[Federal Register Volume 68, Number 249 (Tuesday, December 30, 2003)]
[Rules and Regulations]
[Pages 75116-75119]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-31919]
=======================================================================
-----------------------------------------------------------------------
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
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 separate, dedicated facilities and equipment for work with spore-
forming microorganisms. FDA is amending the regulations due to advances
in facility, system, and equipment design and in sterilization
technologies that will allow work with spore-forming microorganisms to
be performed in multiproduct manufacturing areas. We are publishing
this rule 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regulations on industry and to revise outdated regulations without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. We are issuing these amendments
directly as a final rule because they are noncontroversial and there is
little likelihood that we will receive any significant comments
opposing the rule. 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 June 1, 2004. Submit written or
electronic comments on or before March 15, 2004. If we receive no
significant adverse comments during the specified
[[Page 75117]]
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 June 1, 2004. If we receive
any significant adverse comments during the comment period, we intend
to withdraw the direct final rule before its effective date by
publication of a document in the Federal Register.
ADDRESSES: Submit written comments on the direct final 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
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 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 revising 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 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 direct final 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. Sec. 600.11(e)(2)
and 610.12 (21 CFR 610.12).
II. Highlights of the Direct Final Rule
We are amending 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
[[Page 75118]]
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 microorganisms 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. 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. 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 revise the biologics regulations to allow
greater flexibility in production facilities and procedures for work
with spore-forming microorganisms. 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 date of publication in the Federal Register. If we receive
any significant adverse comments, we intend to withdraw this direct
final rule action 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 subjects 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.
IV. 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, 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
direct final rule is consistent with the regulatory philosophy and
principles identified in the Executive order. In addition, the direct
final rule is not a significant regulatory action as defined by the
Executive order and so 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 direct final 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, we certify that the
direct final rule will not have a significant economic impact on a
substantial number of small entities. Therefore, under the Regulatory
Flexibility Act, no further analysis is required.
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.
[[Page 75119]]
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
We have analyzed this direct final 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.
V. Paperwork Reduction Act of 1995
This direct final 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.
VI. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this direct
final rule. Submit a single copy of electronic comments to http://www.fda.gov/dockets/ecomments or two paper copies of any written
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.
Sec. 600.10 [Amended]
0
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''.
0
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
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. 03-31919 Filed 12-29-03; 8:45 am]
BILLING CODE 4160-01-S