[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]


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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

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Direct final rule.

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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regulations on industry and to revise outdated regulations without 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