[Federal Register Volume 68, Number 249 (Tuesday, December 30, 2003)]
[Proposed Rules]
[Pages 75179-75182]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-31918]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 600
[Docket No. 2003N-0528]
Revision of the Requirements For Spore-Forming Microorganisms;
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 separate, dedicated facilities and equipment for work
with spore-forming microorganisms. FDA is proposing this amendment due
to advances in facility, system, and equipment design and in
sterilization technologies that would allow work with spore-forming
microorganisms to be performed in multiproduct manufacturing areas. We
are amending the regulations because the existing requirement for
always using separate, dedicated facilities and equipment for work with
spore forming microorganisms 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unnecessary regulations on industry and to revise outdated regulations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. We are taking this action because the
proposed changes are noncontroversial and we do not anticipate any
significant adverse comments. 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: Submit written comments on or before March 15, 2004.
ADDRESSES: Submit written or electronic comments on the proposed rule
to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Submit electronic comments to http://www.fda.gov/dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Valerie A. Butler, 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
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 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 received under this companion
rule will also be considered as comments regarding the direct final
rule. We are publishing the direct final rule because the rule contains
noncontroversial changes, and we do not anticipate that it will receive
any significant adverse comments.
An 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. 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 rule change in addition to the rule would not be
considered a significant adverse comment unless the comment states why
the rule would be ineffective without 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 subjects of significant adverse comments.
If no significant adverse comment is received in response to the
direct final rule, no further action will be taken related to this
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 June 1, 2004. Additional information
about direct rulemaking procedures is set forth in a guidance published
in the Federal Register of November 21, 1997 (62 FR 62466).
Spore-forming microorganisms are used in the production of certain
biological products. These microorganisms may be 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. By their very nature, these microorganisms pose a great
challenge to manufacturers. Bacteria produce spores as a means to
survive adverse environmental
[[Page 75180]]
conditions, while some fungi use them as a form of reproduction. Spores
show great resistance to high temperature, freezing, dryness,
antibacterial agents, radiation, and toxic chemicals. Under favorable
conditions, spores can germinate into actively growing bacteria and
fungi. Many of these spore-forming microorganisms are pathogenic to
humans and have been implicated in causing morbidity and mortality. To
ensure the safety of a biological product manufactured in a facility in
which spore-forming microorganisms are present, these microorganisms
must be kept under tight control to avoid the release of spores into
the manufacturing atmosphere and potential contamination of other
products.
Due to the unique survival properties of spore-forming
microorganisms, current FDA regulations require that work with these
microorganisms be conducted separately from manufacturing operations
for other products. (Currently, FDA regulations use the term ``spore-
bearing'' microorganisms. In this rulemaking, we are proposing to
revise these regulations to use the term ``spore-forming'' because it
is a more commonly used term. For the purposes of these regulations,
spore-forming microorganisms include both the spore and vegetative
cells.) Under Sec. 600.11(e)(3) (21 CFR 600.11(e)(3)), all work with
spore-forming microorganisms must be performed in an entirely separate
building, or in a completely walled-off portion of a building if that
portion is constructed so as to prevent contamination of other areas
and if entrances to such portion are independent of the remainder of
the building. Section 600.11(e)(3) further requires that all vessels,
apparatus, and equipment used for spore-forming microorganisms be
permanently identified and reserved exclusively for use with those
organisms. This provision also states that any materials destined for
further manufacturing may be removed from this area only under
conditions that will prevent the introduction of spores into other
manufacturing areas.
In accordance with Executive Order 12866, which directs Federal
agencies to review their regulations and eliminate or modify those that
are outdated or otherwise in need of reform, we are revising Sec.
600.11(e)(3) to allow greater manufacturing flexibility regarding work
with spore-forming microorganisms. The revisions provide that work with
spore-forming microorganisms may be performed in multiproduct
manufacturing areas when appropriate controls to prevent contamination
of other products and areas exist. We recognize that advances in
facility, system, and equipment design and in sterilization
technologies have increased the ability of manufacturers to control and
analyze the manufacture of biological products and the equipment used
in their manufacture. The use of appropriate controls and procedures
and processes provide an adequate degree of confidence that a product
meets the expected levels of safety and purity. Areas of special
concern, such as containment, contamination with pathogenic and/or
toxic agents, sterilization, and disinfection can be addressed using
currently available and required procedures and processes.
This proposed rule does not apply to spore-forming microorganisms
used for testing of biological products to determine the growth-
promoting qualities of test media used to ensure the sterility of each
lot of product or as biological indicators for validation of steam
sterilization cycles. The rule also does not change the requirements
for those products set forth in Sec. 600.11(e)(2) and 21 CFR 610.12.
II. Highlights of the Proposed Rule
We are proposing to amend our regulations involving spore-forming
microorganisms as set forth below.
A. Work With Spore-Forming Microorganisms
We are revising Sec. 600.11(e)(3) to provide greater flexibility
in production facilities and procedures for work with spore-forming
microorganisms.
Revised Sec. 600.11(e)(3)(i) states that manufacturing processes
using spore-forming microorganisms conducted in a multiproduct
manufacturing site must be performed under appropriate controls to
prevent contamination of other products and areas within the site. We
regard a manufacturing site as an entire complex of buildings,
connected or separate, that belongs to one entity engaged in the
manufacture of any one product or multiple products. An area within a
manufacturing site is a specified location within a facility (physical
structure) associated with the manufacturing of any one product or
multiple products. Revised Sec. 600.11(e)(3)(i) further states that
prevention of spore contamination can be achieved by using a separate,
dedicated building or, if manufacturing is conducted in a multiproduct
manufacturing building, by using process containment. Finally, revised
Sec. 600.11(e)(3)(i) states that all product and personnel movement
between the area where the spore-forming microorganisms are
manufactured and other manufacturing areas must be conducted under
conditions that will prevent the introduction of spores into other
areas of the facility.
Revised Sec. 600.11(e)(3)(ii) states that if process containment
is employed in a multiproduct manufacturing area, procedures must be in
place to demonstrate adequate removal of the spore-forming
microorganism(s) from the manufacturing area for subsequent manufacture
of other products. Revised Sec. 600.11(e)(3)(ii) further states that
these procedures must provide for adequate removal or decontamination
of the spore-forming microorganisms on and within manufacturing
equipment, facilities, and ancillary room items as well as the removal
of disposable or product dedicated items from the manufacturing area.
Finally, revised Sec. 600.11(e)(3)(ii) states that environmental
monitoring specific for the spore-forming microorganism(s) must be
conducted in adjacent areas during manufacturing operations and in the
manufacturing area after completion of cleaning and decontamination.
Under revised Sec. 600.11(e)(3(ii), processing and propagation of
spore-forming microorganisms must be conducted in areas and using
systems that are not used for any other purpose at the same time. Prior
to processing and propagation of any organism, procedures must be
designed and in place to prevent contamination with pathogenic and/or
toxic agents, as well as to decontaminate, sterilize and/or disinfect,
as appropriate, all affected areas and systems. It is important to
demonstrate control over and containment of spore-forming
microorganisms during their propagation and processing in order to
prevent contamination of the product. Products derived from spore-
forming microorganisms should not be removed from designated areas
unless this can be done in a manner that prevents contamination of
other products. These containment procedures will provide a level of
assurance that products made using spore-forming microorganism remain
safe, pure, and of high quality.
The agency anticipates developing a guidance document to assist
manufacturers in complying with these more flexible provisions on work
with spore-forming microorganisms.
B. Substitution of ``Spore-Forming'' for ``Spore-Bearing''
As noted previously in this document, we are replacing the term
``spore-bearing'' in our regulations with the term ``spore-forming''
because the latter has become the more commonly used term to describe
these microorganisms.
[[Page 75181]]
Accordingly, in addition to Sec. 600.11(e)(3), we are revising
Sec. Sec. 600.10(c)(3) (21 CFR 600.10(c)(3)) and 600.11(e)(1) and
(e)(2) by substituting the term ``spore-forming'' for the term ``spore-
bearing''.
III. 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, 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). We believe that this
proposal is consistent with the regulatory philosophy and principles
identified in the Executive order. In addition, the proposed rule is
not a significant regulatory action as defined by the Executive order
and is not subject to review under the Executive order.
The Regulatory Flexibility Act requires agencies to analyze whether
a rule may have a significant economic impact on a substantial number
of small entities. Because the proposed rule allows for greater
flexibility in production facilities and procedures for work with
spore-forming microorganisms, it would not result in any increased
burden or costs on small entities. Therefore, FDA certifies that the
proposed rule will not have a significant economic impact on a
substantial number of small entities, and no further analysis is
required under the Regulatory Flexibility Act.
The Unfunded Mandates Reform Act requires that agencies prepare a
written statement under section 202(a) of anticipated costs and
benefits before proposing any rule that may result in an annual
expenditure by State, local and tribal governments, in the aggregate,
or by the private sector, of $100 million (adjusted annually for
inflation). Because the rule does not impose mandates on State, local,
or tribal governments, or the private sector, that will result in an
expenditure in any one year of $100 million or more, FDA is not
required to perform a cost-benefit analysis according to the Unfunded
Mandates Reform Act.
B. Environmental Impact
The agency 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
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have 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, we have concluded that
the rule does not contain policies that have federalism implications as
defined in the order and, consequently, a federalism summary impact
statement is not required.
IV. The Paperwork Reduction Act of 1995
This proposed rule contains no collections of information.
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.
V. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this proposal.
Submit a single copy of electronic comments to http://www.fda.gov/dockets/ecomments 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.
Sec. 600.10 [Amended]
2. Section 600.10 Personnel is amended in paragraph (c)(3) by
removing the words ``spore-bearing'' and adding in their place the
words ``spore-forming''.
3. Section 600.11 is amended in paragraph (e)(1) by removing the
words ``spore-bearing'' and adding in their place the words ``spore-
forming''; in paragraph (e)(2) by removing the words ``spore-bearing''
in the heading and text, and adding in their place the words ``spore-
forming''; and by revising paragraph (e)(3) to read as follows:
Sec. 600.11 Physical establishment, equipment, animals, and care.
* * * * *
(e) * * *
(3) Work with spore-forming microorganisms. (i) Manufacturing
processes using spore-forming microorganisms conducted in a
multiproduct manufacturing site must be performed under appropriate
controls to prevent contamination of other products and areas within
the site. Prevention of spore contamination can be achieved by using a
separate dedicated building or by using process containment if
manufacturing is conducted in a multiproduct manufacturing building.
All product and personnel movement between the area where the spore-
forming microorganisms are manufactured and other manufacturing areas
must be conducted under conditions that will prevent the introduction
of spores into other areas of the facility.
(ii) If process containment is employed in a multiproduct
manufacturing area, procedures must be in place to demonstrate adequate
removal of the spore-forming microorganism(s) from the manufacturing
area for subsequent manufacture of other products. These procedures
must provide for adequate removal or decontamination of the spore-
forming microorganisms on and within manufacturing equipment,
facilities, and ancillary room items as well as the removal of
disposable or product dedicated items from the manufacturing area.
Environmental monitoring specific for the spore-forming
microorganism(s) must be conducted in adjacent areas during
[[Page 75182]]
manufacturing operations and in the manufacturing area after completion
of cleaning and decontamination.
* * * * *
Dated: December 11, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-31918 Filed 12-29-03; 8:45 am]
BILLING CODE 4160-01-S