC system 
because we do not maintain a NHRIC database (see 42 FR 52808 at 52810).
    Proposed Sec.  207.33(c) and (d) describes the information that a 
manufacturer, repacker, or relabeler would be required to submit before 
we assign an NDC number to a drug. As discussed earlier in this 
section, if a drug product salvager simply recovers the drug and sells 
it without repacking or relabeling the drug, the drug product salvager 
would not need to obtain an NDC number for the salvaged drug. However, 
if the drug product salvager repacks or relabels the salvaged drug, 
then the drug product salvager is similar to a repacker or relabeler, 
and proposed Sec.  207.33(b) would require the drug product salvager to 
obtain an NDC number from us for the repacked or relabeled drug. The 
following table illustrates the proposed requirements.

 Table 1.--Information to be Submitted to Obtain an NDC Number, Arranged by Manufacturer, Repacker, or Relabeler
                                                    and Drug
----------------------------------------------------------------------------------------------------------------
  Proposed Section            Type of Drug                          Information to be Submitted
----------------------------------------------------------------------------------------------------------------
Sec.   207.33(c)(1)   Active pharmaceutical         Manufacturer's name, address, telephone number, fax
 (Manufacturer)        ingredient                   number, e-mail address, and labeler code
                                                    Drug's established name and proprietary name (if
                                                    any)
                                                    Package size and type
                                                    Drug Master File number or Veterinary Master File
                                                    number, if any, assigned to the active pharmaceutical
                                                    ingredient
----------------------------------------------------------------------------------------------------------------
Sec.   207.33(c)(2)   Drug other than an active     Manufacturer's name, address, telephone number, fax
 (Manufacturer)        pharmaceutical ingredient    number, e-mail address, and labeler code
                                                    Drug's established name and proprietary name (if
                                                    any)
                                                    Name and quantity of each active pharmaceutical
                                                    ingredient or the approved U.S. application number
                                                    Name of each inactive ingredient (or approved U.S.
                                                    application number) for certain drugs, and whether you
                                                    consider the name of the inactive ingredient to fall under
                                                    Sec.   20.61 (21 CFR 20.61) of this chapter or to be
                                                    otherwise prohibited from disclosure and, if so, why
                                                    Dosage form
                                                     Package size and type, including immediate unit-of-
                                                    use container
                                                    Marketing status (e.g., prescription or OTC)
                                                    Drug or drug product type (human drug or animal
                                                    drug)
                                                    Imprinting information
----------------------------------------------------------------------------------------------------------------

[[Page 51301]]

 
Sec.   207.33(c)(3)   Active pharmaceutical         Manufacturer's name, address, telephone number, fax
 (Manufacturer)        ingredient for a private     number, e-mail address, and labeler code
                       label distributor            Drug's established name and proprietary name (if
                                                    any)
                                                    Package size and type
                                                    Drug Master File number or Veterinary Master File
                                                    number, if any, assigned to the active pharmaceutical
                                                    ingredient
                                                    Private label distributor's name, address, telephone
                                                    number, fax number, e-mail address, labeler code
                                                     Drug's proprietary name (if any) as assigned by the
                                                    private label distributor
----------------------------------------------------------------------------------------------------------------
Sec.   207.33(c)(3)   Drug other than an active     Manufacturer's name, address, telephone number, fax
 (Manufacturer)        pharmaceutical ingredient    number, e-mail address, and labeler code
                       for a private label          Drug's established name and proprietary name (if
                       distributor                  any)
                                                    Name and quantity of each active pharmaceutical
                                                    ingredient or the approved U.S. application number
                                                    Name of each inactive ingredient (or approved U.S.
                                                    application number) for certain drugs, and whether you
                                                    consider the name of the inactive ingredient to fall under
                                                    Sec.   20.61 of this chapter or to be otherwise prohibited
                                                    from disclosure and, if so, why
                                                    Dosage form
                                                    Package size and type, including immediate unit-of-
                                                    use container
                                                    Marketing status (e.g., prescription or OTC)
                                                    Drug or drug product type (human drug or animal
                                                    drug)
                                                    Imprinting information
                                                    Private label distributor's name, address, telephone
                                                    number, fax number, e-mail address, and labeler code
                                                    Drug's proprietary name (if any) as assigned by the
                                                    private label distributor
----------------------------------------------------------------------------------------------------------------
Sec.   207.33(d)(1)   Drug that is repacked or      Repacker's or relabeler's name, address, telephone
 (Repacker or          relabeled                    number, fax number, e-mail address, and labeler code
 relabeler)                                         NDC number assigned to the drug immediately before
                                                    its receipt by the repacker or relabeler
                                                     Type of operation performed for the drug (repacking
                                                    or relabeling)
                                                     Drug's established name and proprietary name (if
                                                    any)
                                                    Package size and type, including immediate unit-of-
                                                    use container, if any (required for repackers only)
----------------------------------------------------------------------------------------------------------------
Sec.   207.33(d)(2)   Drug that is repacked or      Repacker's or relabeler's name, address, telephone
 (Repacker or          relabeled for a private      number, fax number, e-mail address, and labeler code
 relabeler)            label distributor            NDC number assigned to the drug immediately before
                                                    its receipt by the repacker or relabeler
                                                    Type of operation performed for the drug (repacking
                                                    or relabeling)
                                                    Drug's established name and proprietary name (if
                                                    any)
                                                    Package size and type, including immediate unit-of-
                                                    use container, if any (required for repackers only)
                                                    Private label distributor's name, address, telephone
                                                    number, fax number, e-mail address, and labeler code
                                                    Drug's proprietary name (if any) assigned by the
                                                    private label distributor
----------------------------------------------------------------------------------------------------------------

    Proposed Sec.  207.33(c) and (d) are intended to accomplish several 
goals:
    1. The proposal would reduce redundant data submission and improve 
the accuracy of information that we receive. For example, under the 
current system, a manufacturer and a repacker may submit the same drug 
listing information for the same type of drug. However, the repacker 
might not have adequate information from the manufacturer or might 
describe the drug differently than the manufacturer; this would lead to 
data discrepancies and omissions. So, by requiring only manufacturers 
to provide descriptive information about the drugs they make, we would 
eliminate potential duplicate submissions, data discrepancies, and data 
omissions. Instead, the repacker, under the proposal, would simply tell 
us the NDC number of the drug that the repacker receives, and we could 
use the NDC number to link the drug back to its manufacturer.
    2. By having manufacturers, repackers, relabelers, and drug product 
salvagers submit information on behalf of private label distributors, 
the proposal would eliminate the potential for redundant, incomplete, 
or inconsistent submissions by private label distributors. For example, 
under the current system, some manufacturers have submitted information 
for drugs that they manufactured for private label distributors, and 
the private label distributors also submitted information for the same 
drugs; if the manufacturers and private label distributors described 
the drugs differently to us, we then had different information for the 
same drugs.
    3. By linking a repacker's or relabeler's drug to an NDC number, 
the proposal would eliminate a problem that some repackers and 
relabelers have encountered in the past. Under the current listing 
system, repackers and relabelers have sometimes found it difficult to 
obtain necessary information from manufacturers. This difficulty has

[[Page 51302]]

resulted in data errors and omissions and an incomplete or inaccurate 
National Drug Code Directory.
    4. By separating the NDC number process from drug listing and 
creating an electronic drug registration and listing system, the 
proposal should make it easier for manufacturers, repackers, and 
relabelers (and drug product salvagers who obtain NDC numbers for 
private label distributors) to obtain their NDC numbers quickly and, as 
a result, prepare product labels and marketing plans earlier.
    5. Under the proposal, the information submitted about the drug to 
obtain an NDC number would be retained in the electronic drug 
registration and listing system. Thus, when the manufacturer, repacker, 
or relabeler later lists the drug, they would need to provide only the 
additional information required for listing.
    6. By assigning a unique NDC number to each drug, the proposal 
would ensure that the drug has an accurate identifier, allowing us to 
support the implementation of the electronic prescribing provisions of 
the Medicare Modernization Act. We would link the accurate NDC number 
to the product labeling that would be made available through the 
DailyMed initiative.
    i. Information to be submitted to receive an NDC number. We 
describe the information that proposed Sec.  207.33(c) and (d) would 
require and our reasons for proposing to require the information, as 
follows:
     Name, address, telephone and fax numbers, e-mail address, 
and labeler code. Proposed Sec.  207.33(c) and (d) would require 
manufacturers, repackers, and relabelers to provide this information to 
enable us to identify and contact (if necessary) the appropriate 
manufacturer, repacker, or relabeler and identify their labeler code. 
In situations where a manufacturer, repacker, or relabeler 
manufactures, repacks, or relabels a drug for a private label 
distributor, the proposal would also require the manufacturer, 
repacker, or relabeler to provide comparable information for the 
private label distributor. This information would enable us to 
associate the manufacturer's, repacker's, or relabeler's drugs with a 
particular private label distributor and to contact that private label 
distributor if necessary.
     The drug's or active pharmaceutical ingredient's 
established name and proprietary name (if any). The established name 
(sometimes referred to as generic name) is ordinarily either the drug's 
compendial name or, if there is no compendial name, the drug's common 
or usual name. The proprietary name (sometimes referred to as trade 
name) is generally the drug's marketed or advertised name as designated 
by the manufacturer, repacker, relabeler, or private label distributor. 
Most consumers recognize a drug by its proprietary name rather than its 
established name. Proposed Sec.  207.33(c) and (d) would require 
submission of these names because knowing a drug's established name 
would let us determine, for example, which companies market identical 
drugs and which drugs can be substituted in the event of drug shortages 
or recalls. Knowing a drug's proprietary name would enable us to 
identify a drug to the public during a recall or consumer alert. This 
information is currently required under Sec.  207.25(b)(1) and is 
submitted on Form FDA 2657.
     The Drug Master File (DMF) number or Veterinary Master 
File (VMF) number, if any, assigned to the active pharmaceutical 
ingredient. Under proposed Sec.  207.33(c)(1)(iv) (and, if applicable, 
proposed Sec.  207.33(c)(3)), if a DMF number or VMF number is assigned 
to the active pharmaceutical ingredient, the manufacturer would 
identify for us the DMF number or the VMF number. The DMF or VMF may 
contain additional information about the active pharmaceutical 
ingredient that our electronic drug registration and listing system 
could associate with the active pharmaceutical ingredient at other 
points in the registration and listing process. This could reduce the 
burden on the manufacturer of submitting to us the information already 
contained in the DMF or VMF. This information is not currently provided 
to us under current part 207 or Form FDA 2657 or Form FDA 2658.
     Name and quantity of each active pharmaceutical ingredient 
in a drug. Proposed Sec.  207.33(c)(2) and, if applicable, proposed 
Sec.  207.33(c)(3), would require manufacturers to submit this 
information to us (unless the approved U.S. application number is 
provided). Knowing the name and quantity of a drug's active 
pharmaceutical ingredients would help us assign unique product codes 
and help ensure that the assigned NDC numbers are unique to different 
products. For example, assume that a manufacturer makes a drug in two 
different strengths, 100 milligrams (mg) and 500 mg. If we only 
required the manufacturer to identify the active pharmaceutical 
ingredient, we might assume, incorrectly, that the manufacturer made 
two versions of the same drug in the same strength and then assign the 
same product code to both drugs. Instead, by proposing to require 
information about the quantity of the drug's active pharmaceutical 
ingredient, we would be able to assign one product code to the 100 mg 
product and a different product code to the 500 mg product. As an 
alternative to providing the name and quantity of the drug's active 
pharmaceutical ingredient, proposed Sec.  207.33(c)(2) would allow a 
manufacturer to give us the drug's approved U.S. application number; 
the approved U.S. application number would allow us to link the drug to 
a particular application and determine the name and quantity of the 
active pharmaceutical ingredients in that drug.
    The proposed requirement is similar to the requirement regarding 
quantitative listing of active ingredients in current Sec.  207.25(b). 
Current Sec.  207.25(b)(6) requires a quantitative listing of a drug's 
active ingredient(s) for drugs that a registrant regards as not being 
subject to sections 505 or 512 of the act or section 351 of the PHS 
Act. Current 207.25(b)(2) requires, for each drug listed that the 
registrant regards as subject to section 505 or 512 of the act, the 
application number. The act, for purposes of certain drug listing 
requirements, appears to treat drugs differently depending on whether 
those drugs are subject to sections 505 or 512 of the act or not. 
Section 510(j)(1)(A) of the act mandates that the drug list be prepared 
in the form and manner prescribed by us. That drug list, for drugs 
subject to sections 505 or 512 of the act, must be accompanied by ``the 
authority for the marketing of such drug''. In contrast, section 
510(j)(1)(C) of the act states that the drug list, for drugs that are 
not subject to either section 505 or 512 of the act, must be 
accompanied by a ``quantitative listing'' of the drug's active 
ingredient or ingredients and that we may require a quantitative 
listing of all ingredients with respect to a particular product if we 
find such submission is necessary to carry out the act's purposes.
    We believe that these provisions, and others, give us sufficient 
authority to require the submission of active ingredient information 
for all drugs as part of the NDC number assignment process. We already 
have such information for drugs approved under sections 505 and 512 of 
the act because information concerning active ingredients is an 
essential part of the drug's marketing application. Thus, when a 
manufacturer gives us the approved U.S. application number (as proposed 
Sec.  207.33(c)(2)(i) would require and as current Sec.  207.25(b)(2) 
(pertaining to required drug listing information) requires), the 
manufacturer is, in essence, giving us a link to information

[[Page 51303]]

about the drug's active ingredients. As noted previously, section 
510(j)(1)(A) of the act, for drugs subject to sections 505 or 512 of 
the act, requires the ``reference to the authority for the marketing of 
such drug.'' This reference would be the approved U.S. application 
number. The act, for drugs not subject to section 505 or 512, 
explicitly requires a quantitative listing of active ingredients. 
Proposed Sec.  207.33(c)(2)(i) would, therefore, enable us to input the 
active ingredient information into an electronic database. This would 
enable us to link to certain information in the application, and would 
be more efficient than having to review individual marketing 
applications, identify each drug's active ingredients, and then enter 
that data into the database ourselves.
     Name of the inactive ingredient(s). Proposed Sec.  
207.33(c)(2), and, if applicable, (c)(3) would require manufacturers to 
give us the drug's approved U.S. application number or, in the 
alternative, the name of each inactive ingredient for each human and 
animal drug that the manufacturer regards as subject to section 505 or 
section 512 of the act or section 351 of the PHS Act, and for each 
human OTC drug that the manufacturer regards as not subject to section 
505 of the act, and whether the name of an inactive ingredient falls 
under Sec.  20.61 or is otherwise prohibited from disclosure and, if 
so, why. Proposed Sec.  207.33(c)(3) describes the requirements of the 
manufacturer who is manufacturing a drug for a private label 
distributor. Such manufacturers would be required to give us the name 
of each inactive ingredient for certain drugs, as described previously, 
or the drug's U.S. approved application number for the drug it 
manufactures for a private label distributor. Proposed Sec.  
207.33(c)(2) and (c)(3) are authorized under section 510 of the act as 
well as other provisions. We are considering whether to require the 
name of each inactive ingredient to be submitted for other categories 
of drugs as well.
     Dosage form. Proposed Sec.  207.33(c)(2) and (c)(3) would 
require manufacturers to identify a drug's dosage form. This 
information will also help us distinguish between drug products that 
contain the same active ingredient and, consequently, assign unique 
product codes to such drugs. For example, assume that a manufacturer 
makes drug X, in a 100 mg strength, in a tablet form and also in a 
gelatin capsule. If we did not know there were two dosage forms of drug 
X, we might mistakenly assign the same product code to the tablet and 
gelatin capsule. Thus, information about dosage forms will help us 
create an NDC system that ties unique NDC numbers to unique products. 
The drug's dosage form is currently submitted on Form FDA 2657.
     Package size and type. Proposed Sec.  207.33(c)(1), 
(c)(2), (c)(3) (if applicable), (d)(1), and (d)(2) would require 
manufacturers and repackers respectively to provide information about 
package size and type. This information would obviously be relevant in 
helping us assign package codes to a particular drug. For example, a 
drug packaged in a glass container would have a different NDC number 
from the same drug packaged in a plastic container. The proposal would 
require that information about the drug's package size and type be 
provided for each package, including the immediate unit-of-use 
container. For example, a drug packaged in a box containing a card of 
12 unit-of-use blisters would have a different NDC number than each 
individual blister (unit-of-use). In the latter example, the different 
NDC numbers would have a practical impact with respect to our bar code 
requirements. A database system computer reading the bar code for the 
individual unit-of-use blister would see that the health care 
professional is administering a single dose of a particular drug to a 
patient; if the NDC number for the box were the same as that used for 
each unit-of-use blister, then the computer might mistakenly believe 
that the health care professional was administering 12 doses to the 
patient. In these scenarios, distinct NDC numbers for each package 
level would enhance the bar code's accuracy and value. The drug's 
package size and type is currently submitted on Form FDA 2657.
     Marketing status. Proposed Sec.  207.33(c)(2) and, if 
applicable, (c)(3), would require manufacturers to tell us whether the 
drug is available only by prescription or is available OTC. Having such 
information in our electronic database would enable us to determine 
quickly which drugs are available by prescription and which are OTC. In 
addition, some entities that rely on NDC numbers, such as CMS and 
health care insurance companies, might treat prescription drugs 
differently from OTC drugs. For example, an insurer might reimburse 
consumers for prescription drug expenses, but not for OTC drug 
expenses. The drug's marketing status--whether prescription or OTC--is 
currently submitted on Form FDA 2657.
     Drug or drug product type. Under proposed Sec.  
207.33(c)(2) and, if applicable, (c)(3), manufacturers would identify 
whether a drug is a human drug or animal drug. This information would 
enable us to refine our databases to distinguish quickly between human 
and animal drugs. Having such information readily available could help 
us determine the regulatory obligations for a particular drug. For 
example, the bar code requirement applies to human drugs only. Thus, if 
we could differentiate quickly between human and animal drugs based on 
NDC numbers alone and we received a report that a particular drug 
failed to have a bar code on its label, we would be able to determine, 
based on the NDC number alone, whether that drug was subject to the bar 
code requirement. This information is currently submitted under 
``product type'' on Form FDA 2657.
     Imprinting information. For each drug product subject to 
the listing requirements and covered under Sec.  206.1, including 
products that are exempted under Sec.  206.7(b), manufacturers must 
provide the size, shape, color, and code imprint (if any) (proposed 
Sec.  207.33(c)(2)(vii) and, if applicable, proposed Sec.  
207.33(c)(3)). This provision is similar to current Sec.  207.25(c), 
except the current provision also requires that the name of the drug 
product, its active ingredient(s), dosage strength, NDC number, and the 
name of its manufacturer or distributor be submitted. Under the 
proposal, the name of the drug product, its active ingredient(s) 
(proposed Sec.  207.33(c)(2) uses the term ``active pharmaceutical 
ingredient''), and dosage strength (proposed Sec.  207.33(c)(2) uses 
the term ``dosage form'') would be submitted to us under proposed Sec.  
207.33(c) along with the imprinting information. The NDC number would 
be submitted under proposed Sec.  207.49 for listing, the name of the 
private label distributor would be submitted under proposed Sec. Sec.  
207.33 and 207.49 for listing, and the name of the manufacturer would 
be submitted under proposed Sec.  207.25 for registration. All of this 
information would be accessible via our electronic drug registration 
and listing system. The proposal would also delete the requirement in 
current Sec.  207.25(c) that ``any other characteristic that identifies 
the drug product as unique'' must be submitted. We need to know the 
drug's size, shape, color, and code imprint, as well as the other 
information required under proposed Sec.  207.33(c), to assign an NDC 
number to the manufacturer's drug. Imprinting information would enable 
us to investigate reports of medication errors and counterfeiting and 
to assist poison control centers in identifying drugs in overdose and 
accidental poisoning situations.

[[Page 51304]]

     NDC number assigned to the drug immediately before the 
repacker or relabeler received that drug. Proposed Sec.  207.33(d) 
would require repackers and relabelers to give us the NDC number of the 
drug that they receive. This information would enable us to link that 
drug to a particular source and, as we said earlier in this part, 
eliminate the need for repackers and relabelers to obtain certain drug 
information from those sources to obtain an NDC number. For example, 
assume that relabeler Alpha received drug X from manufacturer Beta. If 
Alpha gives us the NDC number for drug X, we will then be able to link 
Alpha's relabeled drug to Beta. We would also eliminate any need for 
Alpha to ask Beta for information about drug X for purposes of getting 
an NDC number and eliminate the possibility that Alpha might report 
incorrect or contradictory information about drug X compared to the 
information given to us by Beta.
     Type of operation. Proposed Sec.  207.33(d) would require 
repackers and relabelers to report the type of operation (that is, 
repacking or relabeling) performed for a drug. This information is 
comparable to the information we currently receive about an 
establishment's ``type of business'' on Form FDA 2657, except that 
proposed Sec.  207.33(d) is limited to repackers and relabelers.
     Information regarding private label distributors. Proposed 
Sec.  207.33(c)(3) and 207.33(d)(2) would require manufacturers, 
repackers, and relabelers who manufacture, repack, or relabel drugs for 
a private label distributor to tell us the private label distributor's 
name, address, telephone number, fax number, e-mail address, labeler 
code, and any proprietary name assigned by the private label 
distributor to the drug. This information will help us link the 
manufacturer's, repacker's, or relabeler's drug to a particular private 
label distributor and, as we stated earlier in this part, eliminate 
potential data duplication, omissions, and inaccuracies that would 
otherwise result if private label distributors were able to seek NDC 
numbers from us. Manufacturers, repackers, and relabelers should be 
able to obtain the necessary information from private label 
distributors. Listing information for private label distributors is 
currently submitted on Form FDA 2658.
    ii. How the information would be submitted. Proposed Sec.  
207.33(e) would require manufacturers, repackers, and relabelers to 
submit information to us electronically, in accordance with proposed 
Sec.  207.61 unless we grant a waiver under proposed Sec.  207.65. We 
discuss proposed Sec. Sec.  207.61 and 207.65 later in this document.
    iii. Types of changes that would require a new NDC number. Proposed 
Sec.  207.33(f) would describe the types of changes in information that 
would require a new NDC number. In brief, proposed Sec.  207.33(f)(1) 
would require a new NDC number for any change of information that would 
be required under proposed Sec.  207.33(c) and (d), except for the 
following contact information: Name; address; telephone and fax 
numbers; and e-mail address for the manufacturer, repacker, relabeler, 
or private label distributor. In addition, Sec.  207.33(f)(2) requires 
manufacturers to obtain a new NDC number when there is a change in an 
inactive ingredient for each human prescription drug that the 
manufacturer regards as not subject to section 505 of the act and for 
each animal drug that the manufacturer regards as not subject to 
section 512 of the act. Although we are not proposing to require, at 
this time, that manufacturers submit the name of each inactive 
ingredient to us when they obtain an NDC number for these drugs, we are 
proposing to require that manufacturers notify us only of the fact that 
there has been a change in an inactive ingredient for these drugs. This 
would ensure that a unique NDC number is assigned to these drugs when 
the drug's inactive ingredient(s) has changed. It is important that 
marketed drugs have unique NDC numbers that are accurate because, as 
discussed in section IV.C.2 of this document, NDC numbers are an 
important, standardized, identification system for drug products and 
are used for many purposes. In addition, identifying marketed drugs in 
our electronic database for which inactive ingredients have changed 
would help us investigate, as discussed in section IV.C.3 of this 
document, incidents of allergic reactions in patients as well as 
possible drug contamination, counterfeiting, or adulteration. Although 
we are not proposing it at this time, we are considering requiring in 
the future that manufacturers submit the name of each inactive 
ingredient to obtain an NDC number for categories of drugs beyond those 
referenced in proposed Sec.  207.33(c)(2)(ii) and 207.33(c)(3). We are 
specifically requesting comments on the feasibility of submitting these 
inactive ingredients. The proposed rule would be similar to current 
Sec.  207.35(b)(4)(i), which requires a registrant to assign a new NDC 
number if any change occurs in a product's characteristics that clearly 
distinguishes one drug product version from another. However, proposed 
Sec.  207.33(f) would differ from the current requirement in several 
important respects. First, proposed Sec.  207.33(f) would require 
changes to be reported to us in accordance with proposed Sec.  
207.33(e) (which would require electronic submission of information) 
and Sec.  207.33(g) (which describes timing requirements discussed 
later in this part). The current regulation has no comparable 
electronic reporting requirement. Second, proposed Sec.  207.33(f) 
would not require us to publish a notice in the Federal Register 
announcing our determination as to whether a change requires assignment 
of a new product code. Because the proposed rule would create an 
electronic drug registration and listing system and have us assign NDC 
numbers quickly that would be accessible in the registration and 
listing database, we find it unnecessary and impractical to publish 
Federal Register notices regarding product code changes. Third, 
although current Sec.  207.35(b)(4)(i) allows registrants to assign 
their own package codes for changes involving trade packages, proposed 
Sec.  207.33(f) would eliminate this provision because we would assign 
the new NDC number ourselves to ensure that the NDC number is unique 
and that our NDC number database is accurate and up-to-date. Fourth, 
proposed Sec.  207.33(f), in conjunction with proposed Sec.  207.33(c) 
and (d), gives a more complete description of which changes would 
require a new NDC number, compared with current Sec.  207.25(b)(4)(i) 
(which currently lists examples of changes). Because manufacturers, 
repackers, and relabelers currently have different practices with 
respect to assigning NDC numbers, this change would eliminate 
inconsistency and would introduce an element of certainty with respect 
to the assignment of new NDC numbers.
    iv. When the information would be provided. Proposed Sec.  
207.33(g) would explain when a manufacturer, repacker, or relabeler 
must provide the information to obtain an NDC number. In brief, the 
proposal would require a manufacturer, repacker, or relabeler to 
provide the information described in proposed Sec.  207.33(c), (d), and 
(f) either before or at the time drug listing information is required 
under proposed Sec. Sec.  207.45 or 207.57. (We discuss proposed 
Sec. Sec.  207.45 and 207.57 later in this document.) The proposed 
requirement differs slightly from current Sec. Sec.  207.21(b), 
207.22(b), and 207.25(b)(8), which allows manufacturers, repackers, and 
relabelers to give us NDC numbers as part of their

[[Page 51305]]

drug listing information, because the proposal would allow companies to 
give us information earlier than the drug listing process would be 
completed. This ability to seek NDC numbers throughout the year should 
help us keep the National Drug Code Directory current and, as a result, 
provide more accurate and useful NDC number information to entities 
that rely on or use NDC numbers. In addition, the proposed scheme would 
give manufacturers, repackers, and relabelers more flexibility to 
obtain an NDC number earlier for their own planning purposes. 
Furthermore, we will know which NDC number corresponds to a drug 
immediately because we will assign it, rather than the current system 
where manufacturers, repackers, and relabelers assign their own NDC 
numbers and only report those numbers to us as part of their drug 
listing information.
    We considered assigning the NDC number as part of the drug listing 
process, but believe that allowing for earlier assignment would provide 
optimal flexibility for manufacturers, repackers, and relabelers. We 
note that the information submitted to have an NDC number assigned is a 
subset of the information submitted to list a drug. Therefore, if a 
manufacturer, repacker, or relabeler provides us the information early 
to get an NDC number, they will only need to provide the additional 
information needed when they later list the drug.
    c. Proposed Sec.  207.37--What restrictions pertain to the use of 
NDC numbers? Proposed Sec.  207.37 would establish four restrictions on 
the use of NDC numbers insofar as FDA-regulated products or activities 
are concerned. The proposed restrictions reflect practical problems or 
difficulties that we have encountered when manufacturers, repackers, or 
relabelers assign their own NDC numbers.
    Proposed Sec.  207.37(a) would state that an NDC number must not be 
used to represent a different drug than the drug to which it was 
assigned. This restriction would prevent manufacturers, for example, 
from using the same NDC number for different drugs and thus prevent 
potential discrepancies among databases that rely on or use NDC numbers 
to distinguish between drugs. The restriction would prevent two 
different drugs from having the same NDC number and avoid medication 
errors that could result if the NDC number encoded in a bar code 
represented more than one drug. Use of an NDC number not assigned to a 
drug would also cause a drug to be misbranded under section 502(a) of 
the act because the drug's label would be misleading.
    Proposed Sec.  207.37(b) would state that a different NDC number 
must not be used if marketing is resumed for a drug that was 
discontinued earlier. If marketing is resumed for a drug, and no 
changes have been made to the drug that would require a new NDC number 
under Sec.  207.33(f), the drug must have the same NDC number that was 
assigned to it earlier before marketing was discontinued. This would 
prevent two NDC numbers from being assigned to or used for the same 
drug. Consistent with this rationale, proposed Sec.  207.37(b) would 
revoke current Sec.  207.35(b)(4)(ii), which states that the product 
code of a discontinued product may be reassigned to another product 5 
years after the expiration date of the discontinued product or, if 
there is no expiration date, 5 years after the last shipment of the 
discontinued product into commercial distribution.
    Proposed Sec.  207.37(c) would state that NDC numbers must not be 
used to denote FDA approval. This is similar to current Sec.  207.39, 
which states, in part, that assignment of an NDC number does not in any 
way denote approval of a product. For drugs subject to sections 505 or 
512 of the act, those drugs must be shown to be safe and effective for 
their intended uses to obtain FDA approval. Mere assignment of an NDC 
number by us is not equivalent to our determining whether a drug is 
safe and effective for its intended uses.
    Proposed Sec.  207.37(d) would state that NDC numbers must not be 
used on products that are not subject to the drug listing requirements 
of part 207, such as dietary supplements and medical devices. We are 
proposing this requirement because the fundamental purpose behind NDC 
numbers was to establish an identification system to help in the 
automated processing of drug data and claims. Use of NDC numbers on 
non-drug products could introduce misleading information in databases, 
lead to inappropriate claims processing, and undermine the accuracy and 
reliability of an NDC system. For example, some human dietary 
supplements bear an NDC number on their labels. FDA considers a human 
dietary supplement that bears an NDC number misbranded under 21 U.S.C. 
343(a)(1), which provides that a food is misbranded if its labeling is 
false or misleading in any particular. A product labeled and marketed 
as a human dietary supplement is not a drug listed with FDA; thus, the 
presence of an NDC number on the label is a false representation about 
the nature of the product.
    d. Proposed Sec. Sec.  610.60(a)(2) and 610.61(b)--Where would the 
NDC number be required for biological products? Under proposed Sec.  
201.2(a), all drugs, including human biological drugs, subject to the 
drug listing requirements of part 207 must have labels that bear the 
appropriate NDC number in human-readable form, in accordance with the 
provisions in proposed Sec.  201.2. Current Sec.  610.60(a) (21 CFR 
610.60(a)) specifies which items must appear on the label affixed to 
each container of a biological product capable of bearing a full label 
and current Sec.  610.61 specifies which items must appear on the label 
affixed to each package containing a biological product. We are 
proposing to amend Sec. Sec.  610.60(a)(2) and 610.61(b) (21 CFR 
610.60(b)) to require that the NDC number appear, in accordance with 
proposed part 207, on these biological product labels. Many individuals 
and companies use NDC numbers and they may not have the technology or 
ability to read an automatic identification technology such as a bar 
code that is required under current Sec.  207.25 or Sec.  610.67. In 
addition, a human-readable NDC number may serve as a ``backup'' in case 
the bar code is damaged, cannot be read, or is otherwise illegible.
4. How Do We Intend to Implement the NDC Number Changes?
    a. When would we expect compliance with the NDC number 
requirements? We are proposing that our electronic drug registration 
and listing system be used to enter and update all NDC number 
information, as well as all registration and listing information, no 
later than 9 months after the effective date of a final rule. If a drug 
already has an NDC number at the time of the effective date of a final 
rule, the drug would retain that NDC number provided that the 
manufacturer, repacker, or relabeler, within 9 months after the 
effective date of a final rule, reviews and updates, in accordance with 
proposed Sec. Sec.  201.2, 207.33, 207.37, 610.60, and 610.61, the 
information in our database for the NDC number. To retain the NDC 
number, new information about the drug's characteristics may need to be 
provided to us. We will, if necessary, assign a new product code and/or 
package code, creating a new NDC number for the drug. If a 
manufacturer, repacker, or relabeler does not review or update its 
information within 9 months after a final rule's effective date, we may 
assign a new NDC number to the drug or take other appropriate steps.
    As discussed in section IV.E.6 of this document, we intend to make 
available guidance on how to provide to us in

[[Page 51306]]

electronic format information required to receive an NDC number, as 
well as registration and listing information. We can assist 
manufacturers, repackers, and relabelers in determining whether their 
NDC numbers are accurate and address any problems with existing NDC 
numbers (such as duplicate or potentially duplicate NDC numbers). We 
are available to work with manufacturers, repackers, and relabelers to 
resolve issues that might arise after a final rule becomes effective. 
Information on how to contact us for assistance will be specified in 
the guidance.
    b. When would we expect NDC numbers to appear on drug labels? 
Although current regulations do not require NDC numbers on drug labels 
(other than NDC numbers encoded in a bar code, where such bar codes are 
required under current Sec.  201.25), almost all human and animal 
prescription drugs already have NDC numbers on their labels because 
government agencies and third-party payers rely on NDC numbers for 
reimbursement and other purposes. Thus, when we issue a final rule 
requiring NDC numbers to appear on drug labels, such a requirement 
should have little impact on human and animal prescription drug labels.
    We intend to phase-in the requirements for NDC number placement and 
appearance on human and animal prescription drug labels over a 3-year 
period, starting from the effective date of a final rule. This 
implementation scheme should lessen the impact on prescription drug 
labels (which might stem from changing the NDC number on the label or 
adding an NDC number, for example, for unit-of-use blisters).
    As for human and animal OTC drugs, we estimate that approximately 
30 percent of these drug labels currently have NDC numbers. (We discuss 
this issue further in section VI of this document.) We intend to phase-
in the requirements for NDC number placement and appearance on OTC drug 
labels over a 7-year period, starting from the effective date of a 
final rule.
    We are considering shortening the compliance dates by which the 
appropriate NDC number must appear on drug labels to 2 years after the 
effective date of a final rule for prescription drugs and 5 years after 
the effective date of a final rule for OTC drugs. We discuss this issue 
further in section VI of this document. We invite comment on whether a 
shorter implementation period would be preferable.
    These implementation periods would permit manufacturers, repackers, 
and relabelers to incorporate the appropriate NDC number at minimal 
additional cost when redesigning their labels in the course of the 
normal relabeling cycle. We should note, however, that manufacturers, 
repackers, relabelers, and private label distributors who are subject 
to the bar code requirements at current Sec.  201.25 might find it 
easier to put human-readable NDC numbers on their labels when they 
revise those labels to accommodate the bar code. We remind readers that 
the bar code requirement became effective on April 26, 2004, and the 
compliance dates varied depending on when we approved a drug relative 
to the April 26, 2004, date. For example, for drugs approved on or 
after April 26, 2004, we expected compliance within 60 days of the 
drug's approval date. For drugs approved before April 26, 2004, we 
expect compliance within 2 years. So, for example, a manufacturer whose 
prescription drug is subject to the bar code requirement might find it 
easier to redesign its label once to add a human-readable NDC number 
and a bar code, rather than redesign its label twice.
    We invite comments on the implementation scheme described here.

D. Listing

1. Who Would Be Required To List Drugs?
    Proposed Sec.  207.41(a) would require manufacturers, repackers, 
relabelers, and drug product salvagers who are subject to the 
registration requirements under proposed Sec.  207.17 (and not exempt 
under proposed Sec.  207.13) to list drugs being manufactured, 
repacked, relabeled, or salvaged by them for commercial distribution. 
Proposed Sec.  207.41(a) is consistent with current Sec.  207.20(a), 
which states that owners or operators of all drug establishments, not 
exempt under section 510(g) of the act or current Sec.  207.10, that 
engage in the manufacture, preparation, propagation, compounding, or 
processing of a drug submit a list of every drug in commercial 
distribution. Section 510(j)(1) of the act requires, among other 
things, that every person who registers with the Secretary must list 
drugs that are being manufactured, prepared, propagated, compounded, or 
processed for commercial distribution.
    Under current Sec.  207.20(a), such drugs must be listed whether or 
not they enter interstate commerce. This is consistent with Congress's 
intention for section 510 of the act to apply to drugs both in 
interstate and intrastate commerce as stated in section 301 of Public 
Law 82-781, in part, as follows: ``[T]he products of all 
[establishments in which drugs are manufactured, prepared, propagated, 
compounded, or processed] are likely to enter the channels of 
interstate commerce and directly affect such commerce; and * * * the 
regulation of interstate commerce in drugs without provision for 
registration and inspection of establishments that may be engaged only 
in intrastate commerce in such drugs would discriminate against and 
depress interstate commerce in such drugs, and adversely burden, 
obstruct, and affect such interstate commerce.''
    Proposed Sec.  207.41(a) also provides that when operations are 
conducted at more than one establishment and there exists joint 
ownership and control among all the establishments, listing information 
may be submitted by the parent, subsidiary, and/or affiliate company 
for drugs at all establishments. This provision would also apply when 
operations are conducted at both domestic and foreign establishments 
and there exists joint ownership and control among all the 
establishments. This provision is consistent with current Sec.  
207.20(a).
    Under proposed Sec.  207.41(a), drug product salvagers would be 
required to list. As discussed in sections IV.A.5 and IV.B.1 of this 
document, and consistent with current Sec.  207.20(a), drug product 
salvagers would continue to be required to register because their 
activities include applying manufacturing controls to drug products and 
segregating drug products. This activity would be covered under the 
scope of manufacturing, preparing, propagating, compounding, or 
processing, and would trigger the requirement to register under the 
act. Because drug product salvagers are conducting one of these 
activities with respect to a given drug for the purpose of commercial 
distribution, this activity would also trigger the requirement to list 
under the act (section 510(j)(1) of the act). (Drug product salvagers 
sometimes repack/relabel drug products and would also have to register 
because of those activities.) Under current Sec.  207.20(a), drug 
product salvagers are not required to list. Because drug product 
salvagers place the salvaged drug in commercial distribution, we are 
proposing to require that drug product salvagers submit listing 
information to us. We specifically invite comments on the scope of 
activities of drug product salvagers, that is, whether drug product 
salvagers salvage drug products for commercial distribution and whether 
these activities should trigger listing under the act.
    Under proposed Sec.  207.41(b), manufacturers, repackers, 
relabelers, and drug product salvagers who engage

[[Page 51307]]

in more than one activity for drugs would list each drug in accordance 
with the requirements for the activity engaged in for that drug. An 
example of a company that engages in more than one activity for drugs 
would be a company that manufactures Drug X and relabels Drug Y. The 
company would provide the listing information described in proposed 
Sec.  207.49 for Drug X and the listing information described in 
proposed Sec.  207.53 for Drug Y. We are proposing this requirement to 
clarify which listing information would be provided by manufacturers, 
repackers, relabelers, and drug product salvagers who engage in more 
than one activity for drugs. As discussed below, manufacturers, 
repackers and relabelers, and drug product salvagers would provide 
similar listing information to us (although some information would be 
provided by reference).
    Under proposed Sec.  207.41(c), manufacturers, repackers, 
relabelers, and drug product salvagers would, in addition to listing 
their own drugs, provide all listing information to us for drugs they 
manufacture, repack, relabel, or salvage for private label 
distributors. In general, private label distributors would not list 
drugs with us. However, private label distributors would be required to 
list a drug with us if they manufacture, repack, relabel, or salvage 
the drug for commercial distribution. Proposed Sec.  207.41(c) would 
revise current Sec.  207.20(b), which states that owners or operators 
of establishments, not otherwise required to register, that distribute 
under their own label or trade name a drug manufactured or processed 
(as defined in current Sec.  207.3(a)(8)) by a registered establishment 
may elect to submit listing information directly to us and obtain a 
labeler code. Under current part 207, if a private label distributor 
does not elect to submit drug listing information to us, the registered 
establishment must submit the drug listing information. Currently, 
private label distributors that elect to submit listing information 
must include the registration number of the establishment that 
manufactured or processed (as defined in current Sec.  207.3(a)(8)) 
each drug listed and must assume full responsibility for compliance 
with all the requirements of part 207. Private label distributors must 
currently certify to the registered establishment that the submission 
has been made by providing a signed copy of Form FDA 2656 to the 
registered establishment. Private label distributors must submit to us 
the original Form FDA 2656 showing this certification. A list showing 
the NDC number assigned to each drug must accompany the certification.
    We are proposing to alter the arrangement permitted under current 
Sec.  207.20(b). Although we recognize that this proposed shift in 
responsibility may alter current business practices, we believe that 
proposed Sec.  207.41(c) will help to ensure that listing information 
is more accurate and complete. The current scheme has caused confusion 
and resulted in inaccurate and incomplete listing information. Some 
private label distributors that have elected to list their drugs have 
not had access to all the information needed to list the drugs 
accurately. Some private label distributors have claimed that 
manufacturers, repackers, and relabelers have been reluctant to provide 
certain information to them. In addition, in some instances, the 
parties have been uncertain about who is responsible for listing.
    As discussed in section IV.B.1 of this document and previously, 
manufacturers, repackers, relabelers, and drug product salvagers would 
be required to register and list the drugs they manufacture, repack, 
relabel, or salvage. They would be required to do so even if they 
conduct such activities on behalf of private label distributors. This 
proposed requirement would be consistent with section 510(j)(1) of the 
act which requires every person who registers to submit listing 
information for drugs ``which are being manufactured, prepared, 
propagated, compounded, or processed by him for commercial 
distribution'' (emphasis added). In addition, private label 
distributors would not be required (nor permitted) to register because 
their activities are not covered under the scope of manufacturing, 
preparing, propagating, compounding, or processing. Nor do private 
label distributors conduct one of these activities with respect to a 
given drug for the purpose of commercial distribution and, thus, would 
not be required (nor permitted) to list. Private label distributors 
only commercially distribute drugs under their own label or trade name. 
Manufacturers, repackers, relabelers, and drug product salvagers often 
manufacture, repack, relabel, or salvage drugs that are distributed by 
a private label distributor, and they have all the information about 
the drug that is necessary to list the drug distributed by the private 
label distributor. Under the proposal, to list a drug that is 
manufactured, repacked, relabeled, or salvaged for a private label 
distributor, manufacturers, repackers, relabelers, and drug product 
salvagers would have to obtain any existing NDC number from the private 
label distributor or would have to obtain the NDC number from FDA for a 
drug distributed by a private label distributor. Manufacturers, 
repackers, relabelers, and drug product salvagers would have to place 
the NDC number assigned to the private label distributor's drug on the 
label. We specifically invite comments on this proposed change in the 
listing responsibilities of manufacturers, repackers, relabelers, drug 
product salvagers, and private label distributors and its potential 
effect on business practices.
2. When Would Initial Listing Information Be Provided?
    Under proposed Sec.  207.45, manufacturers, repackers, relabelers, 
and drug product salvagers would list, at the time of initial 
registration of an establishment, any drug being manufactured, 
repacked, relabeled, or salvaged for commercial distribution at that 
establishment. This provision is consistent with section 510(j)(1) of 
the act, which requires, among other things, that every person who 
registers with the Secretary under sections 510(b), (c), (d), or (i) of 
the act must list drugs that are being manufactured, prepared, 
propagated, compounded, or processed for commercial distribution. 
Proposed Sec.  207.45 pertains to the submission of listing information 
for drugs at the time of the initial registration of an establishment. 
Reviewing and updating information for drugs already listed and 
providing listing information for drugs not previously listed are 
covered under proposed Sec.  207.57. Proposed Sec.  207.57 is discussed 
in section IV.D.8 of this document.
3. What Listing Information Would Be Required?
    To list a drug, manufacturers would be required to provide the 
information in proposed Sec.  207.49, repackers and relabelers would be 
required to provide the information in proposed Sec.  207.53, and drug 
product salvagers who are not repackers or relabelers would be required 
to provide the information in proposed Sec.  207.54. We are proposing 
different listing requirements for manufacturers, repackers and 
relabelers, and drug product salvagers because much of the information 
about a drug is submitted to us by the manufacturer to obtain an NDC 
number and to list the drug. When the repacker, relabeler, and drug 
product salvager provide, during listing, the required NDC number for 
the drug, we can incorporate by reference the information already 
submitted about the drug by the manufacturer. The information required 
to obtain an NDC

[[Page 51308]]

number is explained in section IV.C of this document, and the 
requirements for providing the NDC number during listing are explained 
in section IV.D.4.a of this document.
    The following paragraphs summarize the information that would be 
required for listing from manufacturers, repackers, relabelers, and 
drug product salvagers. These summaries are followed by descriptions of 
each of the listing requirements (see section IV.D.4 of this document).
    a. Summary of proposed listing information for manufacturers. 
Manufacturers would be required to submit to us the following listing 
information (if applicable to the drug being listed) under proposed 
Sec.  207.49:
     NDC number;
     Route of administration;
     Approved U.S. application number or approved U.S. BLA 
number, if any;
     Registration number of each establishment where the 
manufacturing is performed for the drug;
     Schedule of the drug under section 202 of the Controlled 
Substances Act (21 U.S.C. 812);
     With respect to foreign establishments only, the name and 
contact information of each importer of the drug and of each person who 
imports or offers for import the drug;
     Labeling;
     Advertisements; and
     Information about the private label distributor, if any.
    b. Summary of proposed listing information for repackers and 
relabelers. Repackers and relabelers would be required to submit to us 
the following listing information (if applicable to the drug being 
listed) under proposed Sec.  207.53:
     NDC number;
     Registration number of each establishment where the 
repacking or relabeling is performed for the drug;
     With respect to foreign establishments only, the name and 
contact information of each importer of the drug and of each person who 
imports or offers for import the drug;
     Labeling;
     Advertisements; and
     Information about the private label distributor, if any.
    c. Summary of proposed listing information for drug product 
salvagers who are not repackers or relabelers. Drug product salvagers 
who do not otherwise repack or relabel the drugs they salvage would be 
required to submit to us the following listing information (if 
applicable to the drug being listed) under proposed Sec.  207.54:
     NDC number assigned to the drug immediately before the 
drug is received by the drug product salvager;
     Lot number and expiration date of the salvaged drug;
     Registration number of each establishment where the drug 
product salvager salvages the drug;
     With respect to foreign establishments only, the name and 
contact information of each importer and of each person who imports or 
offers for import the drug; and
     Information about the private label distributor, if any.
4. What Listing Information Would Be Required for Manufacturers?
    Under proposed Sec.  207.49, manufacturers would be required to 
provide to us the following listing information for each drug they 
list, including a drug manufactured for a private label distributor.
    a. NDC number. For a drug to be considered listed, manufacturers 
and, as discussed below, repackers, relabelers, and drug product 
salvagers, must submit the NDC number for the drug as part of the 
drug's listing information.\7\ The NDC number, including the 
information that would be submitted to us to obtain an NDC number, is 
explained under proposed Sec.  207.33. Knowing the NDC number of the 
drug would enable us to incorporate by reference information about the 
drug submitted by the manufacturer, repacker, or relabeler to obtain an 
NDC number under proposed Sec.  207.33(c) and (d), as well as 
information submitted by the manufacturer, repacker, or relabeler to 
list the drug. This would reduce the amount of information that must be 
provided to us by manufacturers, repackers, relabelers, and drug 
product salvagers for listing. Current Sec.  207.25(b)(8) requires the 
submission of the NDC number for each drug listed, and this information 
is currently submitted on Form FDA 2657.
---------------------------------------------------------------------------

    \7\The drug product salvager (that does not repack or relabel) 
would submit the NDC number assigned to the drug immediately before 
the drug is received by the drug product salvager; the manufacturer, 
repacker, and relabeler (and the drug product salvager that repacks 
or relabels) would submit the NDC number assigned to their drug 
under proposed Sec.  207.33(c) and (d).
---------------------------------------------------------------------------

    b. Route of administration. The route of administration would 
enable us to identify a specific formulation of a drug. For example, 
drugs having the same active ingredient may have different routes of 
administration. The route of administration is currently submitted on 
Form FDA 2657.
    c. Approved U.S. application number. The approved U.S. application 
number or the approved U.S. BLA number,\8\ if any, would enable us to 
link to the information about the drug that was already submitted to us 
for marketing approval. Section 510(j)(1)(A) of the act requires the 
submission of a reference to the authority for marketing a drug subject 
to section 505 or 512 of the act. In addition, current Sec.  
207.25(b)(2) requires the submission of the application number for each 
drug listed that the registrant regards as subject to section 505 or 
512 of the act. The drug's application number is currently submitted on 
Form FDA 2657. As discussed in section IV.D.4.g of this document, if 
the approved U.S. application number is provided to us when a human 
prescription or OTC drug is listed, the manufacturer would not be 
required to re-submit the labeling for the approved drug. The 
application number would incorporate by reference the labeling for 
approved drugs. This would eliminate unnecessary duplication of effort 
and cost to industry. The application number may have already been 
provided under Sec.  207.33(c)(2)(i) and (c)(2)(ii) instead of 
providing the names of the active pharmaceutical ingredient and the 
inactive ingredient. If so, it will already be in our database and 
would not need to be resubmitted.
---------------------------------------------------------------------------

    \8\Human drugs are approved by FDA under an NDA, ANDA, or a BLA. 
Part 314 (21 CFR part 314) for human drugs and part 601 (21 CFR part 
601) for biologics set forth the approval requirements.
---------------------------------------------------------------------------

    d. Registration number of each establishment. The registration 
number of each establishment where the manufacturing is performed for 
the drug would enable us to identify the establishment where the drug 
is manufactured. This would help our investigators better prepare for 
inspections and collect postmarketing surveillance samples. Although 
this information would already be submitted for registration under 
proposed Sec.  207.25(e), submitting it at listing would enable us to 
link this information to the drug being listed. Current Sec.  
207.25(b)(7) requires, for each drug listed, the submission of the 
registration number of each drug establishment at which the drug is 
manufactured or processed (within the meaning of current Sec.  
207.3(a)(8)). Current Sec.  207.25(b)(3) requires the submission of the 
license number of the manufacturer of drugs subject to section 351 of 
the PHS Act. The ``establishment registration number'' is defined in 
proposed Sec.  207.1 to mean the number assigned by FDA to the 
establishment during the establishment registration process. Currently, 
we plan to assign the FEI number as the establishment registration 
number. In the future, however, we may use a different

[[Page 51309]]

number as the establishment registration number. The establishment 
registration number is currently submitted on Form FDA 2657.
    e. Schedule of the drug. The schedule of the drug under section 202 
of the Controlled Substances Act would enable us to provide yearly 
estimates of medical, scientific, and reserve stock needs for Schedule 
I and II substances (21 CFR part 1303, 21 U.S.C. 826). Under section 
302(a) of the PHS Act (42 U.S.C. 242(a)), the Secretary is responsible 
for providing to the Drug Enforcement Administration estimates of the 
quantities of controlled substances for which production quotas must be 
established that will be required to meet the legitimate medical, 
scientific, and reserve stock needs of the United States for the 
following calendar year. The schedule of the drug is currently 
submitted on Form FDA 2657.
    f. Information about each importer of the drug and each person who 
imports or offers for import the drug to the United States. Foreign 
establishments only must provide the name, address, telephone and fax 
numbers, and e-mail address of each importer of such drug in the United 
States that is known to the establishment, and of each person who 
imports or offers for import such drug to the United States. As 
discussed under section IV.B.3 of this document, the term ``known to'' 
would mean any importer that is known to the foreign establishment as 
well as any importer that the foreign establishment has reason to know 
of. We therefore expect that the person responsible for completing the 
required registration forms on behalf of the foreign establishment 
would undertake appropriate due diligence in completing those forms, 
including to find out and report importers that others in his or her 
establishment know of or have reason to know of. Foreign establishments 
would provide this information for listing unless previously provided 
under proposed Sec.  207.25(h) for registration. The Bioterrorism Act 
requires foreign establishments to submit, among other things, the name 
of each importer of each drug that is known to the establishment, and 
the name of each person who imports or offers for import each drug to 
the United States for purposes of importation. The Bioterrorism Act 
requires submission of such information as part of registration 
information and also specifically requires listing information to be 
submitted for each drug being manufactured for commercial distribution 
(see section IV.A.4.d of this document). We are proposing, under this 
part, to make the submission of information concerning importers of 
drugs and persons who import or offer for import drugs to the United 
States both a registration and a listing requirement. However, if the 
information has been previously provided by the foreign establishment 
at registration, the foreign establishment would not be required to re-
enter that information into the database at listing. Our listing 
database will be populated automatically with the required information. 
This would reduce the amount of information that must be provided to us 
by the foreign establishment at listing. The information about each 
importer of the establishment's drug that is known to the establishment 
and each person who imports or offers for import the drug to the United 
States is not currently required to be submitted under current part 207 
or on Form FDA 2656 or Form FDA 2657.
    g. Labeling. Under proposed Sec.  207.49(g), the following labeling 
would be provided to us for each drug listed:
     Human prescription drugs. If the manufacturer has not 
provided the drug's approved U.S. application number as part of the 
listing information under proposed Sec.  207.49(c), the manufacturer 
would submit a copy of all current labeling, including the content of 
labeling, for each human prescription drug (proposed Sec.  
207.49(g)(1)).
    Under proposed Sec.  207.49(g)(1) and, as discussed below under 
proposed Sec. Sec.  207.49(g)(2) and 207.49(g)(3), only one 
representative container or carton label would be submitted where 
differences exist only in the quantity of contents statement or the bar 
code. This proposed provision is consistent with current Sec.  
207.25(b)(2), although the proposal would add differences in the bar 
code to the provision. This provision would reduce the number of labels 
that must be submitted to us by the manufacturer.
    If the manufacturer provides the drug's approved U.S. application 
number as part of the drug's listing information, the labeling required 
under proposed Sec.  207.49(g)(1) and, as discussed below under 
proposed Sec.  207.49(g)(2), would be deemed to accompany the listing 
information. Incorporating the labeling, including the content of 
labeling, by reference to the application number would eliminate 
unnecessary duplication of effort and cost to industry. This proposed 
exception would not apply to animal drugs approved under section 512 of 
the act because currently these application holders are not required to 
provide the content of labeling electronically with the application for 
those drugs.
    The ``content of labeling'' would be provided to FDA under proposed 
Sec.  207.49(g)(1) and, as discussed below, under proposed Sec.  
207.49(g)(2) and (g)(3). The ``content of labeling'' is defined in 
proposed Sec.  207.1 and discussed in sections IV.A.5 and IV.E.4 of 
this document and would mean, for human prescription drugs that the 
manufacturer regards as subject to section 505 of the act or section 
351 of the PHS Act, the content of the prescription drug labeling, 
including all text, tables, and figures. For human prescription drugs 
that the manufacturer regards as not subject to section 505 of the act 
or section 351 of the PHS Act, the ``content of labeling'' would mean 
the labeling equivalent to the content of the prescription drug 
labeling, including all text, tables, and figures. For human OTC drugs, 
the ``content of labeling'' would mean the content of the drug facts 
labeling required by Sec.  201.66, including all text, tables, and 
figures. For animal drugs, the ``content of labeling'' would mean the 
content of the labeling that accompanies the drug that is necessary to 
enable the safe and proper administration of the drug, including all 
text, tables, and figures.
    The labeling submission requirements in proposed Sec.  207.49(g) 
are almost identical in substance to the labeling submission 
requirements of current Sec.  207.25(b)(2) through (b)(5), except that 
manufacturers would also be required, as discussed previously, to 
submit electronically the ``content of labeling.'' In addition, the 
labeling submission requirements in proposed Sec.  207.49(g) conform to 
the statutory requirements of section 510(j) of the act. The proposed 
requirement to submit labeling, including the content of labeling, for 
human prescription drugs and, as discussed below, for human OTC drugs 
and animal drugs, whether or not the drugs are subject to the pre-
approval provisions of the act or the PHS Act, is consistent with the 
statutory requirements of section 510(j)(1)(A), 510(j)(1)(B)(i), and 
510(j)(1)(B)(ii) of the act. Section 510(j)(1)(A) of the act requires, 
among other things, the submission of a copy of all labeling for drugs 
subject to section 505 or 512 of the act. Section 510(j)(1)(B)(i) 
requires, among other things, the submission of a copy of all labeling 
for prescription drugs not subject to section 505 or 512 of the act, 
and section 510(j)(1)(B)(ii) requires, among other things, the 
submission of the label, package insert, and representative sampling of 
any other labeling for OTC drugs not subject to section 505 or 512 of 
the act. We also

[[Page 51310]]

have the authority to require that labeling be submitted in this format 
under other sections of the act (e.g., sections 201, 301, 501, 502, 
503, 505, 506, 506A, 506B, 506C, 513-516, 518-520, 701, 704, 721, 801 
of the act) and the PHS Act.
     Human OTC drugs that manufacturers regard as subject to 
section 505 of the act or section 351 of the PHS Act. If the 
manufacturer has not provided the drug's approved U.S. application 
number as part of the listing information under proposed Sec.  
207.49(c), the manufacturer would submit a copy of all current 
labeling, including the content of labeling, for each human OTC drug 
that the manufacturer regards as subject to section 505 of the act or 
section 351 of the PHS Act (proposed Sec.  207.49(g)(2)(i)).
    Drugs subject to section 505 of the act or section 351 of the PHS 
Act must be approved by FDA under an NDA, ANDA, or a BLA. Part 314 for 
human drugs and part 601 for biological products set forth the approval 
requirements.
     Human OTC drugs that manufacturers regard as not subject 
to section 505 of the act or section 351 of the PHS Act. The 
manufacturer would submit a copy of the current label, the content of 
labeling, the package insert (if any), and a representative sampling of 
any other labeling for each human OTC drug that the manufacturer 
regards as not subject to section 505 of the act or section 351 of the 
PHS Act (proposed Sec.  207.49(g)(2)(ii)).
    The term ``label'' means the container label as defined at section 
201(k) of the act. ``Content of labeling'' is defined at proposed Sec.  
207.1 (as discussed in section IV.A.5 of this document) and for OTC 
drugs refers to the content of the drug facts labeling as specified at 
Sec.  201.66. Most OTC drugs do not have a package insert. However, for 
those that do, it is currently required to be submitted for drug 
listing under section 510(j)(1)(A) and (j)(1)(B)(ii) of the act and 
current Sec.  207.25(b)(4) and (b)(5). We are proposing to retain that 
requirement in proposed Sec.  207.49(g)(2)(i) and (g)(2)(ii). For OTC 
drugs marketed pursuant to an approved application, any package insert 
would be included within the requirement to submit ``all current 
labeling.'' The term ``representative sampling of any other labeling,'' 
as used in proposed Sec.  207.49(g)(2)(ii) and, as discussed below, in 
proposed Sec.  207.49(g)(3)(ii), is defined in proposed Sec.  207.1 and 
discussed in section IV.A.5 of this document. Examples of OTC drugs 
that a manufacturer may regard as not subject to section 505 of the act 
or section 351 of the PHS Act would include human OTC drugs marketed 
under an OTC monograph and deemed generally recognized as safe and 
effective (see part 330 (21 CFR part 330)).
     Animal drugs that manufacturers regard as subject to 
section 512 of the act. The manufacturer would submit a copy of all 
current labeling, including the content of labeling, for each animal 
drug that the manufacturer regards as subject to section 512 of the act 
(proposed Sec.  207.49(g)(3)(i)).
     Animal drugs that manufacturers regard as not subject to 
section 512 of the act. For all other animal drugs, the manufacturer 
would submit a copy of the current label, the package insert, the 
content of labeling, and a representative sampling of any other 
labeling, for each animal drug that the manufacturer regards as not 
subject to section 512 of the act (proposed Sec.  207.49(g)(3)(ii)).
    h. Advertisements. Under proposed Sec.  207.49(h), and in 
accordance with section 505(j)(1)(B)(i) of the act, the following 
advertisements would be provided by the manufacturer for each drug 
listed:
     A representative sampling of advertisements for human 
prescription drugs that the manufacturer regards as not subject to 
section 505 of the act or section 351 of the PHS Act. Proposed Sec.  
207.49(h)(1) is consistent with section 510(j)(1)(B)(i) of the act and 
current Sec.  207.25(b)(4). The term ``representative sampling of 
advertisements'' is defined in proposed Sec.  207.1 and discussed in 
section IV.A.5 of this document.
     If we request it, for good cause, a copy of all 
advertisements for human prescription drugs that the manufacturer 
regards as not subject to section 505 of the act or section 351 of the 
PHS Act, including those advertisements described in Sec.  202.1(l)(1), 
would be required to be submitted to FDA within 30 calendar days after 
our request. Proposed Sec.  207.49(h)(2) is consistent with section 
510(j)(1)(B)(i) of the act and current Sec.  207.31(a)(1). Section 
510(j)(1)(B)(i) of the act requires, among other things, the submission 
of a representative sampling of advertisements and, upon request for 
good cause, a copy of all advertisements for prescription drugs not 
subject to section 505 of the act. Current Sec.  207.31(a)(1) requires, 
upon request, the submission of a copy of all advertisements for 
prescription drugs that the manufacturer regards as not subject to 
section 505 of the act.
    i. Private label distributor. If the drug is manufactured for a 
private label distributor, the manufacturer would submit the name, 
address, labeler code, telephone and fax numbers, and e-mail address of 
the private label distributor. The manufacturer may obtain this 
information from the private label distributor or other sources. This 
information would indicate whose drug (the manufacturer's or the 
private label distributor's) is being listed and would identify and 
enable us, if needed, to contact the private label distributor. The 
information for a private label distributor is currently submitted on 
Form FDA 2658.
5. What Listing Information Would Be Required for Repackers and 
Relabelers?
    Under proposed Sec.  207.53, repackers and relabelers would be 
required to provide to us all of the following listing information for 
each drug they list, including a drug repacked or relabeled for a 
private label distributor.
    a. NDC number. For a drug to be considered listed, repackers and 
relabelers would submit the NDC number for the drug being repacked or 
relabeled as part of the drug's listing information. This requirement 
is explained in section IV.D.4.a of this document.
    b. Registration number of each establishment. The registration 
number of each establishment where the repacking or relabeling is 
performed for the drug would enable us to identify the establishment 
where the drug is repacked or relabeled. This requirement is explained 
in section IV.D.4.d of this document.
    c. Information about each importer of the drug and each person who 
imports, or offers for import, the drug to the United States. This 
requirement is explained in section IV.D.4.f of this document.
    d. Labeling. Under proposed Sec.  207.53(d), the following labeling 
must be provided for each drug listed:
     Human prescription drugs. If the repacker or relabeler 
makes any change in the labeling of the drug repacked or relabeled, the 
repacker or relabeler would submit a copy of all changed labeling for 
each human prescription drug that is repacked or relabeled (proposed 
Sec.  207.53(d)(1)). We would already have, as required under proposed 
Sec.  207.49(g), the labeling for the drug provided by the manufacturer 
during listing, and the repacker or relabeler would not need to 
resubmit it to us unless they make changes to the labeling. Proposed 
Sec.  207.53(d)(1) is consistent with section 510(j)(1)(A) and 
(j)(1)(B)(i) of the act and current Sec.  207.25(b)(2) and (b)(4), 
except that repackers and relabelers would not need to resubmit 
labeling when no changes have been made.

[[Page 51311]]

     Human OTC drugs that manufacturers regard as subject to 
section 505 of the act or section 351 of the PHS Act. If the repacker 
or relabeler makes any changes, in accordance with the act and FDA 
regulations, in the labeling of the drug repacked or relabeled, the 
repacker or relabeler would submit a copy of all changed labeling for 
each human OTC drug that the manufacturer of the drug regards as 
subject to section 505 of the act or section 351 of the PHS Act 
(proposed Sec.  207.53(d)(2)(i)). As stated previously, we would not 
need a copy of the unchanged labeling because we would already have the 
labeling for the drug provided by the manufacturer during listing. 
Proposed Sec.  207.53(d)(2)(i) is consistent with section 
510(j)(1)(B)(i) of the act and current Sec.  207.25(b)(2), except that 
some of the information required under current Sec.  207.25(b)(2) would 
not need to be provided by the repacker or relabeler under proposed 
Sec.  207.53(d)(2)(i) if the repacker or relabeler provides the 
manufacturer's NDC number. The NDC number would provide a link to that 
information.
     Human OTC drugs that manufacturers regard as not subject 
to section 505 of the act or section 351 of the PHS Act. The repacker 
or relabeler would submit a copy of the current label, a copy of any 
changes made to the package insert, if there is one, and a 
representative sampling of any other labeling for each human OTC drug 
that the manufacturer of the drug regards as not subject to section 505 
of the act or section 351 of the PHS Act (proposed Sec.  
207.53(d)(2)(ii)). The term ``representative sampling of any other 
labeling,'' as used in proposed Sec.  207.53(d)(2)(ii) and, as 
discussed below, in Sec.  207.53(d)(3), is defined in proposed Sec.  
207.1 and discussed in section IV.A.5 of this document. Examples of OTC 
drugs that a manufacturer may regard as not subject to section 505 of 
the act or section 351 of the PHS Act would include human OTC drugs 
marketed under an OTC monograph and deemed generally recognized as safe 
and effective (see part 330). Proposed Sec.  207.53(d)(2)(ii) is 
consistent with section 510(j)(1)(B)(ii) of the act and current Sec.  
207.25(b)(5), except redundant information would not be submitted.
     Animal drugs. The repacker or relabeler would submit a 
copy of the current label, a copy of any changes made to each animal 
drug labeling, and a representative sampling of any other labeling for 
each animal drug (proposed Sec. Sec.  207.53(d)(3)). Proposed Sec.  
207.53(d)(3) is consistent with section 510(j)(1)(B)(ii) of the act and 
current Sec.  207.25(b)(2) and (b)(5), except redundant information 
would not be submitted.
    e. Advertisements. Under proposed Sec.  207.53(e), and in 
accordance with section 505(j)(1)(B)(i) of the act, the following 
advertisements would be provided by the repacker or relabeler for each 
drug listed:
     A representative sampling of advertisements for human 
prescription drugs that the repacker or relabeler regards as not 
subject to section 505 of the act or section 351 of the PHS Act. 
Proposed Sec.  207.53(e)(1) is consistent with section 510(j)(1)(B)(i) 
of the act and current Sec.  207.25(b)(4).
     If we request it, for good cause, a copy of all 
advertisements for human prescription drugs that the repacker or 
relabeler regards as not subject to section 505 of the act or section 
351 of the PHS Act, including those advertisements described in Sec.  
202.1(l)(1), would be required within 30 calendar days after our 
request. Proposed Sec.  207.53(e)(2) is consistent with section 
510(j)(1)(B)(i) of the act and current Sec.  207.31(a)(1).
    f. Private label distributor. If the drug is repacked or relabeled 
for a private label distributor, the repacker or relabeler would submit 
the name, address, labeler code, telephone and fax numbers, and e-mail 
address of the private label distributor. The repacker or relabeler may 
obtain this information from the private label distributor or other 
sources. This information would indicate whose drug (the repacker's, 
relabeler's, or private label distributor's) is being listed and would 
identify and enable us, if needed, to contact the private label 
distributor. The information for a private label distributor is 
currently submitted on Form FDA 2658.
6. What Listing Information Would Be Required for Drug Product 
Salvagers Who Are Not Repackers or Relabelers?
    Drug product salvagers who do not otherwise repack or relabel the 
drugs they salvage would be required to provide all of the following 
listing information to us for each drug they list, including a drug 
salvaged for a private label distributor. Drug product salvagers who 
also repack and relabel the drugs they salvage must list those drugs as 
a repacker or relabeler in accordance with Sec.  207.53.
    a. NDC number. For a drug to be considered listed, the drug product 
salvager would be required to provide the NDC number assigned to the 
drug immediately before the drug is received by the drug product 
salvager. Under the proposal, we would assign an NDC number to a 
manufacturer's, repacker's, or relabeler's drug (or to a drug 
manufactured, repacked, or relabeled for a private label distributor) 
after the information required under proposed Sec.  207.33(c) or (d) is 
provided (see discussion in section IV.D.4.a of this document). The 
drug product salvager who is not also a repacker or a relabeler for the 
drug would provide to us the NDC number that is already on the salvaged 
drug's label (that is, the NDC number of the manufacturer, repacker, 
relabeler, or private label distributor). Knowing the NDC number of the 
drug would enable us to incorporate by reference information about the 
drug submitted by the manufacturer, repacker, or relabeler to obtain an 
NDC number under proposed Sec.  207.33(c) and (d), as well as 
information submitted by the manufacturer, repacker, or relabeler to 
list the drug.
    b. Lot number and expiration date. We need to know the lot number 
and expiration date to properly identify the drug because the drug 
product salvager who is not a repacker or relabeler for the drug would 
not be assigned an NDC number for the drug. The salvaged drug's lot 
number would enable us to specifically identify the salvaged drug and 
determine which batch of a manufacturer's drug has been processed by 
the drug product salvager. Lot number (or control number or batch 
number) is defined at current Sec.  210.3(b)(11) as any distinctive 
combination of letters, numbers, or symbols, or any combination of 
them, from which the complete history of the manufacture, processing, 
packing, holding, and distribution of a batch or lot of drug product or 
other material can be determined. Knowing the drug's expiration date 
would indicate approximately how long the salvaged drug may be 
available for use by consumers. The expiration date would also allow us 
to identify the approximate date that the salvaged drug would no longer 
be marketed.
    c. Registration number of each establishment. The registration 
number of each establishment where the drug product salvager salvages 
the drug would enable us to connect the salvaging activity to a 
particular drug and identify the specific location where the drug 
product salvaging is performed for the drug. This information would 
also be used in conducting our establishment inspections and for 
collecting postmarketing surveillance samples. Current Sec.  
207.25(b)(7) requires, for each drug listed, the submission of the 
registration number of each drug establishment at which the drug is 
manufactured or processed (within the meaning of current Sec.  
207.3(a)(8)), and

[[Page 51312]]

current Sec.  207.25(b)(3) requires the submission of the license 
number of the manufacturer of drugs subject to section 351 of the PHS 
Act. The establishment registration number is currently submitted on 
Form FDA 2657.
    d. Information about each importer of the drug and each person who 
imports, or offers for import, the drug to the United States. This 
requirement is explained under section IV.D.4.f of this document.
    e. Private label distributor. If the drug is salvaged for a private 
label distributor, the drug product salvager would be required to 
submit the name, address, labeler code, telephone and fax numbers, and 
e-mail address of the private label distributor. The drug product 
salvager may obtain this information from the private label distributor 
or other sources. This information would identify the private label 
distributor and enable us, if needed, to contact the private label 
distributor. The information for a private label distributor is 
currently submitted on Form FDA 2658.
7. What Additional Drug Listing Information May Be Required?
    Under proposed Sec.  207.55, if we request it, the manufacturer, 
repacker, relabeler, or drug product salvager would be required to 
briefly state the basis for its belief that a particular drug product 
is not subject to section 505 or 512 of the act or section 351 of the 
PHS Act. This proposed provision, which is consistent with section 
510(j)(1)(D) of the act and current Sec.  207.31(a)(3), is needed 
because some manufacturers, repackers, and relabelers have mistakenly 
considered a drug not to be subject to section 505 or 512 of the act or 
section 351 of the PHS Act. Although in some cases manufacturers, 
repackers, and relabelers have correctly concluded that a drug is not 
subject to section 505 or 512 of the act or section 351 of the PHS Act, 
in other cases we may consider the drug to be subject to section 505 or 
512 despite that conclusion.
    The brief statement that would be requested under proposed Sec.  
207.55 may include, for example, the Federal Register citation for the 
applicable OTC monograph. We anticipate that our electronic drug 
registration and listing system will provide some options for brief 
statements, including Federal Register citations as described in the 
example above, from which manufacturers, repackers, relabelers, and 
drug product salvagers may select as the basis for their belief that a 
particular drug product is not subject to section 505 or 512 of the act 
or section 351 of the PHS Act.
    We are also considering whether to require establishments to 
provide the number of batches and batch size for each drug subject to 
the listing requirements that they manufactured, repacked, or relabeled 
since the establishment last provided listing information. Typically, 
this information would be provided every 6 months, based on the 
obligation to review and update listing information in June and 
December of each year. We would consider ``batch size'' to mean, as a 
general matter, the batch size included in the master production and 
control records for each drug, as required by the regulations governing 
current good manufacturing practice for finished pharmaceuticals in 
part 211, including Sec.  211.186(a) (master production and control 
records). Typically, ``batch size'' would be the number of unit dosage 
forms (such as for tablets) or, if the unit dosage form is not defined 
before primary packaging (such as for liquids), the total batch weight 
or volume before primary packaging.
    We are considering this requirement because it would provide us 
with important data regarding a product's volume in the U.S. 
marketplace to assess the potential impact the product has on the 
public health, which, in turn, will enable us to use our limited 
resources more efficiently, particularly with regard to inspectional 
oversight. For example, we currently use data collected as a surrogate 
for production volume, among many other factors, in our risk-based 
model to prioritize routine inspections. This model is a systematic, 
objective, data-driven method to prioritize inspections. (See ``Risk-
Based Method for Prioritizing CGMP Inspections of Pharmaceutical 
Manufacturing Sites--A Pilot Risk Ranking Model'' at http://www.fda.gov/cder/gmp/gmp2004/risk_based_method.htm.) However, better 
estimates of manufacturing volume would improve our ability to 
implement a more risk-based approach to manufacturing quality oversight 
activities. By requiring establishments to provide the number of 
batches and batch size for each drug subject to the listing 
requirements, we would have objective data regarding production volume 
and be better able to find and address CGMP violations that may have 
the most impact on public health. Actual production data would also 
give us the ability to more efficiently allocate our resources in other 
areas.
    We specifically invite comments on whether we should require 
manufacturers, repackers, relabelers, and drug product salvagers to 
provide the number of batches and batch size for each drug subject to 
the listing requirements.
8. What Are the Proposed Requirements for Reviewing and Updating 
Listing Information?
    Currently, manufacturers, repackers, and relabelers must enter new 
or revised listing information on Form FDA 2657 (Form FDA 2658 is used 
when manufacturers, repackers, and relabelers enter new or revised 
information for a private label distributor's drug) and return the form 
to FDA. Under the proposal, manufacturers, repackers, relabelers, and 
drug product salvagers would access our electronic drug registration 
and listing system and review their current listing information online, 
making any changes where needed. Updating listing information would be 
less time consuming under the proposal because the manufacturer, 
repacker, relabeler, and drug product salvager would be able to easily 
access their information at any time, and only changes to the 
information already in the system would need to be entered in the 
fields provided.
    Under proposed Sec.  207.57, manufacturers who are required to list 
under proposed Sec.  207.41 would review and update all listing 
information provided under proposed Sec. Sec.  207.49, 207.55, and 
207.57; repackers and relabelers (including drug product salvagers who 
repack and/or relabel) who are required to list under proposed Sec.  
207.41 would review and update all listing information provided under 
proposed Sec. Sec.  207.53, 207.55, and 207.57; and drug product 
salvagers (who are not repackers and/or relabelers) who are required to 
list under proposed Sec.  207.41 would review and update all listing 
information provided under proposed Sec. Sec.  207.54, 207.55, and 
207.57. Proposed Sec.  207.57 uses the term ``review and update'' to 
stress the importance of first reviewing all listing information to 
determine if any changes have occurred and then updating the 
information.
    Under proposed Sec.  207.57(a), during the annual review and update 
of registration information, manufacturers, repackers, relabelers, and 
drug product salvagers would provide listing information for any drug 
that has not been previously listed. Proposed Sec.  207.57(a) is 
consistent with section 510(j)(1) of the act, which requires, among 
other things, that a list of all drugs must be provided at the time of 
annual registration.
    Under proposed Sec.  207.57(b), manufacturers, repackers, 
relabelers, and drug product salvagers would

[[Page 51313]]

review and update their listing information each June and December of 
every year. Proposed Sec.  207.57(b) is consistent with the timeframes 
set forth in section 510(j)(2) of the act, which requires, among other 
things, that each person who registers must report certain listing 
information ``once during the month of June of each year and once 
during the month of December of each year.'' Under current Sec.  
207.21(b), an update of listing information must occur each June and 
December.
    Under proposed Sec.  207.57(b)(1) through (b)(5), manufacturers, 
repackers, relabelers, and drug product salvagers would, during the 
review and update, submit the following information:
     Listing information would be provided for any drug 
manufactured, repacked, relabeled, or salvaged for commercial 
distribution that has not been previously listed (proposed Sec.  
207.57(b)(1)). The information would be provided in accordance with 
proposed Sec. Sec.  207.49, 207.53, 207.54, and 207.55. This 
information is currently required under section 510(j)(2)(A) of the act 
and current Sec.  207.30(a)(1).
     The date that the manufacture, repacking, relabeling, or 
salvaging for commercial distribution of a listed drug has been 
discontinued would be provided (proposed Sec.  207.57(b)(2)). The date 
of discontinuation is currently required under section 510(j)(2)(B) of 
the act and current Sec.  207.30(a)(2). Section 510(j)(2)(B) of the act 
requires submission of a ``notice of discontinuance.'' We are proposing 
to also require that the expiration date of the last lot manufactured, 
repacked, relabeled, or salvaged be part of proposed Sec.  
207.57(b)(2). This information would enable us to know when a drug is 
no longer marketed and approximately how long the discontinued drug may 
be available for use by consumers.
    We recognize that because of their business practices, drug product 
salvagers may discontinue commercial distribution of a listed drug 
almost immediately after they salvage the drug. Drug product salvagers 
may salvage a drug, put the drug into commercial distribution by 
selling it to a retailer or other party, and then discontinue salvaging 
the drug. In that case, we intend to minimize the reporting burden on 
drug product salvagers by allowing the drug product salvager to provide 
notice of discontinuation of the drug at the same time the drug product 
salvager lists the drug. We would not expect under proposed Sec.  
207.57(b)(2) that the drug product salvager inform us again, during the 
review and update of listing information in either June or December of 
the year, that the salvaged drug is discontinued. Under this proposal, 
we expect that our electronic drug registration and listing system 
would provide the opportunity for drug product salvagers to first list 
a drug, as required by proposed Sec.  207.54, and then indicate that 
they are discontinuing the drug, as required by proposed Sec.  
207.57(b)(2). Because the drug product salvager would have provided the 
lot number and expiration date for the drug under proposed Sec.  
207.54(b)(2), we would not require that same information be submitted 
again under proposed Sec.  207.57(b)(2).
     The date that the manufacture, repacking, or relabeling 
for commercial distribution of a previously discontinued drug has 
resumed and any other listing information not previously required or 
submitted for the drug would be provided (proposed Sec.  207.57(b)(3)). 
This proposed provision is consistent with section 510(j)(2)(C) of the 
act, which requires, among other things, that if a registrant has 
resumed the manufacture, preparation, propagation, compounding, or 
processing of a discontinued drug for commercial distribution, the 
registrant must provide notice and the date of such resumption, the 
established name and proprietary name of the drug, and other listing 
information required under section 510(j)(1) of the act not previously 
provided. The established name and proprietary name would have 
previously been submitted at the time of listing. Because we would be 
able to reference that information in our listing database, 
manufacturers, repackers, and relabelers would not need to resubmit the 
established name and proprietary name. Current Sec.  207.30(a)(3) 
requires, in addition to the date of resumption of commercial 
distribution, that the NDC number, the established name and proprietary 
name, and any other listing information not previously submitted must 
be provided. Under the proposal, this information would not need to be 
provided at this time because we would have access to it from the 
listing database.
    We anticipate that drug product salvagers would not report 
information under proposed Sec.  207.57(b)(3) because we are unaware of 
instances when drug product salvagers resume salvaging a drug that they 
have already salvaged and returned to the marketplace. Drug product 
salvagers salvage a drug and then put the drug into commercial 
distribution by selling it to a retailer or other party. This activity 
ends the drug product salvager's association with that drug. In 
contrast, manufacturers, repackers, and relabelers may resume the 
manufacture, repacking, or relabeling of a drug (usually a different 
lot of the drug) that they had previously listed but are currently not 
manufacturing, repacking, or relabeling. Thus, we anticipate that 
proposed Sec.  207.57(b)(3) would not be applicable to drug product 
salvagers. We invite comment on whether drug product salvagers resume 
salvaging a drug that they have already salvaged and returned to the 
marketplace.
     The June and December review and update of listing 
information would include the submission of all material changes in any 
information previously submitted under Sec.  207.49, Sec.  207.53, 
Sec.  207.54, Sec.  207.55, or Sec.  207.57 (proposed Sec.  
207.57(b)(4)). Current Sec.  207.30(a)(4) requires that any material 
change in any information previously submitted must be reported every 
June and December or, at the discretion of the registrant, when the 
change occurs. Material changes are listed in the definition of ``any 
material change'' in current Sec.  207.3(a)(3). As discussed in section 
IV.A.5 of this document, we are proposing to broaden this definition to 
mean any change in any listing information provided under proposed 
Sec. Sec.  207.49, 207.53, 207.54, 207.55, and 207.57 (except for 
labeling changes in arrangement or printing or of an editorial nature, 
or the inclusion of a bar code or NDC number on the label). Under the 
proposed definition of ``material change,'' the number of changes in 
listing information that are considered ``material'' would include more 
than the five types of changes considered ``material'' in the current 
definition. We are proposing a broader definition of material change 
because, for the reasons explained in section IV.D of this document, 
the accuracy of all listing information is essential for us to maintain 
a reliable and current drug listing database. Proposed Sec.  
207.57(b)(4) is consistent with section 510(j)(2)(D) of the act, which 
requires that each person who registers shall report once during the 
month of June of each year and once during the month of December of 
each year any material change in any information previously submitted 
pursuant to section 510(j)(1) or section 510(j)(2) of the act. Section 
510 of the act does not define ``material change.''
     If no changes have occurred since the last review and 
update of listing information, manufacturers, repackers, relabelers, 
and drug product salvagers would certify that no changes have occurred 
(proposed Sec.  207.57(b)(5)). Proposed Sec.  207.57(b)(5) also 
provides that if a drug is discontinued and we have received the 
information required under proposed Sec.  207.57(b)(2)

[[Page 51314]]

concerning the discontinuation of a listed drug, no further 
certifications would be necessary for the discontinued drug. We are 
proposing to revoke current Sec.  207.30(b), which states that no 
report is required when no changes have occurred since the previously 
submitted list.
    FDA is proposing this certification to ensure that manufacturers, 
repackers, relabelers, and drug product salvagers have reviewed their 
listing information and have determined that there have been no 
changes. There have been many instances where manufacturers, repackers, 
and relabelers have not updated their listing information on a regular 
basis. It has been difficult for us to determine whether failure to 
update listing information is the result of no changes in information 
or noncompliance. The proposed requirement is intended to reduce these 
instances and improve the accuracy of our drug listing database. 
Furthermore, under section 301(p) of the act, it is a prohibited act to 
fail to submit drug listing information under section 510(j) of the 
act. Failure to submit drug listing information would also render a 
drug misbranded under section 502(o) of the act. In addition, the 
proposed requirement to certify is supported by the statutory provision 
in section 701(a) of the act (21 U.S.C. 371(a)) that the Secretary has 
the authority to promulgate regulations for the efficient enforcement 
of the act.
    We specifically request comment on any burden that may result from 
this proposed requirement that manufacturers, repackers, relabelers, 
and drug product salvagers certify that no changes have occurred.
    Current Sec.  207.30(a) provides that the updates to listing 
information must be submitted during each June and December or, at the 
discretion of the registrant, when the change occurs. Although proposed 
Sec.  207.57(b) would require that listing information be reviewed and 
updated only every June and December, we are requesting that 
manufacturers, repackers, relabelers, and drug product salvagers 
provide all updates to listing information within 30 calendar days of a 
change. We are requesting that this information be provided on an 
expedited basis because our listing database will be more accurate if 
listing information is submitted sooner.

E. Electronic Format

1. How Would Registration and Listing Information Be Provided To FDA?
    Under proposed Sec.  207.61(a)(1), the following information 
required under proposed part 207 would be provided to us using our 
electronic drug registration and listing system:
     Establishment registration information required in 
proposed Sec. Sec.  207.25 and 207.29 (proposed Sec.  207.61(a)(1)(i));
     Information required for an NDC number in proposed Sec.  
207.33 (proposed Sec.  207.61(a)(1)(ii)); and
     Drug listing information required in proposed Sec.  207.49 
(except for labeling and advertising information in proposed Sec.  
207.49(g) and (h)), 207.53 (except proposed Sec. Sec.  207.53(d) and 
(e)), 207.54, 207.55, and 207.57 (proposed Sec.  207.61(a)(1)(iii)). As 
explained in section IV.E.7 of this document, the submission of 
establishment registration and drug listing information and information 
required for an NDC number would be made in accordance with 21 CFR part 
11, except for the requirements under Sec.  11.10(b), (c), and (e), and 
the corresponding requirements in Sec.  11.30.
    Proposed Sec.  207.61(a)(2) would require that the content of 
labeling defined in proposed Sec.  207.1 and required under proposed 
Sec.  207.49(g)(1) through (g)(3) be provided to us in electronic 
format. The NDC number would also be provided with\9\ the content of 
labeling for each drug. As explained in section IV.E.7 of this 
document, the submission of the content of labeling would be made in 
accordance with 21 CFR part 11, except for the requirements under Sec.  
11.10(a), (c) through (h), and (k), and the corresponding requirements 
under Sec.  11.30. As explained in section IV.E.4 of this document and 
stated in proposed Sec.  207.49(g), the labeling, including the content 
of labeling, would not be required if the approved U.S. application 
number is provided by the manufacturer when the drug is listed.
---------------------------------------------------------------------------

    \9\ As explained in section IV.E.4 of this document, the NDC 
number may accompany the content of labeling; it does not need to be 
in the content of labeling.
---------------------------------------------------------------------------

    In addition to the electronic submission of information under 
proposed Sec.  207.61(a)(1)(i), (a)(1)(ii), (a)(1)(iii), and (a)(2)), 
advertisements and labeling (other than the content of labeling) 
required under Sec. Sec.  207.49(g) and (h) and 207.53(d) and (e) would 
be provided to us in either paper or electronic format (proposed Sec.  
207.61(a)(3)). The NDC number would also be provided with\10\ the 
advertisements and labeling. As explained in section IV.E.7 of this 
document, the electronic submission of advertisements and labeling, 
other than the content of labeling, would be made in accordance with 
part 11 (21 CFR part 11), except for the requirements under Sec.  
11.10(a), (c) through (h), and (k), and the corresponding requirements 
under Sec.  11.30.
---------------------------------------------------------------------------

    \10\ See footnote 9.
---------------------------------------------------------------------------

    Under proposed Sec.  207.61(a)(4), electronic format submissions 
must be in a form that we can process, review, and archive. As 
explained in section IV.E.6 of this document, we may periodically issue 
guidance on how to provide registration and listing information in 
electronic format (for example, method of transmission, media, file 
formats, preparation and organization of files).
    The electronic submission of the information covered under proposed 
Sec.  207.61(a) would provide a number of advantages over the current 
submission of FDA paper forms:
     We would receive a greater quantity of accurate 
information in less time than it takes to receive information from 
paper submissions. The information received would also be more accurate 
because our electronic drug registration and listing system would 
eliminate errors associated with inputting paper-based data into an 
electronic system.
     The electronic transmission of the information would be 
easier and more efficient for both industry and us than the current use 
of paper forms. For example, you would receive on-screen feedback if 
the information submitted was not complete, reducing errors and the 
time and cost of communicating with us. Similarly, electronic 
transmission of the information would reduce significantly the time and 
cost associated with our processing paper forms and communicating with 
industry concerning errors on those forms.
     Information search and retrieval time would be reduced, 
allowing quicker access to the information in the database.
    The requirement to provide listing information to us electronically 
is consistent with the requirement to list in section 510(j)(1) of the 
act: ``Every person who registers with the Secretary * * * shall * * * 
file with the Secretary a list of all drugs * * *. Such list shall be 
prepared in such form and manner as the Secretary may prescribe * * 
*.'' The requirement to provide registration information to us 
electronically is consistent with section 510(p) of the act: 
``Registrations * * * (including the submission of updated information) 
shall be submitted to the Secretary by electronic means, upon a finding 
by the Secretary that the electronic receipt of such registrations is 
feasible * * *.'' Persons who register are also required to list drugs 
which are being manufactured, prepared,

[[Page 51315]]

propagated, compounded, or processed for commercial distribution (21 
U.S.C. 510(j)(1)).
2. What Was the Electronic Submission Pilot Project?
    In the Federal Register of January 9, 2001 (66 FR 1684), we 
requested volunteers to participate in a pilot project involving the 
electronic submission of registration and listing information. In a 
September 2001 meeting/teleconference with the pilot project 
volunteers, we provided information on the major functions of the 
electronic drug registration and listing system, including instructions 
on the installation, setup, and testing of the systems. The pilot test 
was held from October 19, 2001, through November 9, 2001, and 
approximately 28 industry representatives voluntarily participated.
    As mentioned previously, our electronic drug registration and 
listing system is expected to be a Web-enabled, integrated system that 
provides controlled database access for you to register establishments 
and list drugs. A separate capability--an extranet--could be used that 
authenticates external users and controls their access to the our 
online registration and listing database. This system would allow you 
to create user accounts and manage additional users.
    Industry representatives accessed the pilot test through our 
extranet to perform the following functions: (l) Initial company setup 
and establishment registration; (2) registration of additional 
establishments; (3) drug listing; (4) updates; and (5) system access, 
logoff, and exit. The pilot test included installation, setup, and 
operational testing of our electronic drug registration and listing 
system.
    The pilot test was intended to get direct input from the pilot 
participants about the usability and functionality of the system. The 
pilot test provided feedback to us on:
     The pilot participants' experience in submitting and 
preparing registration and listing data.
     Web browsers used.
     Acceptability of proposed normal operating hours.
     Page layout and design.
     Ease of navigation within pages and between functions.
     Whether error messages provide sufficient information to 
resolve the error.
     The appropriateness of the style, content, and depth of 
detail of the onpage help.
    The comments we received on our electronic drug registration and 
listing system were generally positive. Those who volunteered to 
participate in the pilot test were able to successfully access the 
system, set up a company account within the system, register 
establishments, and list drugs. Pilot participants encountered a few 
one-time difficulties that we will address, including minor password 
problems and difficulties completing the initial company setup and 
establishment registration process.
    We are using information from the pilot program to develop our 
electronic system.
3. How Would the Electronic Drug Registration and Listing System Work?
    Electronic format submissions of registration and listing 
information, as well as information required for an NDC number, would 
consist of the electronic transmission via the Internet of the required 
information from manufacturers, repackers, relabelers, and drug product 
salvagers into our electronic drug registration and listing system.
    Our electronic drug registration and listing system would be made 
available using an Internet-based data collection system accessed 
through our FDA Internet site.
     To use the Web site, you would need access to the Internet 
using a browser.
     You could arrange for Internet access through one of many 
available Internet Service Providers (ISPs).
     You would need an e-mail address so we can send you 
confirmation of submissions and other related information.
     This e-mail service could be provided by the ISP or by 
other sources.
    Prior to accepting registration and listing information from this 
online system, we would authenticate the source (that is, the 
manufacturer, repacker, relabeler, or drug product salvager) providing 
the data.
     We could, for example, authenticate entry into the 
electronic drug registration and listing system by establishing user 
accounts based on current registration information.
     We anticipate that we may contact manufacturers, 
repackers, relabelers, and drug product salvagers to obtain contact 
information to establish an administration account.
    To register and list electronically, to provide updated 
registration and listing information, and to provide information to 
obtain an NDC number, you would go to our Web site and follow the 
prompts.
     You could sign onto the system by entering the account 
number, user name, and password obtained by following the procedures in 
the guidance we intend to issue on our electronic drug registration and 
listing system, as discussed in section IV.E.6 of this document.
     You would then be prompted to provide general information 
about your company and then specific information about each 
establishment and drug as required in proposed part 207.
     When all of the required information is provided, your 
official contact would receive confirmation electronically that the 
information has been received by us.
     If you provide information to obtain an NDC number, the 
number could be issued electronically.
4. What Are the Proposed Requirements for the Submission of Content of 
Labeling in Electronic Format?
    Under proposed Sec.  207.61(a)(2), the content of labeling would be 
provided to us in an electronic format. The electronic submission of 
the content of labeling would permit us to electronically review, 
compare, and extract data from the labeling.
    The content of labeling would be submitted in electronic format for 
the following drugs:
     Human prescription drugs;
     Human OTC drugs, including those that the manufacturer 
regards as subject to section 505 of the act or section 351 of the 
Public Health Service Act as well as those regarded as not subject to 
sections 505 or 351; and
     Animal drugs, including those that the manufacturer 
regards as subject to section 512 of the act as well as those regarded 
as not subject to section 512.
    The ``content of labeling'' is defined in proposed Sec.  207.1 (and 
discussed in section IV.A.5 of this document) to mean:
     For human prescription drugs that the manufacturer regards 
as subject to section 505 of the act or section 351 of the Public 
Health Service Act: The content of the prescription drug labeling (as 
specified in Sec. Sec.  201.56, 201.57, and 201.80 of this chapter), 
including all text, tables, and figures.
     For human prescription drugs that the manufacturer regards 
as not subject to section 505 of the act or section 351 of the Public 
Health Service Act: The labeling equivalent to the content of the 
prescription drug labeling (as specified in Sec. Sec.  201.56, 201.57, 
and 201.80 of this chapter), including all text, tables, and figures.
     For human OTC drugs: The content of the drug facts 
labeling required by Sec.  201.66 of this chapter, including all text, 
tables, and figures.

[[Page 51316]]

     For animal drugs (including, but not limited to, drugs 
that the manufacturer regards as subject to section 512 of the act): 
The content of the labeling that accompanies the drug that is necessary 
to enable the safe and proper administration of the drug (e.g., the 
labeling specified in Sec. Sec.  201.1 and 201.5 of this chapter), 
including all text, tables, and figures.
    The proposed requirement to provide the content of labeling 
electronically is consistent with (among other things) that part of the 
listing requirement in section 510(j)(1) of the act which states that 
``Such list shall be prepared in such form and manner as the Secretary 
may prescribe.'' The proposed requirement to submit the content of 
labeling for human prescription drugs, human OTC drugs, and animal 
drugs is consistent with the statutory requirements of section 
510(j)(1)(A), (j)(1)(B)(i), and (j)(1)(B)(ii) of the act. Section 
510(j)(1)(A) of the act requires, among other things, the submission of 
a copy of all labeling for drugs subject to sections 505 or 512 of the 
act. Section 510(j)(1)(B)(i) requires, among other things, the 
submission of a copy of all labeling for prescription drugs not subject 
to section 505 or 512 of the act. Section 510(j)(1)(B)(ii) requires, 
among other things, the submission of the label, package insert, and 
representative sampling of any other labeling for OTC drugs not subject 
to section 505 or 512 of the act.
    We are proposing that manufacturers provide the NDC number 
electronically with the content of labeling during listing so that we 
can more easily link the content of labeling to the listed drug and, 
thus, expedite the listing process. The NDC number may accompany the 
content of labeling by being referenced, for example, in the 
transmittal message to us that contains the content of labeling. The 
NDC number does not need to be on the content of labeling.
    As discussed in greater detail in section IV.D.4 of this document, 
we are proposing that you need not submit the content of labeling for 
human prescription or OTC drugs approved under section 505 of the act 
or section 351 of the PHS Act if you provide the application number 
when listing the drug or requesting an NDC number for the drug. 
Incorporating the content of labeling by reference to the application 
number would eliminate unnecessary duplication of effort and cost to 
industry.
    The submission of the content of labeling in an electronic format 
would assist us in several ways:
     The use of computer technology to identify changes in 
different versions of the labeling would greatly enhance our accuracy 
and efficiency in updating our listing database.
     Our ability to protect the public health would be enhanced 
because electronic review and comparison of labeling files would 
provide a higher degree of certainty that all portions of the labeling 
are consistent and up to date.
     Our ability to protect the public health would be enhanced 
because we could provide and make easily accessible up-to-date product 
labeling through the DailyMed initiative, as described in section 
IV.C.2 of this document.
     Our ability to protect the public health would be enhanced 
by supporting the implementation of the electronic prescribing 
provisions of the Medicare Modernization Act. The product labeling 
information we would make available through DailyMed would be 
associated with the unique NDC number for each drug, supporting 
electronic prescribing.
     In the future, the electronic submission of the content of 
labeling would enable us to receive much of the drug listing 
information through the labeling, thus improving efficiency in the drug 
registration and listing system. Industry would be able to satisfy many 
drug listing requirements through the submission of the content of 
labeling.
    The proposed requirement to provide the content of labeling would 
not significantly burden industry because labeling is maintained in 
electronic format by most manufacturers. In addition, our proposal 
seeks to limit industry costs by avoiding unnecessary duplication of 
effort--for example, as mentioned previously, if the content of 
labeling has already been submitted in an approved application, 
supplement, or annual report, the manufacturer would only have to 
reference the application number to comply with this listing 
requirement. In addition, only the manufacturer would be required to 
submit the content of labeling.
    We would require, under proposed 207.61(a)(4), that the information 
in electronic format be submitted in a form we can process, review, and 
archive. We are prepared at this time to receive the content of 
labeling as a portable document format (PDF) file that is searchable. 
Using commercially available software, an electronic source document 
created by any number of programs (for example, word processors and 
desktop publishing programs) can be converted to a PDF file, preserving 
the fonts, formatting, and graphics of the source document, regardless 
of the application and platform used to create it. The PDF file can be 
copied onto a disk or CD-ROM and shared with other users who can use 
PDF reading software to view, navigate through, and print the document, 
as well as view, search, and print the file, and copy text, tables, and 
figures from the file.
    However, to be responsive to technological advances, we may 
recommend in the future that new file formats such as extensible markup 
language and software applications be used to submit labeling 
electronically. The language in proposed Sec.  207.61(a)(4), that 
electronic format submissions must be in a form that we can process, 
review, and archive, will provide us with the flexibility to recommend 
file formats or software other than PDF, if appropriate, such as SPL 
(described earlier in sections III.B and IV.C.2 of this document). We 
will provide advance notice, in accordance with FDA's good guidance 
practice regulations under Sec.  10.115 (21 CFR 10.115), so that 
affected parties will have adequate time to convert to any new format 
or software. In addition, we expect that such format or software will 
be widely available before we switch to a new technology. Changes in 
format and/or software will be identified in public docket number 92S-
0251.\11\ During any such transition, we will accept submissions using 
either file format or software.
---------------------------------------------------------------------------

    \11\ This docket may be accessed on the Internet at http://www.fda.gov/ohrms/dockets.
---------------------------------------------------------------------------

5. Would the Proposal Require Electronic Submission of Advertisements 
and Other Labeling?
    Under proposed Sec.  207.61(a)(3), advertisements and labeling, 
other than the content of labeling, required under proposed Sec. Sec.  
207.49(g) and (h) and 207.53(d) and (e) would be provided to us in 
paper or electronic format. Information on how and where to send 
labeling and advertisements that are not provided electronically will 
be described in the guidance document we intend to develop, as 
discussed in section IV.E.6 of this document. Although we are proposing 
to require that only registration and listing information, information 
submitted to receive an NDC number, and the content of labeling need be 
submitted in electronic format, we expect to identify in public docket 
number 92S-0251 copies and samples of labeling and advertisements as 
types of documents we accept in electronic format. Under the proposal, 
you would have the option of submitting advertisements and labeling 
either electronically or in paper.

[[Page 51317]]

    The proposed requirement to submit advertisements is consistent 
with section 510(j)(1)(B)(i) of the act, which requires, among other 
things, the submission of a representative sampling of advertisements 
and, upon request, a copy of all advertisements for prescription drugs 
not subject to section 505 of the act. The proposed requirement to 
submit labeling is, as explained previously, consistent with the 
statutory requirements of section 510(j)(1)(A), (j)(1)(B)(i), and 
(j)(1)(B)(ii) of the act.
6. What Guidance Documents Do We Intend To Issue on Providing 
Registration and Listing Information Electronically?
    We plan to publish draft guidance and technical specifications on 
the electronic submission of registration and listing information 
through our electronic drug registration and listing system (the draft 
guidance). The draft guidance and technical specifications will explain 
the electronic process for providing registration and listing 
information and for providing the information that would be required to 
obtain an NDC number, including step-by-step instructions on entering 
information required under proposed part 207. We are also planning to 
issue guidance on providing registration and listing information in 
electronic format (concerning the method of transmission, media, file 
formats, and preparation and organization of files), and this guidance 
will be updated regularly to reflect the evolving nature of the 
technology.
    In addition to the draft guidance and the guidance on providing 
registration and listing information in electronic format under 
development, we have issued other guidances that explain the process 
for submitting information to us in electronic format. These guidance 
documents are available at FDA's Web site http://www.fda.gov/cder/guidance/index.htm under the heading ``Electronic Submissions.''
7. How Would Part 11 Apply to the Electronic Submission of Registration 
and Listing Information?
    Under proposed Sec.  207.61(a)(1), the submission of registration 
and listing information (except for the content of labeling and 
advertisements and labeling) and the information required to receive an 
NDC number would be made in accordance with part 11, except for the 
requirements under Sec.  11.10(b), (c), and (e) and the corresponding 
requirements under Sec.  11.30. Under proposed Sec.  207.61(a)(2) and 
(a)(3), the submission of the content of labeling, and advertisements 
and other labeling in electronic format, would be made in accordance 
with part 11, except for the requirements under Sec.  11.10(a), (c) 
through (h), and (k), and the corresponding requirements under Sec.  
11.30. In the Federal Register of March 20, 1997 (62 FR 13430), we 
published regulations on electronic records and electronic signatures 
(part 11). Part 11 regulations, among other things, set forth the 
criteria under which records submitted to us may be submitted in 
electronic format in lieu of paper records. Section 11.2(b) states 
that, for records submitted to us, persons may use electronic records 
in lieu of paper records, in whole or part, provided the requirements 
of part 11 are met and the documents or parts of documents to be 
submitted have been identified by us in public docket number 92S-0251 
as being the type of submission we are prepared to accept in electronic 
format.
    Part 11 permits the widest possible use of electronic technology, 
compatible with our responsibility to promote and protect the public 
health (62 FR 13430). Part 11 helps to ensure the authenticity, 
integrity, and, when appropriate, the confidentiality of electronic 
records. Part 11 also helps to safeguard against the possible 
repudiation of those records. The controls in subpart B of part 11 are 
intended to further this purpose.
    We recently announced in the Federal Register our current thinking 
on part 11. In the Federal Register of September 5, 2003 (68 FR 52779), 
we announced the availability of a guidance for industry entitled 
``Part 11, Electronic Records; Electronic Signatures--Scope and 
Application'' (the part 11 guidance). The part 11 guidance explains our 
current thinking regarding the requirements and application of part 11 
and states that we intend to exercise enforcement discretion in the 
manner specified in the guidance with respect to the validation (Sec.  
11.10 (a)), audit trail (Sec. Sec.  11.10(e) and (k)(2)), record 
retention (Sec.  11.10(c)), and copies of records (Sec.  11.10(b)) 
requirements of part 11, and any corresponding requirements in Sec.  
11.30. In addition, we announced that we intend to exercise enforcement 
discretion and do not intend to take (or recommend) action to enforce 
any part 11 requirements with regard to systems that were operational 
before August 20, 1997, the effective date of part 11 (commonly known 
as legacy systems) under the circumstances described in section III.C.3 
of the part 11 guidance. Although we explain the relationship between 
the part 11 guidance and this proposal, as discussed below, you should 
refer to the guidance we intend to issue on electronic registration and 
listing for information on complying with part 11 when providing 
registration and listing information electronically. The part 11 
requirements from which we propose exemptions in this proposal differ 
from the part 11 requirements for which we intend to exercise 
enforcement discretion, as described in the part 11 guidance. They 
differ because the proposed exemptions in this rule are specific to the 
electronic submission of registration and listing information, 
including information that must be submitted to receive an NDC number 
and the content of labeling, for drugs that would be covered under 
proposed part 207, whereas the part 11 draft guidance applies to the 
maintenance of all electronic records and to all electronic submissions 
subject to part 11.
    With respect to the electronic submission of registration and 
listing information, including the information required to receive an 
NDC number but not including the content of labeling and advertisements 
and other labeling, as previously noted, we believe, as provided in 
proposed Sec.  207.61(a)(1), that several of the requirements in 
subpart B of part 11 are not necessary to further the goals of part 11. 
Because we control the electronic drug registration and listing system, 
certain controls for systems would not apply to the submission of 
registration and listing information, such as:
     The ability to generate accurate and complete copies of 
records in both human readable and electronic form suitable for 
inspection, review, and copying by the agency (Sec.  11.10(b));
     The protection of records to enable their accurate and 
ready retrieval throughout the records retention period (Sec.  
11.10(c));
     The use of secure, computer-generated, time-stamped audit 
trails to independently record the date and time of operator entries 
and actions that create, modify, or delete electronic records (Sec.  
11.10(e)); and
     The corresponding controls of Sec.  11.30.
You would be exempt from these subpart B controls because our 
registration and listing database is designed to ensure the 
authenticity, integrity, and confidentiality of this information in 
several ways. For example, we would control the database, and you would 
only be able to enter and/or revise information in your own account. In 
addition, the database would contain records of registration and 
listing information, and we could generate accurate and complete copies 
of records.

[[Page 51318]]

    With respect to the electronic submission of the content of 
labeling and advertisements and other labeling, as previously noted, we 
believe, as provided in proposed Sec.  207.61(a)(2) and (a)(3), that 
several of the requirements in subpart B of part 11 are not necessary 
to further the goals of part 11. For the reasons described below, 
certain controls for systems would not apply to the submission of the 
content of labeling and advertisements and other labeling, such as:
     The validation of systems to ensure accuracy, reliability, 
consistent intended performance, and the ability to discern invalid or 
altered records (Sec.  11.10(a));
     The protection of records to enable their accurate and 
ready retrieval throughout the records retention period (Sec.  
11.10(c));
     Limiting system access to authorized individuals(Sec.  
11.10(d));
     The use of secure, computer-generated, time-stamped audit 
trails to independently record the date and time of operator entries 
and actions that create, modify, or delete electronic records (Sec.  
11.10(e));
     The use of operational system checks to enforce permitted 
sequencing of steps and events, as appropriate (Sec.  11.10(f));
     The use of authority checks to ensure that only authorized 
individuals can use the system, electronically sign a record, access 
the operation or computer system input or output device, alter a 
record, or perform the operation at hand (Sec.  11.10(g));
     The use of device checks to determine, as appropriate, the 
validity of the source of data input or operational instruction (Sec.  
11.10(h));
     The use of appropriate controls over certain systems 
documentation (Sec.  11.10(k));and
     The corresponding controls of Sec.  11.30.
    We are proposing to exempt the submission of electronic content of 
labeling from certain part 11 requirements because we believe these 
part 11 requirements are not critical to ensure the quality of the 
content of labeling that would be submitted under this proposed rule 
and we do not think it is necessary for industry to expend resources on 
controls that are not necessary to further the goals of part 11. For 
example, validation for the system used to generate the labeling record 
is not necessary because the manufacturer's verification that the 
information in the labeling record is accurate serves the same 
objective. Our review of the content of labeling is based on the 
version of the labeling record submitted to us. Earlier versions of the 
record, as well as changes made to the earlier versions, are not 
relevant to our analysis. In addition, our registration and listing 
database is designed to ensure the authenticity, integrity, and 
confidentiality of this information. As mentioned, we would control the 
database, you would only be able to enter and/or revise information in 
your own account, and the database would contain records of the 
information from which we could generate accurate and complete copies. 
Thus, controls related to the creation, modification, and maintenance 
of the content of labeling are not needed.
    For the content of labeling and advertisements and other labeling, 
we recognize that there are some differences with respect to the 
exemptions from part 11 requirements provided in this proposal (that 
is, Sec.  11.10(a), (c) through (h), and (k), and the corresponding 
requirements of Sec.  11.30), and the part 11 requirements set forth in 
the part 11 guidance for which we intend to exercise enforcement 
discretion (that is, Sec.  11.10(a) through (c), (e), and (k)(2), and 
any other corresponding requirements in Sec.  11.30)). Although the 
proposal does not provide an exemption from Sec.  11.10(b) for the 
content of labeling and advertisements and other labeling, the part 11 
guidance announces that we intend to exercise enforcement discretion 
with respect to that section in the manner described in the guidance.
    If this proposed rule is finalized, we intend to identify in docket 
number 92S-0251 the registration and listing information and the 
content of labeling specified previously as the types of records that 
we are prepared to accept in electronic format.
8. What Language Would Be Used to Provide Registration and Listing 
Information?
    Under proposed Sec.  207.61(b), we would require that all 
registration and listing information be submitted in the English 
language. We are also proposing that labeling be submitted in the 
English language except, as provided under current 21 CFR 201.15(c), 
when drugs are distributed solely in the Commonwealth of Puerto Rico or 
in a Territory where the predominant language is one other than 
English. In those instances, the predominant language may be 
substituted for English. We are proposing Sec.  207.61(b) because 
providing information in languages other than English would lead to 
problems using the registration and listing computerized database and 
problems with our review of registration and listing information and 
the content of labeling. Foreign establishments are currently required 
to submit all registration and listing information in the English 
language under current Sec.  207.40(b). Because all domestic 
manufacturers, repackers, relabelers, and drug product salvagers 
currently submit this information in English, and because foreign 
establishments are already subject to this requirement, we do not 
believe the proposed requirement would increase the burden on industry.
9. Could the Electronic Format Requirements Be Waived?
    Under proposed Sec.  207.65, manufacturers, repackers, relabelers, 
and drug product salvagers may request a waiver from the proposed 
requirement in Sec.  207.61(a) that information be provided to us in 
electronic format. This proposed waiver provision is consistent with 
the Medical Device User Fee and Modernization Act of 2002 (Public Law 
107-250) which amended section 510 of the act to add section 510(p) to 
explicitly give the Secretary discretion to require the electronic 
submission of registration information upon a finding that electronic 
receipt of such registration information is feasible, unless the 
Secretary grants a request for a waiver because the use of electronic 
means is not reasonable for the person requesting the waiver. Under 
proposed Sec.  207.65, we may grant a waiver request if the 
manufacturer, repacker, relabeler, or drug product salvager does not 
have an e-mail address and access to a computer and an ISP that can 
access our Web-based registration and listing database and communicate 
with us. The request must include a telephone number and/or mailing 
address where we can contact the person making the request. We intend 
to provide the mailing address for submitting a waiver request in the 
draft guidance and technical specifications on the electronic 
submission of registration and listing information.
    We do not anticipate many waiver requests because the expenses 
associated with owning a personal computer, obtaining an e-mail 
address, and subscribing to Internet access are low. If owning a 
computer is not possible, however, only access to a computer and an ISP 
as well as having an e-mail address would be needed to input 
information electronically in accordance with the registration and 
listing requirements under this part, including the requirements for 
obtaining an NDC number. There would be no need for you to maintain 
data files on disks or other formats; all data would be

[[Page 51319]]

maintained in our database and accessed electronically via the 
Internet. We would control the database and the information contained 
in it, and you would only enter new information and/or revise your own 
previously submitted information.
    In those instances when we grant a request for a waiver, we would 
provide information on how to submit registration and/or listing 
information. One option may be to make available a paper form for 
submitting the required registration and listing information (including 
the information required to obtain an NDC number).

F. Miscellaneous

1. What Are the Proposed Requirements for an Official Contact and a 
United States agent?
    Under proposed Sec.  207.69(a), manufacturers, repackers, 
relabelers, and drug product salvagers that are subject to the 
registration requirements in proposed part 207 would designate an 
official contact for each establishment. The official contact would be 
responsible for:
     Ensuring the accuracy of registration and listing 
information; and
     Reviewing, disseminating, routing, and responding to 
communications from us.
    We are proposing to require an official contact to facilitate 
communications between you and us and to help ensure compliance with 
the registration and listing requirements. On numerous occasions, we 
have found it difficult to contact certain manufacturers, repackers, 
relabelers, and drug product salvagers to discuss registration and 
listing issues.
    In addition to the proposed requirement to designate an official 
contact, each foreign manufacturer, foreign repacker, foreign 
relabeler, and foreign drug product salvager would be required, under 
proposed Sec.  207.69(b), to designate a single United States agent. 
The United States agent would be responsible for:
     Helping us communicate with the foreign manufacturer, 
foreign repacker, foreign relabeler, and foreign drug product salvager;
     Responding to questions concerning those drugs that are 
imported or offered for import to the United States; and
     Helping us schedule inspections.
    We would not object if the same individual serves as both the 
United States agent and the official contact for a foreign 
manufacturer, foreign repacker, foreign relabeler, or foreign drug 
product salvager, or if the same individual serves as the United States 
agent for more than one foreign manufacturer, foreign repacker, foreign 
relabeler, or foreign drug product salvager.
    We are proposing that each foreign manufacturer, foreign repacker, 
foreign relabeler, and foreign drug product salvager designate a single 
United States agent. (We note, however, the United States agent may be 
a company comprised of more than one person). As we explained in the 
final rule entitled ``Foreign Establishment Registration and Listing'' 
(66 FR 59138 at 59140), we interpret section 510(i) of the act as 
allowing only one United States agent for each foreign establishment 
because section 510(i) of the act refers to the United States agent in 
singular, rather than plural, terms. We also explained in that final 
rule (66 FR 59138 at 59141) that we interpret section 510(i) of the act 
as requiring that the United States agent must be in the United States. 
These proposed provisions are also consistent with the use of ``U.S. 
agent'' in the interim final rule entitled ``Registration of Food 
Facilities Under the Public Health Security and Bioterrorism 
Preparedness Act of 2002'' (68 FR 58894 at 58915, October 10, 2003).
    Currently, the provisions concerning a United States agent, as well 
as other requirements for foreign manufacturers, foreign repackers, 
foreign relabelers, or foreign drug product salvagers, are set forth 
under Sec.  207.40. In addition, current Sec.  207.3(a)(11) defines 
United States agent as a person residing or maintaining a place of 
business in the United States whom a foreign establishment designates 
as its agent. The definition states that ``United States agent'' 
excludes mailboxes, answering machines or services, or other places 
where an individual acting as the foreign establishment's agent is not 
physically present. We are proposing to revoke current Sec. Sec.  
207.3(a)(11) and 207.40 and include these requirements (as revised), 
for example, under proposed Sec. Sec.  207.1, 207.9, 207.13, 207.17, 
207.33, 207.41, 207.61, and 207.69.
    Under proposed Sec.  207.69(b)(2) through (b)(4), the United States 
agent would be required to reside or maintain a place of business in 
the United States. A United States agent may not be a mailbox, 
answering machine or service, or other place where a person acting as 
the United States agent is not physically present. If we are unable to 
contact the foreign manufacturer, foreign repacker, foreign relabeler, 
or foreign drug product salvager directly or expeditiously, we may 
provide information or documents to the United States agent, which we 
would consider equivalent to providing the same information or 
documents to the foreign manufacturer, foreign repacker, foreign 
relabeler, or foreign drug product salvager.
    We are proposing the requirements for a United States agent to 
facilitate communications between you and us and to help ensure 
compliance with the registration and listing requirements. On numerous 
occasions, we have found it difficult to contact certain foreign 
manufacturers, foreign repackers, foreign relabelers, and foreign drug 
product salvagers, resulting in their drugs being detained because 
certain registration and/or listing issues have not been resolved.
2. What Legal Status Is Conferred by Registration and Listing?
    Under proposed Sec.  207.77(a), registration of an establishment or 
listing of a drug does not denote approval of the establishment, the 
drug, or other drugs of the establishment, nor does it mean that a 
product may be legally marketed. Any representation that creates an 
impression of official approval or that a drug is approved or is 
legally marketable because of registration or listing would be 
misleading and would constitute misbranding under section 502 of the 
act. To clarify and consolidate current regulations, we are proposing 
to revise and move a similar provision in current Sec.  207.39 to 
proposed Sec. Sec.  207.77(a) and 207.37. Current Sec.  207.39 states 
that registration of a drug establishment or drug wholesaler, 
assignment of a registration number, or assignment of an NDC number 
does not in any way denote approval of the firm or its products. Any 
representation that creates an impression of official approval because 
of registration or possession of a registration number or NDC number is 
misleading and constitutes misbranding. The registration provisions in 
current Sec.  207.39 would be included in proposed Sec.  207.77(a), and 
the NDC number provisions in current Sec.  207.39 would be included in 
proposed Sec.  207.37. Proposed Sec.  207.37(c) states that the NDC 
number must not be used to denote FDA approval of that drug. We are 
proposing to include in proposed Sec.  207.77(a) that listing a drug 
would not denote approval of the drug and that any such representation 
would be misleading and constitute misbranding.
    Under proposed Sec.  207.77(b), assignment of an establishment 
registration number, inclusion of a drug in our database of drugs, or 
assignment of an NDC number does not denote approval of the 
establishment or the

[[Page 51320]]

drug or any other drugs of the establishment, nor does it mean that the 
drug may be legally marketed. Any representation that creates an 
impression that a drug is approved or is legally marketable because it 
appears in our database of drugs, has been assigned a NDC number, or 
the establishment has been assigned an establishment registration 
number, is misleading and constitutes misbranding. Failure to comply 
with proposed Sec.  207.37 also constitutes misbranding. We are 
proposing to add this provision to clarify that a drug's marketing 
approval status is determined, for example, under section 505 or 512 of 
the act, section 351 of the PHS Act, and parts 314, 514 (21 CFR part 
514), and 601 of the regulations, and not under section 510 of the act 
or part 207 of the regulations.
    Under proposed Sec.  207.77(c), neither registration nor listing 
constitutes a determination by FDA that a product is a drug as defined 
by section 201(g)(1) of the act. This provision reflects a revision and 
relocation of current Sec.  207.20(e) to proposed Sec.  207.77(c). 
Current Sec.  207.20(e) states that registration and listing do not 
constitute an admission, agreement, or determination that a product is 
a drug as defined under section 201(g) of the act. Proposed Sec.  
207.77(c) also states that registration and listing may be evidence 
that a facility is manufacturing, repacking, relabeling, or salvaging 
drugs or that a product is a drug. Thus, the proposed rule revises 
current Sec.  207.20(e) such that, while neither registration nor 
listing constitutes a determination by FDA that a product is a drug as 
defined by the act, registration and listing may be evidence that a 
facility is manufacturing, repacking, relabeling, or salvaging drugs or 
that a product is a drug.
    FDA is proposing to delete the statement in current Sec.  207.35(c) 
that validation of registration and the assignment of a drug listing 
number do not, in themselves, establish that the holder of the 
registration is legally qualified to deal in such drugs. As explained 
in sections IV.B and IV.C of this document, FDA is proposing to 
discontinue the validation of registration. As explained previously in 
this document, the provision on the legal status of registration and 
listing is included in proposed Sec.  207.77, and proposed Sec.  
207.37(c) sets forth restrictions pertaining to the use of the NDC 
number (e.g., the NDC number must not be used to denote FDA approval of 
the drug).
3. What Registration and Listing Information Would Be Made Available 
for Public Disclosure?
    Current Sec.  207.37 pertains to the public availability of 
registration and listing information. Proposed Sec.  207.81 would 
revoke, in part, and revise current Sec.  207.37. The heading 
``Inspection of registrations and drug listings'' in current Sec.  
207.37 would be changed to ``What registration and listing information 
will we make available for public disclosure?'' This heading would more 
accurately describe the scope of the provision in that the provision 
relates to the type of registration and listing information that we 
intend to make available for public disclosure.
    The proposal would revoke the introductory text of current Sec.  
207.37(a), which includes a description of the types of forms available 
for inspection, the addresses at which such forms can be inspected, and 
the addresses that requests for verification of registration numbers 
and requests for locations of registered establishments can be 
directed. We are proposing to revoke this introductory text because 
these forms would no longer be used under the proposed scheme. Instead, 
we intend to make most information that is available for public 
disclosure accessible via the Internet. This initiative would be 
consistent with the GPEA and would also help to reduce the number of 
Freedom of Information Act (5 U.S.C. 552) requests we receive for 
registration and listing information. Accordingly, we are also 
proposing to revoke current Sec.  207.37(b), which sets forth the 
address to which requests for information about drug registration and 
listing can be directed. We note that persons may still submit Freedom 
of Information Act requests to the agency for drug registration and 
listing information that is not available on the Internet.
    Current Sec.  207.37(a)(1) sets forth 11 categories of information 
that, when compiled, will be available for public disclosure. Proposed 
Sec.  207.81(a) would simplify this section to reference the following 
information as generally available for public disclosure: All 
registration information and, after a drug is listed, all information 
obtained for that drug under proposed Sec. Sec.  207.33, 207.49, 
207.53, and 207.54, except for that information obtained under proposed 
Sec. Sec.  207.33(d)(1)(ii) and 207.54(b)(1) or the information that 
would otherwise be exempt from disclosure under proposed Sec.  
207.81(b) or (c).
    Proposed Sec.  207.81(a) would add registration information to the 
list of the types of information that would generally be considered to 
be publicly available. Registration information is currently available 
for public inspection as referenced in Sec.  207.37(a).
    For various reasons, proposed Sec.  207.81(a) would not include 
certain specific categories of information that are listed in current 
Sec.  207.37. The provision relating to a list of all drug products 
arranged by labeled indications or pharmacological category would not 
be included in the proposal because we currently do not compile or 
index drug registration and listing information by labeled indication. 
The provisions related to a list of drug products newly marketed or for 
which marketing is resumed, a list of drug products discontinued, and 
information that has become a matter of public knowledge would be 
deleted because these categories of information would also be 
disclosable under the general provision of proposed Sec.  207.81(a).
    We are proposing to exempt proposed Sec. Sec.  207.33(d)(1)(ii) and 
207.54(b)(1) from proposed Sec.  207.81(a) because this information may 
disclose a business relationship between the manufacturer, repacker, 
relabeler, or drug product salvager and the business from which they 
obtained the drug, and may constitute commercial or financial 
information that is exempt from public disclosure under Sec.  20.61(c). 
We are proposing to exempt from public disclosure the information 
collected under proposed Sec.  207.33(d)(1)(ii), which would require 
that repackers or relabelers, to obtain an NDC number, must provide, 
among other things, the NDC number assigned to the drug immediately 
before the drug is received by the repacker or relabeler. We also are 
proposing to exempt from public disclosure the information collected 
under proposed Sec.  207.54(b)(1), which would require that drug 
product salvagers, to list a drug, must provide, among other things, 
the NDC number assigned to the drug immediately before the drug is 
received by the drug product salvager.
    In addition to these changes, the proposal would make some 
fundamental changes to the disclosure provision in current Sec.  
207.37. We are proposing to add one category of listing information to 
the list of information that would generally be regarded as publicly 
available information. Specifically, proposed Sec.  207.81 generally 
would make available for public disclosure a drug product's inactive 
ingredients when provided under Sec.  207.33(c)(2)(ii) and (c)(3). When 
the firm provides the approved application number, we can link to the

[[Page 51321]]

application and retrieve the names of the inactive ingredients included 
in the approved application. We will then make the names of the 
inactive ingredients available to consumers unless they are subject to 
trade secret protection, as discussed below. Proposed Sec.  207.81 
would change the current provision in Sec.  207.37(a)(2). Current Sec.  
207.37(a)(2)(ii) and (a)(2)(iii) provide that information on inactive 
ingredients will not be available for public disclosure (except that 
any of the information will be available for public disclosure if it 
has become a matter of public knowledge or if we find that it would be 
inconsistent with the protection of the public health).
    We are proposing, under Sec.  207.33(c)(2)(ii), to give 
manufacturers the opportunity at the time of listing to identify 
inactive ingredients that they consider trade secret. Information 
identified by the applicant as trade secret would not be routinely 
posted on the Internet. Public disclosure of inactive ingredients not 
designated as trade secret at the time of listing would be authorized 
by the proposed regulations. We would evaluate claims of trade secret 
protection based on the definition of a trade secret in Sec.  20.61(a) 
when making disclosure decisions in response to requests made under the 
Freedom of Information Act for this information and would withhold the 
information from public disclosure, when appropriate, under Sec.  
207.81(c). This evaluation is consistent with how FDA evaluates 
requests asking for inactive ingredient information that is included in 
approved U.S. applications. When manufacturers submit the approved 
application number instead of listing inactive ingredients under 
proposed Sec.  207.33(c)(2)(ii), they similarly would need to identify 
any inactive ingredients they considered to be trade secret. Proposed 
Sec. Sec.  207.33(c)(2)(ii), 207.81(a), and 207.81(c) would strike a 
balance between manufacturers' commercial interests and the fact that 
it would generally be inconsistent with protection of the public health 
to withhold inactive ingredient information. We expect that 
manufacturers would only avail themselves of the opportunity to claim 
trade secret protection in extremely limited circumstances. We note 
that information in a drug's labeling, including the names of inactive 
ingredients, is not trade secret information.
    The proposal to add information about inactive ingredients to the 
list of categories considered to be public information is also 
consistent with section 510(f) of the act. Section 510(f) of the act 
generally provides that listing information shall be exempt from 
inspection unless the Secretary finds that such an exemption would be 
inconsistent with protection of the public health. We find that 
exempting, among other things, a list of inactive ingredients from 
public disclosure would be inconsistent with the protection of the 
public health. It is important for consumers to know the inactive 
ingredients of the drugs they might be taking because such information 
can be important in certain situations. For example, some inactive 
ingredients can trigger allergic reactions in patients. If a particular 
inactive ingredient appeared to trigger such reactions in an 
individual, and the name of the inactive ingredient was available to 
the public, individuals and their caregivers would be able to access 
such information to prevent potentially serious reactions. 
Additionally, some inactive ingredients may be particularly toxic to 
individuals with certain medical conditions and some may exacerbate a 
person's medical condition. If inactive ingredient information is 
available for drugs, individuals and their caregivers could get this 
information and avoid adverse reactions. We could also use inactive 
ingredients information to help us investigate possible drug 
contamination, counterfeiting, or adulteration. For example, if a drug 
appeared to be linked to an unexpected number of adverse drug events or 
seemed less effective than expected, an analysis of the drug showing 
the presence of unidentified (i.e., not previously listed) inactive 
ingredients in that drug could suggest that the drug was adulterated or 
counterfeit, or that the unidentified inactive ingredient may interfere 
with the drug's mode of action. Additionally, the presence of an 
unidentified inactive ingredient in a drug product may suggest 
contamination or that the drug was not manufactured by the legitimate 
manufacturer. Generally, we believe that knowing about a drug's 
inactive ingredients and having such information readily available in 
an electronic database is consistent with protection of the public 
health.
    We recognize that because we may make a large amount of 
registration and listing information publicly available under proposed 
Sec.  207.81, there may be instances where some of the information 
authorized by this proposed rule for public disclosure could identify 
business relationships. We believe that many of these business 
relationships could be identified currently, but that the electronic 
registration and listing system may make it somewhat easier to do so. 
For example, a contractual relationship that might not otherwise be 
publicly disclosed may be revealed when a manufacturer of a sole source 
material provides the drug's established name under proposed Sec.  
207.33(c)(1)(ii) or when a manufacturer provides registration numbers 
of each establishment where manufacturing is performed under proposed 
Sec.  207.49(d). Also, for example, business relationships between 
private label distributors and manufacturers, repackers, relabelers may 
be revealed when providing information under Sec.  207.33(c) or (d)(2). 
However, we believe this would be a rare event and that exemption of 
the information required by these regulatory provisions from public 
disclosure would be inconsistent with protection of the public health. 
For example, we believe that we should not exempt from public 
disclosure the names of inactive ingredients that would be submitted 
under proposed Sec.  207.33(c)(2)(ii) because of the remote possibility 
that the names, along with other information that may be disclosed 
under this proposal, could reveal a business relationship. We believe 
that the potential public health benefits of releasing the names of the 
inactive ingredients justify our decision not to exempt them from 
public disclosure because they outweigh the remote possibility that a 
business relationship could be revealed. Therefore we have concluded 
that the public interest in disclosure of most registration and listing 
information supports the proposals in the rulemaking.
    We also note that, for foreign manufacturers, foreign repackers, 
foreign relabelers, and foreign drug product salvagers, the name of 
each importer and the names of persons who import a drug or offer a 
drug for import would be required for registration and we are proposing 
that this information would be available for public disclosure. 
Disclosure of this information would be consistent with section 510(f) 
of the act, which requires that any registration filed be made 
available for inspection.
    We invite comments on which specific registration and listing 
information should be available for public disclosure. We request that 
you identify the specific registration and listing information on which 
you are commenting and explain why you believe the information should 
or should not be publicly disclosed.
    Proposed Sec.  207.81(b) would make one other conforming change to 
the current

[[Page 51322]]

disclosure provision. Current Sec.  207.37(a)(2) sets forth three 
categories of information that will not be available for public 
disclosure (except that any of the information will be available for 
public disclosure if it has become a matter of public knowledge or if 
we find that confidentiality would be inconsistent with protection of 
the public health). Proposed Sec.  207.81(b) would retain the category 
treating as nondisclosable any information submitted as the basis upon 
which it has been determined that a particular drug product is not 
subject to section 505 or 512 of the act. As explained previously in 
this document, we are moving two previously nondisclosable categories 
(now disclosable) regarding information on inactive ingredients to 
proposed Sec.  207.81(a) that relate to information generally regarded 
as publicly available. Those categories, in current Sec.  
207.37(a)(2)(ii) and (a)(2)(iii), would be disclosable under proposed 
Sec.  207.81(a). Proposed Sec.  207.81(c) would allow FDA to determine, 
in limited circumstances and on a case-by-case basis, that it would be 
consistent with protection of the public health and the Freedom of 
Information Act to exempt from public disclosure specific information 
in paragraph (a) of this section. As explained previously in this 
document, we are proposing, under Sec.  207.33(c)(2)(ii), to give 
manufacturers the opportunity at the time of listing to identify 
inactive ingredients that they consider trade secret and therefore, 
prohibited from disclosure under Sec.  20.61. There may be other 
appropriate reasons for exempting certain drug listing and registration 
information from public disclosure. For example, FDA may decide for 
security reasons, and consistent with the Freedom of Information Act, 
not to publicly disclose the manufacturing site location for certain 
drugs.

G. Conforming Actions

1. Withdrawal from Sale of Drugs with Approved Marketing Applications
    We are proposing to revise our human drug regulations on 
applications for approval to market a new drug to make them consistent 
with proposed part 207. Under current Sec.  314.81(b)(3)(iii)(a), 
holders of new drug applications must report to us the withdrawal from 
sale of a drug product. Under this provision, the information must be 
submitted on Form FDA 2657 within 15 working days of the drug product's 
withdrawal from sale. The following information must be submitted: The 
NDC number; the identity of the drug by established name and by 
proprietary name; the new drug application number or abbreviated 
application number; and the date of withdrawal from sale. The reason 
for withdrawal of the drug from sale is requested but not required to 
be submitted. Section 314.81(b)(3)(iii)(b) provides the address for 
submitting the completed form, and Sec.  314.81(b)(3)(iii)(c) states 
that reporting under Sec.  314.81(b)(3)(iii) constitutes compliance 
with the requirements under current Sec.  207.30(a) to report ``at the 
discretion of the registrant when the change occurs.''
    We are proposing to revise this requirement to be consistent with 
the requirements in proposed Sec. Sec.  207.57 and 207.61. Proposed 
Sec.  314.81(b)(3)(iii)(a) would provide that within 30 calendar days 
of the withdrawal of an approved drug from sale, applicants who are 
manufacturers, repackers, or relabelers subject to proposed part 207 
would be required to submit certain information about the withdrawn 
drug in electronic format, in accordance with the applicable 
requirements described in Sec.  207.61(a).
    Under proposed Sec.  314.81(b)(3)(iii)(b), applicants who are not 
subject to proposed part 207 would submit the information specified 
under proposed Sec.  314.81(b)(3)(iii)(a) on the appropriate form, 
which would be submitted to the Drug Listing Branch, Food and Drug 
Administration, CDER Central Document Room, 5901B Ammendale Rd., 
Beltsville, MD 20705-1266. We are proposing to require applicants who 
are subject to proposed part 207 to submit the information specified 
under proposed Sec.  314.81(b)(3)(iii)(a) in electronic format, in 
accordance with the applicable requirements described in proposed Sec.  
207.61(a). Consistent with the proposed requirements in Sec.  207.61, 
and discussed in section IV.E.3 of this document, these applicants 
would be required to obtain an account number, user name, and password 
to sign onto the electronic drug registration and listing system. We 
are considering this requirement because we believe the electronic 
submission of this information would be more efficient for applicants 
than the preparation and mailing of paper forms. Electronic submission 
would also make our review and processing of this information more 
efficient. We request comments on requiring applicants who are not 
subject to proposed part 207 to submit electronically the information 
specified in proposed Sec.  314.81(b)(3)(iii)(a).
    Currently, we do not have a provision in our regulations for 
reporting withdrawals from sale of biological products. We are 
proposing to revise our regulations to include such a provision. Under 
proposed Sec.  601.2(f), holders of BLAs must report to us, 
electronically in accordance with part 207, the withdrawal from sale of 
licensed biological products. The information must be submitted to us 
within 30 working days of the biological product's withdrawal from 
sale. The following information would be submitted: The holder's name; 
product name; BLA number; the NDC number, if applicable; and the date 
of withdrawal from sale. The reason for the withdrawal of the 
biological product would be requested but not required.
2. Proposed Revisions to Other Regulations
    In addition to the revisions of regulations discussed previously in 
this document, we are also proposing revisions to other FDA regulations 
as a result of this proposed rule. The proposed revisions are as 
follows:
     Section 20.100(c)(9): The reference to Sec.  207.37 would 
be changed to Sec.  207.81 to correspond to the proposed provision on 
disclosure of registration and listing information.
     Section 20.116: The reference to Sec.  207.37 would be 
changed to Sec.  207.81 to correspond to the proposed provision on 
disclosure of registration and listing information.
     Section 201.1(f): The reference to Sec.  207.3(b) would be 
changed to Sec.  207.1 to correspond to the proposed definitions 
section.
     Section 330.1(b): As explained in section IV.C.5 of this 
document, the NDC number would be required to appear on OTC drug 
labels.
     Section 514.111(a)(12): As explained in section IV.B.2 of 
this document, we would refuse to approve an NADA if the drug is 
manufactured in an establishment that is not registered.
     Section 515.10(b)(8): The reference to ``Sec. Sec.  207.20 
and 207.21'' would be changed to ``part 207'' as a result of the 
proposed reorganization and revision of part 207.
     Section 607.3(b): Current Sec.  607.3(b) defines ``blood 
and blood product'' to mean a drug which consists of human whole blood, 
plasma, or serum or any product derived from human whole blood, plasma, 
or serum, hereinafter referred to as ``blood product.'' The current 
definition also states that ``blood and blood product'' also means 
those products that meet the definition of a device under the act and 
that are licensed under section 351 of the PHS Act. We are proposing to 
amend this definition to add the phrase ``as well as licensed biologic 
components used in the manufacture of a licensed device.'' This 
proposed revision is intended to

[[Page 51323]]

clarify that licensed biologic components used in the manufacture of a 
licensed device are covered under the definition of ``blood and blood 
product'' and that manufacturers of licensed biologic components used 
in the manufacture of a licensed device are required to register and 
list under part 607. It is important that manufacturers of licensed 
biologic components used in the manufacture of a licensed device 
register and list because licensed devices are used to ensure the 
safety of blood and blood products.
     Section 607.3(k): We are proposing to define ``importer'' 
as a company or individual in the United States that is the owner, 
consignee, or recipient of the foreign establishment's blood product 
that is imported into the United States.
     Section 607.7: Current Sec.  607.7(a) states that all 
owners or operators of establishments that engage in the manufacturing 
of blood and blood products are required to register, and that 
registration and listing of blood and blood products must comply with 
part 607. Current Sec.  607.7(a) also states that registration does not 
permit blood banks or similar establishments to ship blood products in 
interstate commerce. Current Sec.  607.7(b) and (c) explain how the 
registration form for these establishments may be obtained from CBER 
and where the completed form should be mailed to.
    We are proposing to delete current Sec.  607.7(b) and (c) and 
explain where to obtain establishment registration forms and where to 
send completed forms in proposed Sec.  607.22(b) (discussed below in 
this document). We are deleting these provisions from current Sec.  
607.7 to eliminate redundancy in part 607. We are proposing to 
redesignate paragraph (a) in Sec.  607.7 as the introductory paragraph.
     Section 607.22: For clarity, we are proposing to revise 
the title of current Sec.  607.22--``How and where to register 
establishments and list blood products''--to read ``How to register 
blood product establishments and list blood products.''
    Current Sec.  607.22(a) requires the first registration of an 
establishment to be on Form FDA 2830 (Blood Establishment Registration 
and Product Listing), provides the mailing address where the Form FDA 
2830 may be obtained and submitted, states that FDA will furnish a Form 
FDA 2830 before November 15 of each year to establishments whose 
registration for that year was validated under Sec.  607.35, and states 
that the completed form must be mailed to us before December 31 of that 
year. Current Sec.  607.22(b) states that the first and subsequent 
blood product listing updates shall be on Form FDA 2830.
    We are proposing to reorganize and update current Sec.  607.22 as 
follows: Initial and subsequent registrations and product listings by a 
blood product establishment for blood products would be on Form FDA 
2830 (Blood Establishment Registration and Product Listing). 
Manufacturers may obtain, complete, and submit the form in the 
following ways:
     Complete the form online and submit electronically at 
http://www.fda.gov/cber/blood/bldreg.htm; this information must be 
submitted in accordance with part 11 of this chapter, except for the 
requirements in Sec.  11.10(b), (c), and (e) and the corresponding 
requirements in Sec.  11.30 (as discussed in section IV.E.7 of this 
document); or
     Download the form from the Internet at http://www.fda.gov/cber/blood/bldreg.htm, and mail the completed form to the address in 
Sec.  607.22(e); or
     Request the form by mail using the address in Sec.  
607.22(e), or by e-mail at [email protected], and mail the 
completed form to the address in Sec.  607.22(e).
     For subsequent annual registration renewals, we will 
furnish the establishment's most recent Form FDA 2830 before November 
15 of each year. The updated Form FDA 2830 would be submitted to us 
before December 31 of that year.
     Forms may be requested from and mailed to: Center for 
Biologics Evaluation and Research (HFM-370), 1401 Rockville Pike, suite 
200N, Rockville, MD 20852-1448.
    We are proposing these revisions to current Sec.  607.22 to make 
the registration and blood product listing process for blood product 
establishments more efficient by utilizing the latest technology for 
completing and submitting registration and listing forms.
     Section 607.25(b)(1): Current Sec.  607.25(b) lists the 
information required for blood product listing. Currently, blood 
establishments that manufacture bulk product substances and finished 
dosage forms must list their products under part 607 and also under 
part 207 to receive a NDC number. We are proposing to revise current 
Sec.  607.25(b)(1) to delete the phrase ``including bulk product 
substances as well as finished dosage forms'' because we are proposing 
to require these manufacturers to list only under part 207 to reduce 
their reporting burden. In addition, we are proposing to add the phrase 
``if any'' after ``by proprietary name'' because not all of these 
products have a proprietary name. We are also proposing to delete the 
reference to Form FDA 2250 (National Drug Code Directory Input) because 
this form is no longer being used by CDER or CBER.
     Section 607.35: For clarity, we are proposing to revise 
the title of current Sec.  607.35--``Notification of registrant; blood 
product establishment registration number and NDC Labeler Code''--to 
read ``Blood product establishment registration number.''
    Current Sec.  607.35(a) states that FDA will send a validated copy 
of Form FDA 2830 as evidence of registration to the registering 
establishment, and that FDA will assign a permanent registration number 
to each establishment. We are proposing to revoke the provision that we 
will send a validated copy of Form FDA 2830 to blood establishments. 
All registration information will be available to registered blood 
establishments on the Internet; therefore, to increase efficiency we 
will discontinue sending the validated copy of Form FDA 2830. Proposed 
Sec.  607.35 would state only that we will assign a permanent 
registration number to each blood product establishment registered in 
accordance with part 607.
    Current Sec.  607.35(b) states that if a registered blood product 
establishment has not previously participated in the NDC system or in 
the National Health Related Items Code system, the NDC numbering system 
must be used. We are proposing to revoke this section because blood 
product manufacturers that obtain a NDC number for their products will 
register under proposed part 207 and not under part 607. We are also 
proposing to delete reference to the National Health Related Items Code 
system because it is a voluntary system for medical device 
manufacturers that is managed by CDRH.
    Current Sec.  607.35(c) states that although establishment 
registration and blood product listing are required, validation of 
registration and the assignment of a NDC Labeler Code do not, in 
themselves, establish that the holder of the registration is legally 
qualified to deal in such products. We are proposing to incorporate 
into proposed Sec.  607.39 the provision that validation of 
registration does not establish that the holder of the registration is 
legally qualified to deal in such products. We are proposing to revoke 
the provision concerning the assignment of a Labeler Code because the 
NDC number requirements would be covered under proposed part 207 and 
not proposed part 607.

[[Page 51324]]

     Section 607.37(a): Current Sec.  607.37(a) states that a 
copy of Form FDA 2830 will be available for inspection under section 
510(f) of the act at FDA headquarters and at each of the FDA district 
offices. In addition, current Sec.  607.37(a) states that FDA will 
provide by mail verification of registration number and location of a 
registered establishment. Current Sec.  607.37(a) also gives examples 
of the blood product listing information that will be available for 
public disclosure.
    Under proposed Sec.  607.37(a), information submitted on Form FDA 
2830 would be available for inspection at http://www.fda.gov/cber/blood/bldregdata.htm and at the Department of Health and Human 
Services, Food and Drug Administration, Office of Communication, 
Training, and Manufacturers Assistance (HFM-40), Center for Biologics 
Evaluation and Research, 1401 Rockville Pike, suite 200N, Rockville, MD 
20852-1448.
     Section 607.39: Current Sec.  607.39 states that 
registration of an establishment or assignment of a registration number 
or assignment of a NDC number does not in any way denote approval of 
the firm or its products, and that any representation that creates an 
impression of official approval because of registration is misleading 
and constitutes misbranding.
    We are proposing to revise current Sec.  607.39 to delete the 
reference to the NDC number, to incorporate the provision from current 
Sec.  607.35(c) that validation of registration does not establish that 
the holder of registration is legally qualified to deal in blood 
products, and to revise the title accordingly. Manufacturers of blood 
products that obtain a NDC number would not register under proposed 
part 607; therefore, it is not necessary to reference NDC numbers under 
this part. Proposed Sec.  607.39 would state that registration of an 
establishment, validating registration, or obtaining a registration 
number does not in any way denote approval of the firm or its products 
nor does it establish legal authority for the holder of the 
registration number to market such products.
     Section 607.40: As discussed in section IV.A.2 of this 
document, we are proposing to revoke current Sec.  207.40, 
establishment registration and drug listing requirements for foreign 
establishments, and revise and move the requirements elsewhere in 
proposed part 207. Consistent with the revisions to proposed part 207, 
we are proposing to revoke certain provisions of current Sec.  
607.40(a) and (b). We are proposing to revoke the exemption in current 
Sec.  607.40(a) relating to foreign establishments whose blood products 
enter a foreign trade zone and are reexported from that foreign trade 
zone without having entered United States commerce. We are also 
proposing to revoke, in part, current Sec.  607.40(b), which allows for 
blood, blood components, Source Plasma, or Source Leukocytes, or a 
component or part, under section 801(d)(4) of the act, to be imported 
or offered for import into the United States even if the product is not 
listed and manufactured, prepared, propagated, compounded, or processed 
at a registered foreign establishment. We are proposing to eliminate 
these two exemptions because of certain statutory changes that have 
occurred since the publication of the final rule on foreign 
establishment registration and listing. Those changes include, as 
discussed in section IV.A.2 of this document, enactment of the 
Bioterrorism Act, which reflects Congress' desire to increase the 
Nation's ability to prepare for and respond effectively to bioterrorism 
and other public health emergencies. Consistent with the provisions of 
the Bioterrorism Act, we are proposing to amend Sec.  607.40(c) to 
require each foreign establishment to submit the name of each importer 
of the foreign establishment's blood products that is known to the 
establishment, and the name of each person who imports or offers for 
import such blood products to the United States.
    We are also proposing to amend Sec. Sec.  607.40(d) and (d)(3) to 
require each foreign establishment to submit the telephone and fax 
numbers and e-mail address of its United States agent. The name, 
address, and phone number of the United States agent is required under 
current Sec.  607.40(d). We are proposing to require the submission of 
the information on importers and persons who import because the 
Bioterrorism Act requires foreign establishments to submit, among other 
things, the name of each importer of such blood product that is known 
to the establishment, and the name of each person who imports or offers 
for import such blood product to the United States for purposes of 
importation. In addition to the name, the proposal would require that 
the address, telephone and fax numbers, and e-mail address of each 
importer and of each person who imports or offers for import be 
provided to enable us to contact these persons. Proposed Sec.  
607.40(d)(3) would also require the foreign establishment to report 
changes in the United States agent's name, address, telephone and fax 
numbers, and e-mail address to FDA within 30 calendar days of the 
change. Currently, Sec.  607.40(d)(3) requires notification to FDA 
within 10-business days.
    Proposed Sec.  607.40(e) would make electronic registration and 
listing mandatory for foreign establishments, consistent with proposed 
Sec.  607.22(a). For those foreign establishments that are unable to 
register and list blood products using the electronic registration and 
listing system, we are proposing waiver provisions in Sec.  
607.40(f)(1). We may grant a request for a waiver from a foreign 
establishment if the foreign establishment does not have an e-mail 
address and access to a computer and an Internet service provider that 
can access the electronic registration and listing system. We are also 
proposing in Sec.  607.40(f)(2) to require that waiver requests include 
a telephone number and/or mailing address where the agency can contact 
the foreign establishment. In addition, we are proposing to add Sec.  
607.40(f)(3) which states that if the agency grants the waiver request, 
the foreign establishment must register and list blood products in 
accordance with Sec.  607.22(b) or (c).
     Section 607.65: Proposed Sec.  607.65 would be amended by 
redesignating paragraph (f) as paragraph (g) and by adding new 
paragraph (f). Proposed Sec.  607.65(f) would exempt certain blood 
product manufacturers from registration and product listing under part 
607 because FDA is proposing that manufacturers of these products 
register and list only under part 207. Because these products routinely 
bear NDC numbers, FDA believes it is more efficient to have 
manufacturers of these products register and list under part 207. The 
products that would be included under proposed Sec.  607.65(f) are all 
plasma derivatives such as albumin, Immune Globulin, Factor VIII, and 
Factor IX, bulk product substances such as fractionation intermediates 
or pastes, recombinant versions of plasma derivatives or animal derived 
plasma derivatives. Under current Sec.  607.20, manufacturers of plasma 
derivatives such as albumin, Immune Globulin, Factor VIII, and Factor 
IX are required to register and list under part 607 and under part 207 
to obtain an NDC number.
     Sections 1271.1(a), 1271.1(b)(2), and 1271.20: We are 
proposing to amend Sec. Sec.  1271.1(a), 1271.1(b)(2), and 1271.20 by 
removing ``207.20(f)'' and by adding in its place ``207.9(c)(2)''.
     Section 1271.3: For consistency with parts 207 and 607, we 
are proposing to define ``importer'' at

[[Page 51325]]

proposed Sec.  1271.3(mm) to mean a company or individual in the United 
States that is the owner or consignee or recipient of the foreign 
establishment's HCT/P that is imported into the United States. For 
consistency with part 607, we are proposing to define ``United States 
agent'' at proposed Sec.  1271.3(nn) to mean a person residing or 
maintaining a place of business in the United States whom a foreign 
establishment designates as its agent. The definition of ``United 
States agent'' would exclude mailboxes, answering machines or services, 
or other places where an individual acting as the foreign 
establishment's agent is not physically present. The United States 
agent would be responsible for helping FDA communicate with you, 
responding to questions concerning your HCT/Ps that are imported or 
offered for import to the United States, and helping FDA schedule 
inspections.
     Section 1271.22: We are proposing to make electronic 
registration and listing mandatory for HCT/P establishments. As a 
result, we are proposing to revise current Sec.  1271.22 as follows:
    Replace ``Form FDA 3356'' in current Sec.  1271.22(a) with ``the 
electronic registration and listing system at http://www.fda.gov/cber/tissue/tisreg.htm'';
    Revise current Sec.  1271.22(b) and (c) to implement the electronic 
registration and listing system at http://www.fda.gov/cber/tissue/tisreg.htm and remove references such as ``Form FDA 3356,'' mailing 
addresses, and telephone numbers.
    In the Federal Register of January 19, 2001 (``Human Cells, 
Tissues, and Cellular and Tissue-Based Products; Establishment 
Registration and Listing,'' (66 FR 5447)), FDA announced its intention 
to develop an electronic submission process for HCT/P registration and 
listing. The agency has developed such a system and it is currently in 
use on a voluntary basis.
    Consistent with proposed Sec.  207.61(a)(4), proposed Sec.  
1271.22(b) states that FDA will periodically issue guidance on how to 
provide registration and listing information in electronic format (for 
example, method of transmission, media, file formats, preparation, and 
organization of files) for HCT/Ps.
    Consistent with proposed Sec.  207.61(a)(1), proposed Sec.  
1271.22(c) states that HCT/P manufacturers must provide the information 
under Sec.  1271.22(a) in accordance with part 11, except for the 
requirements in Sec.  11.10(b), (c), and (e) and the corresponding 
requirements in Sec.  11.30.
     Section 1271.23: Proposed Sec.  1271.23 would permit HCT/P 
establishments that do not have an e-mail address and access to a 
computer and an Internet service provider that can access the Web-based 
FDA registration and listing database to request a waiver from 
electronic registration and listing. This is consistent with proposed 
Sec.  207.65 and the Bioterrorism Act.
     Section 1271.25: We are proposing to amend Sec.  1271.25, 
``What information is required for establishment registration and HCT/P 
listing,'' as follows:
    Delete the reference to ``Form FDA 3356'' in current Sec.  1271.25;
    Amend current Sec.  1271.25(a)(2) and (a)(3) to require the 
submission of the telephone and fax numbers and an e-mail address;
    Add Sec.  1271.25(a)(5) to require each foreign establishment to 
also submit the name, the address, telephone and fax numbers, and e-
mail address of each importer that is known to the establishment and 
the name of each person who imports or offers for import such HCT/P to 
the United States for purposes of importation;
    Add proposed Sec.  1271.25(a)(6) to require each foreign 
establishment to also submit, the name, address, telephone and fax 
numbers, and e-mail address of its United States agent. Under proposed 
Sec.  1271.25(a)(6), each foreign establishment would have only one 
United States agent, and that United States agent must reside or 
maintain a place of business in the United States. Upon request from 
FDA, the United States agent must assist us in communications with the 
foreign establishment, respond to questions concerning the foreign 
establishment's products that are imported or offered for import into 
the United States, and assist us in scheduling inspections of the 
foreign establishment. If we are unable to contact the foreign 
establishment directly or expeditiously, we may provide information or 
documents to the United States agent. The foreign establishment would 
report to FDA changes in the United States agent's name, address, 
telephone and fax numbers, and e-mail address within 30 calendar days 
of the change.
    Add proposed Sec.  1271.25(d) to clarify that if your HCT/P is 
regulated as a drug, device, and/or biological product under current 
Sec.  1271.20, you must submit the information required under part 207 
using the procedures under part 1271.
     Section 1271.26: For consistency with proposed Sec.  
207.29(a), we are proposing to amend current Sec.  1271.26 to include a 
change in the United States agent's name, address, telephone and fax 
numbers, and e-mail address. All changes in proposed Sec.  1271.26 
would be reported within 30 calendar days instead of the current 
requirement to report the change within 5 days.
     Section 1271.37 would be revised to delete the reference 
to ``Form FDA 3356''.
3. Compliance Verification Reports
    On November 26, 2004 (69 FR 68831), FDA withdrew its September 2, 
1993, proposal (58 FR 46587; Docket Number 92N-0291) to amend part 207 
to require the completion of ``compliance verification reports.'' These 
reports are printouts of information as reported to FDA on Form FDA 
2657 or Form FDA 2658. FDA had periodically mailed to domestic 
establishments the compliance verification report for listed 
prescription drugs and requested that the establishments verify or 
correct the information and return it to the agency within 30 calendar 
days. The completion of the report served to satisfy, in most cases, 
the drug listing updates required under current Sec.  207.30(a). FDA 
provided this service to increase the accuracy of its computerized drug 
listing files. Because FDA is now proposing to require the electronic 
submission of all registration and most listing information, FDA in 
anticipation of this proposal has already withdrawn the September 2, 
1993, proposal and has discontinued the use of the compliance 
verification reports. Electronic submission of registration and most 
listing information would make it easier for establishments to register 
and list. In addition, FDA's electronic registration and listing 
database would save registration and listing information that was 
submitted, thereby making it easier for establishments to access, 
review, and update information.

V. Legal Authority

    We have the legal authority to amend our regulations on foreign and 
domestic establishment registration and listing for human drugs, 
including drugs that are regulated under a BLA, and animal drugs. The 
statutory basis for our authority includes sections 201, 301, 501, 502, 
503, 505, 506, 506A, 506B, 506C, 510, 512, 513-516, 518-520, 701, 704, 
721, 801, and 903 of the act (21 U.S.C. 321, 331, 351, 352, 353, 355, 
356, 356a, 356b, 356c, 360, 360b, 360c-360f, 360h-360j, 371, 374, 379e, 
381, and 393); 15 U.S.C. 1451-1561; the PHS Act; and section 122, 
Public Law 105-115, 111 Stat. 2322 (21 U.S.C. 355 note).
    Section 510(c) of the act requires every person upon first engaging 
in the manufacture, preparation, propagation,

[[Page 51326]]

compounding, or processing of a drug to immediately register with the 
Secretary his name, place of business, and the establishment. The 
provisions in section 510(b) and (d) of the act require annual 
registration and registration of additional establishments, 
respectively. Section 510(i) of the act requires any establishment 
within any foreign country engaged in the manufacture, preparation, 
propagation, compounding, or processing of a drug that is imported or 
offered for import into the United States to register with the 
Secretary by providing certain information. These provisions, together 
with section 701(a) of the act (among others), authorize us to require 
the submission of the registration information specified in the 
proposal. The information specified in this proposal would help us 
identify who is manufacturing, repacking, relabeling, or salvaging 
drugs and where those operations are being performed. In addition, some 
information (e.g., official contact information) would help us 
communicate with establishments more effectively and schedule 
inspections more efficiently.
    Section 510(j)(1) of the act requires every person who registers to 
file with the Secretary, at the time of registration, a list of all 
drugs that are being manufactured, prepared, propagated, compounded, or 
processed by the registrant for commercial distribution. That list must 
be prepared in the form and manner prescribed by the Secretary and must 
be accompanied by a copy of labeling (or the label and package insert) 
and, in some cases, advertising. Section 510(j)(2) of the act requires 
listing information updates every June and December. This listing 
information gives us a current inventory of marketed drugs. These 
provisions of the act and others, together with section 701(a) of the 
act, provide authority for requiring the submission of listing 
information set forth in this proposal. The drug listing information 
specified in this proposal would help us: (1) Develop a more current, 
robust inventory of drugs as a counter-terrorism measure; (2) more 
effectively administer our postmarketing surveillance programs; (3) 
facilitate recalls of products; (4) identify drugs or ingredients in 
short supply in the event of a national emergency; and (5) identify 
drugs marketed in violation of the law.
    Sections 510(j)(1), (i), and (p), and 701(a) of the act also give 
us the discretion to require that registration and listing information 
be submitted in electronic format. Electronic receipt of registration 
and listing information would enable us to shift resources from more 
ministerial tasks, such as data entry, to the important public health 
objectives described previously in this document. Additional authority 
for requiring that content of labeling be submitted in electronic form 
stems from, among others, sections 201(n) and (p), 501, 502, 503, 505, 
510(j)(1)(A) and (j)(1)(B), and 512 of the act. The certification 
requirement would help us with the efficient enforcement of the act 
because we would be able to distinguish between situations where there 
has been noncompliance with registration and listing requirements from 
situations where there have been no changes in information. The failure 
to register or list is a prohibited act under section 301(p) of the act 
and the failure to do either renders a drug misbranded under section 
502(o) of the act.
    We also have the authority to require the appropriate NDC number 
(in human-readable form) on certain drug labels for the efficient 
enforcement of various sections of the act. The appropriate NDC number 
in human readable form would, among other things, serve as a backup for 
the appropriate NDC number encoded in the bar code. That is, the human 
readable form of the NDC number could be manually keyed into a computer 
system by a health care provider if the bar code is damaged, cannot be 
read, or is otherwise illegible. Our legal authority to impose the 
human readable NDC number requirement, at least in part, is similar to 
that for requiring bar codes on labels (69 FR 9120, 9147-9149). These 
sections include sections 201(n) and (p), 501, 502, 503, 505, and 
701(a) of the act, and sections 351 and 361 of the PHS Act.
    Other sections of the act also provide authority for the human-
readable NDC number requirement. The failure to register and list are 
prohibited acts and render drugs misbranded under sections 301(p) and 
502(o) of the act. It would be possible for FDA investigators to read 
the NDC number on the drug's label and review information in our 
database to ascertain compliance with registration and listing 
requirements. Where a drug does not bear the appropriate NDC number, 
investigators can conduct further followup to discern, for example, 
whether there has been a failure to comply with registration and 
listing requirements (including those for NDC numbers). Accordingly, 
sections 201, 301(p), 502(o), 510, and 701(a) of the act provide 
additional authority for requiring the appropriate NDC number in human 
readable form on certain drug labels.
    There is also additional legal authority for the rule's 
requirements as to biological products regulated under the PHS Act. 
Section 351(a) of the PHS Act provides for the approval, as well as the 
suspension and revocation, of biologics license applications. The 
human-readable NDC requirement for biological drugs and blood and blood 
components is designed to ensure the continued safe and effective use 
of licensed biological products. Additionally, section 361 of the PHS 
Act authorizes regulations necessary to prevent the introduction, 
transmission, or spread of communicable diseases. With specific regard 
to blood and blood components, the human- readable NDC number 
requirement will aid in the control of units that are at risk of 
spreading communicable diseases.

VI. Analysis of Economic Impacts

A. Introduction

    We have examined the proposed rule under Executive Order 12866 and 
the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded 
Mandates Reform Act of 1995 (Public Law 104-4), and the Congressional 
Review Act.
    Executive Order 12866 directs regulatory agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). This proposed rule is not considered economically significant 
under Executive Order 12866.
    Under the Regulatory Flexibility Act (as amended by the Small 
Business Regulatory Enforcement Fairness Act), if a regulation has a 
significant economic impact on a substantial number of small entities, 
we must analyze regulatory options that would minimize the impact on 
small entities. We have conducted a preliminary regulatory flexibility 
analysis for the proposed rule, and we believe it will not have a 
significant impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 (UMRA) 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in expenditures 
by State, local, and tribal governments, in the aggregate, or by the 
private sector of $100 million (adjusted annually for inflation) in any 
one year. Currently, such a statement is required if costs exceed about 
$115 million for any one year. UMRA does not require us to prepare a 
statement of costs and benefits for the proposed rule because the 
proposed rule is not expected to result

[[Page 51327]]

in any 1-year expenditure that would exceed $115 million.
    The Congressional Review Act requires that regulations determined 
to be major must be submitted to Congress before taking effect.
    We contracted with the Eastern Research Group, Inc. (ERG), to 
collect data, interview industry experts, and estimate the costs and 
benefits of the proposed rule. The analysis and references in support 
of the effects of the proposed rule are summarized in table 2 and are 
included in the docket as Reference 3. Although we were unable to 
quantify specific benefits attributable to the proposed rule, we 
believe the ultimate use of electronic registration and listing data 
justify taking this action.

 Table 2.--Summary of Annual Costs and Benefits of the Proposed Rule\1\
------------------------------------------------------------------------
                  Average Annual                              Average
    Annual          Costs (in          Average Annual        Annual Net
 Discount Rate      Millions)             Benefits            Benefits
------------------------------------------------------------------------
3%                           $5.6  Unquantified. Benefits  N/A
                                    accrue by having
                                    accurate and unique
                                    identification of
                                    drugs that would
                                    allow greater use of
                                    technology.
------------------------------------------------------------------------
7%                           $5.8  Unquantified. Benefits  N/A
                                    accrue by having
                                    accurate and unique
                                    identification of
                                    drugs that would
                                    allow greater use of
                                    technology.
------------------------------------------------------------------------
\1\Based on 10-year evaluation period.

B. Objective

    The objective of the proposed regulation is to update our process 
for registering drug establishments and listing drugs. The current 
system does not allow for timely updates of important information and 
the current system for NDC numbers has introduced the potential for the 
misidentification and mistaken administration of drugs. We believe that 
electronic submission of registration and listing information, as well 
as our assignment of specific identifiers (i.e., the NDC number), would 
improve the quality and timeliness of information available to health 
care professionals and consumers. We further believe that these quality 
improvements would result in safer and more effective use of drugs by 
providing up-to-date and easily accessible relevant information. We 
also believe that we should develop and maintain a high quality 
database of drugs available on the market to enhance future uses of 
technology in the delivery of health care.

C. Baseline Conditions and Scope

    As discussed elsewhere in this preamble, we currently maintain 
databases that contain establishment registration and drug listing 
information. However, these databases rely on paper forms that 
manufacturers, repackers, relabelers, drug product salvagers, and 
private label distributors of drugs (both human and animal) must submit 
to us. The completed forms are then entered into our databases. These 
databases are intended to include identification of establishments 
involved in the manufacturing, preparation, propagation, compounding or 
processing of drugs, including the repacking, relabeling, and salvaging 
of drugs (human and animal prescription and OTC drugs, as well as 
active pharmaceutical ingredients), the procedures that take place at 
each establishment (e.g., repacking, or relabeling), and a list of each 
drug being manufactured, prepared, propagated, compounded, or processed 
for commercial distribution at each site. We rely on these databases to 
identify manufacturers, repackers, relabelers, drug product salvagers, 
and private label distributors, of human and animal drugs, specific 
drugs or ingredients, to facilitate recalls or information alerts in 
the case of potential safety concerns, and to otherwise exercise 
competent oversight of this important industry.
    The quality and completeness of these databases depends on prompt 
submission of updated information from manufacturers, repackers, 
relabelers, drug product salvagers, and (currently) private label 
distributors, as well as our immediate inclusion of the data into our 
system. We are currently unable to verify the accuracy of the 
information submitted, and some manufacturers, repackers, relabelers, 
drug product salvagers, and private label distributors are not prompt 
in informing us of changes. For example, some changes in processing or 
packaging might be submitted periodically rather than when such changes 
actually occur. In addition, forms may be mishandled, or even lost, 
which further reduces confidence in the databases.
    Using a 5-digit labeler code, we estimate that we have the capacity 
for NDC numbers for up to 100,000 registered establishments, each 
having a capacity for up to 100,000 product/package size combinations 
(using the 5 remaining digits). If a registered establishment requires 
more than 100,000 product/package size codes, we could issue that 
establishment an additional labeler code. We currently have about 
25,000 active establishments in our registration database, utilizing 
less than half of the 5-digit labeler code capacity. We currently issue 
about 1,000 new labeler codes annually. If we reach NDC number capacity 
(possibly in 30 to 50 years), we could propose to either add 
alphanumeric capability or expand the number of numeric digits to 11 or 
12 (current Sec.  207.35(b)(2)(i) states that FDA will go from a 5- to 
6-digit labeler code if needed). This change in NDC numbers will 
necessitate advances in current UPC technology (due to the need for bar 
code reading), which we anticipate will likely occur prior to our 
reaching the 10-digit NDC numeric capacity.

                          Table 2a.--Count of Potentially Affected Healthcare Entities
----------------------------------------------------------------------------------------------------------------
       Type of Entity           Establishments         Source                    Additional Comment
----------------------------------------------------------------------------------------------------------------
Pharmaceutical manufacturers                666  Orange Book, 2003  Includes only those pharmaceutical firms
 (human)                                                             that have at least one currently marketed
                                                                     product in the United States. Might be an
                                                                     overestimate due to the possibility of
                                                                     applicant name duplication in the database.
                                                                     Does not include firms that only
                                                                     manufacture unapproved drug products.
----------------------------------------------------------------------------------------------------------------

[[Page 51328]]

 
Pharmaceutical manufacturers                 80  Census, 2004       Includes firms that own establishments that
 (animal)                                                            manufacture animal drugs. Includes some
                                                                     firms that manufacture both human and
                                                                     animal drugs, so overstates the number that
                                                                     manufacture animal drugs exclusively. Does
                                                                     not include firms that only manufacture
                                                                     unapproved drug products.
----------------------------------------------------------------------------------------------------------------
Pharmacies                               67,434  Listed below       Sum of pharmacy categories (chain store
                                                                     headquarters offices are not counted in
                                                                     this total)
  Chain store (headquarters                  25  NWDA, 2000         Covers headquarters for firms ranging from
   office)                                                           CVS (4,100 stores) to companies operating
                                                                     over approximately 35 stores.
  Chain                                  20,493  NACDS, 2001        National Association of Chain Drug Stores
                                                                     Web site (http://www.nacds.org)
  Independent                            24,500  NCPA, 2002         National Community Pharmacists Association
                                                                     Web site (http://www.ncpanet.org)
  Mass merchant                           5,910  NACDS, 2001        National Association of Chain Drug Stores
                                                                     Web site (http://www.nacds.org)
  Supermarket                             8,531  NACDS, 2001        National Association of Chain Drug Stores
                                                                     Web site (http://www.nacds.org)
  Institutional                           7,950  ERG, 2001          Profile of the Pharmaceutical Compounding
                                                                     Industry: Draft Final Report. Submitted to
                                                                     FDA, Office of Policy, Planning, and
                                                                     Legislation, Office of the Commissioner,
                                                                     August 27, 2001.
  Mail order                                 50  ERG, 2001          Based on discussions with Winkelman (2004)
----------------------------------------------------------------------------------------------------------------
Pharmacy benefit management                  76  ERG, 2001          Profile of the Prescription Drug Wholesaling
 companies (PBMs)                                                    Industry: Final Report, February 12, 2001.
                                                                     Submitted to Office of Policy, Planning,
                                                                     and Legislation, Office of the
                                                                     Commissioner, FDA. The figure is reported
                                                                     by SMG Marketing Group, Inc.
----------------------------------------------------------------------------------------------------------------
Hospitals                                 6,116  AHA, 2002          American Hospital Association Web site
                                                                     (http://www.ahadata.org)
----------------------------------------------------------------------------------------------------------------
Compendium companies                          5  ERG, 2004          Estimate based on discussions with Winkelman
                                                                     (2004)
----------------------------------------------------------------------------------------------------------------
Wholesalers/distributors                  6,500  ERG, 2001          Profile of the Prescription Drug Wholesaling
                                                                     Industry: Final Report, February 12, 2001.
                                                                     Submitted to Office of Policy, Planning,
                                                                     and Legislation, Office of the
                                                                     Commissioner, FDA. The report notes that
                                                                     this is probably an underestimate.
----------------------------------------------------------------------------------------------------------------
Group purchasing                            701  ERG, 2001          See note in previous row.
 organizations
----------------------------------------------------------------------------------------------------------------
State Medicare agencies                      50  ERG, 2003          Allocated one per State.
----------------------------------------------------------------------------------------------------------------
Physician offices                       195,655  Census, 2000       NAICS 62111 from County Business Patterns
                                                                     2000, U.S. Census Bureau.
----------------------------------------------------------------------------------------------------------------
Dentist offices                         116,494  Census, 2000       NAICS 62121 from County Business Patterns
                                                                     2000, U.S. Census Bureau.
----------------------------------------------------------------------------------------------------------------
Note: ERG did not include various health care facilities, such as nursing homes and rehabilitative care
  facilities, that generally do not have on-site pharmacies.

    The pharmaceutical and biological products industries (as defined 
by the North American Industrial Classification System (NAICS)) consist 
of 1,218 establishments (NAICS 325412 and NAICS 325414). ERG examined 
the 2003 ``Approved Drug Products With Therapeutic Equivalence 
Evaluations'' (the ``Orange Book'') to estimate the number of companies 
currently operating establishments that are marketing drugs. While the 
Orange Book covers only products approved under section 505 of the act, 
there is sufficient overlap between manufacturers of products listed in 
the Orange Book and manufacturers of other types of products (e.g., 
manufacturers of OTC monograph products and animal drugs) to provide a 
basis for estimating the industry sector affected by the proposed rule. 
ERG estimates that a total of 666 companies own and operate 
manufacturing establishments. In addition, according to U.S. Census 
data, there are an estimated 80 companies that manufacture animal drugs 
in the United States. (There is likely overlap between human and animal 
drug companies.) Finally, the packaging and labeling services industry 
(NAICS 561910) consists of 229 companies. Each of these establishments 
would be affected by the proposed rule.
    Several provisions of the proposed rule affect establishments 
rather than companies. We used FDA's drug registration system to 
estimate that there are approximately 9,700 domestic sites.
    There are approximately 200,000 distinct packaged products of human 
and animal (both prescription and OTC) drugs. The information generated 
by the drug listing process is used by many organizations for many 
purposes. Each specific drug is entered into our listing database. If 
the drug is later withdrawn from the market, for example, this is also 
noted. The pharmaceutical industry is undergoing corporate changes 
through mergers, acquisitions, and closings. These activities result in 
additional reporting requirements (via the current paper system) to 
keep our databases up-to-date. However, the magnitude of information 
required to

[[Page 51329]]

keep the system current and the number of activities that would 
generate changes in the data have weakened our ability to rely on the 
current database.
    In addition, the current drug listing system includes the use of 
the NDC system. Using this system, manufacturers, repackers, and 
relabelers of drugs (including human prescription, human OTC, certain 
biologics, and animal drugs) assign unique NDC numbers to each drug. An 
NDC number consists of 10 characters, including a 4- or 5- character 
labeler code, a 4- or 3- character product code, and a 1- or 2- 
character package code, and is presented in one of three formats (4-4-
2, 5-3-2, or 5-4-1). Manufacturers, repackers, and relabelers notify us 
of the assigned NDC number at the time of drug listing, and the numbers 
may be printed on the label and labeling of each drug.
    As discussed earlier in this document, we currently assign the 
labeler code to registered manufacturers, repackers, and relabelers of 
drugs. The manufacturer, repacker, or relabeler assigns the product 
code and package code to its drugs and must report the NDC number to 
us. Currently, when a manufacturer, repacker, or relabeler withdraws a 
drug from the distribution chain, NDC numbers for the discontinued 
drugs may be reused after 5 years.
    This process and format for NDC numbers was introduced over 20 
years ago as a means of identifying individual drugs by distinguishing, 
among other things, between specific strengths and package sizes for 
reimbursement purposes. Since the NDC system was created in 1969, a 
variety of uses for the NDC number have developed within the healthcare 
industry.
    We have used the NDC number to facilitate recalls of drugs for a 
number of years. The identification system allows for notification 
throughout the distribution chain in the event of a recall or other 
warning about specific drugs.
    The development of computerized systems and the ability to 
electronically transmit information have had a major effect on the ways 
NDC numbers are used. Because the NDC numbers are designed to be unique 
identifiers, many sectors of the industry have built systems to 
maximize the usefulness of this information. Compendium service 
companies assemble and distribute information to retail stores, 
hospitals, prescription benefit managers (PBMs), insurance companies, 
and electronic medical record companies among other users. These users 
rely on NDC numbers to identify drugs within their tracking or 
processing systems. The NDC numbers are incorporated into their 
internal software to facilitate scanning (such as by cashiers or 
hospital personnel) or for the operation of data processing systems for 
reimbursement (both private and public) or inventory management. In 
addition, these compendium databases often include drug price 
information directly associated with the NDC numbers.
    In some cases, the designers of the information systems that use 
NDC numbers convert the NDC number for use in industry databases. They 
add a zero to result in a consistent 11-digit format (5-4-2). Also, 
while visual use of NDC numbers uses hyphens to differentiate between 
the labeler-product-package codes, these hyphens are not read when 
scanned (as a bar code, for example). Because three formats are used 
within the current NDC system, removing hyphens introduces potential 
duplicates.
    Other government entities, such as the Center for Medicare and 
Medicaid Services (CMS) and the Drug Enforcement Administration (DEA) 
use the NDC numbers to meet their mission requirements. The numbers are 
used to provide data for negotiated rebates or notification of 
distribution of controlled substances.
    Companies are continually updating their drug information and price 
data. Generic relabeling companies and OTC manufacturers often 
repackage or remarket their products. These fairly constant revisions 
present a challenge to both compendium companies and us because 
maintaining the accuracy of the NDC database relies on prompt 
notification of any changes, but notification is not always prompt or 
consistent.
    The NDC components (labeler, product, and package codes) have 
presented issues that may compromise the current database. For example, 
we assign only one labeler code to each manufacturer, repacker, or 
relabeler, but many companies have multiple labeler codes due to 
mergers and acquisitions and may use them to distinguish between 
different divisions within the new company. Pharmaceutical companies 
have taken different approaches to handling product codes. For example, 
some firms assign product codes sequentially while others use 
predefined blocks of numbers for each operating division. Similarly, 
the methods used to assign package codes are not uniform.
    Many repackers currently use the manufacturer's NDC number instead 
of their own when repacking drugs into smaller packages for pharmacies. 
Among the reasons such repackers do this is because Medicaid and other 
third-party payers use the NDC number presented on the drug to file 
rebate claims with the manufacturers. Such repackers sometimes present 
the manufacturer's NDC number in an effort to fall under the 
manufacturer's agreement with payers.

D. The Proposed Regulation

    This proposed regulation would require the electronic submission of 
registration and listing information. The proposed rule would require, 
for example, drug product salvagers to list drugs and would not permit 
private label distributors to register establishments or list drugs, 
and would specifically define the responsibilities associated with each 
type of establishment covered by the proposal. The proposed rule would 
not permit manufacturers, repackers, and relabelers to assign the 
product code and package code for newly listed drugs. We would assign 
the entire NDC number for drugs.
    Under the proposed rule, the electronic establishment registration 
and drug listing system must be used to enter and update all 
registration, listing, and NDC number information no later than 9 
months after the effective date of a final rule. (We are proposing that 
any final rule based on the proposal become effective 90 days after 
publication in the Federal Register.) Manufacturers, repackers, and 
relabelers would have until 9 months after the effective date of a 
final rule to review and update the NDC number information in our 
databases for each of their drugs to ensure that it complies with the 
proposal. In addition, manufacturers, repackers, and relabelers would 
have, for prescription drugs, 3 years after the effective date of a 
final rule and, for OTC drugs, 7 years after the effective date of a 
final rule, to ensure that the appropriate NDC number correctly appears 
on the label of each of their listed drugs, in accordance with the 
proposal. These costs have been accounted elsewhere in this analysis.
    By requiring electronic drug registration and listing, this 
proposed rule would enhance the use of technology and provide the basis 
for efficiencies in the proper use of drugs. For example, the use of 
bar coded information to avoid adverse events associated with 
medication errors requires consistent information on the drug label. 
Other initiatives, such as electronic prescribing, may require the 
electronic accessibility of this information. This proposed rule would 
be an important step for the timely and useful availability of 
information that would benefit patients.

[[Page 51330]]

E. Costs

    The major potential cost of the proposed rule is the assignment of 
NDC numbers by FDA. Although the proposed rule includes a selected 
alternative to minimize this cost, the potential impact could be very 
large, and is discussed in the Alternatives section of this document. 
Other costs associated with electronically submitting registration and 
listing information are discussed later. Costs have been analyzed and 
discounted using the methodology suggested by OMB's Circular A-4 
(September 2003).
1. Costs of a Single Method of Assigning NDC Numbers
    Currently, each manufacturer, repacker, and relabeler has its own 
method for assigning the product code and package code to its drugs. 
Under the proposed rule, we would assign the product code and package 
code. Existing NDC numbers would not be affected, as long as they meet 
the proposed requirement for NDC numbers.
    Because, the proposed changes to the NDC numbering system would 
affect product codes and package codes, and because NDC numbers are 
used by some sectors of the health care industry for reimbursement or 
inventory purposes, we expect that the proposed changes would have some 
effect on the data processing infrastructure. The primary area of 
impact would be in PBM tasks such as generation and maintenance of drug 
formularies for insurance coverage purposes. Other areas that would be 
affected include data analyses conducted by manufacturers, repackers, 
and relabelers, especially with respect to rebate predictions and 
market forecasts.
    a. Pharmaceutical manufacturers. Changes to the NDC number would 
likely affect rebate processing by manufacturers as well as the ability 
of pharmaceutical firms to conduct market research analyses.
    Common practice in the prescription pharmaceutical industry 
includes agreements that provide rebates from manufacturers to large 
insurance payers for use of a manufacturer's drugs by the insurer's 
enrollees. Medicaid and other large programs have negotiated these 
rebates with individual manufacturers. Each firm's staff reviews 
invoices, makes corrections, resolves disputes, and remits rebate 
payments to insurers based on reported volumes of sales to patients 
enrolled in the insurance plans. Most manufacturers use the current NDC 
numbers to identify the dispensed products during this process. A 
common practice among manufacturers is to group reimbursement data by 
product code in order to analyze payment history and resolve disputes 
with insurance carriers.
    Because new product codes may be assigned without sequencing under 
the proposed rule, this may require manufacturers to devote more staff-
time to manually group products for rebate processing. Additional data 
entry work would be required if, for example, an additional data field 
were added to reports in order to retain the ability to sort products 
on the basis of product codes.
    Market research departments within the pharmaceutical industry also 
use the current configuration of NDC numbers when conducting analyses 
that affect product pricing and packaging. The ability to sort by 
product code allows for efficient use of data records, and 
randomization of product codes would result in additional staff-time to 
conduct rebate processing.
    Initially, the loss of the ability to group products based on 
sequential product codes could require staff to either manually sort 
products or map the new randomized NDC number into another, internal 
sorting system. Over time, as new NDC numbers are assigned with new 
product codes and package codes, we expect that all manufacturers, 
repackers, and relabelers would eventually use automated mapping 
systems to track product codes. ERG has determined through interviews 
with industry information technology staff that it would take 
approximately 80 hours of programming to devise, validate, and 
introduce an automated mapping system for each affected company. In 
addition, ERG interviews determined that approximately 100 new packaged 
products are marketed per year for each manufacturer, and it would take 
approximately 0.083 hours (5 minutes) per product to map and validate 
the assigned NDC number to a new internal number for each internal 
database. ERG further determined that an average manufacturer is likely 
to have three internal databases that would utilize the new NDC 
numbers. Each manufacturer would require about 25 hours of programmer 
time per year in maintenance of these systems. The 2003 Bureau of Labor 
Statistics (BLS) has published hourly pay and benefit rates of $64 for 
senior computer programmers. Thus, each manufacturer would incur first-
year costs of about $5,100 (80 hours x $64 per hour) and annual costs 
of about $1,600 (100 product packages x 0.083 hours x 3 databases x $64 
per hour). During 2003, according to estimates based on FDA's Orange 
Book and the Census of Manufacturers, 746 manufacturing companies 
marketed at least one prescription, OTC, or animal drug product in the 
United States (666 domestic human drug manufacturers and 80 domestic 
animal drug manufacturers). These manufacturers would incur first-year 
costs of $3.8 million ($5,100 x 746 companies) and annual costs of $1.2 
million ($1,600 x 746 companies) because of newly assigned product 
codes and package codes.
    Although not included as a cost of the proposed regulation, we 
estimate that foreign manufacturers of drug and biological products 
would incur first-year and annual costs due to the proposed rule. The 
magnitude of any costs would depend on the specific prevailing wage 
rate for computer programmers in the respective countries. We note that 
foreign establishments would also experience some increase in costs 
because of the proposed rule. OMB Circular A-4 allows for the 
consideration of regulatory costs to foreign establishments, and 
requires such an analysis if the costs are significant. However, the 
relatively small marginal costs of the proposed rule and the 
undertainty of the effect, if any, on consumer prices convinced us to 
limit the analysis on the costs to domestic establishments and 
companies.
    b. Pharmacies. We believe that retail pharmacies (that would not be 
required to register or list) would generally be unaffected by the 
proposed rule because most pharmacy processing systems do not use the 
internal component of NDC codes. In those cases where pharmacies use 
the components, we believe software vendors will make any appropriate 
revisions.
    However, ERG found that large pharmacy chains were concerned about 
possible changes in NDC numbers. Some large chains use the current NDC 
numbers for the adjudication of claims. (``Adjudication'' refers to the 
process by which pharmacists submit reimbursement claims to customer 
health plans.) Most formularies are built and maintained by PBMs or 
individual State Medicaid plans, but the chains have noted an increase 
in smaller plans that are maintained by individual retail stores. In 
order to serve these small, local insurance plans, data entry staff at 
the participating stores enter NDC numbers of the requested drugs using 
``wild card'' symbols (such as asterisks) to indicate that any number 
in the wild card position is acceptable. For example, the package code 
of an NDC number may be entered as a wild card

[[Page 51331]]

symbol to indicate that any package or strength of the indicated 
product is acceptable for reimbursement under that specific insurance 
plan. This ability allows data entry clerks to add groups of products 
quickly.
    The proposed assignment by us of product codes and package codes 
could affect this practice. Several executives in the chain drug 
industry asserted to ERG that this change would result in possibly 
hiring as many as four additional data entry clerks. Although other 
respondents felt that this claim overstated the expected increased 
effort, they could not provide alternative estimates. According to the 
BLS, the annual salary for a data entry operator in 2003 was $33,240 
plus about 38 percent in benefits. We have used approximately $50,000 
per year as typical annual compensation for this industry. Therefore, 
using this estimate of additional staff, each affected chain would 
experience an increased annual cost of $200,000 (4 additional clerks x 
$50,000).
    According to the National Wholesale Drug Association, there are 25 
large chain headquarters offices of corporations that operate at least 
35 separate retail drug store outlets. ERG expects that only 10 percent 
of these corporations would potentially be affected by the proposed 
rule because relatively few chain stores use software that enables the 
use of ``wild card'' data entry for portions of the NDC numbers. This 
results in total industry annual operating costs of $500,000 (25 large 
chain operations x 0.10 x $200,000).
    c. Pharmaceutical benefit managers. PBMs are the entities that 
build formularies and adjudication services for insurance plans. The 
software used for these services usually makes use of the NDC number. 
For example, when a PBM builds a formulary for an insurance plan, the 
data entry staff may enter the NDC numbers of the selected drugs into 
processing software. As discussed previously in the section on the 
expected effect on retail pharmacy chains, wild card symbols may be 
used to indicate that any number in the position of the wild card 
symbol is acceptable to the formulary and, thus, reimbursable. This 
practice works in cases where the product code of the NDC number is in 
sequence. In some cases, only the labeler code may be entered and wild 
card symbols are used for the rest of the NDC number to signify that 
any product from that company (i.e., manufacturer, repacker, relabeler, 
or private label distributor) is acceptable. This use of wild card 
symbols allows data entry clerks to quickly add groups of products, and 
according to respondents of ERG interviews, saves substantial time. 
Several managers of PBMs suggested that manual entry of all NDC numbers 
would be similar to those of pharmacy chain operators and could result 
in hiring as many as four additional employees (FTEs) per year. Using 
the BLS data, the annual salary of $33,240 and industry benefits of 
approximately 38 percent of salary results in typical compensation of 
around $50,000 per FTE. If so, then increased costs to PBMs would be 
approximately $200,000 per year per affected PBM (4 additional clerks x 
$50,000).
    However, not all PBMs would be affected by this change in NDC 
numbers. In discussions with ERG, only one supplier of adjudication 
software was identified as providing the ``wild card'' feature. This 
provider estimated that his clients constituted about 10 percent of the 
industry, so we have assumed that about 10 percent of the PBMs use this 
feature. Therefore, ERG has estimated that only 10 percent of PBMs 
would likely experience increased costs because of the proposed rule. 
ERG identified 76 PBMs for a 2001 profile of the prescription drug 
wholesaling industry (Ref. 4). Using this estimate, annual costs of the 
proposed rule for this industry segment are estimated to be $1.5 
million (76 PBMs x 0.10 affected by the proposed rule x $200,000).
    d. Other entities. ERG examined the potential effect of the 
proposed revisions to the NDC number on hospitals, compendium 
companies, wholesalers/distributors, group purchasers, State Medicaid 
agencies, physician offices, and dental offices. None of these sectors 
were identified as being significantly affected by the proposed rule. 
These sectors maintained that as long as the NDC number maintained its 
format, any adjustments would be minimal. In particular, respondents 
asserted that preservation of the labeler code in the NDC number would 
be sufficient for many of these users of NDC numbers. Other users of 
the NDC numbers (such as hospitals) are expected to be able to 
accommodate any changes without major modifications to their data 
systems.
    e. Total costs of NDC number revision. Overall, we expect that 
revising the process by which NDC numbers are assigned will have a one-
time cost during the first year of $3.8 million and annual, recurring 
costs of $3.2 million.
2. Other Costs of the Proposed Rule
    Potential costs of the proposed rule also include: (1) The costs 
and cost savings for obtaining NDC numbers and recurring electronic 
registration and listing submissions; (2) the costs of label revisions 
for some drugs to include NDC numbers; (3) the costs of setting up 
electronic submissions of registration information, listing 
information, and content of labeling; and (4) the costs of continuing 
the submission of content of labeling. In addition, discussions with 
industry revealed two areas of potential concern that are not specific 
costs of the proposed rule. The first area of concern is potential 
delay in the assignment of NDC numbers, and the second area of concern 
is the use of repacker or relabeler NDC numbers on drug labels (rather 
than the manufacturer's NDC number) and the effect on negotiated 
reimbursements with third-party payers, including CMS.
    a. Costs and cost savings for obtaining NDC numbers and recurring 
electronic registration and listing submissions. This category consists 
of eight types of identified costs or cost savings:
     Costs for prospectively obtaining NDC numbers for human 
prescription drug products, human OTC drug products, animal 
prescription drug products, animal OTC drug products, and active 
pharmaceutical ingredients.
     Costs for electronic submission of new drug listings.
     Costs for electronic submission of changes to drug 
listings.
     Costs to certify no drug listing changes.
     Costs for drug product salvagers to list.
     Costs to register new establishments electronically.
     Costs to review and update establishment registration 
electronically, including certifying no changes.
     Costs to obtain user accounts from FDA.
    Currently, manufacturers, repackers, relabelers, and drug product 
salvagers register establishments and (except for salvagers) list their 
drugs. This can be a time-consuming procedure involving different forms 
that collect data for later computer entry. Forms must be completed by 
hand and changes to information to be submitted to us require that the 
entire form be redone.
    With electronic submission of this information under the proposed 
rule, information may be keyed in and any changes may be made to the 
information submitted. Information would not have to be resubmitted 
each time. We expect the proposed rule will result in substantial time 
and cost savings in the use of electronic submissions.
    New NDC numbers for drugs: ERG used FDA drug listing data to 
determine that over 11,000 new domestic drug

[[Page 51332]]

listings occur each year (foreign drug listings are not counted in this 
analysis). The time required to submit information and coordinate with 
FDA for an NDC number is estimated to be 0.5 hours per drug 
(incremental to the time required for a firm to assign NDC numbers to 
themselves.) The BLS reports that the compensation (including benefits) 
for a mid-level manager within this industry is $51.73. We expect the 
annual cost to obtain NDC numbers for new drugs to equal about $0.3 
million (11,000 new drug listings x 0.5 hours x $51.73 per hour.)
    Electronic submission of new drug listings: Currently, it takes 
approximately 2.5 hours to compile, copy, and mail drug listings to 
FDA. The annual cost for this activity is currently $1.4 million 
(11,000 drug listings x 2.5 hours x $51.73 per hour.) We expect that 
this activity will only require approximately 1 hour per drug listing 
if submitted electronically under the proposed rule. The annual cost 
would then be $0.6 million (11,000 new drug listings x 1 hour x $51.73 
per hour.) Electronic submission of drug listings would result in 
annual cost savings of $0.8 million.
    Electronic submission of changes to drug listings: Currently, any 
changes to drug listings entail that the entire form be redone by hand. 
Therefore, approximately 2.5 hours is currently required to compile, 
copy, and mail any change to FDA. FDA's drug listing data estimate that 
there are approximately 36,000 changes to domestic drug listings each 
year. The current cost of this activity is $4.7 million (36,000 annual 
changes x 2.5 hours x $51.73 per hour.) Electronic submission of 
changes is expected to require only 0.5 hours per submission. The 
expected annual cost of using electronic submissions would be $0.9 
million (36,000 annual changes x 0.5 hours x $51.73 per hour). 
Electronic submission of changes to drug listings would result in 
annual cost savings of $3.8 million.
    Electronic certification of no drug listing changes: As discussed 
earlier in this document, there are 83,600 domestic drug listings that 
must be reviewed twice a year to certify that there are no changes to 
the listing. There are approximately 36,000 annual changes to domestic 
drug listings, so we expect 131,200 annual certifications ((83,600 drug 
listings x 2 annual reviews)--36,000 changes). The time required to 
electronically certify that there have been no changes is not expected 
to be more than 0.25 hours (15 minutes.) The total cost of 
certification of no drug listing changes is $1.7 million (131,200 
annual certifications x 0.25 hours x $51.73.)
    Drug product salvagers: According to industry experts, only about 5 
percent of all listed drugs may be salvaged during any year. According 
to our listing data, there are approximately 83,600 domestic drug 
listings (foreign listings are not counted here), so approximately 
4,200 domestic drugs are estimated to be salvaged each year (83,600 x 
0.05.) Since the original manufacturer usually acts as the salvager, 
under the proposed rule, the original drug listing would be available 
electronically and could be easily copied to produce the drug listing 
for the salvaged drug. We expect that copying and submitting that drug 
listing (or withdrawal) would take 0.167 hours (10 minutes) and result 
in total annual costs of only $36,000 (4,200 salvaged drugs x 0.167 
hours x $51.73 per hour.)
    Electronic submission of new establishment registrations: According 
to our registration database, there are an average of approximately 
1,100 new sites registered each year, of which about 900 are domestic. 
The current registration process for new establishments takes 2.5 
hours. The annual cost to register new establishments is about $0.1 
million (900 new domestic registrations x 2.5 hours x $51.73 per hour). 
The proposed rule will require new registrations to be done 
electronically and we expect this will take approximately 1 hour per 
registration. The cost of registering new establishments with the 
proposed rule would equal about $47,000 (900 new domestic registrations 
x 1 hour x $51.73 per hour.) The use of electronic submissions for new 
establishments would result in cost savings of about $0.1 million.
    Electronic review and update of establishment registration: There 
are currently 9,700 domestic registered sites that must reregister each 
year, including certification of no changes to their registration 
information, and there are about 1,500 annual updates to domestic 
registration forms. The current estimate for this activity is 2.5 hours 
per submission for a current cost of about $1.4 million ((9,700 
registered sites + 1,500 annual updates) x 2.5 hours x $51.73 per 
hour). We expect each annual registration will take 0.5 hours and each 
amendment will be expedited and take only 0.25 hours under the proposed 
rule. Annual registration would have a cost of about $0.3 million 
(9,700 registered sites x 0.5 hours x $51.73 per hour). FDA has 
estimated that expedited updates of changes to registration under the 
proposed rule would require only 0.25 hours (15 minutes) per update. 
The cost of this activity under the proposed rule would be only $20,000 
(1,500 annual updates x 0.25 hours x $51.73 per hour.) This includes 
the costs to review and certify that there are no changes to 
registration information. The proposed rule is expected to result in 
annual cost savings of $1.1 million from electronic review and update 
of establishment registration.
    FDA user accounts: Prior to submitting electronic registration and 
listing information, the proposed rule requires manufacturers, 
repackers, relabelers, and drug product salvagers to obtain a user 
account from FDA. The proposed rule has us contacting each 
manufacturer, repacker, relabeler, and drug product salvager to request 
information to establish an account. FDA data suggest that 8,300 such 
requests would be made, based on primary registrants, of which 6,700 
would be domestic firms. We expect each request to take about 0.25 
hours (15 minutes.) The total one-time cost of this requirement is 
about $0.1 million (6,700 companies x 0.25 hours x $51.73 per hour.)
    Total cost savings of electronic registration and listing: Overall, 
the proposed rule is expected to result in annual cost savings of 
approximately $3.8 million due to electronic submission of registration 
and listing information. There is a one-time cost of $0.1 million for 
obtaining FDA user accounts.
    Some manufacturers expressed concerns about potential time lags due 
to our assignment of product codes and package codes, but the 
electronic process should provide for prompt responses to requests for 
NDC numbers from FDA. Also, manufacturers commented that if labeler 
codes must be consolidated across subsidiaries or divisions, additional 
costs would occur.
    We do not anticipate that we will receive requests for waiver of 
the requirement to submit registration and listing information 
electronically. However, if we receive waiver requests, we do not 
expect the costs to exceed those that would be incurred by paper 
submission of the information.
    b. Costs of label revisions to include NDC numbers. The proposed 
rule would require that appropriate human-readable NDC numbers appear 
on the labels of all drugs that are required to be listed, including 
biological products and active pharmaceutical ingredients.
    Prescription human drugs: Many manufacturers, repackers, relabelers 
and private label distributors, particularly those subject to the 
regulation addressing bar code label requirements (``Bar Code Label 
Requirements for

[[Page 51333]]

Human Drug Products and Human Biological Products''; 69 FR 9120, 
February 26, 2004), already voluntarily include the NDC number in 
human-readable form under the barcode representation, as space permits. 
This proposed rule would require the appropriate human-readable NDC 
number to appear on drug labels for drugs subject to the listing 
requirements. Some packaging lines for prescription drugs have already 
been retooled to accommodate the unit-of-use requirement as set forth 
in the bar code rule. The costs of retooling these package lines have 
been analyzed in the bar code rule. However, we still expect as many as 
60 percent of all prescription separately packaged drug products\12\ to 
be revised because of the proposed rule.
---------------------------------------------------------------------------

    \12\ The number of separately packaged drug products is the 
number of drugs times the number of dosage forms times the number of 
concentrations times the number of package sizes. There are 
currently about 78,000 separate domestic prescription separately 
packaged drug products based on NDC number listings.
---------------------------------------------------------------------------

    Currently, human-readable NDC numbers appear with an ``N'' or 
``NDC'' prefix. The proposed rule would require use of only the ``NDC'' 
prefix. In addition, there are classes of prescription drugs that are 
exempt from the bar code rule that would be subject to the requirement 
in this proposed rule (i.e., that the drug labels for drugs subject to 
listing requirements bear the appropriate NDC number in human-readable 
form). There are some products (e.g. allergenic extracts) that do not 
currently print NDC numbers on labels that would be obligated to do so 
under the proposed rule.
    We lack specific data on the proportion of affected labels, but 
believe that 50 percent would be revised to include the ``NDC'' prefix 
and an additional 10 percent may be accounted in one of the other 
categories. (Although the exact proportion of labels affected by this 
provision is unknown, we expect between 25 and 75 percent of all drug 
labels to require revisions. We have assumed that 50 percent of all 
labels will be affected for analytic purposes.) Therefore, ERG 
estimated that 46,800 separately packaged drug products would need 
revised relabels under the proposed rule.
    Prescription drugs would be required to have revised labels that 
include appropriate human-readable NDC numbers within 3 years of the 
effective date of the final rule. Therefore, incremental regulatory 
costs would occur for any product label not revised during routine 
label changes that may occur during the 3-year period. (ERG has assumed 
that no incremental cost occurs if required label changes occur during 
other label revisions.) FDA has examined a number of prescription drug 
files and found that prescription products are sometimes revised as 
frequently as once a year. However, some prescription products rarely 
have label revisions in response to market conditions. We have assumed 
that 25 percent of prescription drug labels would not be revised during 
the 3-year implementation period in the absence of the proposed rule, 
or 11,700 separately packaged drug products.
    ERG has estimated weighted label revisions as costing an average of 
about $1,600 per separately packaged product (Ref. 5.) The cost of 
revising prescription human drug labels to include NDC numbers is 
estimated to total $18.7 million (11,700 separately packaged drug 
products x $1,600 per label revision.) However, these costs are not 
expected until 3 years after the implementation of the final rule 
because companies would not know if there would be market driven label 
changes and therefore wait until the end of the implementation period. 
The present values of the cost of these label revisions are $17.1 
million (using a 3-percent annual discount rate) and $15.3 million 
(using a 7-percent annual discount rate.)
    OTC human drugs: FDA has estimated that only 30 percent of all 
human OTC separately packaged products currently have human-readable 
NDC numbers printed on labels. However, the proposed rule allows for a 
7-year implementation period for OTC drugs to include NDC numbers on 
labels. Based on previous studies of the OTC drug industry (Ref. 5), 
ERG has estimated that virtually all OTC drugs have label revisions 
within 6-year periods. Label changes over this period are mostly 
motivated by marketing trends and because ample space is usually 
available on most OTC labels, the inclusion of NDC numbers could be 
accommodated during these revisions at minimal additional cost.
    However, ERG discussions with industry contacts raised concerns 
about the new label requirements as they apply at the OTC unit-of-use 
level (e.g., blister packs). Most drugs marketed as units-of-use, 
including those subject to the bar code rule, would require label 
changes, but not changes to packaging or printing equipment, and are of 
sufficient size to accommodate human-readable NDC numbers. However, 
some packaging lines for unit-of-use OTC products not subject to the 
bar code rule might need to be retooled to accommodate human-readable 
NDC numbers. These modifications are expected to be fairly challenging 
and the costs of applying NDC numbers to blister packs would be in 
addition to normal label revisions. ERG discussed the costs of these 
changes and found that line retooling costs to be approximately 150 
percent of a normal label revision, or $2,400 for each affected drug. 
Industry consultants estimated that as many as 5,000 units-of-use 
packaged OTC human drugs could be affected. The cost to label units-of-
use drugs is $12.0 million (5,000 drugs x $2,400 per drug). Unlike 
voluntary label revisions, manufacturers are not expected to routinely 
retool production lines during the implementation period. Therefore, 
affected companies are expected to upgrade lines during the 7-year 
implementation period with an industry cost of $1.7 million each year. 
The present values of this cost are equal to $10.6 million (using a 3-
percent annual discount rate) and $9.2 million (using a 7-percent 
discount rate).
    Prescription and OTC animal drugs: ERG estimated that each of the 
2,100 registered domestic animal drug sites produce 4 separately 
packaged drug products and that normal label revisions occur at the 
same rate as for human drugs. In addition, industry consultants have 
estimated that approximately 40 percent of animal drugs currently have 
readable NDC numbers on labels and would not be affected by the 
proposed rule. Thus, ERG expects that of the 60 percent of labels that 
would need revisions, 75 percent would be revised in the normal course 
of business during the 3 years after implementation of the final rule. 
Therefore, a total of approximately 1,300 animal drugs would require 
revised labels to include human readable NDC numbers (both prescription 
and OTC) (2,100 sites x 4 separately packaged products x 0.6 needing 
label revisions x 0.25). Using a weighted cost per labeling revision of 
$1,600, the cost during the third year to the industry of applying NDC 
numbers to labels due to the proposed rule would be $ 2.1 million 
(2,100 separately packaged products x $1,600 per label change). The 
present value of this cost is $1.9 million (using a 3-percent annual 
discount rate) and $1.7 million (using a 7-percent discount rate). We 
do not believe there will be costs associated with retooling package 
lines for animal drugs.
    Active pharmaceutical ingredients. Active pharmaceutical 
ingredients would be required to bear appropriate human-readable NDC 
numbers on drug labels under the proposed rule. Currently, many active 
pharmaceutical ingredients are shipped with bills of

[[Page 51334]]

lading that are prepared for each shipment and an NDC number could be 
easily added for a negligible incremental cost. For the purposes of 
this analysis, we have assumed that 50 percent of all active 
pharmaceutical ingredients will be required to add human-readable NDC 
numbers as a result of this proposed rule. According to FDA's current 
registration and listing data, there are about 4,300 domestic bulk drug 
substances so about 2,150 are expected to require label changes because 
of the proposed rule. The costs of providing label changes for active 
pharmaceutical ingredients are assumed to be equal to the cost of label 
revisions for prescription drug products, or $1,600 per revised label. 
The total cost of revising active pharmaceutical ingredient labels is 
$3.4 million (2,150 labels x $1,600 per label). We have no data on 
voluntary label revisions for active pharmaceutical ingredients and 
have assumed that the revisions will occur throughout the 
implementation period (approximately $1.1 million per year). The 
present values for this cost are $3.2 million (using a 3-percent annual 
discount rate) and $3.0 million (using a 7-percent annual discount 
rate).
    Total costs of label revisions. The overall incremental costs of 
label revisions under the proposed rule have present values of $34.0 
million (using a 3-percent annual discount rate) and $30.3 million 
(using a 7-percent discount rate).
    c. Costs of setting up electronic submission of registration, 
listing, and content of labels. The proposed rule would require 
manufacturers, repackers, relabelers, and drug product salvagers of 
drugs, including human and animal drug products, active pharmaceutical 
ingredients, and biological products to register establishments, list 
drugs, and, for manufacturers, to provide the content of labeling 
electronically using specific software. Most, but not all, 
manufacturers of human prescription drug and biological drug products 
are already subject to requirements to submit content of labeling in 
electronic format, but manufacturers of OTC monograph and animal drug 
products not currently subject to these labeling requirements would not 
necessarily have this software. The current requirement to submit 
content of labeling in electronic form does not extend to repackers and 
relabelers. In addition, active pharmaceutical manufacturers producing 
ingredients for OTC drug products may not have the correct software to 
submit registration and listing information electronically.
    According to discussions with industry consultants, approximately 
75 percent of drug product manufacturers market only OTC monograph 
products. Using U.S. Census estimates of the industry, we believe about 
550 firms would need to purchase needed software for electronic 
submissions for content of labeling. We note that this estimate is 
based on the first level of ownership and does not account for multiple 
layers of corporate hierarchy. We surveyed a range of prices for 
software (such as Adobe Acrobat Standard, for example) that would be 
expected to be used in a professional environment. The estimated price 
of this software is approximately $250, with some variance for the 
specific desired features and sophistication. We note that this cost 
represents the marginal difference between any current software and new 
software with the capability to work with assigned NDC numbers, and is 
an incremental cost of the proposed rule. After discussing this 
estimate with industry IT personnel, we expect $250 to represent a 
reasonable cost of software acquisition. In addition, training for 2 
employees is expected to cost $150 per employee. Training is expected 
to require 6 hours for each employee at a cost of $51.73 per hour 
(based on fully loaded BLS wage rates for mid-level management within 
this industry). The total cost per firm is about $1,000 ($250 + (2 
employees x $150) + (2 employees x 6 hours x $51.73) for a total cost 
to the OTC monograph industry for software acquisition and training to 
be $0.6 million to submit content of labeling electronically.
    We expect similar costs of $1,000 would accrue for all 350 
companies that are predominantly involved in medicinal and botanical 
manufacturing (Census, 2004), which includes active pharmaceutical 
ingredient manufacturers, in order for these companies to 
electronically submit registration and listing information. According 
to Small Business Administration data, as well as industry consultants, 
there are approximately 250 repackers and relabelers that serve the 
pharmaceutical industry. Each of these entities would require software 
and training in order to register and list. Finally, there are 80 firms 
that, according to U.S. Census data, predominantly or secondarily 
manufacture animal drugs that would require software and training to 
electronically submit content of labeling. The total costs of software 
acquisition and training for these segments is an additional $0.7 
million ((350 active pharmaceutical ingredient manufacturers + 250 
repackers and relabelers + 80 animal drug manufacturers) x $1,000).
    The overall cost of software acquisition and training under the 
proposed rule is $1.4 million.
    d. Costs of continuing submissions of content of labeling. 
Additional costs might be incurred to submit the incremental content of 
labeling for a small proportion of drugs for which there have been 
labeling changes. The content of labeling, as described elsewhere in 
this proposal, must be submitted electronically. Makers of active 
pharmaceutical ingredients are not affected by this provision because 
they would not be expected to submit content of labeling 
electronically.
    For affected OTC drugs, we have assumed that two content of 
labeling submissions per listed drug will occur twice a year to account 
for the possibility of multiple dosage forms and concentrations in a 
product line. Animal products are expected to have an average of 1.5 
content of labeling submissions per product twice a year. According to 
our drug listing system, there are about 30,400 domestic OTC drugs and 
about 4,200 domestic animal drugs. Using the assumption that each 
submission would entail 0.25 hours (15 minutes), and using the industry 
wage rate of $51.73 per hour, the annual cost of this provision is $1.7 
million ((((30,400 domestic OTC drugs x 2 content of labeling 
submittals) + (4,200 domestic animal drugs x 1.5 content of labeling 
submittals)) x 2 times per year) x 0.25 hours per submission x $51.73 
per hour).
    e. Delays in NDC Assignment. We understand from discussions with 
manufacturers that many manufacturing processes are dependent on timely 
assignment of NDC numbers. According to industry consultants, before 
drugs can be mass-produced, manufacturers of both prescription and OTC 
drug products need to know the NDC number for the production run. 
Currently, manufacturers control the assignment of NDC numbers once 
they have a labeler code, so this is not a problem that could affect 
the production process. There is concern about delays in production 
because new NDC numbers assigned by us might not be timely from a 
manufacturer's viewpoint and could result in major costs.
    However, in discussions with several manufacturers, comments to ERG 
reflected that if the assignment of NDC numbers by FDA was done 
electronically and transmitted to the companies electronically, there 
would likely be a negligible impact on operations. Since FDA intends to 
assign and transmit NDC numbers

[[Page 51335]]

electronically, we do not believe this provision would result in 
additional costs to industry.
    f. Effect of the proposed rule on third-party reimbursement. Under 
the proposal, repackers and relabelers would not be allowed to use the 
manufacturer's human-readable NDC numbers on their drug labels. Many 
companies noted that reimbursement arrangements are contracted between 
drug manufacturers and third-party payers (including Medicaid programs) 
that provide for rebates for sales of a manufacturer's drug. Most 
reimbursement plans use NDC numbers as the appropriate billing code, 
and repackers and relabelers note that they are not part of the 
negotiated rebate plans between manufacturers and third-party payers. 
Repackers and relabelers further claim that profit margins for their 
firms will not allow for such reimbursements. Thus, the process of 
negotiating these payments would be affected by the proposed rule, but 
we did not estimate the outcome of future negotiations.
    g. Other potential costs. The proposed rule might have other 
impacts on various industry sectors. For example, the relationships 
between drug manufacturers and private label distributors may be 
altered because of the proposed registration, listing, and NDC 
requirements. Some industry sources have asserted that the proposed 
rule may make private label distributors unprofitable and that 
manufacturers would directly supply drugs to retailers. We are unable 
to assess this impact, and are unsure whether it would, in fact, result 
in market inefficiencies, but note that there would likely be changes 
in the current relationships between these sectors. We specifically 
request comment on any economic impact the proposal would have on this 
relationship between drug manufacturers and private label distributors.
3. Costs to FDA for Implementing the Proposed Rule
    We do not expect a major increase in the need for internal 
resources associated with the proposed rule. Activities related to the 
assignment of NDC numbers are expected to be equivalent to our current 
activity of receiving notifications from industry and manually 
inputting the information into our databases. Similarly, we expect any 
increased workloads caused by increased submissions of registration or 
listing information or content of labeling to be approximately 
equivalent to the internal reduction in workload from electronically 
updating our databases. The database of NDC numbers for marketed drugs 
would require maintenance and updating to ensure the quality of the 
data, and we would make this database available for other users, but 
the costs associated with activity have been accounted for in previous 
rule-making (see Bar Code Label Requirements for Human Drug Products 
and Human Biological Products, 69 FR 9120 at 9156). The registration 
and listing information will also be included in the database and we do 
not expect any additional costs to be associated with maintenance of 
this information.
    However, the requirement that manufacturers, repackers, relabelers, 
and drug product salvagers obtain a user account from us would require 
increased use of our resources. We have estimated that 6,700 entities 
would be contacted in order to provide them with their user accounts, 
and that each contact would require 0.25 hours (15 minutes). This would 
require about 1,600 hours of FDA resources, or about 0.8 FTEs. The 
current weighted cost per FTE is approximately $120,000, so the one-
time cost to FDA for providing access codes for the proposed rule would 
be approximately $0.1 million.
4. Total Costs of the Proposed Rule
    Table 3 shows the initial investment costs and annual costs of the 
proposed rule over a 10-year period by cost category.

 Table 3.--Undiscounted Costs of Proposed Rule by Category (in Millions
                               of Dollars)
------------------------------------------------------------------------
                         Initial Investment/One
     Cost Category                Time            Annual Costs/Recurring
------------------------------------------------------------------------
Single Method of                           $3.8                     $3.2
 Assigning NDC Numbers
------------------------------------------------------------------------
Electronic Drug                            $0.2                  (-$3.8)
 Registration and
 Listing
------------------------------------------------------------------------
Label Revisions                           $36.2                   ------
------------------------------------------------------------------------
Software Acquisition                       $1.3                   ------
 and Training
------------------------------------------------------------------------
Continued COL                           -------                     $1.7
 Submissions
------------------------------------------------------------------------

    Table 4 shows the expected expenditures per year for the evaluation 
period and includes total present values based on 7 percent and 3 
percent discount rates. Recurring costs include the retooling of OTC 
packaging systems to provide NDC numbers for units-of-use during the 
first 7 years of the proposed regulation.

 Table 4.--Costs per Year for the Proposed Rule (in Millions of Dollars)
------------------------------------------------------------------------
          Year                One-Time Costs          Recurring Costs
------------------------------------------------------------------------
1                         $8.1                    $1.1
------------------------------------------------------------------------
2                         $2.8                    $1.1
------------------------------------------------------------------------
3                         $23.7                   $1.1
------------------------------------------------------------------------
4                         $1.7                    $1.1
------------------------------------------------------------------------
5                         $1.7                    $1.1
------------------------------------------------------------------------
6                         $1.7                    $1.1
------------------------------------------------------------------------
7                         $1.8                    $1.1
------------------------------------------------------------------------
8                         -                       $1.1
------------------------------------------------------------------------
9                         -                       $1.1
------------------------------------------------------------------------
10                        -                       $1.1
------------------------------------------------------------------------
Present Value             3% - $38.1              3% - $9.4
------------------------------------------------------------------------
                          7% - $33.0              7% - $7.7
------------------------------------------------------------------------


[[Page 51336]]

    Average annualized costs of the proposed rule are estimated to be 
$5.6 million using a 3 percent annual discount rate or $5.8 million 
using a 7 percent annual discount rate.

F. Benefits

    Benefits of the proposed rule will result because the improved 
processes in the proposed regulation would generate up-to-date, 
complete medication information, including NDC numbers, to support a 
growing number of medical and health information technology 
initiatives. The potential benefits of these initiatives are 
significant. For example, the final regulation that required bar coded 
NDC numbers on some human drugs and biological products (69 FR 9120) 
estimated benefits of approximately $5 billion per year for the 
avoidance of over 500,000 adverse drug events associated with 
medication errors. These benefits are dependent on correct and unique 
NDC numbers being read by scanners at patient bedsides. The lack of 
accurate NDC numbers may delay the acceptance of this technology and 
decrease the potential patient benefits. We have estimated that if the 
lack of reliable NDC numbers would delay the rate of technological 
acceptance by 1 year, the potential benefits of the bar code regulation 
would be reduced by about $600 million per year and an average of 
25,000 additional adverse drug events would occur.
    We believe it is critical to other patient safety initiatives, such 
as DailyMed or electronic prescribing, that a reliable and consistent 
NDC numbering system be in place. The potential benefits of these 
initiatives could be similar to the benefits of the bar code rule, and 
any delay in implementing these programs because of the lack of 
electronic access to reliable identifying information could seriously 
limit their impacts.
    The proposed rule would allow increased access to information in 
our databases. Increased use of these databases to efficiently treat 
patients would rely on the availability of information electronically. 
A key element for encouraging the use of technology to ensure public 
health will be the assurance that NDC numbers are unique and accurately 
identify drugs. The proposed rule would accomplish this by making 
assignment of NDC numbers our responsibility, rather than a 
responsibility diffused throughout the industry. In addition, by 
ensuring that these NDC numbers are available in human-readable format, 
patients and others would be able to access important patient safety 
information from the DailyMed system, the NDC Directory, or other drug 
information electronic systems without the use of bar code scanners. 
Human-readable NDC numbers would allow patients to report any adverse 
events easily and ensure that our adverse event reporting system is as 
accessible as possible. Also, the human-readable NDC number would 
enable us to trace the origin of each product (a particularly important 
issue when dealing with recalls or drug quality issues) and more easily 
identify drug products and their sources (this is particularly 
important when dealing with import and counterfeiting issues). We 
specifically request comments on quantitative benefits resulting from 
the requirement that the NDC number be included on the drug label.
    The proposed rule would increase the efficiency of the registration 
and listing process by eliminating most paper submissions. We would be 
able to review the submitted information more quickly and contact 
submitting firms immediately if any additional information were needed. 
The resulting database of registered establishments and listed drugs 
would provide the basis for increased patient safety by being complete 
and up-to-date. For example, an electronic database of drugs would 
allow for timely notification of any recalls of unsafe drugs and 
identification of affected manufacturers, repackers, relabelers, or 
drug product salvagers.
    By changing the way that NDC numbers are assigned, we would 
increase the confidence that each drug being manufactured, repacked, or 
relabeled for commercial distribution has a unique identifier that we 
have assigned. After we have introduced increased oversight for new 
product codes and package codes, the likelihood of unsafe counterfeit 
drug products entering the supply chain would decline because would-be 
counterfeiters would be unsure of numerical sequences used for NDC 
numbers. Our assignment of NDC numbers would reduce the possibility of 
duplicate numbers appearing in various medical and reimbursement 
databases. Currently, firms have been reusing NDC numbers at times 
without informing us, and this practice has added uncertainty into 
these systems. There has been reported confusion about coverage of 
drugs for reimbursement and our control of the NDC system would ensure 
that only qualified drugs are subject to reimbursement.
    In addition, the current NDC number makeup (using dashes to 
distinguish between the components) allows for potential duplicate 
numbers when the dashes are not read by scanners reading NDC numbers 
encoded in bar codes. This happens because the components used to 
indicate labeler codes, product codes, and package codes are of 
differing lengths, and are currently separated by hyphens. If those NDC 
numbers are barcoded, the differing components may lead to duplicate 
numbers since bar code scanners don't read hyphens. This would not 
happen under the proposed rule.
    Although we know that the proposed rule will result in significant 
benefits, we are not able to quantify these benefits. We are confident 
that moving to electronic registration and listing processes, as well 
as assignment of NDC numbers, would encourage development of technology 
in the delivery of health care. We know that the successful development 
of medical and health information technology initiatives (such as the 
DailyMed, bar code label, and the electronic prescription drug program 
described below) will depend in large part on an accurate, reliable NDC 
number and that this proposed rule would further that development. 
Therefore, there are real benefits associated with the proposed changes 
to the NDC number and the NDC number assignment process. However, we 
are not able to quantify those benefits because they rely in part on 
further development of technology initiatives. Similarly, there are 
significant benefits associated with the proposed changes to the 
collection of registration and listing information. For example, ready 
access to complete and accurate registration and listing information 
helps to ensure the success of many of our programs, such as 
postmarketing surveillance (including FDA inspections), bioterrorism 
initiatives, responses to drug shortages, and user fee assessments. We 
know there are benefits associated with the efficiencies achieved by 
improved access to more complete information, but we are not able to 
quantify those benefits.
    We also note that continuation of a paper registration and listing 
system is likely to act as a deterrent to investment in new 
initiatives. As discussed earlier in this document, the recently issued 
final regulation that requires NDC numbers to be encoded in bar codes 
on certain prescription drugs, certain OTC products, and human blood 
products helps to avoid adverse drug events due to medication errors. 
The benefits for that rule would be reduced by as much as $600 million 
per year if unique NDC numbers are not universally available and this 
results in delays in the use of this technology. Lack of universal

[[Page 51337]]

identifiers would likely discourage investment in machine-readable 
technology and make access to electronic information difficult.
    The proposed rule would provide necessary assurances to health 
professionals and patients that they have access to up-to-date labeling 
information and that the safety of the drug supply is assured. It would 
also encourage investment in installed scanners and readers at points 
of administration such as hospitals or physician clinics that rely on 
this information. The existence of this system may support the 
development of electronic prescribing or other efficiencies in health 
care that may save money and reduce medication errors that may cause 
adverse reactions in patients. The electronic prescription drug program 
(electronic prescribing) established by the Medicare Modernization Act 
promotes uniform standards that permit (among other things) electronic 
exchange of drug labeling and drug listing information maintained by us 
and by the National Library of Medicine. The goal behind the program is 
to reduce transcription and dispensing errors (which, in turn, lead to 
medication errors) and to prevent adverse drug interactions. The 
proposal to assign the NDC number, resulting in an accurate and 
reliable NDC number, would also facilitate development of the 
DailyMed). The DailyMed is an up-to-date, computerized repository of 
medication information, including drug product labeling. The DailyMed, 
maintained by the National Library of Medicine in cooperation with FDA, 
is a new way to distribute current and comprehensive medication 
information in a computerized format for use in health care information 
systems. Health care information suppliers will be able to use the 
information from the DailyMed in their computer systems, allowing 
providers, patients, and the public access to reliable, up-to-date 
information on the medications they use. The DailyMed would enable drug 
product users and health care providers to have electronic access to 
up-to-date information about a drug.
    Although the scope of the proposed rule does not extend beyond 
registration and listing, the high-quality, electronic database that 
would result from the proposed rule would enable future uses of 
technology for the public benefit.

G. Small Business Analysis and Discussion of Alternatives

    We believe the proposed rule is unlikely to have a significant 
impact on a substantial number of small entities. Despite this, we have 
prepared an initial regulatory flexibility analysis and invite comment 
from affected entities.
1. Affected Sectors and Nature of Impacts
    The proposed rule would directly affect manufacturers of 
pharmaceutical and biological products (NAICS 325412 and NAICS 325414), 
packaging services (NAICS 561910), retail pharmacy chains (NAICS 
446110; Pharmacies), and prescription benefit managers (NAICS 524292; 
Insurance Plan Administrative Services, Third Party). We assessed data 
on these industries from the 2002 Economic Censuses and estimated 
revenues per establishment. The affected establishments are shown in 
table 2a of this document. Although other economic measures, such as 
profitability, may provide preferable alternatives to revenues as a 
basis for estimating the significance of regulatory impacts in some 
cases, use of any reasonable estimate of profits would not change the 
results of this analysis. As discussed earlier in the Analysis of 
Economic Impacts (see section VI.B of this document), we are proposing 
this rule in order to improve the quality and timeliness of information 
available to patients and health care professionals. We believe this 
improvement would result in improved outcomes by providing better uses 
of medicines by patients.
    a. Pharmaceutical manufacturers (NAICS 325412). The Small Business 
Administration (SBA) has defined as small any entity in this industry 
with fewer than 750 employees. According to census data, 94 percent of 
the industry is considered small. The average annual revenue for these 
small entities is $54.7 million per entity. Small entities would be 
affected by the proposed rule. We estimate the annualized compliance 
cost for small entities in this industry to average $30,200. This is 
about 0.1 percent of their annual revenue. We believe this cost does 
not constitute a significant impact on a substantial number of small 
entities in this industry.
    b. Biological product manufacturers (NAICS 325414). The SBA has 
defined as small any entity in this industry with fewer than 750 
employees. According to census data, 97 percent of the industry is 
considered small. The average annual revenue for these small entities 
is $15.5 million per entity. Small manufacturers of biological products 
would be affected by the proposed rule. We estimate the annualized 
compliance cost for a small entity in this industry to be $30,200. This 
is about 0.2 percent of their annual revenues. We believe this does not 
constitute a significant impact on a substantial number of small 
entities in this industry.
    c. Packaging services (NAICS 561910). The SBA has defined as small 
any entity in this industry that has less than $6.5 million in annual 
revenue. On this basis, almost 94 percent of the industry is considered 
small. The average annual revenue for small entities is $1.4 million 
per entity. We have not identified specific regulatory costs of 
compliance to this industry. We have no confident data that the extent 
of electronic registration and listing would increase or decrease costs 
to these entities. At this point, we tentatively believe the proposed 
rule would not constitute a significant impact on a substantial number 
of small entities in this industry and solicit comment in this area.
    d. Retail pharmacy chains (NAICS 446110). The SBA has defined as 
small any entity in this industry that has less than $6.5 million in 
revenue. On this basis, almost 100 percent of the industry is 
considered small. The average annual revenue for small entities is $3.8 
million per entity. We expect that some large pharmacy chains with 35 
or more operations would experience increased operating cost of 
$200,000 due to the proposed rule. However, these large chains do not 
meet the criteria for small entities because their annual revenues are 
at least $133 million ($3.8 million times 35 outlets). We do not 
believe this impact constitutes a significant impact on a substantial 
number of small entities in this industry.
    We do not believe that independent retail pharmacies will be 
adversely affected by the proposed rule because most pharmacy systems 
do not use the internal component of NDC numbers. We found no evidence 
of any impacts, but specifically request comment on this issue.
    e. Prescription benefit managers (NAICS 524292). The SBA has 
defined as small any entity in this industry that has less than $6.5 
million in annual revenues. On this basis, over 92 percent of the 
industry is considered small. The average annual revenue for small 
entities is $1.6 million per entity. We are unable to distinguish PBMs 
from other insurance administrative services, but have used aggregate 
industry data. Some PBMs would be expected to experience annual cost 
increases of $200,000 due to the proposed rule. This constitutes 12.5 
percent of annual revenues for the affected entities. However, of the 
11,584 small entities in this industry (there are only 76 PBMs of any 
size) we expect that between 7 and 8 entities would be affected. We do 
not believe this constitutes a significant

[[Page 51338]]

impact on a substantial number of small entities in this industry.
2. Alternatives
    We considered several alternatives to the proposed rule. Each is 
discussed below.
    a. Completely reassign NDC numbers, including existing numbers. We 
considered removing the existing format of the NDC number and 
reassigning randomized numbers for all products. We believe this would 
improve the robustness of the NDC and allow more numbers to be 
available for future drugs as well as improve our industry oversight 
responsibilities. However, discussions with industry representatives 
suggested that the first-year cost of such an approach could reach more 
than $900 million. Pharmaceutical manufacturers would be required to 
completely remap the newly assigned NDC numbers so that existing data 
processing, rebate, and market analyses tasks could continue. While 
individual retail pharmacies would not likely be affected, chain stores 
and PBMs would require large internal reprogramming in order to manage 
repayment options. Additional quality control procedures would be 
required to ensure proper reimbursement. Wholesalers and distributors 
would also require major internal reprogramming to account for the loss 
of sequential NDC numbers. For this alternative, each State Medicaid 
program would require an estimated $3 million to reprogram 
reimbursement software so that each prescription could be tracked. This 
alternative is described in more detail in Reference 3.
    b. Implementation period. We considered (and are still considering) 
different implementation periods. Under the proposal, manufacturers, 
repackers, and relabelers of prescription drugs would have 3 years to 
provide NDC numbers on their labels, while manufacturers, repackers, 
and relabelers of OTC drugs would have 7 years. We examined a total of 
25 different implementation plans. These plans include prescription 
products having between 1 year and 5 years to comply and OTC products 
having between 5 years and 9 years to comply with the proposed rule. 
Table 5 shows the difference in average annualized costs between the 
current implementation plan and the other 24 combinations.

Table 5.--Differences in Annualized Costs of Differing Implementation Periods (in Millions of Dollars; 7 Percent
                                                 Discount Rate)
----------------------------------------------------------------------------------------------------------------
                       5 Year OTC         6 Year OTC         7 Year OTC         8 Year OTC         9 Year OTC
----------------------------------------------------------------------------------------------------------------
1 Year                         +$2.1              +$2.0              +$1.9              +$1.9              +$1.9
 Prescription
----------------------------------------------------------------------------------------------------------------
2 Year                         +$1.4              +$1.2              +$1.2              +$1.2              +$1.1
 Prescription
----------------------------------------------------------------------------------------------------------------
3 Year                         +$0.2                  0               ----              -$0.1              -$0.1
 Prescription
----------------------------------------------------------------------------------------------------------------
4 Year                         -$0.9              -$1.0              -$1.0              -$1.0              -$1.1
 Prescription
----------------------------------------------------------------------------------------------------------------
5 Year                         -$1.4              -$1.5              -$1.5              -$1.6              -$1.6
 Prescription
----------------------------------------------------------------------------------------------------------------

    There was relatively little difference in changes to the OTC drug 
implementation period because of the ongoing normal revisions to 
labeling. Only if a 5-year implementation period is selected are there 
noticeable cost increases. However, shorter implementation periods for 
prescription products increase costs by about 20 percent for a 2-year 
implementation period and about 33 percent for a 1-year period. 
Conversely, while longer implementation periods would reduce annualized 
costs by similar amounts, the delay in ensuring that medical 
information technologies would be able to use efficiencies expected 
from the proposed rule seemed high. Therefore, we selected the proposed 
implementation periods as a reasonable balance. We solicit public 
comment on the proposed implementation period and the effect on 
expected costs and benefits.
    c. Exemption for small entities. We considered exempting small 
entities, but rejected the alternative due to the relatively modest 
impact of this initiative on small businesses and the lack of label 
standardization that would result. Any potential exemptions to this 
proposed rule would be on a product basis, not an entity basis. In 
addition, benefits of having a standardized identification system would 
be reduced by such blanket exemptions.
    Outreach: We will specifically solicit comment from affected small 
entities on the proposed rule.
    d. Conclusion. We have analyzed the expected impacts of the 
proposed rule. This proposal is expected to have average annualized 
costs of $5.6 million (using a 3 percent annual discount rate) or $5.8 
million (using a 7 percent annual discount rate). The benefits include 
assurance of correct NDC numbers, which would also mean correct bar-
coded information, and electronic access to important product 
information for patients that will improve public health. Despite the 
fact that we are unable to specifically quantify patient benefits 
directly attributable to the proposed rule, we believe the benefits 
would be greater than the expected costs and the proposed rule should 
be implemented.

VII. Paperwork Reduction Act of 1995

    This proposed rule contains collections of information that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501 3520). 
``Collection of information'' includes any request or requirement that 
persons obtain, maintain, retain, or report information to the agency, 
or disclose information to a third party or to the public (44 U.S.C. 
3502(3) and 5 CFR 1320.3(c)). The title, description, and respondent 
description of the information collection are shown under this section 
with an estimate of the annual reporting burden. Included in the 
estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing the collection of information.
    We invite comments on these topics: (1) Whether the collection of 
information is necessary for proper performance of FDA's functions, 
including whether the information will have practical utility; (2) the 
accuracy of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be

[[Page 51339]]

collected; and (4) ways to minimize the burden of the collection of 
information on respondents, including through the use of automated 
collection techniques, when appropriate, and other forms of information 
technology.
    Title: Requirements for Foreign and Domestic Establishment 
Registration and Listing for Human Drugs, Including Drugs that are 
Regulated Under a Biologics License Application, and Animal Drugs
    Description: The proposed rule would reorganize, consolidate, 
clarify, and modify current regulations on registering establishments 
and listing human and animal drugs under part 207, blood and blood 
products under part 607, and HCT/Ps under part 1271. The proposal 
describes when and how to register and list and what information must 
be submitted for registration and listing. The proposal makes certain 
changes to the NDC system for drugs and would require the appropriate 
NDC number to appear on drug labels (for drugs subject to the drug 
listing requirements). The proposed regulations would require the 
electronic submission of all registration and most listing information 
instead of the current use of paper forms.\13\
---------------------------------------------------------------------------

    \13\ The electronic submission of registration and listing 
information would remain voluntary for blood products.
---------------------------------------------------------------------------

    FDA currently reviews completed registration and listing forms and 
other submissions required under current parts 207, 607, and 1271. The 
information collection for current part 207 is approved by OMB until 
December 31, 2007, under OMB Control Number 0910-0045. The information 
collection for current part 607 and Form FDA 2830 is approved by OMB 
until March 31, 2009, under OMB Control Number 0910-0052. The 
information collection for current part 1271 and Form FDA 3356 is 
approved by OMB until July 31, 2007, under OMB Control Number 0910-
0469.
    FDA has estimated, in Tables 6, 7, and 8 of this document, the 
burden to comply with all of the information collection requirements 
for proposed parts 207, 607, and 1271. These estimates are based on 
FDA's experience in reviewing registration and listing submissions and 
on the number of submissions currently received, the number of 
respondents submitting this information, and the number of registered 
establishments and listed drugs, blood products, and HCT/Ps currently 
in FDA's database. The estimates discussed below are for each section 
of proposed parts 207, 607, and 1271 that contain a reporting burden 
under the PRA.

A. Registration Information Under Part 207

1. Proposed Requirements
    Under proposed Sec.  207.17, manufacturers, repackers, relabelers, 
and drug product salvagers must register establishments. This is 
consistent with current registration requirements, except that 
currently private label distributors may submit information (similar to 
registration information) to obtain a labeler code from FDA. In 
addition, the estimates include PET drug producers who would not be 
exempt from registration under the proposal.
    Under proposed Sec.  207.21, domestic manufacturers, domestic 
repackers, domestic relabelers, and domestic drug product salvagers 
must complete initial registration of each establishment no later than 
5 calendar days after beginning to manufacture, repack, relabel, or 
salvage a drug. In addition, foreign manufacturers, foreign repackers, 
foreign relabelers, and foreign drug product salvagers must register 
each establishment before the drug is imported or offered for import 
into the United States. This is consistent with current registration 
requirements, except that the proposal would include additional foreign 
establishments as a result of the revocation of the exemption for drugs 
that enter a foreign trade zone and are re-exported from that foreign 
trade zone without having entered U.S. commerce, and for drugs imported 
under section 801(d)(3) of the act.
    The information that must be provided to FDA for registration is 
described under proposed Sec.  207.25. The information that would be 
required under proposed Sec.  207.25 differs from the information 
currently required for registration. The following currently required 
information would not be required under the proposal: The kind of 
ownership or operation and the title of each corporate officer and 
director. New information required under the proposal would be the type 
of operations performed at each establishment and contact information 
about the official contact and the United States agent, each importer 
of the drug that is known to the establishment, and each person who 
imports or offers for import the drug to the United States.
    Under proposed Sec.  207.29, manufacturers, repackers, relabelers, 
and drug product salvagers must review annually their registration 
information. During the review, manufacturers, repackers, relabelers, 
and drug product salvagers must report all changes to their 
registration information or certify that no changes have occurred. In 
addition to the annual review and update, manufacturers, repackers, 
relabelers, and drug product salvagers must submit expedited reports of 
certain changes within 30 calendar days of the change. Currently, 
manufacturers, repackers, relabelers, and drug product salvagers must 
renew their registration information annually and submit certain 
amendments to registration within 5 days of a change. Proposed Sec.  
207.29 differs from the current requirement to submit amendments to 
registration in the following ways: The proposal would lengthen the 
current time period for reporting changes to registration information 
from 5 days (10 business days for a change in United States agent 
information) to 30 calendar days. The proposal would revoke the current 
requirement to report a change in individual ownership and corporate or 
partnership structure, and the current requirement to submit a signed 
statement for a change in a registered establishment's firm name. New 
requirements under the proposal would be to certify that no changes 
have occurred and to report as expedited updates certain changes within 
30 calendar days, such as the close or sale of an establishment. 
Modified requirements would be to submit within 30 calendar days a 
change in the name or address of an establishment and a change in 
contact information for the official contact and United States agent.
2. Burden Estimates
    Based on the number of new establishments that currently register 
each year by submitting Form FDA 2656, we estimate that approximately 
987 manufacturers, repackers, relabelers, and drug product salvagers 
will provide electronically approximately 1,128 new establishment 
registrations annually. Based on the number of registered 
establishments in our database, we estimate that approximately 8,343 
manufacturers, repackers, relabelers, and drug product salvagers will 
provide approximately 12,137 annual reviews and updates of registration 
information or reviews and certifications that no changes have 
occurred. Based on the number of changes to registration information 
that have been submitted annually on Form FDA 2656e, we estimate that 
approximately 775 manufacturers, repackers, relabelers, and drug 
product salvagers will provide approximately 1,921 expedited updates.
    The estimates include the registration of establishments for both 
domestic and

[[Page 51340]]

foreign manufacturers, repackers, relabelers, and drug product 
salvagers. The estimates for the number of manufacturers, repackers, 
relabelers, and drug product salvagers excludes the number of private 
label distributors currently in the database that submit information to 
receive a labeler code. The estimates include an additional 80 PET drug 
producers who would not be exempt from registration under the proposal, 
and approximately 30 manufacturers of plasma derivatives. In addition, 
the estimates include five additional foreign establishments that would 
be required to register as a result of the revocation of the exemption 
for drugs that enter a foreign trade zone and are reexported from that 
foreign trade zone without having entered U.S. commerce, and for drugs 
imported under section 801(d)(3) of the act.
    We estimate that it will take approximately 60 minutes to provide 
electronically the initial registration information for each new 
establishment. This estimate is only until manufacturers, repackers, 
relabelers, and drug product salvagers become familiar with using the 
electronic drug registration and listing system. We intend to lower 
this burden estimate to approximately 30 minutes when we submit to OMB 
the request to renew approval of this information collection.
    We also estimate that it will take approximately 30 minutes for 
each annual review and update of registration information or each 
review and certification that no changes have occurred. This estimate 
is only until manufacturers, repackers, relabelers, and drug product 
salvagers become familiar with using the electronic drug registration 
and listing system. We intend to lower this burden estimate to 
approximately 15 minutes when we submit to OMB the request to renew 
approval of this information collection.
    We also estimate that it will take approximately 15 minutes to 
provide each expedited update. This estimate is only until 
manufacturers, repackers, relabelers, and drug product salvagers become 
familiar with using the electronic drug registration and listing 
system. We intend to lower this burden estimate to approximately 5 
minutes when we submit to OMB the request to renew approval of this 
information collection.
    The burden hour estimates above are based on our familiarity with 
the content of current registration forms and submissions and the times 
required by industry volunteers to input registration information 
during our electronic drug registration and listing system pilot 
project (discussed in section IV.E.3 of this document). The estimates 
are an average of the time it would take to register a domestic or 
foreign establishment and an average of the time it would take to 
review registration information and update several registration items 
in the database or review registration information and only certify 
that no changes have occurred. We note that these estimates for the 
electronic submission of this information would be a reduction in the 
currently approved estimate of 2.50 hours (OMB Control Number 0910-
0045) for preparing and mailing to FDA Form FDA 2656.
    We intend to migrate into our new database current registration 
information that had been submitted using paper forms. As a result, 
current manufacturers, repackers, relabelers, and drug product 
salvagers would require additional time to review in the new database 
all current registration information and make any necessary revisions. 
We assume that this one-time initial review will be the first annual 
review and update using the electronic system, and we estimate it will 
take an average of 30 minutes for each review and update.

B. Listing Information Under Part 207

1. Proposed Requirements
    Under proposed Sec.  207.41, manufacturers, repackers, relabelers, 
and drug product salvagers must list drugs they manufacture, repack, 
relabel, or salvage for commercial distribution (this includes drugs 
they manufacture, repack, relabel, or salvage for a private label 
distributor). This proposed requirement is consistent with the current 
listing requirements, except that drug product salvagers are not 
currently required to list under part 207 and private label 
distributors may submit listing information directly to FDA.
    Under proposed Sec.  207.45, manufacturers, repackers, relabelers, 
and drug product salvagers must list, at the time of initial 
registration of an establishment, any drug being manufactured, 
repacked, relabeled, or salvaged for commercial distribution at that 
establishment. This is consistent with the current listing 
requirements, except that drug product salvagers are not currently 
required to list under part 207.
    Under the proposal, the human-readable NDC number must appear on 
the drug's label (for drugs subject to the listing requirements). The 
information that must be provided electronically to us by 
manufacturers, repackers, and relabelers (including drug product 
salvagers who repack and relabel) to receive an NDC number is described 
under proposed Sec.  207.33. Currently, the human-readable NDC number 
is not required to appear on the drug's label, but most prescription 
drugs and about one-third of the OTC drug products have the NDC number 
on the label. We currently assign a labeler code to each manufacturer, 
repacker, relabeler, and private label distributor to be part of the 
NDC number, and the manufacturer, repacker, relabeler, and private 
label distributor assigns the remainder of the NDC number to each drug 
product. Under the proposal, for drugs listed after the effective date 
of the proposal, the NDC number for a drug must be obtained from us 
before (or at the time) that drug is listed. Some of the information 
currently required to list the drug would be submitted under the 
proposal to receive the NDC number. The assigned NDC number would be 
submitted as part of the listing information and would serve as a link 
to the information already submitted for the drug to obtain the NDC 
number.
    The information that must be provided electronically to us by 
manufacturers, repackers, and relabelers to list a drug is described 
under proposed Sec. Sec.  207.49, 207.53, 207.54, 207.55, and 207.61. 
As mentioned previously in this document, drug product salvagers are 
not currently required to list the drugs they salvage. The listing 
information and the NDC number information required under the proposal 
is consistent with the information currently submitted to FDA on Forms 
FDA 2657 or 2658, except for the following: (1) The proposal would 
require identification information about the name of each importer of 
the drug that is known to the establishment and each person who imports 
or offers for import a drug to the United States (importer information 
is currently required under the Bioterrorism Act); (2) the content of 
labeling would be submitted electronically (for approved human drugs, 
the information collection burden for this requirement is accounted for 
under current Sec.  314.50(l)(1)(i), approved under OMB Control Number 
0910-0001); (3) the quantity of the active pharmaceutical ingredient 
would be required for all drugs subject to the listing requirements 
(unless the approved application number is provided) (this requirement 
is substantially the same as the current requirement); (4) the name of 
the inactive ingredients for certain drugs would be required under the 
proposal (unless the approved application number is provided); (5) 
repackers and relabelers would be required to submit

[[Page 51341]]

the NDC number assigned to the drug immediately before they received 
the drug; (6) additional information to identify the manufacturer, 
repacker, relabeler, and drug product salvager would be required (such 
as e-mail address, fax number, and labeler code); (7) the submission of 
a representative sampling of labeling would include advertisements 
under Sec.  202.1(l)(1); (8) certain listing information would not have 
to be submitted if the approved U.S. application number for the drug is 
provided; (9) the DMF number would be submitted by the manufacturer to 
obtain an NDC number for an active pharmaceutical ingredient; and (10) 
drug product salvagers (who do not repack or relabel) would submit the 
lot number and expiration date and NDC number assigned to the drug 
immediately before the drug is received by the drug product salvager.
    Under proposed Sec.  207.57, manufacturers, repackers, relabelers, 
and drug product salvagers must review each June and December all drug 
listing information that has been provided to us and must report all 
material changes or certify that no changes have occurred. 
Manufacturers, repackers, and relabelers must also notify us at this 
time if any listed drug has been discontinued from marketing or if any 
discontinued drug has resumed marketing and provide listing information 
for any drug not yet listed. Under the proposal, all manufacturers, 
repackers, relabelers, and drug product salvagers must review the 
listing information for each drug listed and report any material 
changes. Current regulations do not specify that the information for 
each listed drug needs to be reviewed, nor is a certification required 
if there are no changes. Only material changes to listing information 
must be reported. Under the proposal and consistent with section 510 of 
the act, manufacturers, repackers, relabelers, and drug product 
salvagers must also update their listing information for drug products 
that have not been previously listed at the time registration 
information for each establishment is updated.
    Under proposed Sec.  207.33(f), manufacturers, repackers, and 
relabelers must notify us of a change in any of the drug 
characteristics (except certain identifying information) for an NDC 
number in Sec.  207.33, and we would assign a new NDC number for that 
drug.
    Under proposed Sec.  314.81(b)(3)(iii), applicants under part 314 
must report electronically within 30 calendar days the withdrawal of an 
approved drug product from sale (the current requirement is to report 
within 15 days).
2. Burden Estimates
    Based on the current receipts of Forms FDA 2657 and 2658 for new 
listings, we estimate that approximately 1,812 manufacturers, 
repackers, relabelers, and drug product salvagers will provide 
electronically approximately 13,821 new listings annually.
    Based on the number of drugs in our listing database and the 
current receipts of Forms FDA 2657 and 2658 for changes to listing 
information (and, until recently, the number of receipts of compliance 
verification reports), we estimate that approximately 2,278 
manufacturers, repackers, relabelers, and drug product salvagers will 
provide approximately 22,568 June and 22,568 December reviews and 
updates of listing information (a total of 45,136 submissions 
annually), and that approximately 5,594 manufacturers, repackers, 
relabelers, and drug product salvagers will provide approximately 
81,980 June and 81,980 December reviews and certifications that no 
changes have occurred (a total of 163,960 submissions annually).
    The estimates for the number of drug listings submitted by 
manufacturers, repackers, relabelers, and drug product salvagers 
include both domestic and foreign listings and the listings that would 
be submitted by manufacturers, repackers, relabelers, and drug product 
salvagers for private label distributors. The estimates also include 
the time for submitting information for an NDC number under proposed 
Sec.  207.33. The drugs that would be listed include PET drugs, an 
additional 57 drugs listed by approximately 5 foreign establishments as 
a result of the revocation of the exemptions for foreign 
establishments, and approximately 30 plasma derivatives. The estimates 
for the number of June and December reviews and updates of listing 
information or reviews and certifications that no changes have occurred 
would include the number of changes to drug characteristics submitted 
to obtain a new NDC number under proposed Sec.  207.33(f) and the 
reports of the withdrawal of an approved drug from sale under Sec.  
314.81(b)(3)(iii) and, for biological products, under Sec.  601.2(f).
    Based on our familiarity with the content of current listing forms 
and submissions and the time required to input listing information 
during our electronic drug registration and listing system pilot 
project, we estimate that it will take manufacturers, repackers, 
relabelers, and drug product salvagers approximately 1 hour and 30 
minutes to provide electronically information for each drug they list 
for the first time (for both foreign and domestic listings). This 
estimate is an average of the time it will take manufacturers, 
repackers, relabelers, and drug product salvagers, with drug product 
salvagers taking considerably less time than manufacturers. This 
estimate includes the time for submitting the content of labeling in 
electronic format under proposed Sec.  207.61(a)(2) and for submitting 
other labeling and advertisements in paper or electronic format under 
proposed Sec. Sec.  207.49(g) and (h) and 207.53(d) and (e). This 
estimate is only until manufacturers, repackers, relabelers, and drug 
product salvagers become familiar with using the electronic drug 
registration and listing system. We intend to lower this burden 
estimate to approximately 45 minutes when we submit to OMB the request 
to renew approval of this information collection.
    We also estimate that it will take approximately 30 minutes for 
each June and December review and update of listing information, and 
approximately 15 minutes for each review and certification that no 
changes have occurred. These estimates include the time for submitting 
any labeling and advertisements for each drug, changes to the drug's 
characteristics submitted for a new NDC number under proposed Sec.  
207.33(f), and reports of the withdrawal of an approved drug from sale 
under Sec.  314.81(b)(3)(iii). This estimate is only until 
manufacturers, repackers, relabelers, and drug product salvagers become 
familiar with using the electronic drug registration and listing 
system. We intend to lower this burden estimate to approximately 15 
minutes for each review and update and approximately 5 minutes for each 
review and certification when we submit to OMB the request to renew 
approval of this information collection. We note that these estimates 
for the electronic submission of this information would be a reduction 
in the currently approved estimate of 2.50 hours (OMB Control Number 
0910-0045) for preparing and mailing to FDA Form FDA 2657 and FDA Form 
FDA 2658.
    We intend to migrate into our new electronic drug registration and 
listing system current listing information that had been submitted 
using paper forms. As a result, current manufacturers, repackers, 
relabelers, and drug product salvagers will need additional time to 
review all current listing information in the new database and make any 
necessary revisions. We estimate that it will take on average 45 
minutes to review and update each drug's listing

[[Page 51342]]

information (the listing information includes information submitted for 
an NDC number).

C. Registration and Listing Information Under Part 607

1. Proposed Requirements
    Under proposed Sec.  607.22, manufacturers may electronically 
obtain, complete, and submit to FDA Form FDA 2830 (Blood Establishment 
Registration and Product Listing) or may request a copy of the form by 
e-mail. Currently, under Sec.  607.22, manufacturers must register 
establishments and list blood products on Form FDA 2830. The proposal 
is consistent with the current requirement to register establishments 
and list products approved under OMB Control Number 0910-0052.
    Under proposed Sec.  607.25(b)(1), blood establishments are 
required to list blood products by the established and proprietary 
name. This proposal is consistent with the current listing requirement 
approved under OMB Control Number 0910-0052. Currently, blood 
establishments list bulk product substances as well as finished dosage 
forms under both parts 607 and 207 to obtain an NDC number. The 
proposal would reduce reporting burden by requiring blood 
establishments to list only under part 607. To be consistent with part 
207, we are also proposing to delete the reference in part 607 to Form 
FDA 2250 (National Drug Code Directory Input) because this form is no 
longer being used by CDER or CBER.
    Under proposed Sec.  607.40, foreign establishments must register 
each establishment before their blood product enters a foreign trade 
zone and are reexported from that foreign trade zone without having 
entered U.S. commerce. This proposal is consistent with the current 
registration requirement in that establishments must register before 
their blood products are imported or offered for import into the United 
States. The proposal would also include additional foreign 
establishments as a result of the revocation of the exemption under 
section 801(d)(4) of the act for blood products that enter a foreign 
trade zone and are reexported from that foreign trade zone without 
having entered U.S. commerce. Under the proposal, we are requiring 
additional information for each foreign establishment. The proposal 
would also require the foreign establishment to report to FDA changes 
in the United States agent's name, address, telephone and fax numbers, 
and e-mail address within 30 calendar days of the change. The proposal 
would lengthen the time period from 10 business days to 30 calendar 
days for reporting changes in the United States agent to FDA.
2. Burden Estimates
    Based on the number of new establishments that currently register 
with FDA each year, we estimate that approximately 15 foreign 
establishments would provide new establishment registrations annually. 
Based on the number of registered establishments in our database, we 
estimate that approximately 21 foreign establishments would provide 
approximately 105 annual reviews and updates of registration 
information or reviews and certifications that no changes have 
occurred. Based on the number of changes to registration information 
that have been submitted annually on Form FDA 2830, we estimate that 
approximately 21 foreign establishments would provide approximately 80 
product listing updates.
    The estimates above include 10 foreign establishments with blood 
products that enter a foreign trade zone and are reexported from that 
foreign trade zone without having entered U.S. commerce under section 
801(d)(4) of the act.We estimate that it would take approximately 60 
minutes to provide the initial registration and listing information for 
each new establishment.
    We estimate that it would take approximately 30 minutes for each 
annual review and update of registration and listing information, 
including each review and certification that no changes have occurred.
    We estimate that it would take approximately 15 minutes to provide 
the product listing update for each establishment.
    The burden hour estimates above are based on institutional 
experience with the current registration and listing requirements. The 
estimates are an average of the time it would take to register a 
foreign establishment and an average of the time it would take to 
review registration and listing information and update several 
registration and listing items in the database or review information 
and only certify that no changes have occurred.

D. Registration and Listing Information Under Part 1271

1. Proposed Requirements
    Under proposed Sec.  1271.22, establishments must register, list 
products, and provide updates electronically. The current regulation 
requires registration, listing, and updates either electronically or in 
paper form using Form FDA 3356 and is approved under OMB Control Number 
0910-0469.
    Under proposed Sec.  1271.25, establishments would submit the 
telephone and fax numbers, and e-mail address of the reporting 
official. Each foreign establishment would submit the name, the 
address, telephone and fax numbers, and e-mail address of each importer 
that is known to the establishment and the name of each person who 
imports or offers for import such HCT/P to the United States. Foreign 
establishments would also submit the name, the address, telephone and 
fax numbers, and e-mail address of their United States agent.
    Under proposed Sec.  1271.26, establishments must report a change 
to the United States agent's name, address, telephone and fax number, 
and e-mail address. The proposal would also lengthen to 30 calendar 
days the current requirement of reporting the changes within 5 days.
2. Burden Estimates
    Based on the number of new establishments that currently register 
with FDA each year, we estimate that approximately 300 establishments 
would provide new establishment registration annually. Based on 
information from FDA's database, we estimate that approximately 2,000 
establishments are registered and listed with FDA. The number of 
establishments that currently register and list with FDA include both 
foreign and domestic establishments. Based on information from FDA's 
database, we estimate that approximately 1,400 establishments would 
provide establishment and listing updates. If no change has occurred, 
an update is not required. Based on the number of establishments from 
FDA's database, we estimate that approximately 1,800 establishments 
would provide approximately 2,100 changes to establishment ownership or 
location, or changes to the United States agent's information.
    We estimate that it would take approximately 45 minutes to provide 
the initial registration and listing information for each new 
establishment.
    We estimate that it would take approximately 30 minutes for each 
annual review and update of registration and listing information for 
each establishment.
    We estimate that it would take approximately 15 minutes for each 
establishment to provide a change in ownership and location, or a 
change to the United States agent's information.

[[Page 51343]]

    The burden hour estimates above are based on institutional 
experience with the current registration and listing requirements. The 
estimates are an average of the time it would take to register an 
establishment, and an average of the time it would take to review 
registration and listing information, and update several registration 
and listing items in the database.

E. User Account Information for Electronic System

    Under proposed Sec.  207.61, establishment registration and drug 
listing information must be submitted to us in electronic format. In 
addition, the content of labeling must be submitted in electronic 
format. Other labeling and advertisements may be provided in paper or 
electronic format. Electronic format submissions must be in a form that 
we can process, review, and archive. Prior to accepting registration 
and listing information from the online system, we may need to 
authenticate the source (that is, manufacturer, repacker, relabeler, or 
drug product salvager) providing the data. We are proposing to 
authenticate entry into the electronic drug registration and listing 
system by establishing user accounts based on the current registration 
information. We would contact currently registered manufacturers, 
repackers, relabelers, or drug product salvagers and request that they 
provide electronic contact information to establish an administration 
account.
    We estimate that approximately 8,343 manufacturers, repackers, 
relabelers, and drug product salvagers will provide this information 
(approximately 8,343 submissions) and that it will take approximately 
15 minutes to provide the requested information.

F. Waiver Request Information

1. Part 207
    Under proposed Sec.  207.65, manufacturers, repackers, relabelers, 
and drug product salvagers may request a waiver from the requirement in 
Sec.  207.61 that information must be provided to us in electronic 
format. We expect very few waiver requests because only a computer, 
Internet access, and an email address are needed to register and list.
    We estimate that approximately two manufacturers, repackers, 
relabelers, or drug product salvagers would request a waiver annually, 
and that each request would take approximately 1 hour to prepare and 
submit to us.
    In those instances when we grant a request for a waiver, we intend 
to make available to the manufacturer, repacker, relabeler, or drug 
product salvager paper forms--revised Form FDA 2656 for registration 
and revised Form FDA 2657 for listing (the listing form would include a 
section for submitting the information required to obtain an NDC 
number). We intend to request public comment and OMB approval for the 
revised forms before the effective date of any final rule. The proposed 
form will be available from the Division of Compliance Risk Management 
and Surveillance, Office of Compliance, Center for Drug Evaluation and 
Research (HFD-330), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-8920, [email protected] or 
[email protected].
2. Part 607
    Under proposed Sec.  607.40(f)(1), foreign establishments may 
request a waiver from the requirement in Sec.  607.40(e) that 
information must be provided to FDA in electronic format. We expect 
very few waiver requests because only a computer, Internet access, and 
an e-mail address are needed to register and list.
    We estimate that approximately two manufacturers would request a 
waiver annually, and that each request would take approximately 1 hour 
to prepare and submit to us.
    In those instances when we grant a request for a waiver, we intend 
to make available to the manufacturer the paper form--Form FDA 2830 for 
registration and listing.
3. Part 1271
    Under proposed Sec.  1271.23, manufacturers may request a waiver 
from the requirement in Sec.  1271.22 that information must be provided 
to FDA in electronic format. We expect few waiver requests because only 
a computer, Internet access, and an e-mail address are needed to 
register and list.
    We estimate that approximately 100 manufacturers would request a 
waiver annually, and that each request would take approximately 1 hour 
to prepare and submit to FDA.
    In those instances when we grant a request for a waiver, we intend 
to make available to the manufacturer the paper form--revised Form FDA 
3356 for registration and listing. We intend to request public comment 
and OMB approval for the revised form before the effective date of any 
final rule.

G. Public Disclosure Exemption Requests

    Under proposed Sec.  207.81(c), manufacturers, repackers, 
relabelers, and drug product salvagers may request that certain 
information in proposed Sec.  207.81(a) not be made available from 
their registration and listing information. Based on our experience 
with registration and listing information inspection requests under 
current Sec.  207.37, we estimate that approximately 100 manufacturers, 
repackers, relabelers, or drug product salvagers would submit this 
request annually, and that each request would take approximately 1 hour 
to prepare and submit to us.

H. Revised Labeling Submitted With Annual Report

    Under the proposal, the NDC number must appear on all drug labels 
for drugs subject to the listing requirements. Manufacturers, 
repackers, and relabelers for drug products that do not already have an 
NDC number on the label would be required to include the NDC number 
assigned by us. Manufacturers, repackers, and relabelers for drug 
products that have an NDC number on the label as it is currently 
required would be required to examine their current NDC number to 
ensure that it complies with the NDC number requirements in proposed 
Sec. Sec.  201.2, 207.33, and 207.37, and would have to obtain a new 
NDC number from us if necessary.
    When there is a change in the NDC number on a drug label, or when 
an NDC number is added to a label, application holders must submit 
revised labeling to us with their annual reports under Sec.  
314.81(b)(2) for human drugs, Sec.  514.80(b)(4) for animal drugs 
(``periodic reports'' are required instead of ``annual reports''), and 
Sec.  601.12(f)(3) for biological drugs. The submission of annual 
reports (or periodic reports for animal drugs) under these regulations 
is already approved by OMB under Control Number 0910-0001 for human 
drugs (approval expires 5/31/08), Control Number 0910-0284 for animal 
drugs (approval expires 9/30/06), and Control Number 0910-0338 for 
biological products (approval expires 9/30/08). There would be no 
additional information collection burden associated with any labeling 
revision because of a new NDC number assigned by us because it would be 
``public disclosure of information originally supplied by the Federal 
government to the recipient for the purpose of disclosure to the 
public'' and exempt under the PRA (5 CFR 1320.3(c)(2)). However, we 
have estimated a burden of approximately 5 minutes per annual report as 
the time required to state in the annual report that the labeling has 
been revised to include a new NDC number and the additional time

[[Page 51344]]

required to submit to us the revised labeling with the annual report. 
For the number of submissions, we estimate that no more than 
approximately one-half of all annual reports submitted for products 
already listed with FDA on the effective date of the final rule would 
include this information.

I. Capital Costs

    There are one-time capital costs associated with this proposed 
rulemaking. These costs are discussed in section VI of this document, 
``Analysis of Economic Impacts.''
    We specifically request comments on the burden hour estimates 
described previously in this document and in tables 6, 7, and 8 of this 
document.
    Description of Respondents: Manufacturers, repackers, relabelers, 
and drug product salvagers.
    Burden Estimate: Tables 6, 7, and 8 of this document provide an 
estimate of the annual reporting burden for the proposed registration 
and listing requirements.

                       Table 6.--Estimated Annual Reporting Burden Under Proposed Part 207
----------------------------------------------------------------------------------------------------------------
                                                                                       Hours Per
 21 CFR Sections and Reporting       No. of       No. of Responses   Total Annual    Registration    Total Hours
          Requirements             Respondents     Per Respondent      Responses      and Listing
----------------------------------------------------------------------------------------------------------------
Initial Establishment                       987               1.14           1,128          1 hour      1,128
 Registration (207.25)
Annual Review and Update of               8,343               1.45          12,137       .50 hours      6,068.5
 Registration Information
 (207.29)
Expedited Updates (207.29)                  775               2.46           1,921       .25 hours        480.25
Initial Listing and NDC Number            1,812               7.63          13,821       1.50 hrs.     20,731.50
 Information (207.33, 207.49,
 207.53, 207.54, 207.55)
Review and Update of Listing              2,278              19.81          45,136       .50 hours     22,568
 Information (June and
 December) (207.33, 207.37,
 207.57, 314.81(b)(3)(iii),
 601.2(f))
Review and Certification of               5,594              29.29         163,960       .25 hours     40,990
 Listing Information (June and
 December) (207.57, 601.2(f))
----------------------------------------------------------------------------------------------------------------
Review of registration                    8,343               1.45          12,137       .50 hours      6,068.5
 information already in FDA
 database on effective date of
 final rule
----------------------------------------------------------------------------------------------------------------
Review of listing information             7,962              13.13         104,548       .75 hours     78,411
 already in FDA database on
 effective date of final rule
----------------------------------------------------------------------------------------------------------------
User accounts for electronic              8,343                  1           8,343       .25 hours      2,085.75
 system
----------------------------------------------------------------------------------------------------------------
Waiver requests (207.65)                      2                  1               2          1 hour          2
 Revised Forms FDA 2656 and
 2657
----------------------------------------------------------------------------------------------------------------
Public disclosure exemption                 100                  1             100          1 hour        100
 requests (207.81(c))
----------------------------------------------------------------------------------------------------------------
Annual report revision for new            3,981              13.13          52,289       5 minutes        871.5
 NDC number (314.81(b)(2),
 514.80(b)(4), 601.12(f)(3))
----------------------------------------------------------------------------------------------------------------
Total Reporting Burden                                                                                179,505
----------------------------------------------------------------------------------------------------------------


                       Table 7.--Estimated Annual Reporting Burden Under Proposed Part 607
----------------------------------------------------------------------------------------------------------------
                                                                                       Hours Per
        21 CFR Sections              No. of       No. of Responses   Total Annual    Registration    Total Hours
                                   Respondents     Per Respondent      Responses      and Listing
----------------------------------------------------------------------------------------------------------------
Initial Establishment                        15                  1              15               1         15
 Registration and Blood Product
 Listing (607.40)
----------------------------------------------------------------------------------------------------------------
Annual Review and Update of                  21                  5             105             0.5         52.5
 Establishment Registration and
 Blood Product Listing (607.40)
----------------------------------------------------------------------------------------------------------------
Product Listing Update (607.40)              21                3.8              80            0.25         20
----------------------------------------------------------------------------------------------------------------
Waiver requests (607.40(f)(1))                2                  1               2               1          2
 Revised Form FDA 2830
----------------------------------------------------------------------------------------------------------------
Total Reporting Burden                                                                                     89.5
----------------------------------------------------------------------------------------------------------------


[[Page 51345]]


                      Table 8.--Estimated Annual Reporting Burden Under Proposed Part 1271
----------------------------------------------------------------------------------------------------------------
                                                                                       Hours Per
        21 CFR Sections              No. of       No. of Responses   Total Annual    Registration    Total Hours
                                   Respondents     Per Respondent      Responses      and Listing
----------------------------------------------------------------------------------------------------------------
Initial Establishment                       300                  1             300            0.75        225
 Registration and Listing
 (1271.25)
----------------------------------------------------------------------------------------------------------------
Annual Review and Update of               2,000                1.4           1,400             0.5        501.5
 Establishment Registration and
 Listing (1271.25)
----------------------------------------------------------------------------------------------------------------
Waiver requests (1271.23)                   100                  1             100               1        100
 Revised Form FDA 3356
----------------------------------------------------------------------------------------------------------------
Amend Establishment                        1800               1.16            2100            0.25        525
 Registration (1271.26)
----------------------------------------------------------------------------------------------------------------
Total Reporting Burden                                                                                   1550.5
----------------------------------------------------------------------------------------------------------------

    In compliance with section 3507(d) of the PRA, we have submitted 
the information collection provisions of this proposed rule to OMB for 
review. Interested persons are requested to fax comments regarding 
information collection to the Office of Information and Regulatory 
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235, 
Washington DC 20503, Attn: Desk Officer for FDA, FAX: (202) 395-6974.

VIII. Environmental Impact

    We have determined under 21 CFR 25.30(h) and 25.30(k) that this 
action is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

IX. Proposed Effective Date

    We propose that any final rule based on this proposal become 
effective 90 days after publication in the Federal Register.

X. Proposed Compliance Dates

    We are proposing that our electronic drug registration and listing 
system be used to enter and update all registration, listing, and NDC 
number information no later than 9 months after the effective date of a 
final rule. As discussed in section IV.C.4.a of this document, 
manufacturers, repackers, and relabelers would have until 9 months 
after the effective date of a final rule to review and update the NDC 
number information in our database for each of their drugs to ensure 
that it complies with proposed Sec. Sec.  201.2, 207.33, 207.37, 
610.60, and 610.61. In addition, as discussed in section IV.C.4.b of 
this document, manufacturers, repackers, and relabelers would have, for 
prescription drugs, 3 years after the effective date of a final rule 
and, for OTC drugs, 7 years after the effective date of a final rule, 
to ensure that the appropriate NDC number correctly appears on the 
label of each of their listed drugs, in accordance with the 
requirements in proposed Sec. Sec.  201.2, 207.33, 207.37, 610.60, and 
610.61. We are considering shortening the compliance dates by which the 
appropriate NDC number must appear on drug labels to 2 years after the 
effective date of a final rule for prescription drugs and 5 years after 
the effective date of a final rule for OTC drugs. We discuss this issue 
further in section VI of this document, ``Analysis of Economic 
Impacts.''
    We specifically request comments on these proposed compliance 
dates.

XI. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
the rule does not contain policies that have substantial direct effects 
on the States, on the relationship between the National Government and 
the States, or on the distribution of power and responsibilities among 
the various levels of government. Accordingly, we have concluded that 
the rule does not contain policies that have federalism implications as 
defined in the Executive order and, consequently, a federalism summary 
impact statement is not required.

XII. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this proposal. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

XIII. References

    The following references have been placed on display at the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Letter from John M. Coster, Vice President, Policy and 
Programs, NACDS, and Lisa Clowers, Senior Vice President, Industry 
Relations, HDMA, to Michael D. Jones, FDA, dated September 27, 2004.
    2. Letter from the Deputy Director, Division of Prescription 
Drug Compliance and Surveillance, CDER, FDA to John M. Coster, 
National Association of Chain Drug Stores, August 24, 1997.
    3. Eastern Research Group, Inc., Foreign and Domestic 
Establishment Registration and Listing Requirements for Human Drugs, 
Certain Biological Drugs, and Animal Drugs, August 2005.
    4. Eastern Research Group, Inc., Profile of the Prescription 
Drug Wholesale Industry, February 2001.
    5. Eastern Research Group, Inc., Cost Impacts of the Over-the-
Counter Pharmaceutical Labeling Regulation, March 1999.

List of Subjects

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 207

    Drugs, Reporting and recordkeeping requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

[[Page 51346]]

21 CFR Part 330

    Over-the-counter drugs.

21 CFR Parts 514 and 515

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

21 CFR Part 607

    Blood.

21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 1271

    Biologics, Drugs, Human cells and tissue-based products, Medical 
devices, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 20, 
201, 207, 314, 330, 514, 515, 601, 607, 610, and 1271 be amended as 
follows:

PART 20--PUBLIC INFORMATION

    1. The authority citation for 21 CFR part 20 continues to read as 
follows:

    Authority:  5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 
21 U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n, 
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-l.


Sec.  20.100   [Amended]

    2. Section 20.100 is amended in paragraph (c)(9) by removing 
``Sec.  207.37'' and by adding in its place ``Sec.  207.81''.
    3. Section 20.116 is revised to read as follows:


Sec.  20.116   Drug and device registration and listing information.

    Information submitted to the Food and Drug Administration pursuant 
to section 510(a) through (j) of the act shall be subject only to the 
special disclosure provisions established in Sec. Sec.  207.81 and 
807.37 of this chapter.

PART 201--LABELING

    4. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.


Sec.  201.1   [Amended]

    5. Section 201.1 is amended in paragraph (f) by removing ``Sec.  
207.3(b)'' and by adding in its place ``Sec.  207.1''.
    6. Section 201.2 is revised to read as follows:


Sec.  201.2   Drugs; National Drug Code (NDC) number.

    (a) What drugs must have an NDC number in human-readable form on 
the label? Drugs subject to the drug listing requirements of part 207 
of this chapter must have labels that bear the appropriate NDC number 
in human-readable form, in accordance with the provisions of this 
section.
    (b) What is the appropriate NDC number? The appropriate NDC number 
is the NDC number of the manufacturer, repacker or relabeler (including 
a drug product salvager who repacks or relabels the drug), or private 
label distributor, as defined in Sec.  207.1 of this chapter, that is 
the last manufacturer, repacker, relabeler, or private label 
distributor responsible for the drug immediately before it is received 
by the wholesaler or retailer. The appropriate NDC number is assigned 
to the drug as described in Sec. Sec.  207.33 and 207.37 of this 
chapter. The unique NDC number assigned to each package size and type 
of a drug must appear on the corresponding label for the particular 
package size and type of the drug.
    (c) May any other NDC number appear on the label? No. Only the 
appropriate NDC number required by paragraph (b) of this section to 
appear on the label may appear on the label.
    (d) What prefix must be used to identify the NDC number on the 
label? The NDC number in human-readable form must be immediately 
preceded by the letters NDC.
    (e) Must the NDC number appear at a specific location on the label? 
No. However, the appropriate NDC number must appear clearly on the 
drug's label as defined by section 201(k) of the Federal Food, Drug, 
and Cosmetic Act.
    7. Section 201.25 is amended in paragraph (c)(1) introductory text 
by adding a sentence after the first sentence and by adding paragraph 
(e) to read as follows:


Sec.  201.25   Bar code label requirements.

* * * * *
    (c) * * *
    (1) * * * For purposes of this section ``appropriate NDC number'' 
is described in Sec.  201.2(b). * * *
* * * * *
    (e) Can a drug that is not subject to the bar code requirement 
display a bar code? A drug product that is subject to the drug listing 
requirements of part 207 of this chapter but is not subject to this 
section may display a bar code on the label only if the bar code meets 
the requirements of paragraph (c) of this section.
    8. Part 207 is revised to read as follows:

PART 207--REQUIREMENTS FOR FOREIGN AND DOMESTIC ESTABLISHMENT 
REGISTRATION AND LISTING FOR HUMAN DRUGS, INCLUDING DRUGS THAT ARE 
REGULATED UNDER A BIOLOGICS LICENSE APPLICATION, AND ANIMAL DRUGS

Subpart A--General
Sec.
207.1 What definitions and interpretations of terms apply to this 
part?
207.5 What is the purpose of this part?
207.9 Who does this part cover?
207.13 Who is exempt from the registration and listing requirements?
Subpart B--Registration
207.17 Who must register?
207.21 When must initial registration information be provided?
207.25 What information is required for registration?
207.29 What are the requirements for reviewing and updating 
registration information?
Subpart C--National Drug Code Number
207.33 What is the National Drug Code (NDC) number, who must obtain 
it, and what information must be submitted?
207.37 What restrictions pertain to the use of NDC numbers?
Subpart D--Listing
207.41 Who must list drugs?
207.45 When must initial listing information be provided?
207.49 What listing information is required for manufacturers?
207.53 What listing information is required for repackers and 
relabelers?
207.54 What listing information is required for drug product 
salvagers who are not repackers or relabelers?
207.55 What additional drug listing information may be required?
207.57 What are the requirements for reviewing and updating listing 
information?
Subpart E--Electronic Format for Registration and Listing
207.61 How is registration and listing information provided to FDA?
207.65 How is a waiver from the electronic format requirement 
requested?
Subpart F--Miscellaneous
207.69 What are the requirements for an official contact and a 
United States agent?
207.77 What legal status is conferred by registration and listing?
207.81 What registration and listing information will we make 
available for public disclosure?


[[Page 51347]]


    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360b, 371, 
374, 381, 393; 42 U.S.C. 262, 264, 271.

Subpart A--General


Sec.  207.1  What definitions and interpretations of terms apply to 
this part?

    The definitions and interpretations of terms in section 510 of the 
act apply to the terms used in this part. The following definitions 
also apply to this part:
    Act means the Federal Food, Drug, and Cosmetic Act (52 Stat. 1040, 
et seq., as amended (21 U.S.C. 301, et seq.)), except as otherwise 
provided.
    Active pharmaceutical ingredient means any substance that is 
intended to furnish pharmacological activity or other direct effect in 
the diagnosis, cure, mitigation, treatment, or prevention of disease, 
or to affect the structure or any function of the body. Active 
pharmaceutical ingredient does not include intermediates used in the 
synthesis of the substance.
    Commercial distribution means any distribution of a human drug 
except for investigational use under part 312 of this chapter, and any 
distribution of an animal drug or an animal feed bearing or containing 
an animal drug for noninvestigational uses, but the term does not 
include internal or interplant transfer of an active pharmaceutical 
ingredient between registered establishments within the same parent, 
subsidiary, and/or affiliate company. For foreign manufacturers, 
foreign repackers, foreign relabelers, foreign drug product salvagers, 
foreign private label distributors, and foreign establishments, the 
term ``commercial distribution'' has the same meaning except the term 
does not include distribution of any drug that is neither imported nor 
offered for import into the United States.
    Content of labeling means: (1) For human prescription drugs that 
the manufacturer regards as subject to section 505 of the act or 
section 351 of the Public Health Service Act: The content of the 
prescription drug labeling (as specified in Sec. Sec.  201.56, 201.57, 
and 201.80 of this chapter), including all text, tables, and figures.
    (2) For human prescription drugs that the manufacturer regards as 
not subject to section 505 of the act or section 351 of the Public 
Health Service Act: The labeling equivalent to the content of the 
prescription drug labeling (as specified in Sec. Sec.  201.56, 201.57, 
and 201.80 of this chapter), including all text, tables, and figures.
    (3) For human over-the-counter (OTC) drugs: The content of the drug 
facts labeling required by Sec.  201.66 of this chapter, including all 
text, tables, and figures.
    (4) For animal drugs (including, but not limited to, drugs that the 
manufacturer regards as subject to section 512 of the act): The content 
of the labeling that accompanies the drug that is necessary to enable 
safe and proper administration of the drug (e.g., the labeling 
specified in Sec. Sec.  201.1 and 201.5 of this chapter), including all 
text, tables, and figures.
    Domestic for the purposes of registration and listing under this 
part, when used to modify the term ``manufacturer,'' ``repacker,'' 
``relabeler,'' ``drug product salvager,'' ``private label 
distributor,'' or ``establishment,'' refers to a manufacturer, 
repacker, relabeler, drug product salvager, private label distributor, 
or establishment within any State or Territory of the United States, 
the District of Columbia, or the Commonwealth of Puerto Rico.
    Drug(s) for the purposes of registration and listing under this 
part, has the meaning given in section 201(g)(1) of the act.
    Drug product salvager means a person who owns or operates an 
establishment that engages in drug product salvaging. When not modified 
by ``domestic'' or ``foreign,'' the term includes both domestic drug 
product salvagers and foreign drug product salvagers.
    Drug product salvaging means applying manufacturing controls such 
as those required by current good manufacturing practice in parts 210 
and 211 of this chapter to drug products and segregating out those drug 
products that may have been subjected to improper storage conditions 
(such as extremes in temperature, humidity, smoke, fumes, pressure, 
age, or radiation) for the purpose of returning the products to the 
marketplace.
    Establishment for purposes of registration and drug listing means a 
place of business under one management at one geographic location. One 
geographic location may include separate buildings within the same city 
if their activities are closely related to the same business enterprise 
and are under the supervision of the same local management. When not 
modified by ``domestic'' or ``foreign,'' the term includes both 
domestic and foreign establishments.
    Establishment registration number means the number assigned by FDA 
to the establishment during the establishment registration process 
required in this part.
    Foreign for the purposes of registration and listing under this 
part:
    (1) When used to modify the term ``manufacturer,'' ``repacker,'' 
``relabeler,'' ``drug product salvager,'' or ``private label 
distributor'' refers to a manufacturer, repacker, relabeler, drug 
product salvager, or private label distributor who is located in a 
foreign country and who manufactures, repacks, relabels, salvages, or 
distributes a drug that is imported or offered for import into the 
United States.
    (2) When used to modify the term ``establishment'' refers to an 
establishment that is located in a foreign country and is the site 
where a drug that is imported or offered for import into the United 
States was manufactured, repacked, relabeled, salvaged, or distributed.
    Importer means, for purposes of this part, a company or individual 
in the United States that is an owner, consignee, or recipient, even if 
not the initial owner, consignee, or recipient, of the foreign 
establishment's drug that is imported into the United States. An 
importer does not include the consumer or patient who ultimately 
purchases, receives, or is administered the drug, unless the foreign 
establishment ships the drug directly to the consumer or patient.
    Manufacture means each step in the manufacture, preparation, 
propagation, compounding, or processing of a drug. Manufacture includes 
the making by chemical, physical, biological, or other procedures or 
manipulations of a drug, including control procedures applied to the 
final product or to any part of the process. Manufacture includes 
manipulation, sampling, testing, or control procedures applied to the 
final product or to any part of the process, including, for example, 
analytical testing of drugs, for another registered establishment's 
drug. For purposes of this part, and in order to clarify the 
responsibilities of the different parties, the term manufacture is 
defined and used separately from the terms relabel, repackage, and 
salvage, although the term ``manufacture, preparation, propagation, 
compounding, or processing,'' as used in section 510 of the act, 
includes relabeling, repackaging, and drug product salvaging 
activities.
    Manufacturer means a person who owns or operates an establishment 
that manufactures a drug. This term includes, but is not limited to, 
control laboratories, contract laboratories, contract manufacturers, 
contract packers, contract labelers, and other entities that 
manufacture a drug as defined in this paragraph. For purposes of this 
part, and in order to clarify the responsibilities of the different 
parties,

[[Page 51348]]

the term manufacturer is defined and used separately from the terms 
relabeler, repacker, and drug product salvager, although the term 
``manufacture, preparation, propagation, compounding, or processing,'' 
as used in section 510 of the act, includes the activities of 
relabelers, repackers, and drug product salvagers. Repackers, 
relabelers, and drug product salvagers are subject to the provisions of 
this part that are applicable to repackers, relabelers, and drug 
product salvagers, but are not subject to the provisions of this part 
that are applicable to manufacturers. When not modified by ``domestic'' 
or ``foreign,'' the term includes both domestic manufacturers and 
foreign manufacturers.
    Material change means any change in any drug listing information, 
as required under Sec. Sec.  207.49, 207.53, 207.54, 207.55, or 207.57 
except changes in arrangement or printing of labeling, labeling changes 
of an editorial nature, or inclusion of a bar code or NDC number on the 
label.
    Person who imports or offers for import means, for purposes of this 
part, an agent, broker, or other entity, other than a carrier, that the 
foreign establishment uses to facilitate the import of its drug into 
the United States.
    Private label distributor means a person who owns or operates an 
establishment that commercially distributes, under its own label or 
trade name, any drug manufactured, repacked, relabeled, or salvaged by 
a registered establishment. When not modified by ``domestic'' or 
``foreign,'' the term includes both domestic private label distributors 
and foreign private label distributors.
    Relabel means to change the label or labels on a drug or drug 
package, or add to the labeling for a drug or drug package, without 
repacking the drug or drug package.
    Relabeler means a person who owns or operates an establishment that 
relabels a drug. When not modified by ``domestic'' or ``foreign,'' the 
term includes both domestic relabelers and foreign relabelers.
    Repack means to repack or repackage or otherwise change the 
container or wrapper of a drug or drug package.
    Repacker means a person who owns or operates an establishment that 
repacks a drug or drug package. When not modified by ``domestic'' or 
``foreign,'' the term includes both domestic repackers and foreign 
repackers.
    Representative sampling of advertisements means typical advertising 
material (including the promotional material described in Sec.  
202.1(l)(1) of this chapter, but excluding labeling as determined in 
Sec.  202.1(l)(2) of this chapter), that gives a balanced picture of 
the promotional claims used for the drug.
    Representative sampling of any other labeling means typical 
labeling material (including the promotional material described in 
Sec.  202.1(l)(2) of this chapter, but excluding labels and package 
inserts) that gives a balanced picture of the promotional claims used 
for the drug.


Sec.  207.5  What is the purpose of this part?

    Establishment registration information helps us to identify who is 
manufacturing, repacking, relabeling, or salvaging drugs and where 
those operations are being performed. Drug listing information gives us 
a current inventory of marketed drugs. Both types of information 
facilitate our implementation and enforcement of the act and are used 
for many important public health purposes.


Sec.  207.9  Who does this part cover?

    (a) This part applies to domestic manufacturers, domestic 
repackers, domestic relabelers, and domestic drug product salvagers, 
not exempt under section 510(g) of the act or Sec.  207.13, regardless 
of whether their drugs enter interstate commerce.
    (b) This part applies to foreign manufacturers, foreign repackers, 
foreign relabelers, and foreign drug product salvagers, not exempt 
under Sec. Sec.  207.13(c) through (h).
    (c) This part applies to certain manufacturers of drugs regulated 
under a biologics license application (BLA):
    (1) Except as provided in paragraphs (c)(2) and (c)(3) of this 
section, this part applies to manufacturers of drugs regulated under a 
BLA, including but not limited to the following:
    (i) Plasma derivatives such as albumin, Immune Globulin, Factor 
VIII and Factor IX, and recombinant versions of plasma derivatives or 
animal derived plasma derivatives;
    (ii) Vaccines;
    (iii) Allergenic products;
    (iv) Bulk product substances such as fractionation intermediates or 
pastes; and
    (v) Therapeutic biological products.
    (2) This part, as well as part 1271 of this chapter, applies to 
establishments solely engaged in the manufacture (as defined in Sec.  
1271.3(e) of this chapter) of human cells, tissues, and cellular and 
tissue-based products (HCT/Ps) (as defined in Sec.  1271.3(d) of this 
chapter) that, under Sec.  1271.20 of this chapter, are also drugs 
regulated under section 351 of the Public Health Service Act or section 
505 of the act. These establishments must:
    (i) Register and list those HCT/Ps with the Center for Biologics 
Evaluation and Research by following the procedures described in 
subpart B of part 1271 of this chapter, instead of the procedures for 
registration and listing described in this part, and
    (ii) Submit to the Center for Biologics Evaluation and Research the 
information specified in Sec. Sec.  207.33(c)(2)(i) and (c)(2)(ii), 
207.49(a), (b), (g), and (h)(2), 207.53(a), (c), (d), and (e)(2), 
207.54(b)(1), and 207.55.
    (3) This part does not apply to owners and operators of human blood 
and blood product establishments, except as provided in paragraphs 
(c)(1)(i) and (c)(1)(iv) of this section. Establishments that collect 
or process whole blood and blood products as well as establishments 
involved in testing of whole blood and blood products must register and 
list under part 607 of this chapter. Manufacturers of licensed devices 
and manufacturers of licensed biologic components used in a licensed 
device must register and list under part 607 of this chapter.
    (d) This part does not apply to establishments that solely 
manufacture, prepare, propagate, compound, assemble, or process medical 
devices. Registration and listing regulations for such establishments 
are codified in part 807 of this chapter.


Sec.  207.13  Who is exempt from the registration and listing 
requirements?

    Except as provided in Sec.  207.13(i), the following classes of 
persons are exempt from registration and drug listing in accordance 
with this part under section 510(g) of the act or because we have 
found, under section 510(g)(5) of the act, that their registration is 
not necessary for the protection of the public health. This exemption 
is limited to establishment registration and drug listing requirements 
and does not relieve a person from other statutory or regulatory 
obligations.
    (a) Pharmacies. (1) Pharmacies that:
    (i) Operate in conformance with all applicable local laws 
regulating the practice of pharmacy, including all applicable local 
laws regulating the dispensing of prescription drugs;
    (ii) Regularly engage in dispensing prescription drugs upon 
prescription of practitioners licensed by law to administer these drugs 
to patients under their professional care; and
    (iii) Do not manufacture (as defined in Sec.  207.1), repack, or 
relabel drugs for sale other than in the regular course of the

[[Page 51349]]

practice of pharmacy, including dispensing and selling drugs at retail.
    (2) The exemption in paragraph (a) of this section is limited to 
pharmacies located in any State as defined in section 201(a)(1) of the 
act.
    (b) Hospitals, clinics, other health care entities, and public 
health agencies. (1) Hospitals, clinics, other health care entities, 
and public health agencies that:
    (i) Operate establishments in conformance with all applicable local 
laws regulating the practice of pharmacy and medicine, including all 
applicable local laws regulating the dispensing of prescription drugs;
    (ii) Regularly engage in dispensing prescription drugs, other than 
human blood or blood products, upon prescription of practitioners 
licensed by law to administer these drugs to patients under their 
professional care; and
    (iii) Do not manufacture (as defined in Sec.  207.1), repack, or 
relabel drugs other than in the regular course of the practice of 
pharmacy, including dispensing.
    (2) The exemption in paragraph (b) of this section is limited to 
hospitals, clinics, other health care entities, and public health 
agencies located in any State as defined in section 201(a)(1) of the 
act.
    (c) Practitioners who are licensed by law to prescribe or 
administer drugs and who manufacture, repack, or relabel drugs solely 
for use in their professional practice.
    (d) Manufacturers, repackers, relabelers, or drug product salvagers 
who manufacture, repack, relabel, or salvage drugs solely for use in 
research, teaching, or chemical analysis and not for sale.
    (e) Manufacturers, repackers, relabelers, and drug product 
salvagers of harmless inactive ingredients that are excipients, 
colorings, flavorings, emulsifiers, lubricants, preservatives, or 
solvents that become components of drugs.
    (f) Manufacturers, repackers, relabelers, or drug product salvagers 
of Type B or Type C medicated feeds, except for manufacturers, 
repackers, relabelers, or drug product salvagers of Type B or Type C 
medicated feeds made from Category II, Type A medicated articles. This 
exemption does not apply to persons that would otherwise be required to 
register (such as manufacturers, repackers, relabelers, or drug product 
salvagers of certain free-choice feeds, as defined in Sec.  510.455 of 
this chapter, or certain liquid feeds, as defined in Sec.  558.5 of 
this chapter, where the specifications and/or formulas are not 
published and a feed mill license is required). All manufacturers, 
repackers, relabelers, or drug product salvagers of Type B or Type C 
medicated feeds are exempt from listing.
    (g) Any manufacturer, repacker, relabeler, or drug product salvager 
of a virus, serum, toxin, or analogous product intended for the 
treatment of domestic animals who holds an unsuspended and unrevoked 
license issued by the Secretary of Agriculture under the animal virus-
serum-toxin law of March 4, 1913 (37 Stat. 832 (21 U.S.C. 151 et 
seq.)), provided that this exemption from registration applies only to 
the manufacturer, repacker, relabeler, or drug product salvager of that 
animal virus, serum, toxin, or analogous product.
    (h) Carriers, in their receipt, carriage, holding, or delivery of 
drugs in the usual course of business as carriers.
    (i) The exemptions provided in paragraphs (a) through (h) of this 
section do not apply to such persons if they:
    (1) Manufacture (as defined in Sec.  207.1), repack, relabel, or 
salvage compounded positron emission tomography drugs as defined in 
section 201(ii) of the act.
    (2) Manufacture (as defined in Sec.  600.3(u) of this chapter) a 
biological product subject to licensing under section 351 of the Public 
Health Service Act;
    (3) Manufacture (as defined in Sec.  1271.3(e) of this chapter) an 
HCT/P that, under Sec.  1271.20 of this chapter, are also drugs 
regulated under section 351 of the Public Health Service Act or section 
505 of the act; or
    (4) Engage in activities that would otherwise require them to 
register under this part.

Subpart B--Registration


Sec.  207.17  Who must register?

    (a) All manufacturers, repackers, relabelers, and drug product 
salvagers must register establishments in accordance with this part. 
When operations are conducted at more than one establishment and joint 
ownership and control among all the establishments exists, the parent, 
subsidiary, and/or affiliate company may submit registration 
information for all establishments.
    (b) Private label distributors must not register with us unless 
they also manufacture, repack, relabel, or salvage drugs and are 
required to register under paragraph (a) of this section.


Sec.  207.21  When must initial registration information be provided?

    Domestic manufacturers, domestic repackers, domestic relabelers, 
and domestic drug product salvagers must register each establishment no 
later than 5 calendar days after beginning to manufacture, repack, 
relabel, or salvage a drug. Foreign manufacturers, foreign repackers, 
foreign relabelers, and foreign drug product salvagers must register 
each establishment before a drug manufactured, repacked, relabeled, or 
salvaged at the establishment is imported or offered for import into 
the United States.


Sec.  207.25  What information is required for registration?

    Manufacturers, repackers, relabelers, and drug product salvagers 
must provide the following information to us:
    (a) Name of the owner or operator of each establishment; if a 
partnership, the name of each partner; if a corporation, the name of 
each corporate officer and director, and the place of incorporation;
    (b) Name of each establishment;
    (c) Any trade name(s) of the establishment, names under which the 
establishment conducts business, and additional names by which the 
establishment is known;
    (d) Address of each establishment;
    (e) Registration number of each establishment, if previously 
assigned by us; if not previously assigned by us, we will assign a 
registration number after we receive the registration information;
    (f) Type of operations performed at each establishment (for 
example, manufacturing, repacking, relabeling, or salvaging);
    (g) Name, address, telephone and fax numbers, and e-mail address of 
the official contact, as provided in Sec.  207.69(a), for each 
establishment; and
    (h) With respect to foreign establishments only, for drugs 
manufactured, repacked, relabeled, or salvaged at the establishment, 
the name, address, telephone and fax numbers, and e-mail address must 
also be provided for:
    (1) The United States agent, as provided in Sec.  207.69(b);
    (2) Each importer of such drug in the United States that is known 
to the establishment; and
    (3) Each person who imports or offers for import such drug to the 
United States.


Sec.  207.29  What are the requirements for reviewing and updating 
registration information?

    (a) Expedited updates. Manufacturers, repackers, relabelers, and 
drug product salvagers must update their registration information no 
later than 30 calendar days after:
    (1) Closing or selling an establishment;
    (2) Changing an establishment's name or address; or

[[Page 51350]]

    (3) Changing the name, address, telephone and fax numbers, or e-
mail address of the official contact or the United States agent. A 
manufacturer, repacker, relabeler, and drug product salvager, official 
contact, or United States agent may notify us about a change of 
information for the designated official contact or United States agent, 
but only a manufacturer, repacker, relabeler, or drug product salvager 
may designate a new official contact or United States agent.
    (b) Annual review and update of registration information. 
Manufacturers, repackers, relabelers, and drug product salvagers must 
review and update all registration information required under Sec.  
207.25 for each establishment.
    (1) The first review and update must occur no later than 1 year 
after the date of initial registration, and subsequent reviews and 
updates must occur no later than annually thereafter from the date of 
initial registration.
    (2) The updates must reflect all changes that have occurred since 
the last annual review and update.
    (3) If no changes have occurred since the last annual registration 
(accomplished through the review and update of registration 
information), manufacturers, repackers, relabelers, and drug product 
salvagers must certify that no changes have occurred.

Subpart C--National Drug Code Number


Sec.  207.33  What is the National Drug Code (NDC) number, who must 
obtain it, and what information must be submitted?

    (a) What is the NDC number? The NDC number is a unique 10 digit 
number with 3 segments. The three segments are the labeler code, the 
product code, and the package code. We will assign the complete NDC 
number (that will include the existing labeler code, if any) to each 
drug that is subject to the listing requirements in this part.
    (b) Who must obtain an NDC number?
    (1) Manufacturers, repackers, or relabelers, must obtain an NDC 
number from us for each drug that is subject to the drug listing 
requirements in this part.
    (2) Drug product salvagers must obtain an NDC number from us for 
each drug that is subject to the drug listing requirements in this part 
only if they repack or relabel the salvaged drug. Drug product 
salvagers must follow the requirements for repackers and relabelers in 
paragraphs (d), (e), (f), and (g) of this section.
    (3) If you are a private label distributor, the manufacturer, 
repacker, relabeler or drug product salvager (described in paragraph 
(b)(2) of this section) who manufactures, repacks, or relabels a drug 
for you is responsible for obtaining an NDC number from us for each 
drug that is subject to the drug listing requirements in this part.
    (c) What information must a manufacturer submit before we will 
assign an NDC number to a drug? Before we assign an NDC number to a 
drug, the manufacturer must submit the information required under 
paragraphs (c)(1), (c)(2), or (c)(3) of this section. If that 
information changes (or as otherwise specified in paragraph (f) of this 
section), we will assign a new NDC number as described in paragraph (f) 
of this section.
    (1) Assigning an NDC number to an active pharmaceutical ingredient. 
We will assign a unique NDC number to a drug that is an active 
pharmaceutical ingredient when the manufacturer provides the following 
information for the drug:
    (i) The manufacturer's name, address, telephone and fax numbers, e-
mail address, and labeler code;
    (ii) The drug's established name and proprietary name, if any;
    (iii) The package size and type; and
    (iv) The Drug Master File number or Veterinary Master File number, 
if any, assigned to the active pharmaceutical ingredient.
    (2) Assigning an NDC number to a manufacturer's drug other than an 
active pharmaceutical ingredient. We will assign a unique NDC number to 
a drug when the manufacturer provides, in addition to the information 
described in paragraphs (c)(1)(i) and (c)(1)(ii) of this section, the 
following information for the drug:
    (i) The name and quantity of each active pharmaceutical ingredient 
unless the approved U.S. application number is provided;
    (ii) Unless the approved U.S. application number is provided, the 
name of each inactive ingredient for each human and animal drug that 
the manufacturer regards as subject to section 505 or section 512 of 
the act or section 351 of the Public Health Service Act, and for each 
human over-the-counter drug that the manufacturer regards as not 
subject to section 505 of the act, and whether the name of the inactive 
ingredient falls under Sec.  20.61 of this chapter or is otherwise 
prohibited from disclosure and, if so, why;
    (iii) The dosage form;
    (iv) The package size and type, including immediate unit-of-use 
container;
    (v) The drug's marketing status (e.g., prescription or OTC);
    (vi) The drug or drug product type (e.g., human drug or animal 
drug); and
    (vii) For each drug product subject to the listing requirements and 
covered under Sec.  206.1, including products that are exempted under 
Sec.  206.7(b), manufacturers must provide the size, shape, color, and 
code imprint (if any).
    (3) Assigning an NDC number to a drug manufactured for a private 
label distributor. We will assign a unique NDC number to a drug 
manufactured for a private label distributor when the manufacturer 
provides, in addition to the information described in paragraph (c)(1) 
of this section (for active pharmaceutical ingredients manufactured for 
a private label distributor) or paragraph (c)(2) of this section (for 
all other drugs manufactured for a private label distributor), the 
following information for the drug:
    (i) The private label distributor's name, address, telephone and 
fax numbers, e-mail address, and labeler code; and
    (ii) The drug's proprietary name, if any, assigned by the private 
label distributor.
    (d) What information must the repacker or relabeler submit before 
we will assign an NDC number to a drug? Before we assign an NDC number 
to a drug, the repacker or relabeler must submit the information 
required under paragraphs (d)(1) or (d)(2) of this section. If that 
information changes, we will assign a new NDC number as described in 
paragraph (f) of this section.
    (1) Assigning an NDC number to a repacker's or relabeler's drug. We 
will assign a unique NDC number to a drug, including an active 
pharmaceutical ingredient, when the repacker or relabeler of the drug 
provides the following information for the drug:
    (i) The repacker or relabeler's name, address, telephone and fax 
numbers, e-mail address, and labeler code;
    (ii) The NDC number assigned to the drug immediately before the 
drug is received by the repacker or relabeler;
    (iii) The type of operation performed for the drug (that is, 
whether repacking or relabeling);
    (iv) The drug's established name and proprietary name, if any; and
    (v) For the repacker only, the package size and type, including 
immediate unit-of-use container, if any.
    (2) Assigning an NDC number to the drug repacked or relabeled for a 
private label distributor. We will assign a unique NDC number to a drug 
repacked or relabeled for a private label distributor when the repacker 
or relabeler provides, in addition to the

[[Page 51351]]

information described in paragraph (d)(1) of this section, the 
following information for the drug:
    (i) The private label distributor's name, address, telephone and 
fax numbers, e-mail address, and labeler code; and
    (ii) The drug's proprietary name, if any, assigned by the private 
label distributor.
    (e) How must the information be submitted to us? The information 
required in paragraphs (c), (d), and (f) of this section must be 
provided to us in accordance with Sec.  207.61(a)(1)(ii) and (b), 
unless we grant a waiver under Sec.  207.65.
    (f) What changes in the information will require a new NDC number? 
(1) Manufacturers, repackers, and relabelers must obtain a new NDC 
number for a drug when there is a change in any of the information for 
the drug required under paragraphs (c) and (d) of this section. Changes 
must be submitted to us in accordance with paragraphs (e) and (g) of 
this section. However, we will not assign a new NDC number when the 
change involves only the following contact information for the 
manufacturer, repacker, relabeler, or private label distributor: Name, 
address, telephone and fax numbers, and e-mail address.
    (2) In addition to the requirements in paragraph (f)(1) of this 
section, manufacturers must obtain a new NDC number when there is a 
change in an inactive ingredient for each human prescription drug that 
the manufacturer regards as not subject to section 505 of the act and 
for each animal drug that the manufacturer regards as not subject to 
section 512 of the act.
    (g) When must a manufacturer, repacker, or relabeler provide the 
information for an NDC number? A manufacturer, repacker, or relabeler 
must provide the information in paragraphs (c), (d), and (f) of this 
section to us either before or at the time drug listing information is 
required under Sec.  207.45 or Sec.  207.57.


Sec.  207.37  What restrictions pertain to the use of NDC numbers?

    Manufacturers, repackers, and relabelers must not:
    (a) Use an NDC number to represent a different drug than the drug 
to which the NDC number has been assigned under Sec.  207.33.
    (b) Use a different NDC number if marketing is resumed for a drug 
that was discontinued earlier. If marketing is resumed for a drug, and 
no changes have been made to the drug that would require a new NDC 
number under Sec.  207.33(f), the drug must have the same NDC number 
that was assigned to it under Sec.  207.33 before marketing was 
discontinued.
    (c) Use the NDC number to denote FDA approval of that drug.
    (d) Use the NDC number on products that are not subject to this 
part, such as dietary supplements and medical devices.

Subpart D--Listing


Sec.  207.41  Who must list drugs?

    (a) Manufacturers, repackers, relabelers, and drug product 
salvagers who are subject to the registration requirements under Sec.  
207.17 must list their drugs being manufactured, repacked, relabeled, 
or salvaged for commercial distribution. Domestic manufacturers, 
domestic repackers, domestic relabelers, and domestic drug product 
salvagers who are subject to the registration requirements under Sec.  
207.17 must list such drugs regardless of whether the drugs enter 
interstate commerce. When operations are conducted at more than one 
establishment and there exists joint ownership and control among all 
the establishments, listing information may be submitted by the parent, 
subsidiary, and/or affiliate company for drugs at all establishments.
    (b) Manufacturers, repackers, relabelers, and drug product 
salvagers who engage in more than one activity for drugs must list each 
drug in accordance with the requirements for the activity engaged in 
for that drug. For example, a company may manufacture Drug X and 
relabel Drug Y. The company must provide the information described in 
Sec.  207.49 for Drug X and the information described in Sec.  207.53 
for Drug Y.
    (c) Manufacturers, repackers, relabelers, and drug product 
salvagers must provide all listing information to us for drugs that 
they manufacture, repack, relabel, or salvage for private label 
distributors. Private label distributors must not list drugs that they 
do not manufacture, repack, relabel, or salvage for commercial 
distribution.


Sec.  207.45  When must initial listing information be provided?

    At the time of initial registration of an establishment, 
manufacturers, repackers, relabelers, and drug product salvagers must 
list any drug being manufactured, repacked, relabeled, and salvaged for 
commercial distribution at that establishment.


Sec.  207.49  What listing information is required for manufacturers?

    Manufacturers must provide all of the following listing information 
to us for each drug they list, including a drug manufactured for a 
private label distributor:
    (a) The NDC number, assigned by us under Sec.  207.33, for each 
drug; the NDC number must be provided for the drug to be considered 
listed;
    (b) The route of administration of the drug;
    (c) The approved U.S. application number or approved U.S. BLA 
number, if any;
    (d) The registration number of each establishment where the 
manufacturing is performed for the drug;
    (e) The schedule of the drug under section 202 of the Controlled 
Substances Act, if applicable;
    (f) With respect to foreign establishments only, unless previously 
provided under Sec.  207.25(h), the name, address, telephone and fax 
numbers, and e-mail address of each importer of such drug in the United 
States that is known to the establishment, and of each person who 
imports or offers for import such drug to the United States;
    (g) Labeling--(1) Human prescription drugs. Unless the approved 
U.S. application number is provided under paragraph (c) of this 
section, a copy of all current labeling (except that only one 
representative container or carton label need be submitted where 
differences exist only in the quantity of contents statement or the bar 
code), including the content of labeling for each human prescription 
drug;
    (2) Human OTC drugs--(i) Manufacturer regards as subject to section 
505 of the act or section 351 of the Public Health Service Act. A copy 
of all current labeling (except that only one representative container 
or carton label need be submitted where differences exist only in the 
quantity of contents statement or the bar code), including the content 
of labeling for each human OTC drug that the manufacturer regards as 
subject to section 505 of the act or section 351 of the Public Health 
Service Act, unless the approved U.S. application number is provided 
under paragraph (c) of this section;
    (ii) Manufacturer regards as not subject to section 505 of the act 
or section 351 of the Public Health Service Act. A copy of the current 
label (except that only one representative container or carton label 
need be submitted where differences exist only in the quantity of 
contents statement or the bar code), the content of labeling, the 
package insert (if any), and a representative sampling of any other 
labeling for each human OTC drug that the manufacturer regards as not 
subject to section 505 of the act or section 351 of the Public Health 
Service Act;

[[Page 51352]]

    (3) Animal drugs--(i) Manufacturer regards as subject to section 
512 of the act. A copy of all current labeling (except that only one 
representative container or carton label need be submitted where 
differences exist only in the quantity of contents statement), 
including the content of labeling, for each animal drug that the 
manufacturer regards as subject to section 512 of the act;
    (ii) Manufacturer regards as not subject to section 512 of the act. 
For all other animal drugs, a copy of the current label (except that 
only one representative container or carton label need be submitted 
where differences exist only in the quantity of contents statement), 
the package insert, the content of labeling, and a representative 
sampling of any other labeling, for each drug that the manufacturer 
regards as not subject to section 512 of the act;
    (h) Advertisements. (1) A representative sampling of advertisements 
for human prescription drugs that the manufacturer regards as not 
subject to section 505 of the act or section 351 of the Public Health 
Service Act;
    (2) If we request it, for good cause, a copy of all advertisements 
for a particular drug described in paragraph (h)(1) of this section, 
including those described in Sec.  202.1(l)(1) of this chapter. Such 
advertisements must be submitted within 30 calendar days after our 
request; and
    (i) If the drug is manufactured for a private label distributor, 
the name, address, labeler code, telephone and fax numbers, and e-mail 
address of the private label distributor.


Sec.  207.53  What listing information is required for repackers and 
relabelers?

    Repackers and relabelers must provide all of the following listing 
information to us for each drug they list, including a drug repacked or 
relabeled for a private label distributor:
    (a) The NDC number, assigned by us under Sec.  207.33, for each 
drug; the NDC number must be provided for the drug to be considered 
listed;
    (b) The registration number of each establishment where the 
repacking or relabeling is performed for the drug;
    (c) With respect to foreign establishments only, unless previously 
provided under Sec.  207.25(h), the name address, telephone and fax 
numbers, and e-mail address of each importer of such drug in the United 
States that is known to the establishments, and of each person who 
imports or offers for import such drug to the United States;
    (d) Labeling--(1) Human prescription drugs. If any change in 
labeling is made to the drug repacked or relabeled, a copy of all 
changed labeling for each human prescription drug that is repacked or 
relabeled;
    (2) Human OTC drugs--(i) Manufacturer regards as subject to section 
505 of the act or section 351 of the Public Health Service Act. If any 
change in labeling is made to the drug repacked or relabeled, a copy of 
all changed labeling for each human OTC drug that is repacked or 
relabeled;
    (ii) Manufacturer regards as not subject to section 505 of the act 
or section 351 of the Public Health Service Act. A copy of the current 
label, a copy of any changes made to the package insert, if there is 
one, and a representative sampling of any other labeling for each human 
OTC drug that the manufacturer of the drug regards as not subject to 
section 505 of the act or section 351 of the Public Health Service Act;
    (3) Animal drugs. A copy of the current label, a copy of changes 
made to each animal drug labeling, and a representative sampling of any 
other labeling for each animal drug;
    (e) Advertisements. (1) A representative sampling of advertisements 
for human prescription drugs that the repacker or relabeler regards as 
not subject to section 505 of the act or section 351 of the Public 
Health Service Act;
    (2) If we request it for good cause, a copy of all advertisements 
for a particular drug described in paragraph (e)(1) of this section, 
including those described in Sec.  202.1(l)(1) of this chapter. Such 
advertisements must be submitted within 30 calendar days after our 
request; and
    (f) If the drug is repacked or relabeled for a private label 
distributor, the name, address, labeler code, telephone and fax 
numbers, and e-mail address of the private label distributor.


Sec.  207.54  What listing information is required for drug product 
salvagers who are not repackers or relabelers?

    (a) Drug product salvagers who also repack and relabel the drugs 
they salvage must list those drugs as a repacker or relabeler in 
accordance with Sec.  207.53.
    (b) Drug product salvagers who do not otherwise repack or relabel 
drugs they salvage must provide all of the following listing 
information to us for each drug they list, including a drug salvaged 
for a private label distributor:
    (1) The NDC number assigned to the drug immediately before the drug 
is received by the drug product salvager; the NDC number must be 
provided for the drug to be considered listed;
    (2) The lot number and expiration date of the salvaged drug 
product;
    (3) The registration number of each establishment where the drug 
product salvager salvages the drug;
    (4) With respect to foreign establishments only, unless previously 
provided under Sec.  207.25(h), the name address, telephone and fax 
numbers, and e-mail address of each importer of such drug in the United 
States that is known to the establishment, and of each person who 
imports or offers for import such drug to the United States; and
    (5) If the drug is salvaged for a private label distributor, the 
name, address, labeler code, telephone and fax numbers, and e-mail 
address of the private label distributor.


Sec.  207.55  What additional drug listing information may be required?

    For a particular drug product, upon our request, the manufacturer, 
repacker, relabeler, or drug product salvager must briefly state the 
basis for its belief that the drug product is not subject to section 
505 or 512 of the act or section 351 of the Public Health Service Act.


Sec.  207.57  What are the requirements for reviewing and updating 
listing information?

    Manufacturers, repackers, relabelers, and drug product salvagers 
must review and update their drug listing information required under 
Sec. Sec.  207.49, 207.53, 207.54, and 207.55.
    (a) Manufacturers, repackers, relabelers, and drug product 
salvagers must provide listing information, during the annual review 
and update of registration information, for any drug that has not been 
previously listed.
    (b) Manufacturers, repackers, relabelers, and drug product 
salvagers must review and update their listing information each June 
and December of every year. They must:
    (1) Provide listing information, in accordance with Sec. Sec.  
207.49, 207.53, 207.54, and 207.55, for any drug manufactured, 
repacked, relabeled, or salvaged for commercial distribution that has 
not been previously listed;
    (2) Submit the date that they discontinued the manufacture, 
repacking, relabeling, or salvaging for commercial distribution of a 
listed drug and provide the expiration date of the last lot 
manufactured, repacked, relabeled, or salvaged;
    (3) Submit the date that they resumed the manufacture, repacking, 
or relabeling for commercial distribution of a drug previously 
discontinued and provide any other listing information not previously 
required or submitted;
    (4) Submit any material changes in any information previously 
submitted

[[Page 51353]]

pursuant to Sec. Sec.  207.49, 207.53, 207.54, 207.55, or this section; 
or
    (5) Certify that no changes have occurred if no changes have 
occurred since the last review and update. If a drug is discontinued 
and we have received the information required under paragraph (b)(2) of 
this section, no further certifications are necessary for the 
discontinued drug.

Subpart E--Electronic Format for Registration and Listing


Sec.  207.61  How is registration and listing information provided to 
FDA?

    (a) Electronic format. (1) Manufacturers, repackers, relabelers, 
and drug product salvagers that are subject to the registration and 
listing requirements of this part must provide the following 
information to us by using our electronic drug registration and listing 
system, in accordance with part 11 of this chapter, except for the 
requirements in Sec.  11.10(b), (c), and (e) and the corresponding 
requirements in Sec.  11.30:
    (i) Establishment registration information in Sec. Sec.  207.25 and 
207.29;
    (ii) Information required for an NDC number in Sec.  207.33; and
    (iii) Drug listing information in Sec. Sec.  207.49 (except 
paragraphs (g) and (h)), 207.53 (except paragraphs (d) and (e)), 
207.54, 207.55, and 207.57.
    (2) The content of labeling required under Sec.  207.49(g)(1) 
through (g)(3) must be provided to us in an electronic format, in 
accordance with part 11 of this chapter, except for the requirements in 
Sec.  11.10(a), (c) through (h), and (k) and the corresponding 
requirements in Sec.  11.30. The NDC number must also be provided with 
the content of labeling for each drug.
    (3) Advertisements and labeling (other than the content of 
labeling) required under Sec. Sec.  207.49(g) and (h) and 207.53(d) and 
(e) may be provided to us in paper or electronic format in accordance 
with part 11 of this chapter, except for the requirements in Sec.  
11.10(a), (c) through (h), and (k) and the corresponding requirements 
in Sec.  11.30. The NDC number must also be provided with such 
advertisements and labeling for each drug.
    (4) The information provided in electronic format must be in a form 
that we can process, review, and archive. We may periodically issue 
guidance on how to provide registration and listing information in 
electronic format (for example, method of transmission, media, file 
formats, preparation and organization of files).
    (b) English language. Registration and listing information must be 
provided in the English language. Labeling must also be provided in the 
English language, except as provided in Sec.  201.15(c) of this 
chapter.


Sec.  207.65  How is a waiver from the electronic format requirement 
requested?

    (a) If the information under Sec.  207.61(a) cannot be submitted 
electronically, a waiver may be requested. We may grant a waiver 
request if the manufacturer, repacker, relabeler, or drug product 
salvager does not have an e-mail address and access to a computer and 
an Internet service provider that can access our electronic drug 
registration and listing system.
    (b) Waiver requests must include a telephone number and/or mailing 
address where we can contact the manufacturer, repacker, relabeler, or 
drug product salvager.
    (c) If we grant the waiver request, we will provide information on 
how to submit registration and/or listing information.

Subpart F--Miscellaneous


Sec.  207.69  What are the requirements for an official contact and a 
United States agent?

    (a) Official contact. Manufacturers, repackers, relabelers, and 
drug product salvagers that are subject to the registration 
requirements of this part must designate an official contact for each 
establishment. The official contact is responsible for:
    (1) Ensuring the accuracy of registration and listing information; 
and
    (2) Reviewing, disseminating, routing, and responding to 
communications from us.
    (b) United States agent. (1) Each foreign manufacturer, foreign 
repacker, foreign relabeler, or foreign drug product salvager must 
designate a single United States agent. The United States agent is 
responsible for:
    (i) Helping us communicate with the foreign manufacturer, foreign 
repacker, foreign relabeler, or foreign drug product salvager;
    (ii) Responding to questions concerning those drugs that are 
imported or offered for import to the United States; and
    (iii) Helping us schedule inspections.
    (2) The United States agent must reside or maintain a place of 
business in the United States.
    (3) A United States agent may not be a mailbox, answering machine 
or service, or other place where a person acting as the United States 
agent is not physically present.
    (4) If we are unable to contact a foreign manufacturer, foreign 
repacker, foreign relabeler, or foreign drug product salvager directly 
or expeditiously, we may provide information or documents to the United 
States agent. We will consider such an action to be equivalent to 
providing the same information or documents to the foreign 
manufacturer, foreign repacker, foreign relabeler, or foreign drug 
product salvager.


Sec.  207.77  What legal status is conferred by registration and 
listing?

    (a) Registration of an establishment or listing of a drug does not 
denote approval of the establishment, the drug, or other drugs of the 
establishment, nor does it mean that a product may be legally marketed. 
Any representation that creates an impression of official approval or 
that a drug is approved or is legally marketable because of 
registration or listing is misleading and constitutes misbranding.
    (b) Assignment of an establishment registration number, inclusion 
of a drug in our database of drugs, or assignment of an NDC number does 
not denote approval of the establishment or the drug or any other drugs 
of the establishment, nor does it mean that the drug may be legally 
marketed. Any representation that creates an impression that a drug is 
approved or is legally marketable because it appears in our database of 
drugs, has been assigned a NDC number, or the establishment has been 
assigned an establishment registration number, is misleading and 
constitutes misbranding. Failure to comply with Sec.  207.37 also 
constitutes misbranding.
    (c) Neither registration nor listing constitutes a determination by 
FDA that a product is a drug as defined by section 201(g)(1) of the 
act. Registration and listing may, however, be evidence that a facility 
is manufacturing, repacking, relabeling, or salvaging drugs or that a 
product is a drug.


Sec.  207.81  What registration and listing information will we make 
available for public disclosure?

    (a) Except as provided in paragraphs (b) and (c) of this section, 
the following information will be made available for public disclosure 
upon request or at our own discretion:
    (1) All registration information; and
    (2) After a drug is listed, all information obtained for that drug 
under Sec. Sec.  207.33, 207.49, 207.53, and 207.54, except for that 
information obtained under 207.33(d)(1)(ii) and 207.54(b)(1).
    (b) Unless information is publicly available or we find that 
confidentiality would be inconsistent with the protection of the public 
health, we will

[[Page 51354]]

not make publicly available any information submitted as the basis upon 
which it has been determined that a particular drug product is not 
subject to section 505 or 512 of the act.
    (c) We may determine, in limited circumstances and on a case-by-
case basis, that it would be consistent with the protection of the 
public health and the Freedom of Information Act to exempt from public 
disclosure specific information in paragraph (a) of this section. In 
such instances, a manufacturer, repacker, relabeler, or drug product 
salvager must demonstrate that specific information is exempt or is 
otherwise prohibited by law from public disclosure. If we agree, we 
will not make such information publicly available.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

    8. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356, 
356a, 356b, 356c, 371, 374, 379e.
    9. Section 314.81 is amended by revising paragraph (b)(3)(iii) to 
read as follows:


Sec.  314.81  Other postmarketing reports.

* * * * *
    (b) * * *
    (3) * * *
    (iii) Withdrawal of approved drug product from sale. (a) Within 30 
calendar days of the withdrawal of an approved drug from sale, 
applicants who are manufacturers, repackers, or relabelers subject to 
part 207 of this chapter must submit the following information about 
the drug in electronic format, in accordance with the applicable 
requirements described in Sec.  207.61(a):
    (1) The National Drug Code (NDC) number;
    (2) The identity of the drug by established name and by proprietary 
name, if any;
    (3) The new drug application number or abbreviated application 
number;
    (4) The date of withdrawal from sale. We request that the reason 
for withdrawal of the drug from sale be included with the information.
    (b) Within 30 calendar days of the withdrawal of an approved drug 
from sale, applicants who are not subject to part 207 of this chapter 
must submit the information listed in paragraphs (a)(1) through (a)(4) 
of this section. The information must be submitted on the appropriate 
form, which must be submitted to the Drug Listing Branch, Food and Drug 
Administration, CDER Central Document Room, 5901B Ammendale Rd., 
Beltsville, MD 20705-1266.
* * * * *


Sec.  314.125  [Amended]

    10. Section 314.125 is amended in paragraph (b)(11) by removing the 
words ``or processed''.

PART 330--OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY 
RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED

    11. The authority citation for 21 CFR part 330 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    12. Section 330.1 is amended by revising paragraph (b) to read as 
follows:


Sec.  330.1  General conditions for general recognition as safe, 
effective, and not misbranded.

* * * * *
    (b) The establishment(s) in which the drug is manufactured is 
registered, and the drug is listed, in compliance with part 207 of this 
chapter. The appropriate National Drug Code (NDC) number must appear on 
the drug's label in accordance with Sec. Sec.  201.2, 207.33, and 
207.37 of this chapter.
* * * * *

PART 514--NEW ANIMAL DRUG APPLICATIONS

    13. The authority citation for 21 CFR part 514 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e, 
381.
    14. Section 514.111 is amended by adding paragraph (a)(12) to read 
as follows:


Sec.  514.111  Refusal to approve an application.

    (a) * * *
    (12) The drug will be produced in whole or in part in an 
establishment that is not registered and not exempt from registration 
under section 510 of the act and part 207 of this chapter.
* * * * *

PART 515--MEDICATED FEED MILL LICENSE

    15. The authority citation for 21 CFR part 515 continues to read as 
follows:

    Authority: 21 U.S.C. 360b, 371.


Sec.  515.10  [Amended]

    16. Section 515.10 is amended in paragraph (b)(8) by removing the 
phrase ``Sec. Sec.  207.20 and 207.21'' and by adding in its place the 
phrase ``part 207''.

PART 601--LICENSING

    17. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).
    18. Section 601.2 is amended by adding paragraph (f) to read as 
follows:


Sec.  601.2  Applications for biologics licenses; procedures for 
filing.

* * * * *
    (f) Withdrawal from sale of approved biological products. A holder 
of a biologics license application (BLA) must report to FDA, 
electronically in accordance with part 207 of this chapter, the 
withdrawal from sale of an approved biological product. The information 
must be submitted to FDA within 30 working days of the biological 
product's withdrawal from sale. The following information must be 
submitted: The holder's name; product name; BLA number; the National 
Drug Code number, if applicable; and the date of withdrawal from sale. 
The reason for the withdrawal of the biological product is requested 
but not required to be submitted.

PART 607--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR 
MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS

    19. The authority citation for 21 CFR part 607 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374, 
381, 393; 42 U.S.C. 262, 264, 271.
    20. Section 607.3 is amended by revising the second sentence in 
paragraph (b), and by adding new paragraph (k) to read as follows:


Sec.  607.3  Definitions.

* * * * *
    (b) * * * For the purposes of this part only, blood and blood 
product also means those products that meet the definition of a device 
under the Federal Food, Drug, and Cosmetic Act and that are licensed 
under section 351 of the Public Health Service Act, as well as licensed 
biologic components used in the manufacture of a licensed device.
* * * * *
    (k) Importer means a company or individual in the United States 
that is the owner, consignee, or recipient of the foreign 
establishment's blood product that is imported into the United States.
    21. Section 607.7 is revised to read as follows:

[[Page 51355]]

Sec.  607.7  Establishment registration and product listing of blood 
banks and other firms manufacturing human blood and blood products.

    All owners or operators of establishments that engage in the 
manufacturing of blood products are required to register, pursuant to 
section 510 of the Federal Food, Drug, and Cosmetic Act. Registration 
and listing of blood products shall comply with this part. Registration 
does not permit any blood bank or similar establishment to ship blood 
products in interstate commerce.
    22. Section 607.22 is revised to read as follows:


Sec.  607.22  How to register blood product establishments and list 
blood products.

    Initial and subsequent registrations and product listings by a 
blood product establishment for blood products must be on Form FDA 2830 
(Blood Establishment Registration and Product Listing). Manufacturers 
may obtain, complete, and submit the form in the following ways:
    (a) Complete the form online and submit electronically at http://www.fda.gov/cber/blood/bldreg.htm; this information must be submitted 
in accordance with part 11 of this chapter, except for the requirements 
in Sec.  11.10(b), (c), and (e), and the corresponding requirements in 
Sec.  11.30; or
    (b) Download the form from the Internet at http://www.fda.gov/cber/blood/bldreg.htm, and mail the completed form to the address in Sec.  
607.22(e); or
    (c) Request the form by mail using the address in Sec.  607.22(e), 
or by e-mail at [email protected], and mail the completed form to 
the address in Sec.  607.22(e).
    (d) For subsequent annual registration renewals, FDA will furnish 
the establishment's most recent Form FDA 2830 before November 15 of 
each year. The updated Form FDA 2830 must be submitted to FDA before 
December 31 of that year.
    (e) Forms may be requested from and mailed to: Center for Biologics 
Evaluation and Research (HFM-370), 1401 Rockville Pike, suite 200N, 
Rockville, MD 20852-1448.
    23. Section 607.25 is amended by revising paragraph (b)(1) to read 
as follows:


Sec.  607.25  Information required for establishment registration and 
blood product listing.

* * * * *
    (b) * * *
    (1) A list of blood products by established name as defined in 
section 502(e) of the act and by proprietary name, if any, which are 
being manufactured for commercial distribution and which have not been 
included in any list previously submitted on Form FDA 2830 (Blood 
Establishment Registration and Product Listing).
* * * * *
    24. Section 607.35 is revised to read as follows:


Sec.  607.35  Blood product establishment registration number.

    A permanent registration number will be assigned to each blood 
product establishment registered in accordance with this part.
    25. Section 607.37 is amended by revising the introductory text of 
paragraph (a) to read as follows:


Sec.  607.37  Inspection of establishment registrations and blood 
product listings.

    (a) Information submitted on the Form FDA 2830 (Blood Establishment 
Registration and Product Listing) will be available for inspection 
under section 510(f) of the act, on the Internet at http://www.fda.gov/cber/blood/bldregdata.htm, and at the Department of Health and Human 
Services, Food and Drug Administration, Office of Communication, 
Training and Manufacturers Assistance (HFM-40), Center for Biologics 
Evaluation and Research, 1401 Rockville Pike, suite 200N, Rockville, MD 
20852-1448. The following information submitted under the blood product 
listing requirements is illustrative of the type of information that 
will be available for public disclosure when it is compiled:
* * * * *
    26. Section 607.39 is revised to read as follows:


Sec.  607.39  Misbranding by reference to establishment registration, 
validation of registration, or to registration number.

    Registration of an establishment, validation of registration, or 
assignment of a registration number does not in any way denote approval 
of the firm or its products nor does it mean that the products may be 
legally marketed. Any representation that creates an impression of 
official approval because of establishment registration, validation of 
registration, or possession of a registration number is misleading and 
constitutes misbranding.
    27. Section 607.40 is amended by revising paragraphs (a), (b), (c), 
the introductory text of (d), and (d)(3), and by adding new paragraphs 
(e) and (f) to read as follows:


Sec.  607.40  Establishment registration and blood product listing 
requirements for foreign blood product establishments.

    (a) Every foreign blood product establishment must comply with the 
requirements for domestic blood product establishments in subpart B of 
this part, unless exempt under subpart D of this part.
    (b) No blood product may be imported or offered for import into the 
United States unless it complies with the blood product listing 
requirements in subpart B of this part and is manufactured, prepared, 
propagated, compounded, or processed at a registered foreign 
establishment. Blood products imported or offered for import under the 
investigational use provisions of part 312 of this chapter are not 
subject to the requirements in subpart B of this part. All 
establishment registration and blood product listing information must 
be in the English language.
    (c) Each foreign establishment required to register under paragraph 
(a) of this section must, as part of the establishment registration and 
blood product listing, submit the name and address of the 
establishment, the name of each importer of the foreign establishment's 
blood products that is known to the establishment, the name of each 
person who imports or offers for import such blood products to the 
United States, and the name of the individual responsible for 
submitting establishment registration and blood product listing 
information. Any changes in this information must be reported to FDA at 
the intervals specified for updating establishment registration 
information in Sec.  607.26.
    (d) Each foreign establishment required to register under paragraph 
(a) of this section must submit the name, address, telephone and fax 
numbers, and e-mail address of its United States agent as part of its 
initial and updated registration information in accordance with subpart 
B of this part. Each foreign establishment must designate only one 
United States agent.
* * * * *
    (3) The foreign establishment or the United States agent must 
report changes in the United States agent's name, address, telephone 
and fax numbers, and e-mail address to FDA within 30 calendar days of 
the change.
    (e) Each foreign establishment required to register under paragraph 
(a) of this section must register and list blood products using the 
electronic registration and listing system, in accordance with Sec.  
607.22(a).
    (f)(1) If the foreign establishment cannot submit the information 
electronically under Sec.  607.40(e), the

[[Page 51356]]

establishment may request a waiver. FDA may grant a waiver request if 
the foreign establishment does not have an e-mail address and access to 
a computer and an Internet service provider that can access the 
electronic registration and listing system.
    (2) Waiver requests must include a telephone number and/or mailing 
address where the agency can contact the foreign establishment.
    (3) If the agency grants the waiver request, the foreign 
establishment must register and list blood products in accordance with 
Sec.  607.22(b) or (c).
    28. Section 607.65 is amended by redesignating paragraph (f) as 
paragraph (g) and by adding new paragraph (f) to read as follows:


Sec.  607.65  Exemptions for blood product establishments.

* * * * *
    (f) Persons who engage solely in the production of any plasma 
derivative, such as albumin, Immune Globulin, Factor VIII and Factor 
IX, bulk product substances such as fractionation intermediates or 
pastes, or recombinant versions of plasma derivatives or animal derived 
plasma derivatives. This paragraph does not exempt such persons from 
registration and listing under part 207 of this chapter.
* * * * *

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

    29. The authority citation for 21 CFR part 610 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 
264.
    30. Section 610.60 is amended by revising paragraph (a)(2) to read 
as follows:


Sec.  610.60  Container label.

    (a) * * *
    (2) The name, address, license number of the manufacturer, and the 
NDC number in accordance with part 207 of this chapter.
* * * * *
    31. Section 610.61 is amended by revising paragraph (b) to read as 
follows:


Sec.  610.61  Package label.

* * * * *
    (b) The name, address, license number of the manufacturer, and the 
NDC number in accordance with part 207 of this chapter.
* * * * *

PART 1271--HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED 
PRODUCTS

    32. The authority citation for 21 CFR part 1271 continues to read 
as follows:

    Authority: 42 U.S.C. 216, 243, 263a, 264, 271.


Sec.  1271.1  [Amended]

    33. Section 1271.1 is amended in paragraphs (a) and (b)(2) by 
removing ``207.20(f)'' and by adding in its place ``207.9(c)(2)''.
    34. Section 1271.3 is amended by adding paragraphs (mm) and (nn) to 
read as follows:


Sec.  1271.3  How does FDA define important terms in this part?

* * * * *
    (mm) Importer means a company or individual in the United States 
that is the owner, consignee, or recipient of the foreign 
establishment's HCT/P that is imported into the United States.
    (nn) United States agent means a person residing or maintaining a 
place of business in the United States whom a foreign establishment 
designates as its agent. This definition excludes mailboxes, answering 
machines or services, or other places where an individual acting as the 
foreign establishment's agent is not physically present.


Sec.  1271.20  [Amended]

    35. Section 1271.20 is amended by removing ``207.20(f)'' and by 
adding in its place ``207.9(c)(2)''.
    36. Section 1271.22 is added to read as follows:


Sec.  1271.22  How do I register and submit an HCT/P list?

    (a) You must use the electronic registration and listing system at 
http://www.fda.gov/cber/tissue/tisreg.htm in accordance with Sec.  
1271.25 for:
    (1) Establishment registration,
    (2) HCT/P listings, and
    (3) Updates of registration and HCT/P listing.
    (b) FDA will periodically issue guidance on how to provide 
registration and listing information in electronic format (for example, 
method of transmission, media, file formats, preparation, and 
organization of files).
    (c) You must provide the information under paragraph (a) of this 
section in accordance with part 11 of this chapter, except for the 
requirements in Sec.  11.10(b), (c), and (e) and the corresponding 
requirements in Sec.  11.30.
    37. Section 1271.23 is added to part 1271 to read as follows:


Sec.  1271.23  How is a waiver from the electronic format requirements 
requested?

    (a) You may request a waiver from the requirement in Sec.  1271.22 
that information must be provided to FDA in electronic format if you do 
not have an e-mail address and access to a computer and an Internet 
service provider that can access the Web-based FDA registration and 
listing database.
    (b) Requests for a waiver must include a telephone number and/or 
mailing address where FDA can contact the person making the request.
    (c) If FDA grants the request for a waiver, FDA will inform you how 
to submit your registration and/or listing information.
    38. Section 1271.25 is amended by revising introductory paragraph 
(a), paragraphs (a)(2) and (a)(3), and by adding new paragraphs (a)(5), 
(a)(6), and (d) to read as follows:


Sec.  1271.25  What information is required for establishment 
registration and HCT/P listing?

    (a) Your establishment registration must include:
* * * * *
    (2) Each location, including the street address, telephone and fax 
numbers, email address, and the postal service zip code of the 
establishment;
    (3) The name, address, telephone and fax numbers, e-mail address, 
and title of the reporting official;
* * * * *
    (5) Each foreign establishment must also submit the name, address, 
telephone and fax numbers, and e-mail address of each importer that is 
known to the establishment, and the name of each person who imports or 
offers for import such HCT/P to the United States for purposes of 
importation; and
    (6) Each foreign establishment must also submit the name, address, 
telephone and fax numbers, and e-mail address of its United States 
agent. Each foreign establishment must designate only one United States 
agent.
    (i) The United States agent must reside or maintain a place of 
business in the United States.
    (ii) Upon request from FDA, the United States agent must assist FDA 
in communications with the foreign establishment, respond to questions 
concerning the foreign establishment's products that are imported or 
offered for import into the United States, and assist FDA in scheduling 
inspections of the foreign establishment. If the agency is unable to 
contact the foreign establishment directly or expeditiously, FDA may 
provide information or documents to the United States agent, and such 
an action must be considered

[[Page 51357]]

to be equivalent to providing the same information or documents to the 
foreign establishment.
    (iii) The foreign establishment or the United States agent must 
report changes in the United States agent's name, address, telephone 
and fax numbers, and e-mail address to FDA within 30 calendar days of 
the change.
* * * * *
    (d) In addition, if your HCT/P is described under Sec.  1271.20, 
you must submit the information required under part 207 of this chapter 
using the procedures under this subpart.
    39. Section 1271.26 is revised to read as follows:


Sec.  1271.26  When must I amend my establishment registration?

    If the ownership or location of your establishment changes, or if 
there is a change in the United States agent's name, address, telephone 
and fax numbers, and e-mail address, you must submit an amendment to 
registration within 30 calendar days of the change.


Sec.  1271.37  [Amended]

    40. Section 1271.37 is amended in the introductory text of 
paragraph (a) by removing the phrase ``Form FDA 3356'' and adding in 
its place the phrase ``registration and listing information''.

    Dated: August 22, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-7172 Filed 8-23-06; 3:48 pm]
BILLING CODE 4160-01-S