[Federal Register Volume 63, Number 147 (Friday, July 31, 1998)]
[Proposed Rules]
[Pages 40858-40871]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-20427]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 3, 5, 10, 20, 207, 310, 312, 316, 600, 601, 607, 610, 
640, and 660

[Docket No. 98N-0144]
RIN 0910-AB29


Biological Products Regulated Under Section 351 of the Public 
Health Services Act; Implementation of Biologics License; Elimination 
of Establishment License and Product License

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the biologics regulations to eliminate references to establishment 
licenses and product licenses for all products regulated under the 
Public Health Service Act (PHS Act). In lieu of filing an establishment 
license application (ELA) and product license application (PLA) in 
order to market a biological product in interstate commerce, a 
manufacturer would file a single biologics license application (BLA) 
with the agency. Upon approval of the BLA, a manufacturer would receive 
a biologics license to market the product in interstate commerce. This 
action is part of FDA's continuing effort to achieve the objectives of 
the President's ``Reinventing Government'' initiatives and is intended 
to reduce unnecessary burdens for industry without diminishing public 
health protection. This action also proposes regulations to implement 
certain sections of the Food and Drug Administration Modernization Act 
of 1997 (FDAMA).

DATES: Submit written comments by October 14, 1998. Submit written 
comments on the information collection requirements by August 31, 1998.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Submit written comments on the information 
collection requirements to the Office of Management and Budget (OMB), 
New Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 
20503.

FOR FURTHER INFORMATION CONTACT: Robert A. Yetter, Center for Biologics 
Evaluation and Research (HFM-10), Food and Drug Administration, 1401 
Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-827-0373.

SUPPLEMENTARY INFORMATION: 

I. Background

    Currently, most manufacturers requesting approval to market a 
biological product in interstate commerce must submit a PLA and an ELA 
to FDA. FDA's Center for Biologics Evaluation and Research (CBER) 
currently requires manufacturers to use one of three ELA forms and 1 of 
16 PLA forms for each biological product (see the Federal Register of 
July 8, 1997 (62 FR 36558)). Upon approval of the ELA and PLA, the 
agency issues a product license and an establishment license to the 
manufacturer. As discussed in the next three paragraphs, FDA has 
reviewed its process of licensing biological products and has already 
taken a number of actions to reduce the regulatory burdens imposed by 
the licensing process and to make the licensing process more consistent 
with the process for the approval of new drugs.
    Manufacturers of certain biological products are already required 
to submit a BLA and obtain FDA approval of the BLA before the product 
may be introduced into interstate commerce. In the Federal Register of 
May 14, 1996 (61 FR 24227), FDA issued a final rule to amend the 
biologics regulations by eliminating the ELA requirement for specified 
biotechnology and synthetic biological products licensed under section 
351 of the PHS Act (42 U.S.C. 262 et seq.). The specified biotechnology 
and synthetic biological products are: (1) Therapeutic deoxyribonucleic 
acid (DNA) plasmid products; (2) therapeutic synthetic peptide products 
of 40 or fewer amino acids; (3) monoclonal antibody products for in 
vivo use; and (4) therapeutic recombinant DNA-derived products. This 
provision applies only to those products that FDA determines pursuant 
to principles articulated in the ``Intercenter Agreement Between the 
Center for Drug Evaluation and Research and the Center for Biologics 
Evaluation and Research'' (effective on October 31, 1991) to be subject 
to licensure under Section 351 of the PHS Act. Thus, upon approval, 
manufacturers of the specified biotechnology and synthetic biological 
products receive a single biologics license instead of a product 
license and an establishment license (see Sec. 601.2(c) (21 CFR 
601.2(c))).
    In the Federal Register of July 8, 1997 (62 FR 36558), FDA 
announced the availability of a revised FDA Form 356h. FDA Form 356h 
was revised as a ``Reinventing Government'' initiative to

[[Page 40859]]

harmonize application procedures with the Center for Drug Evaluation 
and Research (CDER) as outlined in the President's November 1995 
National Performance Review Report, ``Reinventing the Regulation of 
Drugs Made From Biotechnology.'' FDA intended that applicants for 
biologics licenses for products specified in Sec. 601.2(c) as well as 
autologous somatic cell therapy products could begin to use FDA Form 
356h immediately and would be required to do so beginning January 8, 
1998. FDA also intended to advise applicants for licenses for other 
biological products when they can voluntarily begin and will be 
required to use FDA Form 356h. Upon approval of a BLA submitted on FDA 
Form 356h, FDA will issue a single biologics license. FDA believes that 
this licensing procedure will greatly simplify the application process, 
harmonize application procedures with those of CDER, and reduce 
industry and agency paperwork burdens. FDA intends as a result of this 
proposed rule to require that all manufacturers requesting approval to 
introduce, or deliver for introduction, a biological product into 
interstate commerce use FDA Form 356h to submit a BLA in lieu of 
separate establishment and product applications.
    With the consolidation of the establishment and product license 
applications into a single biologics license application, the amount of 
information formerly included in the establishment license application 
would be reduced but not eliminated. Some information formerly included 
in the ELA would now be submitted as ``chemistry, manufacturing, and 
controls'' (CMC) information and under the ``establishment 
description'' section of FDA Form 356h. The type and amount of 
information related to the establishment would vary according to the 
specific biological product for which licensure is being requested. To 
describe what information should be included for each type of 
biological product, CBER is preparing a series of guidance documents. 
Many of these guidance documents have already been made available, 
including but not limited to: (1) ``Guidance for Industry for the 
Submission of Chemistry, Manufacturing, and Controls Information for a 
Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody 
Product for In Vivo Use'' (61 FR 56243, October 31, 1996); (2) 
``Guidance for the Submission of Chemistry, Manufacturing, and Controls 
Information and Establishment Description for Autologous Somatic Cell 
Therapy Products'' (62 FR 1460, January 10, 1997); (3) ``Guidance for 
Industry for the Submission of Chemistry, Manufacturing and Controls 
Information for Synthetic Peptide Substances;'' and (4) ``Draft 
Guidance for Industry for the Submission of Chemistry, Manufacturing 
and Controls and Establishment Description Information for Human 
Plasma-Derived Biological Product or Animal Plasma or Serum-Derived 
Products'' (63 FR 3145, January 21, 1998). All of these guidance 
documents can be downloaded from the CBER Guidelines/Guidance document 
World Wide Web page at ``www.fda.gov/cber/guidelines.htm''. These 
guidance documents can also be obtained by written request to the 
Office of Communication, Training, and Manufacturers Assistance (HFM-
40), Center for Biologics Evaluation and Research, Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. Send one self-addressed adhesive label to assist the office in 
processing your requests. These documents may also be obtained by mail 
by calling the CBER Voice Information System at 1-800-835-4709 or 301-
827-1800, or by fax by calling the FAX information System at 1-888-
CBER-FAX or 301-827-3844. FDA intends in the future to announce in the 
Federal Register the availability of additional CMC guidance documents 
for various biological product classes.

II. Legal Authority

    FDA licenses biological products under the authority of section 
351(a) of the PHS Act. Although the PHS Act requires that biological 
products be licensed and be safe, pure, potent, and manufactured in 
facilities designed to assure that the product continues to be safe, 
pure, and potent; it does not mandate the number or form of licenses 
that FDA shall issued for each approvable biological product. The PHS 
Act also does not specify the license application forms that 
manufacturers must submit to FDA. Except for the biological products 
listed under Sec. 601.2(c), FDA has required manufacturers to submit a 
PLA and an ELA for each biological product. Accordingly, upon approval, 
FDA issues two licenses for each product.
    On November 21, 1997, the President signed into law the FDAMA 
(Public Law 105-115). Section 123 of FDAMA, in pertinent part, amended 
section 351 of the PHS Act to specify that a biologics license shall be 
in effect for a biological product prior to such product's introduction 
into interstate commerce. FDAMA thereby statutorily codified FDA's 
administrative BLA/biologics license ``Reinventing Government'' 
initiative. Section 123(a)(1) of FDAMA further states that the 
Secretary of Health and Human Services (delegated to the Commissioner 
of Food and Drugs, at 21 CFR 5.10(a)(5)) shall approve a ``biologics 
license application'' on the basis of a demonstration that the 
biological product that is the subject of the application is safe, 
pure, and potent; and the facility in which the biological product is 
manufactured, processed, packed, or held meets standards designed to 
ensure that the biological product continues to be safe, pure, and 
potent.
    The regulatory standards for establishments manufacturing 
biological products can be found in the biologics regulations in parts 
600 through 680 (21 CFR parts 600 through 680) and in the drug and 
device good manufacturing practice regulations in parts 210 and 211 (21 
CFR parts 210 and 211). The licensed manufacturer must also adhere to 
product and establishment standards established and agreed upon in the 
biologics license application. These standards from applicable 
regulations and as established in licenses for different biological 
products, will continue to constitute the requirements for the approval 
of biologics licenses under section 123 of FDAMA. For consistency and 
to reduce confusion, FDA will continue to use the terms 
``establishment'' and ``licensed establishment'' in the biologics 
regulations when referring to a place of manufacturing, processing, or 
packing instead of the term ``facility'' as used in section 123 of 
FDAMA. FDA is proposing to amend Sec. 600.3(w) to make clear that the 
term ``establishment'' in the biologics regulations has the same 
meaning as ``facility'' in section 123 of FDAMA.
    Section 123(a)(2) of FDAMA eliminated section 351(d) of the PHS Act 
that required licenses for the maintenance of establishments for the 
propagation or manufacture and preparation of biological products. 
Section 123(f) of FDAMA states that the Secretary of Health and Human 
Services shall take measures to minimize differences in the review and 
approval of products licensed under section 351 of the PHS Act and 
products approved through new drug applications (NDA's) under the 
Federal Food, Drug, and Cosmetic Act (the act).
    Therefore, this proposal is intended to amend regulations in 
chapter 21 of the Code of Federal Regulations (CFR) in order to 
implement the regulatory changes concerning biologic license 
applications and biologics licenses in the PHS Act codified by FDAMA. 
This proposal would: (1) Amend the

[[Page 40860]]

regulations in chapter 21 CFR by eliminating almost all references to 
establishment and product applications and licenses and substituting 
the terms ``biologics license application'' and ``biologics license;'' 
(2) codify in the biologics regulations that FDA would issue a 
``biologics license'' upon approval of a BLA; (3) require a 
manufacturer of a biological product to submit a BLA on FDA Form 356h 
to obtain approval of the license in order to market the product in 
interstate commerce; (4) harmonize application procedures with products 
approved under a NDA; and (5) update the format of certain regulations.
    FDA believes that its administrative approach towards reviewing 
regulatory submissions under the PHS Act can and should evolve in 
response to changing technology, knowledge, and experience in reviewing 
the safety, purity, and potency of biological products.

III. Summary of Proposed Rule

A. Definition and Deletion of Terms

    In order to reduce any confusion that may result from use of the 
term ``facility'' in section 351 of the PHS Act as amended by FDAMA, 
FDA is proposing to amend the definition of ``establishment'' in 
Sec. 601.3(w) to include that the term has the same meaning as 
``facility'' in section 351 of the PHS Act.
    FDA is proposing to modify the definition of ``standards'' in 
Sec. 600.3(n) to indicate that the term refers to specifications and 
procedures established in biologics license applications designed to 
insure the continued safety, purity, and potency of biological products 
as well as to specifications and procedures in applicable regulations. 
FDA has authority under Section 351 of the PHS Act to establish 
standards in the review and approval of BLA's. Section 351(d) of the 
PHS Act which previously stated that standards designed to insure the 
continued safety, purity, and potency of biological products be 
``prescribed in regulations'' was removed by FDAMA. FDA believes that 
allowing standards to be established in the BLA will enable the 
manufacturer and FDA to keep pace with evolving science and technology. 
Establishing standards in the BLA is consistent with FDA's previous 
effort to streamline the license review process by deleting certain 
additional standards in the biologics regulations (see 61 FR 40153, 
August 1, 1996). This proposed change to Sec. 600.3(n) would also 
reduce confusion in the biologics regulations by establishing 
consistency with FDA's current regulation at Sec. 601.5(b)(4) regarding 
the revocation of licenses.
     FDA is proposing to delete the term ``licensee'' as used in the 
biologics regulations in order to reduce confusion and to make clear 
the fact that it is the licensed manufacturer who is responsible for 
compliance with product and establishment requirements. The term 
``licensed manufacturer'' would be inserted in all instances that 
currently read ``licensee.''

B. Elimination of PLA/ELA and Implementation of BLA

    In the past, in order to help ensure that biological products were 
safe, pure, and potent, FDA, and prior to FDA, the U.S. Public Health 
Service believed that it was necessary to have both the biological 
product and the establishment in which it was manufactured licensed 
separately. In light of FDA's accumulated experience and expertise 
regulating biological products and due to technical advances that have 
significantly increased the ability of manufacturers to control and 
analyze the manufacture of biological products, FDA, and the biologics 
industry to a great extent, no longer find the separate licensing 
scheme for biological products and establishments to be necessary. 
After much consideration and in a ``Reinventing Government'' initiative 
to reduce burden on industry by implementing a single biologics 
licensing scheme, FDA had already begun drafting this proposal when 
FDAMA was signed into law on November 21, 1997. Section 123 of FDAMA in 
effect codifies FDA's BLA initiative by requiring that FDA issue a 
``biologics license'' to a manufacturer that has submitted a BLA to FDA 
and has demonstrated in the agency's view that the product is and will 
be manufactured in a manner that ensures the product's continued 
safety, purity, and potency.
     This proposal substitutes the terms ``biologics license'' or 
``biologics license application'' in lieu of references to product and 
establishment applications and product and establishment licenses in 
all regulations in chapter 21 CFR. In a few instances references to 
product and establishment licenses would be retained for historical 
accuracy (e.g., Secs. 601.25 and 601.26).
    Under the proposed regulations, a manufacturer applying for 
approval to market a biological product under section 351 of the PHS 
Act would submit to FDA the appropriate establishment and product 
information on the recently approved FDA Form 356h (see 62 FR 36558). 
Manufacturers would no longer be required to submit product or 
establishment information on the many different PLA and ELA forms 
currently in use. Upon approval of the BLA, FDA would issue an approval 
letter that in general terms states that FDA hereby grants the licensed 
manufacturer a biologics license to manufacture the particular 
biological product. FDA would not issue license certificates separate 
from the approval letter as is current agency practice. The approval 
letter would serve as the functional equivalent of a biologics license 
within the meaning of section 351 of the PHS Act.
    FDA is proposing in Sec. 601.2(a) that manufacturers would list in 
the BLA the addresses of all locations of manufacture of a biological 
product. FDA believes this would simplify and clarify the licensing 
processes by having necessary establishment information in the BLA and 
also by allowing FDA to approve all locations involved in the 
manufacture of the product without having to issue an establishment 
license for each location.
    FDA is proposing under Sec. 601.9(c) that manufacturers of some 
biological products would be able to list multiple products in a BLA 
and FDA would be able to issue a single biologics license to the 
manufacturer for more than one product. FDA would most likely use this 
approach with products that have been on the market for a long period 
of time, and for which FDA has considerable knowledge and expertise 
regulating, such as blood and blood components and nonstandardized 
allergenic products (see sections III.E and III.F of this document).

C. Specified Products Outlined in Current Sec. 601.2(c)

    In order to continue harmonized review of specified biotechnology 
and specified synthetic biological products by CDER and CBER, the 
products outlined in the May 14, 1996, final rule (61 FR 24227) would 
continue to be exempt from regulations at Secs. 600.10(b) and (c), 
600.11, 600.12, 600.13, 610.11, 610.53, and 610.62.

D. Radioactive Biological Products

    The agency believes that the regulations for the licensing of 
radioactive biological products under Sec. 601.2(b) may be confusing to 
the industry and do not accurately reflect the current policies of CBER 
and CDER. FDA is therefore proposing to amend Sec. 601.2(b) to clarify 
procedures for submitting an application for marketing approval for a 
radioactive biological product in order to help ensure consistency with 
current CBER and CDER policies and procedures. These proposed 
regulations are intended to merely clarify when a manufacturer of

[[Page 40861]]

a radioactive biological product should submit a NDA to CDER or a BLA 
to CBER and should not be construed as an attempt to address or 
implement the requirements of section 122 of FDAMA, ``Requirements for 
Radiopharmaceuticals.'' FDA intends in a separate rulemaking to issue 
proposed regulations regarding the approval of radiopharmaceuticals as 
required by section 122 of FDAMA. The proposed provision provides that 
when the biological component of a radioactive coupled antibody 
determines the site of action, normally a BLA should be submitted. The 
regulation provides sufficient flexibility to take into account 
situations that may arise in the future where the scientific issues 
associated with the radionuclide or other chemically synthesized 
component are more significant than the scientific issues associated 
with the biological component. In such cases jurisdiction will be 
determined in accordance with principles articulated in the 
``Intercenter Agreement Between the Center for Drug Evaluation and 
Research and the Center for Biologics Evaluation and Research'' 
effective on October 31, 1991.

E. Blood and Blood Components

    Currently CBER requires manufacturers to use as many as 10 
different forms for the submission of ELA's and PLA's for blood and 
blood components. In addition, the agency currently issues a product 
and establishment license for each of seven product types covered by 
the forms (e.g. Whole Blood, Platelets, Plasma, Red Blood Cells, 
Cryoprecipitate, Source Plasma). Under the proposed rule, the agency 
would require a manufacturer of blood and blood components 
participating in interstate commerce to use FDA Form 356h to request 
approval to market. However, a manufacturer of blood and blood 
components would only need to submit one BLA to request approval to 
market one or more blood or blood components (e.g. Whole Blood, 
Platelets, Plasma, Red Blood Cells, Cryoprecipitate, Source Plasma). 
FDA believes this consolidation of forms and submissions would result 
in a reduced regulatory burden for the blood industry because 
information previously duplicated in the many blood and blood component 
product and establishment applications would be submitted only once in 
the BLA.
    In addition, the proposed BLA system would simplify submission of 
supplements to blood and blood component applications. Currently, 
manufacturers desiring to make a single manufacturing change that would 
affect multiple products are required to submit a supplement to each 
individual product and establishment application. Under this proposal a 
manufacturer would only need to submit one supplement to the BLA. For 
example, under the current PLA/ELA system if a manufacturer desired to 
make a single change to the irradiation procedure for its Whole Blood, 
Red Blood Cells, Platelets, and Plasma products manufactured at 3 
locations, the manufacturer would be required to submit 12 supplements 
to 4 PLA's. Under the proposed BLA system, the manufacturer would only 
be required to submit one supplement to the BLA describing the change 
for all of the products and locations involved. FDA intends to continue 
to streamline the blood and blood components application process in the 
future as part of FDA's Reinvention of Blood Regulation initiative.
    In vitro diagnostic kits (IVD's) and blood grouping reagents 
involving blood and blood products are often licensed as individual 
products under section 351 of the PHS Act. Unlike other blood and blood 
component products, applications to market IVD's and blood grouping 
reagents are unique and specific for each product. In order for FDA to 
evaluate the safety, purity, potency, and effectiveness of each IVD or 
blood grouping reagent, manufacturers submit detailed product and 
establishment information to FDA in the application to market the 
product. FDA would continue to evaluate IVD's and blood grouping 
reagents on an individual basis and would therefore require a BLA for 
each product. Accordingly, upon approval of the BLA, FDA would issue a 
single biologics license for each IVD or blood reagent grouping 
product.

F. Allergenic Products

     A significant number of manufacturers of allergenic products 
manufacture many different types of non-standardized allergenic 
extracts for immunotherapeutic and/or diagnostic indications. 
Currently, a manufacturer of multiple non-standardized allergenic 
extract products holds a single product license for all of the non-
standardized allergenic extracts manufactured by the firm. FDA 
estimates that requiring or issuing a biologics license for each type 
of non-standardized allergenic extract from each manufacturer would be 
burdensome to the allergenics industry and FDA. Therefore, in order to 
simplify application procedures and reduce burden on industry and FDA, 
under the BLA/biologics license scheme a manufacturer of multiple non-
standardized allergenic extracts wishing to market these products in 
interstate commerce would only be required to submit a single BLA to 
the agency.
    However, under this proposed rule, standardized allergenic products 
would be regulated as individual biological products. Therefore, a 
manufacturer that wishes to market single or multiple standardized 
allergenic products would be required to submit a single BLA for each 
standardized product because of the detailed product and establishment 
specifications necessary to manufacture such products.
    Under proposed Sec. 601.2(e) FDA is proposing that every 
manufacturer of biological products, including allergenic product 
manufacturers, holding an unsuspended and unrevoked product license and 
establishment license would be considered to have a biologics license. 
Thus, an allergenic manufacturer holding an establishment license and 
product license for multiple non-standardized allergenic extracts would 
be considered to have a single biologics license for those products. 
Likewise, a manufacturer holding an establishment license and product 
license for a single standardized allergenic extract would be 
considered to have a biologics license for that product.

G. Current Good Manufacturing Practice Requirements

    The establishment requirements for biological products regulated 
under Section 351 of the PHS Act would continue to include the current 
good manufacturing practice (CGMP) regulations found in parts 210, 211, 
600, 606, and 820 (21 CFR part 820). FDA would review compliance with 
CGMP's during inspections; applicants would be required to demonstrate 
such compliance in order to obtain a biologics license.
    Under section 501(a)(2)(B) of the act (21 U.S.C. 351(a)(2)(B) et 
seq.) the methods used in, and the facilities or controls used for the 
manufacture, processing, packing, or holding of a drug must conform to 
CGMP. Because bulk drug substance, drug component, and bulk drug 
product meet the definition of ``drug'' in section 201(g)(1) of the act 
(21 U.S.C. 321(g)(1)), their manufacture also must conform to CGMP. The 
CGMP regulations set forth in parts 210 and 211 are intended to apply 
to the preparation of a finished dosage form, whether or not in 
packaged form. (See Secs. 210.3(b)(4) and 211.1(a).) Although these 
CGMP regulations are not specifically applicable to the manufacture of 
bulk drug components, there are numerous instances where CGMP, within 
the meaning of 501(a)(2)(B) of the act, for bulk drug

[[Page 40862]]

substances and bulk drug product components would parallel the 
requirements set forth in part 211 (see 43 FR 45076, September 29, 
1978). Because biological products can be susceptible to contamination, 
adequate control over bulk manufacturing is important. FDA intends to 
use the requirements of part 211 during inspections of manufacturers of 
bulk biological drug substances and bulk biological drug product 
components, to help assure that biological products will have the 
proper raw materials controls, process validation and controls, and 
sensitive and validated test methods and specifications that are 
necessary to ensure the safety, purity, potency, and effectiveness of 
the product. The establishment requirements in Secs. 600.10 through 
600.15 and the inspection regulations in Secs. 600.20 through 600.22 
would continue to apply to all biological products licensed under 
section 351 of the PHS Act except for those exemptions allowed under 
Sec. 601.2(c) for specified biotechnology and synthetic products. 
Therefore, for clarity and to reduce confusion FDA would make clear in 
new Sec. 601.2(d) that the CGMP requirements in parts 210, 211, 600, 
606, and 820 are included, as applicable, as part of the establishment 
requirements for the production of a biological product. FDA is 
currently reviewing the biological product licensing and inspection 
regulations in order to update them as part of CBER's review of general 
biologics and licensing regulations (see 59 FR 3043, January 20, 1994; 
and 59 FR 28821, June 3, 1994).

H. Required Use of FDA Form 356h

    Manufacturers of the four classes of specified biotechnology 
products specified in Sec. 601.2(c) are currently required to use FDA 
Form 356h when requesting permission to market one of these biological 
products in interstate commerce. Manufacturers of autologous somatic 
cell therapy products subject to licensure under section 351 of the PHS 
Act should also use FDA Form 356h. Manufacturers of other biological 
products should continue to use the current forms until such time as 
final CMC and establishment guidance documents are made available. Ten 
months after the effective date of any final rule based on this 
proposal, all manufacturers of biological products licensed under 
section 351 of the PHS Act would be required to use FDA Form 356h as 
the form prescribed for such purpose under Sec. 601.2(a). Regardless of 
which form(s) has been submitted for application to market, CBER will 
begin issuing biologics licenses in lieu of establishment and product 
licenses for any biological product that is approved on and after 
February 19, 1998, the effective date of FDAMA.

IV. Administrative Implementation Issues

A. CBER Policy on Use of the Terms ``Licensed Establishment'' and 
``Licensed Manufacturer''

    In order to be clear, consistent, and reduce confusion that may 
result from the proposed BLA scheme, FDA will continue to use the terms 
``licensed establishment'' and ``licensed manufacturer'' in the 
biologics regulations. Under the proposed BLA scheme there would be no 
establishment license issued along with an approved BLA, however, all 
establishments listed in the approved biologics license application as 
engaged in the manufacture of any part of the biological product or the 
whole biological product would be considered a licensed establishment 
under the biologics regulations (including contract manufacturers and 
short suppliers). FDA believes it is important to continue to use the 
term ``licensed establishment'' in the regulations in order to convey 
the importance of the establishment in the BLA scheme as FDA reviews, 
inspects and approves the establishment as part of the biologics 
license approval process.
    The term ``licensed manufacturer'' as used to pertain to biological 
products regulated under section 351 of the PHS Act would continue to 
mean any legal person or entity holding an unsuspended and unrevoked 
biologics license and who is therefore ultimately responsible for 
compliance with all product and establishment requirements under the 
applicable regulations and agreed upon in the BLA. FDA believes it is 
important to continue to use the term ``licensed manufacturer'' in the 
biologics regulations in order to emphasize that the manufacturer must 
have a U.S. license number issued by FDA and must also hold a biologics 
license for the biological product.

B. Applications in Preparation

    FDA recognizes that it may take applicants time to switch format 
from PLA's and ELA's to BLA's. Therefore, FDA proposes to continue to 
accept PLA's and ELA's in lieu of a BLA for 10 months after the 
effective date of a final rule based on this proposal. However, all 
applications submitted to the agency after the effective date of the 
final rule would be required to include all information indicated in 
FDA Form 356h in order for the application to be considered as filed by 
CBER. PLA's and ELA's received after the effective date of the final 
rule would be administratively handled by FDA as a BLA. Any 
manufacturer planning to file a PLA and an ELA during the 10-month time 
period after the effective date of these regulations should contact FDA 
for further guidance.

C. Applications Currently Under Review

    FDA proposes that any biological products for which a PLA and an 
ELA are pending on the effective date of these regulations would be 
reviewed as submitted. Not withstanding the new regulations, new 
submissions by the manufacturer would not be necessary for these 
products. If the PLA and ELA are sufficient for licensure, FDA would 
issue a biologics license as required by section 351 of the PHS Act as 
amended by FDAMA.

D. PLA's and ELA's Currently in Effect

    FDA proposes under new Sec. 601.2(e) that a manufacturer already 
holding an approved ELA and PLA for a biological product would not be 
required to file supplements to comply with the amended regulations. 
The approved PLA together with portions of the approved ELA relevant to 
the new requirements for the BLA, would be deemed to constitute a 
biologics license under section 351 of the PHS Act .

E. BLA Tracking Number and U.S. License Number of the Manufacturer

1. BLA Tracking Number
    Consistent with the proposed BLA scheme, FDA intends to use a new 
internal BLA tracking and numbering system to track applications, 
manufacturers, and approvals. Each biological product would be assigned 
a BLA tracking number at the time the BLA is submitted by the 
manufacturer. The BLA tracking number assigned by CBER upon receipt of 
a BLA would remain indefinitely associated with the biological product. 
Use of the BLA tracking number would be similar to the use of the NDA 
number for drugs approved under section 505(b) of the act (21 U.S.C. 
355(b)). After publication of a final rule based on this proposal, CBER 
intends to assign a BLA tracking number to each currently approved 
application and notify each licensed manufacturer of their respective 
BLA tracking numbers. Licensed manufacturers will be requested to use 
the BLA tracking number in all correspondence to the agency concerning 
a particular biological product.

[[Page 40863]]

2. U.S. License Number of the Manufacturer
    FDA issues biologics licenses (U.S. licenses) to new manufacturers 
of biological products. Upon approval of a BLA, a manufacturer if not 
previously licensed would receive a U.S. license number that is 
required under section 351 of the PHS Act to appear on the label of the 
biological product. The U.S. license number would also be used to 
satisfy all regulatory requirements regarding ``license numbers'' and 
in all of the same instances that the ``establishment license number'' 
is currently used by industry and CBER. A manufacturer already holding 
a U.S. license number from CBER on the effective date of any final 
regulations would continue to use its current U.S. license number as 
required in the biologics regulations.
    FDA would NOT issue a separate ``biologics license number'' with 
the approval of each biological product. In summary: (1) The biologics 
tracking number would be assigned by FDA when the BLA is filed, it 
would stay with the biological product for its life, and it would be 
used on all correspondence regarding the product; (2) the U.S. license 
number would be assigned to each manufacturer (if not already holding 
one) at the time of licensure of a biological product and would be used 
on all of the manufacturer's labeling for approved biological products; 
and (3) the approval letter for each biological product would serve as 
the biologics license under section 351 of the PHS Act.

F. CMC and Establishment Information Guidance

    As stated earlier in this proposed rule, CBER has made available 
certain guidance documents that outline the recommended information to 
be provided in the CMC and establishment sections of FDA Form 356h. 
Biological product classes for which CBER is currently drafting CMC and 
establishment information guidance documents include but are not 
limited to: Vaccines, allergenic products, in vitro diagnostic 
products, therapeutic plasmid DNA products, therapeutic naturally-
derived protein products, human plasma and animal serum derived 
products, and human blood and blood component products. As these 
guidance documents are completed and made available for various 
biological products, FDA will encourage manufacturers to begin to use 
Form FDA 356h. FDA intends to make CMC and establishment information 
guidance documents available for all biological product classes by the 
time a final rule on this subject is published. The CMC guidance 
documents are intended to help manufacturers comply with product and 
establishment requirements in applicable regulations including but not 
limited to parts 210, 211, 600, 601, 606, and 820.

G. Public Meeting

    FDA intends to hold a public workshop during the comment period of 
this proposed rule to discuss the BLA/biologics license scheme. The 
date, time, and location of the meeting will be announced in a document 
in a future issue of the Federal Register.

V. Proposed Effective Date

    FDA proposes that a final rule resulting from this proposal become 
effective 60 days after its date of publication in the Federal 
Register. FDA understands that considerable resources are committed to 
the preparation of applications and therefore would continue to accept 
applications in the current two application format for 10 months after 
the effective date of any final rule based on this proposal. However, 
after the effective date of the final rule all information indicated in 
FDA Form 356h must be submitted in these submissions in order for the 
application to be considered by CBER as complete. Applications 
submitted in the current two application format after the effective 
date of the final rule will be administratively handled by FDA as a 
BLA. After the 10-month grace period FDA would no longer accept the two 
application format (ELA and PLA) and would only accept for filing BLA's 
submitted on FDA Form 356h.

VI. Analysis of Impacts

A. Reduction in Burden

    The proposed harmonized use of FDA form 356h for all biological 
products and drugs regulated by CBER and CDER would reduce burden on 
industry by enabling manufacturers to submit applications for 
biological products and drugs in a consistent format.
    Manufacturers intending to introduce biological products into 
interstate commerce would no longer have to prepare a PLA and an ELA to 
submit to the agency for approval. The amount of information that 
manufacturers would need to provide in a BLA would be less than that 
currently required in a PLA and ELA. These proposed changes would 
enable manufacturers to devote fewer resources to submitting 
documentation to the agency. Much of the information currently reviewed 
in an ELA at FDA headquarters would be reviewed at the manufacturing 
site during a preapproval inspection. According to many biological 
product manufacturers, preparation, submission, and approval of a 
separate PLA and ELA for each biological product adds substantially to 
the cost of licensing the product.
    The inclusion of parts 210, 211, 600, 606, and 820 in the proposed 
rule as establishment requirements would only serve to clarify existing 
requirements and would not impose any additional burden on industry. 
Human drugs, including biological products regulated under section 351 
of the PHS Act, are already subject to the CGMP's in parts 210, 211, 
600, 606, and 820.

B. Review Under Executive Order 12866 and the Regulatory Flexibility 
Act

    FDA has examined the impact of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
Executive Order 12866 directs 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 impact; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in Executive Order 12866. In addition, the 
proposed rule is a significant regulatory action as defined in 
Executive Order 12866 and is subject to review because it deals with a 
novel policy issue.
    In accordance with the principles of Executive Order 12866, the 
overall result of the proposed rule would be a substantial reduction in 
burdens on a manufacturer filing an application to market a biological 
product. In addition, FDA anticipates that the proposed rule would 
facilitate a manufacturer's ability to improve its licensed products 
and methods of manufacture by decreasing the burden and cost associated 
with filing applications and supplements.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because, as stated previously, the overall result of 
the proposed rule would be substantial reduction in reporting burdens, 
the agency certifies that the proposed rule would not have a 
significant negative economic impact on a substantial number of small 
entities. Therefore, under the Regulatory Flexibility Act, no further 
analysis is required.

[[Page 40864]]

C. The Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by the Office of Management and Budget (OMB) 
under the PRA (44 U.S.C. 3501-3520). A description of these provisions 
is shown below with an estimate of the annual reporting burden. 
Included in the estimate is the time for reviewing the instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for the 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 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: Biological Products Regulated Under Section 351 of the 
Public Health Service Act; Implementation of Biologics License; 
Elimination of Establishment License and Product License.
    Description: FDA is proposing to revise the regulations regarding 
the procedures for application for approval to market a biological 
product regulated under section 351 of the PHS Act. Currently, most 
manufacturers must submit an ELA and a PLA when requesting approval to 
market a biological product in interstate commerce. Under the proposed 
regulations, a manufacturer would submit to FDA the appropriate 
establishment and product information in a single BLA in lieu of filing 
a separate ELA and PLA. The BLA is intended to replace the many 
different ELA and PLA forms currently in use. Upon approval of the BLA, 
a manufacturer would receive a single biologics license to market the 
product in interstate commerce.
    Description of Respondents: Manufacturers of biological products.
    The proposed rule amends the regulations for filing an application 
to market a biological product under Sec. 601.2 to eliminate references 
to establishment licenses and product licenses for all products 
regulated under the PHS Act. The proposed rule would require biologics 
manufacturers to file a single BLA, rather than either an ELA or PLA, 
to market a biological product. The agency estimates that the total 
paperwork burden for manufacturers filing one application that 
consolidates the information currently required under both the PLA and 
ELA will net a decrease of approximately 10 percent. The estimate 
reduces the number of annual responses from a combined PLA/BLA/ELA 
total of 76 to a BLA total of 60. This estimate is derived from the 
total number of license applications received by FDA in fiscal year 
1997 (76) minus the total number of ELA's filed in the same period 
(17). Based on information provided by industry, the time estimated to 
prepare an application for FDA approval to market a product is 
approximately 1,600 hours. In addition to Sec. 601.2, there are other 
regulations included in the proposed rule that relate to certain 
information to be included in a license application including 
Secs. 640.21(c), 640.22(c), 640.65(a), and 660.21(a)(3) and (d). The 
information collection requirements in the preceding regulations are 
included in the burden estimate below for Sec. 601.2.
    The proposed regulation also makes several technical amendments to 
conform the language throughout the biological product regulations to 
the changes proposed here for Sec. 601.2. Specifically, the proposed 
rule makes the following technical term changes: References to product 
and establishment license, and product and establishment applications 
are replaced with ``biologics license'' or ``biologics license 
application;'' ``licensee'' is replaced with ``licensed manufacturer;'' 
and ``licensed establishments'' is replaced with ``licensed 
manufacturer.'' These technical changes impact neither the substantive 
requirements nor the paperwork burden of these regulations, each of 
which carry separate OMB clearance numbers as follows: Secs. 207.20(c) 
and 207.21(a) (0910-0045); 600.80(c)(2) (0910-0308); 601.25(b)(3) 
(0910-0039); 607.20(b) and 607.21 (0910-0052); 610.63 and 640.71(b)(1) 
(0910-0116).
    The following regulations relate to the submission of additional 
information in a supplement to a BLA. Sections 600.15(b) and 610.53(d) 
require submission of a request for an exemption or modification 
regarding the temperature requirements during shipment and from dating 
periods, respectively, for certain biological products. The preparation 
of an exemption request is estimated to be 8 hours; however, no 
requests were received by the agency under either regulations in fiscal 
year 1997. To account for the rare instance in which a request for an 
exemption may be made, the agency has estimated one respondent per year 
in Table 1. Section 640.6 requires that an applicant submit a request 
to make a certain modification of Whole Blood. The number of any 
supplement relating to Whole Blood filed by an applicant in fiscal year 
1997 totaled 74. Because the agency could not determine the number of 
supplements filed specific to Sec. 640.6, the estimate below is based 
on last year's total number of supplements related to Whole Blood.
    The remaining regulations, Secs. 640.21(c), 640.22(c), 640.64(c), 
and 640.74(a) and (b)(2), refer to information that is collected under 
Sec. 601.12, under which the collection of information burden is 
calculated. Moreover, the proposed rule would make only technical 
changes to these regulations. For example, the term ``product license'' 
is changed to ``biologics licence,'' and the term ``product licensee'' 
is changed to ``licensed manufacturer.''

                                  Table 1.--Estimated Annual Reporting Burden1                                  
----------------------------------------------------------------------------------------------------------------
                                                      Annual                                                    
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours 
                                    Respondents      Response        Responses       Response                   
----------------------------------------------------------------------------------------------------------------
601.2                                  60               1              60           1,600          96,000       
600.15(b)                               1               1               1               8               8       
610.53(d)                               1               1               1               8               8       
640.6                                  74               1              74               8             592       
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of            
  information.                                                                                                  


[[Page 40865]]

    In compliance with section 3507(d) of the PRA (44 U.S.C. 3507(d)), 
the agency has submitted the information collection provisions of this 
proposed rule to OMB for review. Interested persons are requested to 
send written comments regarding information collection by August 31, 
1998, 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.

D. Environmental Impact

    The agency has determined under 21 CFR 25.30 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.
    Interested persons may, on or before October 14, 1998, submit to 
the Dockets Management Branch (address above) written comments 
regarding the proposal. Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. The comments received are available for public 
examination in the Dockets Management Branch between 9 a.m. and 4 p.m., 
Monday through Friday. Submit written comments on the information 
collection requirements to the Office of Information and Regulatory 
Management, OMB (address above).

List of Subjects

21 CFR Part 3

    Administrative practice and procedure, Biologics, Drugs, Medical 
devices.

21 CFR Part 5

    Authority delegations (Government agencies), Imports, Organization 
and functions (Government agencies).

21 CFR Part 10

    Administrative practice and procedure, News media.

21 CFR Part 20

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

21 CFR Part 207

    Drugs, Reporting and recordkeeping requirements.

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 316

    Administrative practice and procedure, Drugs, Reporting and 
recordkeeping requirements.

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

21 CFR Part 607

    Blood.

21 CFR Parts 610 and 660

    Biologics, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 640

    Blood, Labeling, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and authority delegated to the Commissioner 
of Food and Drugs, it is proposed that 21 CFR parts 3, 5, 10, 20, 207, 
310, 312, 316, 600, 601, 607, 610, 640, and 660 be amended to read as 
follows:

PART 3--PRODUCT JURISDICTION

    1. The authority citation for 21 CFR part 3 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 357, 360, 360c-
360f, 360h-360j, 360gg-360ss, 371(a), 379e, 381, 394; 42 U.S.C. 216, 
262.

    2. Section 3.2 is amended by revising paragraph (k) to read as 
follows:


Sec. 3.2   Definitions.

* * * * *
    (k) Premarket review includes the examination of data and 
information in an application for premarket review described in 
sections 505, 507, 510(k), 513(f), 515, or 520(g) or 520(l) of the act 
or section 351 of the Public Health Service Act of data and information 
contained in any investigational new drug (IND) application, 
investigational device exemption (IDE), new drug application (NDA), 
antibiotic application, biologics license application, device premarket 
notification, device reclassification petition, and premarket approval 
application (PMA).
* * * * *

PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION

    3. The authority citation for 21 CFR part 5 continues to read as 
follows:

     Authority: 5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15 
U.S.C. 638, 1261-1282, 3701-3711a; 15 U.S.C. 1451-1461; 21 U.S.C. 
41-50, 61-63, 141-149, 321-394, 467f, 679(b), 801-886, 1031-1309; 35 
U.S.C. 156; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263, 
264, 265, 300u-300u-5, 300aa-1; 1395y, 3246b, 4332, 4831(a), 10007-
10008; E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp., p. 124-131; E.O. 
12591, 52 FR 13414, 3 CFR, 1988 Comp., p. 220-223.

    4. Section 5.58 is amended by revising paragraph (a)(3) to read as 
follows:


Sec. 5.58  Orphan products.

    (a) * * *
    (3) Applications for biologics licenses for biological products; or
* * * * *
    5. Section 5.67 is amended by revising paragraphs (a), (b), and (c) 
to read as follows:

Sec. 5.67   Issuance of notices of opportunity for a hearing on 
proposals for denial of approval of applications for licenses or 
revocation of licenses and certain notices of revocation of licenses.

* * * * *
     (a) Notices of opportunity for a hearing on proposals to deny 
approval or filing of applications for biologics licenses under 
Sec. 601.4(b) of this chapter.
     (b) Notices of opportunity for a hearing on proposals to revoke 
biologics licenses under Sec. 601.5(b) of this chapter.
     (c) Notices of revocation, at the manufacturer's request, of 
biologics licenses under Secs. 601.5(a) and 601.8 of this chapter.
* * * * *

 PART 10--ADMINISTRATIVE PRACTICES AND PROCEDURES

    6. The authority citation for 21 CFR part 10 is revised to read as 
follows:

    Authority: 5 U.S.C. 551-558, 701-706; 15 U.S.C. 1451-1461; 21 
U.S.C. 141-149, 321-397, 467f, 679, 821, 1034; 28 U.S.C. 2112; 42 
U.S.C. 201, 262, 263b, 264.

    7. Section 10.50 is amended by revising paragraph (c)(19) to read 
as follows:


Sec. 10.50  Promulgation of regulations and orders after an opportunity 
for a formal evidentiary public hearing.

* * * * *
    (c) * * *

[[Page 40866]]

    (19) Section 351(a) of the Public Health Service Act on a biologics 
license for a biological product.
* * * * *

 PART 20--PUBLIC INFORMATION

    8. The authority citation for 21 CFR part 20 is revised 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-1.

    9. Section 20.100 is amended by revising paragraph (c)(24) to read 
as follows:


Sec. 20.100  Applicability; cross-reference to other regulations.

* * * * *
     (c) * * *
    (24) Applications for biologics licenses for biological products, 
in Sec. 601.51 of this chapter.
* * * * *

PART 207--REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS 
IN COMMERCIAL DISTRIBUTION

    10. The authority citation for 21 CFR part 207 continues to read as 
follows:

    Authority: 21 U.S.C. 331, 351, 352, 355, 357, 360, 360b, 371, 
374; 42 U.S.C. 262.

    11. Section 207.20 is amended by revising paragraph (c) to read as 
follows:


Sec. 207.20  Who must register and submit a drug list.

* * * * *
     (c) Before beginning manufacture or processing of a drug subject 
to one of the following applications, an owner or operator of an 
establishment is required to register before the agency approves it: A 
new drug application, a new animal drug application, a medicated feed 
application, an antibiotic application, or a biologics license 
application.
* * * * *
    12. Section 207.21 is amended by revising the second sentence of 
paragraph (a) to read as follows:

Sec. 207.21  Times for registration and drug listing.

     (a) *  * *  If the owner or operator of the establishment has not 
previously entered into such an operation, the owner or operator shall 
register within 5 days after submitting a new drug application, new 
animal drug application, medicated feed application, antibiotic 
application, or a biologics license application. * * *
* * * * *

PART 310--NEW DRUGS

    13. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b-
360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 
262, 263b-263n.

    14. Section 310.4 is revised to read as follows:


Sec. 310.4  Biologics; products subject to license control.

     (a) Except for radioactive biological products intended for human 
use as described in Sec. 601.2(b) of this chapter, a new drug shall not 
be deemed to be subject to section 505 of the act if it is a drug 
licensed under section 351 of the Public Health Service Act (42 U.S.C. 
262 et seq.) or under the animal virus, serum, and toxin law of March 
4, 1913 (21 U.S.C. 151 et seq.).
     (b) A radioactive biological product (as defined in Sec. 600.3(ee) 
of this chapter) intended for human use, except as identified in 
Sec. 601.2(b)(1) of this chapter, is subject to section 505 of the act. 
Any license for such a radioactive biological product which was issued 
under section 351 of the Public Health Service Act (42 U.S.C. 262 et 
seq.) and which was not revoked or suspended as of August 25, 1975, 
shall constitute an approved new drug application in effect under the 
same terms and conditions as set forth in such license application and 
such portions of the establishment license relating to such product, 
which include data and information required under part 314 of this 
chapter for a new drug application. Any such radioactive biological 
product for which licensure under the Public Health Service Act was 
pending on August 25, 1975, shall, upon determination that it is 
acceptable for licensure, be approved as a new drug application in lieu 
of issuance of a biological product license.
    15. Section 310.503 is amended by revising the first sentence of 
paragraph (b) to read as follows:


Sec. 310.503  Requirements regarding certain radioactive drugs.

* * * * *
     (b) It is the opinion of the Nuclear Regulatory Commission, and 
the Food and Drug Administration that this exemption should not apply 
for certain specific drugs and that these drugs should be appropriately 
labeled for uses for which safety and effectiveness can be demonstrated 
by new drug applications or through licensing under the Public Health 
Service Act (42 U.S.C. 262 et seq.) in the case of biologics. * * *
* * * * *

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    16. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371; 42 
U.S.C. 262.

    17. Section 312.3 is amended in paragraph (b) by revising the 
definition for Marketing application to read as follows:


Sec. 312.3  Definitions and interpretations.

* * * * *
     (b) * * *
     Marketing application means an application for a new drug 
submitted under section 505(b) of the act, a request to provide for 
certification of an antibiotic submitted under section 507 of the act, 
or a biologics license application for a biological product submitted 
under the Public Health Service Act.
* * * * *

PART 316--ORPHAN DRUGS

    18. The authority citation for 21 CFR part 316 continues to read as 
follows:

    Authority: 21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.

    19. Section 316.3 is amended by revising paragraph (b)(9) to read 
as follows:


Sec. 316.3  Definitions.

* * * * *
    (b) * * *
    (9) Marketing application means an application for approval of a 
new drug filed under section 505(b) of the act, a request for 
certification of an antibiotic under section 507 of the act, or an 
application for a biologics license submitted under section 351 of the 
Public Health Service Act (42 U.S.C. 262).
* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    20. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

    21. Section 600.3 is amended by revising paragraph (n) and (w) to 
read as follows:


Sec. 600.3  Definitions.

* * * * *
    (n) The word standards means specifications and procedures 
applicable to an establishment or to the manufacture or release of 
products, which are prescribed in this subchapter

[[Page 40867]]

or established in the biologics license application designed to insure 
the continued safety, purity, and potency of such products.
* * * * *
    (w) Establishment has the same meaning as ``facility'' in section 
351 of the Public Health Service Act and includes all locations.
* * * * *
    22. Section 600.15 is amended by revising paragraph (b) to read as 
follows:


Sec. 600.15  Temperatures during shipment.

* * * * *
     (b) Exemptions. Exemptions or modifications shall be made only 
upon written approval, in the form of a supplement to the biologics 
license application, approved by the Director, Center for Biologics 
Evaluation and Research.
    23. Section 600.21 is amended by revising the first sentence to 
read as follows:


Sec. 600.21  Time of inspection.

      The inspection of an establishment for which a biologics license 
application is pending need not be made until the establishment is in 
operation and is manufacturing the complete product for which a 
biologics license is desired. * * *
    24. Section 600.80 is amended by revising the first sentence of 
paragraph (b), the first and second sentences of paragraph (c)(2)(i), 
and by revising paragraphs (g) and (j) to read as follows:


Sec. 600.80  Postmarketing reporting of adverse experiences.

* * * * *
     (b) Review of adverse experiences. Any person having a biologics 
license under Sec. 601.20 of this chapter shall promptly review all 
adverse experience information pertaining to its product obtained or 
otherwise received by the licensed manufacturer from any source, 
foreign or domestic, including information derived from commercial 
marketing experience, postmarketing clinical investigations, 
postmarketing epidemiological/surveillance studies, reports in the 
scientific literature, and unpublished scientific papers. * * *
* * * * *
      (c) * * *
    (2) Periodic adverse experience reports. (i) The licensed 
manufacturer shall report each adverse experience not reported under 
paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years 
from the date of issuance of the biologics license, and then at annual 
intervals. The licensed manufacturer shall submit each quarterly report 
within 30 days of the close of the quarter (the first quarter beginning 
on the date of issuance of the biologics license) and each annual 
report within 60 days of the anniversary date of the issuance of the 
biologics license. * * *
* * * * *
    (g) Multiple reports. A licensed manufacturer should not include in 
reports under this section any adverse experience that occurred in 
clinical trials if they were previously submitted as part of the 
biologics license application. If a report refers to more than one 
biological product marketed by a licensed manufacturer, the licensed 
manufacturer should submit the report to the biologics license 
application for the product listed first in the report.
* * * * *
     (j) Revocation of biologics license. If a licensed manufacturer 
fails to establish and maintain records and make reports required under 
this section with respect to a licensed biological product, FDA may 
revoke the biologics license for such a product in accordance with the 
procedures of Sec. 601.5 of this chapter.
* * * * *

PART 601--LICENSING

    25. The authority citation for 21 CFR part 601 is revised to read 
as follows:

    Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 321, 351, 352, 353, 
355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 
241, 262, 263.

Sec. 601.1  [Removed]

    26. Section 601.1 Two forms of licenses is removed.
    27. Section 601.2 is revised to read as follows:


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

    (a) General. To obtain a biologics license under section 351 of the 
Public Health Service Act for any biological product, the manufacturer 
shall submit an application to the Director, Center for Biologics 
Evaluation and Research, on forms prescribed for such purposes, and 
shall submit data derived from nonclinical laboratory and clinical 
studies which demonstrate that the manufactured product meets 
prescribed requirements of safety, purity, and potency; with respect to 
each nonclinical laboratory study, either a statement that the study 
was conducted in compliance with the requirements set forth in part 58 
of this chapter, or, if the study was not conducted in compliance with 
such regulations, a brief statement of the reason for the 
noncompliance; statements regarding each clinical investigation 
involving human subjects contained in the application, that it either 
was conducted in compliance with the requirements for institutional 
review set forth in part 56 of this chapter; or was not subject to such 
requirements in accordance with Sec. 56.104 or Sec. 56.105, and was 
conducted in compliance with requirements for informed consent set 
forth in part 50 of this chapter. A full description of manufacturing 
methods; data establishing stability of the product through the dating 
period; sample(s) representative of the product to be sold, bartered, 
or exchanged or offered, sent, carried or brought for sale, barter, or 
exchange; summaries of results of tests performed on the lot(s) 
represented by the submitted sample(s); specimens of the labels, 
enclosures, and containers proposed to be used for the product and; the 
address of each location involved in the manufacture of the biological 
product shall be listed in the biologics license application. An 
application for a biologics license shall not be considered as filed 
until all pertinent information and data have been received from the 
manufacturer by the Center for Biologics Evaluation and Research. The 
applicant shall also include either a claim for categorical exclusion 
under Sec. 25.30 or Sec. 25.31 of this chapter or an environmental 
assessment under Sec. 25.40 of this chapter. In lieu of the procedures 
described in this paragraph, applications for radioactive biological 
products shall be handled as set forth in paragraph (b) of this 
section. The applicant, or the applicant's attorney, agent, or other 
authorized official shall sign the application. An application for any 
of the following specified categories of biological products subject to 
licensure shall be handled as set forth in paragraph (c) of this 
section:
      (1) Therapeutic DNA plasmid products;
      (2) Therapeutic synthetic peptide products of 40 or fewer amino 
acids;
      (3) Monoclonal antibody products for in vivo use; and
      (4) Therapeutic recombinant DNA-derived products.
      (b) Radioactive biological products. To obtain marketing approval 
for a radioactive biological product, as defined in Sec. 600.3(ee) of 
this chapter, the manufacturer of such product shall comply with the 
following:
    (1) An applicant for a radioactive coupled antibody, which means a 
product that consists of an antibody component coupled with a 
radionuclide component (or an antibody component intended solely to be 
coupled with a radionuclide) in which both components provide a 
pharmacological effect but the biological component determines the site 
of action, shall

[[Page 40868]]

submit a biologics license application to the Director, Center for 
Biologics Evaluation and Research, Food and Drug Administration, except 
if, as determined by FDA, there are significant scientific issues 
associated with the radionuclide or other chemically synthesized 
component, in which case a new drug application shall be submitted to 
the Center for Drug Evaluation and Research, Food and Drug 
Administration;
    (2) An applicant for a radioactive biological product other than as 
described in paragraph (b)(1) of this section, shall submit a new drug 
application to the Center for Drug Evaluation and Research, Food and 
Drug Administration.
    (c)(1) To obtain marketing approval for a biological product 
subject to licensure which is a therapeutic DNA plasmid product, 
therapeutic synthetic peptide product of 40 or fewer amino acids, 
monoclonal antibody product for in vivo use, or therapeutic recombinant 
DNA-derived product, an applicant shall submit a biologics license 
application in accordance with paragraph (a) of this section except 
that the following sections in parts 600 through 680 of this chapter 
shall not be applicable to such products: Secs. 600.10(b) and (c), 
600.11, 600.12, 600.13, 610.11, 610.53, and 610.62 of this chapter.
    (2) To the extent that the requirements in this paragraph (c) 
conflict with other requirements in this subchapter, this paragraph (c) 
shall supersede other requirements.
    (d) Approval of a biologics license application or issuance of a 
biologics license shall constitute a determination that the 
establishment(s) and the product meet applicable requirements to ensure 
the continued safety, purity, and potency of such products. Applicable 
requirements for the maintenance of establishments for the manufacture 
of a product subject to this section shall include but not be limited 
to the good manufacturing practice requirements set forth in parts 210, 
211, 600, 606, and 820 of this chapter.
    (e) Any establishment and product license for a biological product 
issued under section 351 of the Public Health Service Act (42 U.S.C. 
201 et seq.) that has not been revoked or suspended as of (insert 
effective date of final rule), shall constitute an approved biologics 
license application in effect under the same terms and conditions set 
forth in such product license and such portions of the establishment 
license relating to such product.


Sec. 601.3  [Removed]

    28. Section 601.3 License forms is removed.
    29. Section 601.4 is amended by revising paragraph (a) and the 
first sentence of paragraph (b) to read as follows:


Sec. 601.4  Issuance and denial of license.

     (a) A biologics license shall be issued upon a determination by 
the Director, Center for Biologics Evaluation and Research that the 
establishment(s) and the product meet the applicable requirements 
established in this chapter. A biologics license shall be valid until 
suspended or revoked.
    (b) If the Commissioner, determines that the establishment or 
product does not meet the requirements established in this chapter, the 
biologics license application shall be denied and the applicant shall 
be informed of the grounds for, and of an opportunity for a hearing on, 
the decision. * * *
    30. Section 601.5 is revised to read as follows:


Sec. 601.5  Revocation of license.

    (a) A biologics license shall be revoked upon application of the 
manufacturer giving notice of intention to discontinue the manufacture 
of all products manufactured under such license or to discontinue the 
manufacture of a particular product for which a license is held and 
waiving an opportunity for a hearing on the matter.
    (b)(1) The Commissioner shall notify the licensed manufacturer of 
the intention to revoke the biologics license, setting forth the 
grounds for, and offering an opportunity for a hearing on, the proposed 
revocation if the Commissioner finds any of the following:
     (i) Authorized Food and Drug Administration employees after 
reasonable efforts have been unable to gain access to an establishment 
or a location for the purpose of carrying out the inspection required 
under Sec. 600.21 of this chapter,
    (ii) Manufacturing of products or of a product has been 
discontinued to an extent that a meaningful inspection or evaluation 
cannot be made,
    (iii) The manufacturer has failed to report a change as required by 
Sec. 601.12,
    (iv) The establishment or any location thereof, or the product for 
which the license has been issued, fails to conform to the applicable 
standards established in the license and in this chapter designed to 
ensure the continued safety, purity, and potency of the manufactured 
product,
    (v) The establishment or the manufacturing methods have been so 
changed as to require a new showing that the establishment or product 
meets the requirements established in this chapter in order to protect 
the public health, or
    (vi) The licensed product is not safe and effective for all of its 
intended uses or is misbranded with respect to any such use.
    (2) Except as provided in Sec. 601.6 or in cases involving 
willfulness, the notification required in this paragraph shall provide 
a reasonable period for the licensed manufacturer to demonstrate or 
achieve compliance with the requirements of this chapter, before 
proceedings will be instituted for the revocation of the license. If 
compliance is not demonstrated or achieved and the licensed 
manufacturer does not waive the opportunity for a hearing, the 
Commissioner shall issue a notice of opportunity for hearing on the 
matter under Sec. 12.21(b) of this chapter.
    31. Section 601.6 is revised to read as follows:


Sec. 601.6   Suspension of license.

     (a) Whenever the Commissioner has reasonable grounds to believe 
that any of the grounds for revocation of a license exist and that by 
reason thereof there is a danger to health, the Commissioner may notify 
the licensed manufacturer that the biologics license is suspended and 
require that the licensed manufacturer do the following:
    (1) Notify the selling agents and distributors to whom such product 
or products have been delivered of such suspension, and
    (2) Furnish to the Director, Center for Biologics Evaluation and 
Research, complete records of such deliveries and notice of suspension.
     (b) Upon suspension of a license, the Commissioner shall either:
    (1) Proceed under the provisions of Sec. 601.5(b) to revoke the 
license, or
    (2) If the licensed manufacturer agrees, hold revocation in 
abeyance pending resolution of the matters involved.
    32. Section 601.9 is revised to read as follows:


Sec. 601.9  Licenses; reissuance.

    (a) Compliance with requirements. A biologics license, previously 
suspended or revoked, may be reissued or reinstated upon a showing of 
compliance with requirements and upon such inspection and examination 
as may be considered necessary by the Director, Center for Biologics 
Evaluation and Research.
    (b) Exclusion of noncomplying location. A biologics license, 
excluding a location or locations that fail to

[[Page 40869]]

comply with the requirements in this chapter, may be issued without 
further application and concurrently with the suspension or revocation 
of the license for noncompliance at the excluded location or locations.
    (c) Exclusion of noncomplying product(s). In the case of multiple 
products included under a single biologics license application, a 
biologics license may be issued, excluding the noncompliant product(s), 
without further application and concurrently with the suspension or 
revocation of the biologics license for a noncompliant product(s).


Sec. 601.10  [Removed]

    33. Section 601.10 Establishment licenses; issuance and conditions 
is removed.
    34. Section 601.20 is revised to read as follows:


Sec. 601.20  Biologics licenses; issuance and conditions.

    (a) Examination--compliance with requirements. A biologics license 
application shall be approved only upon examination of the product and 
upon a determination that the product complies with the standards 
established in biologics license application and the requirements 
prescribed in the regulations in this chapter including but not limited 
to the good manufacturing practice requirements set forth in parts 210, 
211, 600, 606, and 820 of this chapter.
     (b) Availability of product. No biologics license shall be issued 
unless:
    (1) The product intended for introduction into interstate commerce 
is available for examination, and
    (2) Such product is available for inspection during all phases of 
manufacture.
    (c) Manufacturing process--impairment of assurances. No product 
shall be licensed if any part of the process of or relating to the 
manufacture of such product, in the judgment of the Director, Center 
for Biologics Evaluation and Research, would impair the assurances of 
continued safety, purity, and potency as provided by the regulations 
contained in this chapter.
    (d) Inspection--compliance with requirements. A biologics license 
shall be issued or a biologics license application approved only after 
inspection of the establishment(s) listed in the biologics license 
application and upon a determination that the establishment(s) complies 
with the standards established in the biologics license application and 
the requirements prescribed in applicable regulations.
    (e) One biologics license to cover all locations. One biologics 
license shall be issued to cover all locations meeting the 
establishment standards identified in the approved biologics license 
application and each location shall be subject to inspection by FDA 
officials.
    35. Section 601.21 is revised to read as follows:


Sec. 601.21  Products under development.

      A biological product undergoing development, but not yet ready 
for a biologics license, may be shipped or otherwise delivered from one 
State or possession into another State or possession provided such 
shipment or delivery is not for sale, barter, or exchange, except as 
provided in section 505(i) of the Federal Food, Drug, and Cosmetic Act, 
as amended, and the regulations thereunder (21 CFR parts 312 and 812).
    36. Section 601.22 is amended by revising the section heading and 
the first and second sentences to read as follows:


Sec. 601.22  Products in short supply; initial manufacturing at other 
than licensed location.

     A biologics license issued to a manufacturer and covering all 
locations of manufacture shall authorize persons other than such 
manufacturer to conduct at places other than such locations the 
initial, and partial manufacturing of a product for shipment solely to 
such manufacturer only to the extent that the names of such persons and 
places are registered with the Commissioner of Food and Drugs and 
either of the following is found upon application of such manufacturer, 
that the product is in short supply due either to the peculiar growth 
requirements of the organism involved or to the scarcity of the animal 
required for manufacturing purposes, and such manufacturer has 
established with respect to such persons and places such procedures, 
inspections, tests or other arrangements as will assure full compliance 
with the applicable regulations of this subchapter related to continued 
safety, purity, and potency. Such persons and places shall be subject 
to all regulations of this subchapter except Secs. 601.2 to 601.6, 
601.9, 601.10, 601.20, 601.21 to 601.33, and Secs. 610.60 to 610.65 of 
this chapter. * * *
    37. Sections 601.25 is amended in paragraph (b)(3) under 
``Biological Products Review Information'' by revising section VIII and 
by revising the third sentence of paragraph (f)(3) to read as follows:


Sec. 601.25  Review procedures to determine that licensed biological 
products are safe, effective, and not misbranded under prescribed, 
recommended, or suggested conditions of use.

* * * * *
    (b) * * *
    (3) * * *
    BIOLOGICAL PRODUCTS REVIEW INFORMATION
* * * * *
    VIII. If the submission is by a licensed manufacturer, a 
statement signed by the authorized official of the licensed 
manufacturer shall be included, stating that to the best of his or 
her knowledge and belief, it includes all information, favorable and 
unfavorable, pertinent to an evaluation of the safety, 
effectiveness, and labeling of the product, including information 
derived from investigation, commercial marketing, or published 
literature. If the submission is by an interested person other than 
a licensed manufacturer, a statement signed by the person 
responsible for such submission shall be included, stating that to 
the best of his knowledge and belief, it fairly reflects a balance 
of all the available information, favorable and unfavorable 
available to him, pertinent to an evaluation of the safety, 
effectiveness, and labeling of the product.
* * * * *
     (f) * * *
    (3) * * * Where the Commissioner determines that the potential 
benefits outweigh the potential risks, the proposed order shall provide 
that the biologics license for any biological product, falling within 
this paragraph will not be revoked but will remain in effect on an 
interim basis while the data necessary to support its continued 
marketing are being obtained for evaluation by the Food and Drug 
Administration. * * *
* * * * *
    38. Section 601.26 is amended by revising the second sentence of 
the introductory text of paragraph (e), the first, fourth and fifth 
sentences of paragraph (f)(1), the second sentence of paragraph (f)(2), 
and the first sentence of paragraph (f)(3) to read as follows:


Sec. 601.26  Reclassification procedures to determine that licensed 
biological products are safe, effective, and not misbranded under 
prescribed, recommended, or suggested conditions of use.

* * * * *
    (e) * * * Where the Commissioner determines that there is a 
compelling medical need and no suitable alternative therapeutic, 
prophylactic, or diagnostic agent for any biological product that is 
available in sufficient quantities to meet current medical needs, the 
final order shall provide that the biologics license application for 
that biological product will not be revoked, but will remain in effect 
on an interim basis while the data

[[Page 40870]]

necessary to support its continued marketing are being obtained for 
evaluation by the Food and Drug Administration. * * *
    (f) Additional studies and labeling. (1) Within 60 days following 
publication of the final order, each licensed manufacturer for a 
biological product designated as requiring further study to justify 
continued marketing on an interim basis, under paragraph (e) of this 
section, shall submit to the Commissioner a written statement intended 
to show that studies adequate and appropriate to resolve the questions 
raised about the product have been undertaken. * * * The Commissioner 
may extend this 60-day period if necessary, either to review and act on 
proposed protocols or upon indication from the licensed manufacturer 
that the studies will commence at a specified reasonable time. If no 
such commitment is made, or adequate and appropriate studies are not 
undertaken, the biologics license or licenses shall be revoked. * * *
    (2) * * * If the progress report is inadequate or if the 
Commissioner concludes that the studies are not being pursued promptly 
and diligently, or if interim results indicate the product is not a 
medical necessity, the biologics license or licenses shall be revoked.
    (3) Promptly upon completion of the studies undertaken on the 
product, the Commissioner will review all available data and will 
either retain or revoke the biologics license or licenses involved. * * 
*
* * * * *
    39. Section 601.51 is amended by revising the section heading, the 
first sentence of paragraph (a), and paragraph (b) to read as follows:


Sec. 601.51  Confidentiality of data and information in applications 
for biologics licenses.

     (a) For purposes of this section the biological product file 
includes all data and information submitted with or incorporated by 
reference in any application for a biologics license, IND's 
incorporated into any such application, master files, and other related 
submissions. * * *
     (b) The existence of a biological product file will not be 
disclosed by the Food and Drug Administration before a biologics 
license application has been approved unless it has previously been 
publicly disclosed or acknowledged. The Director of the Center for 
Biologics Evaluation and Research will maintain a list available for 
public disclosure of biological products for which a license 
application has been approved.
* * * * *

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

     40. 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; 42 
U.S.C. 216, 262.

    41. Section 607.20 is amended by revising paragraph (b) to read as 
follows:


Sec. 607.20  Who must register and submit a blood product list.

* * * * *
    (b) Preparatory to engaging in the manufacture of blood products, 
owners or operators of establishments who are submitting a biologics 
license application to manufacture blood products are required to 
register before the biologics license application is approved.
* * * * *
    42. Section 607.21 is amended by revising the second sentence to 
read as follows:


Sec. 607.21  Times for establishment registration and blood product 
listing.

    * * * If the owner or operator of the establishment has not 
previously entered into such operation (defined in Sec. 607.3(d)) for 
which a license is required, registration shall follow within 5 days 
after the submission of a biologics license application in order to 
manufacture blood products. * * *

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

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

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 216, 262, 263, 263a, 264.

    44. Section 610.13 is amended by revising the introductory 
paragraph and the first sentence of paragraph (a)(1) to read as 
follows:


Sec.  610.13  Purity.

     Products shall be free of extraneous material except that which is 
unavoidable in the manufacturing process described in the approved 
biologics license application. In addition, products shall be tested as 
provided in paragraphs (a) and (b) of this section.
     (a)(1) Test for residual moisture. Each lot of dried product shall 
be tested for residual moisture and shall meet and not exceed 
established limits as specified by an approved method on file in the 
biologics license application. * * *
* * * * *
    45. Section 610.53 is amended by revising paragraph (d) to read as 
follows:


Sec. 610.53  Dating periods for licensed biological products.

* * * * *
    (d) Exemptions. Exemptions or modifications shall be made only upon 
written approval, in the form of a supplement to the biologics license 
application, issued by the Director, Center for Biologics Evaluation 
and Research.
    46. Section 610.63 is revised to read as follows:


Sec. 610.63  Divided manufacturing responsibility to be shown.

     If two or more licensed manufacturers participate in the 
manufacture of a biological product, the name, address, and license 
number of each must appear on the package label, and on the label of 
the container if capable of bearing a full label.

 PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS

    47. The authority citation for 21 CFR part 640 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 216, 262, 263, 263a, 264.

    48. Section 640.6 is amended by revising the introductory text to 
read as follows:


Sec. 640.6  Modifications of Whole Blood.

      Upon approval by the Director, Center for Biologics Evaluation 
and Research, of a supplement to the biologics license application for 
Whole Blood a manufacturer may prepare Whole Blood from which the 
antihemophilic factor has been removed, provided the Whole Blood meets 
the applicable requirements of this subchapter and the following 
conditions are met:
* * * * *
    49. Section 640.21 is amended by revising paragraph (c) to read as 
follows:


Sec. 640.21  Suitability of donors.

* * * * *
    (c) Plateletpheresis donors shall meet criteria for suitability as 
described in a biologics license application or a supplement to the 
biologics license application, and must have the written approval of 
the Director, Center for Biologics Evaluation and Research, Food and 
Drug Administration.

[[Page 40871]]

    50. Section 640.22 is amended by revising paragraph (c) to read as 
follows:


Sec. 640.22  Collection of source material.

* * * * *
    (c) If plateletpheresis is used, the procedure for collection shall 
be as described in a biologics license application or a supplement to a 
biologics license application, and must have the written approval of 
the Director, Center for Biologics Evaluation and Research, Food and 
Drug Administration.
* * * * *
    51. Section 640.64 is amended by revising the second sentence of 
the introductory text of paragraph (c) to read as follows:


Sec. 640.64  Collection of blood for Source Plasma.

* * * * *
    (c) * * * One of the following formulas shall be used in the 
indicated volumes, except that a different formula may be used for 
plasma for manufacture into noninjectable products if prior written 
approval is obtained from the Director of the Center for Biologics 
Evaluation and Research at the time of licensing or in the form of a 
supplement to the biologics license application for Source Plasma.
* * * * *
    52. Section 640.65 is amended by revising the last sentence of 
paragraph (a) to read as follows:


Sec. 640.65  Plasmapheresis.

    (a) * * * This procedure shall be described in detail in the 
biologics license application.
* * * * *
    53. Section 640.71 is amended by revising the introductory text of 
paragraphs (a) and (b) and by revising paragraph (b)(1) to read as 
follows:


Sec. 640.71  Manufacturing responsibility.

    (a) All steps in the manufacture of Source Plasma, including donor 
examination, blood collection, plasmapheresis, laboratory testing, 
labeling, storage, and issuing shall be performed by personnel of the 
licensed manufacturer of the Source Plasma, except that the following 
tests may be performed by personnel of a manufacturer licensed for 
blood or blood derivatives under section 351(a) of the Public Health 
Service Act, or by a clinical laboratory that meets the standards of 
the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C. 
263a): Provided, The establishment or the clinical laboratory is 
qualified to perform the assigned test(s).
* * * * *
    (b) Such testing shall not be considered divided manufacturing, 
which requires two biologics licenses for Source Plasma: Provided, That
    (1) The results of such tests are maintained by the licensed 
manufacturer of the Source Plasma whereby such results may be reviewed 
by a licensed physician as required in Sec. 640.65(b)(2) and by an 
authorized representative of the Food and Drug Administration.
* * * * *
    54. Section 640.74 is amended by revising paragraph (a) and the 
last sentence of paragraph (b)(2) to read as follows:


Sec. 640.74  Modification of Source Plasma.

    (a) Upon approval by the Director, Center for Biologics Evaluation 
and Research, Food and Drug Administration, of a supplement to the 
biologics license application for Source Plasma, a manufacturer may 
prepare Source Plasma as a liquid product for a licensed blood 
derivative manufacturer who has indicated a need for a liquid product.
    (b) * * *
    (2) * * * Such evidence may be submitted by either the licensed 
manufacturer of the Source Plasma Liquid or the manufacturer of the 
final blood derivative product who has requested the Source Plasma 
Liquid.
* * * * *

 PART 660--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR 
LABORATORY TESTS

    55. The authority citation for 21 CFR part 660 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 216, 262, 263, 263a, 264.

    56. Section 660.21 is amended by revising paragraphs (a)(3) and (d) 
to read as follows:


Sec. 660.21  Processing.

     (a) * * *
    (3) A lot may be subdivided into clean, sterile vessels. Each 
subdivision shall constitute a sublot. If lots are to be subdivided, 
the manufacturer shall include this information in the biologics 
license application. The manufacturer shall describe the test 
specifications to verify that each sublot is identical to other sublots 
of the lot.
* * * * *
    (d) Volume of final product. Each manufacturer shall identify the 
possible final container volumes in the biologics license application.
* * * * *
     57. Section 660.30 is amended by revising paragraph (b) to read as 
follows:


Sec. 660.30  Reagent Red Blood Cells.

* * * * *
    (b) Source. Reagent Red Blood Cells shall be prepared from human 
peripheral blood meeting the criteria of Secs. 660.31 and 660.32, or 
from umbilical cord cells which shall be collected and prepared 
according to the manufacturer's biologics license application.
    58. Section 660.33 is amended by revising the fifth sentence to 
read as follows:


Sec. 660.33  Testing of source material.

    * * * Where fewer than three donor sources of an antibody 
specificity are available, test discrepancies shall be resolved in 
accordance with the manufacturer's biologics license application. * * *

    Dated: July 22, 1998.
Michael A. Friedman,
Acting Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-20427 Filed 7-30-98; 8:45 am]
BILLING CODE 4160-01-F