[Federal Register: October 18, 2007 (Volume 72, Number 201)]
[Proposed Rules]
[Page 59041-59044]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18oc07-18]
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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unnecessary regulations on industry and to revise outdated regulations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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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]
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