[Federal Register Volume 72, Number 201 (Thursday, October 18, 2007)]
[Rules and Regulations]
[Pages 59000-59003]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-20610]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 600

[Docket No. 2007N-0284]


Revision of the Requirements for Live Vaccine Processing

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the 
biologics regulations by providing options to the existing requirement 
for the processing of live vaccines. FDA is amending the regulations 
due to advances in technology that will allow processing of live 
vaccines to be performed in multiproduct manufacturing areas. We are 
publishing this rule because the existing requirement regarding 
facilities and equipment for live vaccine processing is too 
prescriptive and is no longer necessary. We are taking this action as 
part of our continuing effort to reduce the burden of unnecessary 
regulations on industry and to revise outdated regulations without 
diminishing public health protection. Elsewhere in this issue of the 
Federal Register, we are publishing a companion proposed rule under our 
usual procedures for notice and comment in the event that we receive 
any significant adverse comments on the direct final rule. If we 
receive any significant adverse comments that warrant terminating the 
direct final rule, we will consider such comments on the proposed rule 
in developing the final rule.

DATES: This rule is effective March 18, 2008. Submit written or 
electronic comments by January 2, 2008. If we receive no significant 
adverse comments during the specified comment period, we intend to 
publish a confirmation document on or before the effective date of this 
direct final rule confirming that the direct final rule will go into 
effect on March 18, 2008. If we receive any significant adverse 
comments during the comment period, we intend to withdraw this direct 
final rule before its effective date by publication of a notice in the 
Federal Register.

ADDRESSES: You may submit comments, identified by Docket No. 2007N-
0284, by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:

[[Page 59001]]

     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described previously, in 
the ADDRESSES portion of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name 
and Docket No. 2007N-0284 for this rulemaking. All comments received 
may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm, including any personal information provided. For 
additional information on submitting comments see the ``Request for 
Comments'' heading in section VII of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number, found in brackets in the heading of this 
document, into the ``Search'' box and follow the prompts and/or go to 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Nathaniel L. Geary, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

    Live organisms are used in the production of certain vaccine 
products. These live organisms are generally used as source material 
for further manufacture into final products used in the prevention, 
treatment, or cure of a disease or condition of human beings. Live 
organisms pose a challenge to manufacturers in the prevention of cross 
contamination of other products and manufacturing areas. Some live 
organisms used in manufacturing may be harmful to humans, especially 
immunocompromised patients. To ensure the safety of a biological 
product manufactured in the same building or area in which live 
organisms are utilized, tight controls are needed to avoid the release 
of any live organisms into the manufacturing environment and to prevent 
cross contamination of other products manufactured in the same building 
or area.
    Current FDA regulations strictly limit how live vaccine processing 
may be performed. Current Sec.  600.11(e)(4) (21 CFR 600.11(e)(4)) 
requires that: (1) Space used for processing a live vaccine must be 
decontaminated before processing is started and must not be used for 
any other purpose during the vaccine processing; (2) live vaccine 
processing areas must be isolated from and independent of any space 
used for any other purpose by being either in a separate building, in a 
separate wing of a building, or in quarters at the blind end of a 
corridor; (3) the processing area must include adequate space and 
equipment for all processing steps up to, but not including, filling 
into final containers; and (4) test procedures that potentially involve 
the presence of microorganisms other than the vaccine strains, or the 
use of tissue culture cell lines other than primary cultures, must not 
be conducted in space used for processing live vaccine.
    We are revising Sec.  600.11(e)(4) to allow greater flexibility for 
vaccine manufacturers regarding the buildings and equipment used for 
live vaccine processing. The revisions provide for the use of modern 
manufacturing approaches to assist vaccine manufacturers who engage in 
live vaccine processing, e.g., manufacturers of influenza virus 
vaccines. The revisions provide that live vaccine processing steps may 
be performed in multiproduct manufacturing buildings and areas when 
appropriate controls exist to prevent cross contamination of other 
products and areas. We recognize that advances in facility, utility, 
system, and equipment design, as well as in sterilization, 
decontamination, and disinfection technologies have increased the 
ability of manufacturers to control the manufacture of biological 
products and the equipment used in their manufacture. The use of 
appropriate controls, procedures, and processes provides an adequate 
degree of confidence that a product meets the expected levels of 
safety, purity, and potency. Areas of special concern, such as 
containment, decontamination, sterilization, and disinfection can be 
addressed using currently available controls, procedures, and 
processes. The scope of this regulation is limited to all live vaccine 
processing steps up to, but not including, filling into final 
containers. In section II of this document, we identify each of the 
changes included in this direct final rule.

II. Highlights of the Direct Final Rule

    We are revising Sec.  600.11(e)(4) to require that live vaccine 
processing be performed under appropriate controls to prevent cross 
contamination of other products and other manufacturing areas within 
the building. We regard an area as a specific room or set of rooms 
within a building associated with the manufacturing of any one product 
or multiple products.
    Revised Sec.  600.11(e)(4)(i) is analogous to the preexisting Sec.  
600.11(e)(4). In revised Sec.  600.11(e)(4)(i)(A), we provide that a 
manufacturer can use an area that is either in a separate building, in 
a separate wing of a building, or in quarters at the blind end of a 
corridor and includes adequate space and equipment for all processing 
steps up to, but not including, filling into final containers. In 
revised Sec.  600.11(e)(4)(i)(B), we require that a manufacturer not 
use the manufacturing space for conducting test procedures that 
potentially involve the presence of microorganisms other than the 
vaccine strains or the use of tissue culture cell lines other than 
primary cultures.
    In revised Sec.  600.11(e)(4)(ii), if manufacturing is conducted in 
a multiproduct manufacturing building or area, we require appropriate 
controls including procedural controls, and where necessary, process 
containment, to prevent cross contamination of other products and other 
manufacturing areas within the building. In addition, we are requiring 
that all product, equipment, and personnel movement between distinct 
live vaccine processing areas and between live vaccine processing areas 
and other manufacturing areas up to, but not including, filling in 
containers, must be conducted under conditions that will prevent cross 
contamination of other products and manufacturing areas within the 
building, including the introduction of live vaccine organisms into 
these other areas. Process containment is a system designed to 
mechanically isolate equipment or an area that involves manufacturing 
using live vaccine organisms. Procedural controls establish and perform 
effective decontamination, sterilization, and disinfection, as well as

[[Page 59002]]

execute manufacturing procedures in such a manner as to prevent cross 
contamination with live vaccine organisms.
    As part of their procedural controls, manufacturers must have 
written procedures and effective processes in place to adequately 
remove or decontaminate live vaccine organisms from manufacturing areas 
and from equipment for subsequent manufacture of other products. 
Written procedures must be in place for verification that processes to 
remove or decontaminate live vaccine organisms have been followed. All 
potential routes of cross contamination to other manufacturing areas 
should be addressed, including movement of persons (e.g., technical, 
maintenance, delivery, management personnel, and visitors), equipment, 
and in-process materials. Live vaccine organisms should not be removed 
from designated areas unless this can be done in a manner that prevents 
the cross contamination of other products and manufacturing areas. 
These procedural controls will provide a level of assurance that 
products made in areas where live vaccines are manufactured remain 
safe, pure, and potent.

III. Legal Authority

    FDA is issuing this regulation under the biological products 
provisions of the Public Health Service Act (PHS Act) (42 U.S.C. 262 
and 264), and the drugs and general administrative provisions of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321, 331, 
351-353, 355, 360, 371, and 374). Under these provisions of the PHS Act 
and the act, we have the authority to issue and enforce regulations 
designed to ensure that biological products are safe, effective, pure, 
and potent, and to prevent the introduction, transmission, and spread 
of communicable disease.

IV. Rulemaking Action

    In the Federal Register of November 21, 1997 (62 FR 62466), FDA 
described its procedures on when and how the agency will employ direct 
final rulemaking. We have determined that this rule is appropriate for 
direct final rulemaking because we believe that it includes only 
noncontroversial amendments and we anticipate no significant adverse 
comments. Consistent with our procedures on direct final rulemaking, 
FDA is publishing elsewhere in this issue of the Federal Register a 
companion proposed rule to amend FDA's regulations to allow greater 
flexibility in live vaccine processing. The companion proposed rule 
provides a procedural framework within which the rule may be finalized 
in the event that the direct final rule is withdrawn because of any 
significant adverse comments. The comment period for the direct final 
rule runs concurrently with the companion proposed rule. Any comments 
received in response to the companion proposed rule will be considered 
as comments regarding the direct final rule.
    We are providing a comment period on the direct final rule of 75 
days after the date of publication in the Federal Register. If we 
receive any significant adverse comments, we intend to withdraw this 
direct final rule before its effective date by publication of a notice 
in the Federal Register. A significant adverse comment is defined as a 
comment that explains why the rule would be inappropriate, including 
challenges to the rule's underlying premise or approach, or would be 
ineffective or unacceptable without a change. In determining whether an 
adverse comment is significant and warrants terminating a direct final 
rulemaking, we will consider whether the comment raises an issue 
serious enough to warrant a substantive response in a notice-and-
comment process in accordance with section 553 of the Administrative 
Procedure Act (5 U.S.C. 553). Comments that are frivolous, 
insubstantial, or outside the scope of the rule will not be considered 
significant or adverse under this procedure. A comment recommending a 
regulation change in addition to those in the rule would not be 
considered a significant adverse comment unless the comment states why 
the rule would be ineffective without the additional change. In 
addition, if a significant adverse comment applies to an amendment, 
paragraph, or section of this rule and that provision can be severed 
from the remainder of the rule, we may adopt as final those provisions 
of the rule that are not the subject of a significant adverse comment.
    If any significant adverse comments are received during the comment 
period, FDA will publish, before the effective date of this direct 
final rule, a document withdrawing the direct final rule. If we 
withdraw the direct final rule, any comments received will be applied 
to the proposed rule and will be considered in developing a final rule 
using the usual notice-and-comment procedures.
    If FDA receives no significant adverse comments during the 
specified comment period, FDA intends to publish a confirmation 
document, before the effective date of the direct final rule, 
confirming the effective date.

V. Analysis of Impacts

A. Review Under Executive Order 12866, the Regulatory Flexibility Act, 
and the Unfunded Mandates Reform Act of 1995

    FDA has examined the impacts of the direct final rule under 
Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). 
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 impacts; and equity). The agency believes that 
this direct final rule is not an economically significant regulatory 
action as defined by the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this direct final rule will provide 
increased flexibility for the processing of live vaccines, it would 
decrease overall compliance costs. Therefore, the agency certifies that 
this direct final rule will not have a significant economic impact on a 
substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $127 million, using the most current (2006) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
direct final rule to result in any 1-year expenditure that would meet 
or exceed this amount.

B. Environmental Impact

    The agency has determined under 21 CFR 25.31(h), 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.

[[Page 59003]]

C. Federalism

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

VI. The Paperwork Reduction Act of 1995

    This direct final rule contains no new collections of information. 
The collection of information under Sec.  600.11(e)(4) is covered by 
OMB control numbers 0910-0139 (expires September 30, 2008) and 0910-
0308 (expires July 31, 2008). Therefore, clearance by the Office of 
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3520) is not required.

VII. Request for Comments

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

List of Subjects in 21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 600 is amended as follows:

PART 600--BIOLOGICAL PRODUCTS: GENERAL

0
1. 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.

0
2. Section 600.11 is amended by revising paragraph (e)(4) to read as 
follows:


Sec.  600.11  Physical establishment, equipment, animals, and care.

* * * * *
    (e) * * *
    (4) Live vaccine processing. Live vaccine processing must be 
performed under appropriate controls to prevent cross contamination of 
other products and other manufacturing areas within the building. 
Appropriate controls must include, at a minimum:
    (i)(A) Using a dedicated manufacturing area that is either in a 
separate building, in a separate wing of a building, or in quarters at 
the blind end of a corridor and includes adequate space and equipment 
for all processing steps up to, but not including, filling into final 
containers; and
    (B) Not conducting test procedures that potentially involve the 
presence of microorganisms other than the vaccine strains or the use of 
tissue culture cell lines other than primary cultures in space used for 
processing live vaccine; or
    (ii) If manufacturing is conducted in a multiproduct manufacturing 
building or area, using procedural controls, and where necessary, 
process containment. Process containment is deemed to be necessary 
unless procedural controls are sufficient to prevent cross 
contamination of other products and other manufacturing areas within 
the building. Process containment is a system designed to mechanically 
isolate equipment or an area that involves manufacturing using live 
vaccine organisms. All product, equipment, and personnel movement 
between distinct live vaccine processing areas and between live vaccine 
processing areas and other manufacturing areas, up to, but not 
including, filling in final containers, must be conducted under 
conditions that will prevent cross contamination of other products and 
manufacturing areas within the building, including the introduction of 
live vaccine organisms into other areas. In addition, written 
procedures and effective processes must be in place to adequately 
remove or decontaminate live vaccine organisms from the manufacturing 
area and equipment for subsequent manufacture of other products. 
Written procedures must be in place for verification that processes to 
remove or decontaminate live vaccine organisms have been followed.
* * * * *

    Dated: July 30, 2007.
Randall W. Lutter,
Deputy Commissioner for Policy.
[FR Doc. E7-20610 Filed 10-17-07; 8:45 am]
BILLING CODE 4160-01-S