[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unnecessary regulations on industry and to revise outdated regulations 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