[Federal Register: October 18, 2007 (Volume 72, Number 201)]
[Rules and Regulations]
[Page 59000-59003]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18oc07-3]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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regulations on industry and to revise outdated regulations without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://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. 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