[Federal Register Volume 72, Number 201 (Thursday, October 18, 2007)]
[Proposed Rules]
[Pages 59041-59044]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-20609]


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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; 
Companion to Direct Final Rule

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 by providing options to the existing 
requirement for the processing of live vaccines. FDA is proposing to 
amend 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 processing live 
vaccines 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unnecessary regulations on industry and to revise outdated regulations 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. This proposed rule is a 
companion document to the direct final rule published elsewhere in this 
issue of the Federal Register.

DATES: Submit written comments or electronic comments by January 2, 
2008.

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:
     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.

[[Page 59042]]

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 proposing to revise Sec.  600.11(e)(4) to allow greater 
flexibility for vaccine manufacturers regarding the buildings and 
equipment used for live vaccine processing. The proposed 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 proposed 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 proposed rule.

II. Highlights of the Proposed Rule

    We are proposing to revise 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.
    Proposed Sec.  600.11(e)(4)(i) is analogous to the preexisting 
Sec.  600.11(e)(4). In proposed 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 proposed 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 proposed 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 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. Companion Document to Direct Final Rulemaking

    This proposed rule is a companion to the direct final rule 
published in the final rules section of this issue of the Federal 
Register. This companion proposed rule provides the procedural 
framework to finalize the rule in the event that the direct final rule 
receives any significant adverse comment and is withdrawn. The comment 
period for this companion proposed rule runs concurrently with the 
comment period for the direct final rule. Any comments

[[Page 59043]]

received under this companion proposed rule will also be considered as 
comments regarding the direct final rule. We are publishing the direct 
final rule because the rule is noncontroversial, and we do not 
anticipate that it will receive any significant adverse comments.
    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 no significant adverse comment is received in response to the 
direct final rule, no further action will be taken related to this 
companion proposed rule. Instead, we will publish a confirmation 
document, before the effective date of the direct final rule, 
confirming that the direct final rule will go into effect on March 18, 
2008. Additional information about direct rulemaking procedures is set 
forth in a guidance published in the Federal Register of November 21, 
1997 (62 FR 62466).

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 proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). 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 proposed 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 proposed rule would provide increased 
flexibility for the processing of live vaccines, it would decrease 
overall compliance costs. Therefore, the agency certifies that the 
proposed 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 
proposed 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.

C. Federalism

    FDA has analyzed this proposed 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 proposed 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 proposed 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.
    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, it is proposed that 21 CFR part 600 be 
amended as follows:

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    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.
    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

[[Page 59044]]

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. E7-20609 Filed 10-17-07; 8:45 am]
BILLING CODE 4160-01-S