DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 600 [Docket No.

2003N-05281 Revision of the Requirements For Spore-Forming Microorganisms;

Companion to Direct Final Rule

Food and Drug Administration, Proposed rule.



The Food and Drug Administration regulations by providing

(FDA) is proposing

to amend for

the biologics

options to the existing requirement for work with spore-forming

separate, dedicated microorganisms.


and equipment

FDA is proposing

this amendment

due to advances in facility, technologies that would in because and

system, and equipment

design and in sterilization microorganisms

allow work with spore-forming multiproduct manufacturing

to be performed

areas. We are amending

the regulations

the existing requirement equipment

for always using separate, dedicated facilities

for work with spore forming microorganisms

is no longer necessary.

We are taking this action as part of our continuing of unnecessary without regulations on industry

effort to reduce the burden

and to revise outdated regulations This proposed rule is a elsewhere in this issue

diminishing document

public health protection.


to the direct final rule published

of the Federal Register. We are taking this action because the proposed changes are noncontroversial comments.

and we do not anticipate

any significant


If we receive any significant

adverse comments that warrant

2 terminating the direct final rule, we will consider such comments on the the final rule. on or before [insert date 75 days after date

proposed rule in developing

Submit written



in the Federal Register]. Submit written or electronic comments on the proposed rule to

the Division Administration, electronic

of Dockets Management


Food and Drug MD 20852. Submit ts.

5630 Fishers Lane, rm. 1061, Rockville,

comments to h ttp://


Valerie A. Butler, Center for Biologics Food and Drug Administration, MD 20852-1448, 301-827-6210. 1401

Evaluation Rockville

and Research (HFM-17), Pike, suite 2OON, Rockville,


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 and is

event that the direct final rule receives any adverse comment withdrawn. concurrently The comment period for this companion

proposed rule runs

with the comment

period for the direct final rule. Any comments rule will also be considered as comments

received under this companion

regarding the direct final rule. We are publishing the rule contains noncontroversial will receive any significant An adverse comment would be inappropriate,

the direct final rule because that it

changes, and we do not anticipate

adverse comments. is defined as a comment that explains why the rule premise


challenges to the rule’s underlying or unacceptable without

or approach, or would be ineffective

a change. In

3 determining terminating whether an adverse comment a direct final rulemaking, is significant and warrants

we will consider whether the comment response in a noticeor outside

raises an issue serious enough to warrant a substantive and-comment process. Comments that are frivolous, significant


the scope of the rule will not be considered procedure. A comment recommending a significant

or adverse under this to the rule

a rule change in addition adverse comment without

would not be considered

unless the comment change. In

states why the rule would be ineffective addition, if a significant adverse comment


applies to an amendment, can be severed from the of the rule that

paragraph, or section of this rule and that provision remainder

of the rule, we may adopt as final those provisions adverse comments.

are not subjects of significant 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 [insert in the Federal Register]. Additional procedures is set forth in a guidance 21, 1997 (62 FR 62466). of certain for or

date 5 months after date of publication information published about direct rulemaking

in the Federal Register of November microorganisms

Spore-forming biological products.

are used in the production

These microorganisms

may be used as source material treatment

further manufacture

into final products used in the prevention,

cure of a disease or condition microorganisms

of human beings. By their very nature, these Bacteria produce while some

pose a great challenge to manufacturers.

spores as a means to survive adverse environmental fungi use them as a form of reproduction.


Spores show great resistance to high

4 temperature, chemicals. freezing, dryness, antibacterial Under favorable conditions, agents, radiation, and toxic into actively are and in a

spores can germinate

growing bacteria and fungi. Many of these spore-forming pathogenic mortality. facility to humans and have been implicated To ensure the safety of a biological in which spore-forming microorganisms


in causing morbidity

product manufactured are present, these


must be kept under tight control to avoid the release of spores atmosphere and potential contamination of other

into the manufacturing products.

Due to the unique survival properties current FDA regulations conducted (Currently,

of spore-forming

microorganisms, be

require that work with these microorganisms operations

separately from manufacturing FDA regulations

for other products. microorganisms. In

use the term “spore-bearing”

this rulemaking, “spore-forming”

we are proposing

to revise these regulations

to use the term

because it is a more commonly spore-forming

used term. For the purposes include both the spore and

of these regulations,


vegetative cells.) Under 5 600.11(e)(3) (21 CFR 600.11(e)(3)), all work with spore-forming building, microorganisms must be performed walled-off portion in an entirely separate

or in a completely

of a building

if that portion

is constructed to such portion

so as to prevent contamination are independent

of other areas and if entrances of the building. Section used

of the remainder

600.11(e)(3) further requires that all vessels, apparatus, and equipment for spore-forming exclusively materials microorganisms be permanently identified

and reserved

for use with those organisms. destined for further manufacturing

This provision

also states that any

may be removed from this area

5 only under conditions manufacturing areas. Order 12866, which or modify directs Federal agencies that will prevent the introduction of spores into other

In accordance with Executive to review their regulations or otherwise manufacturing The revisions performed

and eliminate

those that are outdated

in need of reform, we are revising 5 600.11(e)(3) to allow greater flexibility regarding work with spore-forming microorganisms. may be controls to

provide that work with spore-forming manufacturing


in multiproduct

areas when appropriate

prevent contamination advances in facility, technologies

of other products

and areas exist. We recognize that design and in sterilization to control and analyze used in their and processes

system, and equipment

have increased the ability of biological

of manufacturers

the manufacture manufacture. provide

products and the equipment

The use of appropriate
I v

controls and procedures

an adeouate degree of confidence

that a nroduct meets the exnected

levels of safety and purity. contamination disinfection procedures

Areas of special concern, such as containment, and/or toxic agents, sterilization, and

with pathogenic

can be addressed using currently and processes.

available and required

This proposed rule does not apply to spore-forming for testing of biological products to determine



the growth-promoting


of test media used to ensure the sterility indicators for validation

of each lot of product or as biological cycles. The rule also does not

of steam sterilization

change the requirements CFR 610.12.

for those products set forth in 5 600.11(e)(2) and 21

II. Highlights of the Proposed Rule to amend our regulations involving spore-forming

We are proposing microorganisms

as set forth below. Microorganisms in production

A. Work With Spore-Forming

We are revising § 600.11(e)(3) to provide greater flexibility facilities and procedures for work with spore-forming states that manufacturing in a multiproduct

microorganisms. processes using sporemanufacturing site must of other

Revised § 600.11(e)(3)(i) forming microorganisms be performed


under appropriate

controls to prevent contamination

products and areas within complex of buildings, in the manufacture a manufacturing

the site. We regard a manufacturing

site as an entire


or separate, that belongs to one entity engaged or multiple within products. a facility An area within (physical structure)

of any one product site is a specified


associated with the manufacturing Revised 5 600.11(e)(3)(i)

of any one product

or multiple


further states that prevention

of spore contamination or, if manufacturing by using process

can be achieved by using a separate, dedicated building is conducted containment. personnel in a multiproduct Finally, manufacturing building,

revised 5 600.11(e)(3)(i)

states that all product and


between the area where the spore-forming and other manufacturing areas must be of spores into

microorganisms conducted

are manufactured

under conditions

that will prevent the introduction

other areas of the facility. Revised § 600.11(e)(3)(ii) in a multiproduct demonstrate manufacturing states that if process containment area, procedures is employed


must be in place to microorganism(s) from the Revised

adequate removal of the spore-forming area for subsequent manufacture

of other products.

7 § 600.11(e)(3)(ii) further states that these procedures of the spore-forming facilities, must provide for adequate on and

removal or decontamination within manufacturing



and ancillary

room items as well

as the removal of disposable manufacturing monitoring area. Finally,

or product


items from the states that environmental must be conducted

revised 5 600.11(e)(3)(ii)

specific for the spore-forming

microorganism(s) operations

in adjacent areas during manufacturing area after completion

and in the manufacturing

of cleaning and decontamination. p recessing and propagation of spore-

Under revised 5 600.11(e)(3(ii), 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 with pathogenic and/or disinfect, to demonstrate must be designed and in place to and/or toxic agents, as well as to as appropriate, all affected areas and of spore-

prevent contamination decontaminate, sterilize

systems. It is important forming microorganisms prevent contamination microorganisms

control over and containment

during their propagation of the product.

and processing in order to

Products derived from spore-forming

should not be removed from designated areas unless this can of other products. These

be done in a manner that prevents contamination containment procedures will provide microorganism

a level of assurance that products made remain safe, pure, and of high quality. a guidance document to assist on work with

using spore-forming

The agency anticipates manufacturers spore-forming in complying


with these more flexible




B. Substitution

of “Spore-Forming”

for “Spore-Bearing” we are replacing the term “sporebecause the latter

As noted previously bearing” in our regulations

in this document,

with the term “spore-forming”

has become the more commonly Accordingly, in addition

used term to describe these microorganisms. (21

to § 600.11(e)(3), we are revising 5s 600.10(c)(3) and (e)(2) by substituting

CFR 600.10(c)(3)) forming”

and 600.11(e)(l)

the term “spore-

for the term “spore-bearing”. of Impacts Order 12866, the Regulatory Flexibility Act, and

III. Analysis

A. Review Under Executive the Unfunded

Mandates Reform Act of 1995 the impacts of the proposed rule under Executive Flexibility Act (5 U.S.C. 601-612), and the Executive Order

FDA has examined

Order 12866, the Regulatory Unfunded

Mandates Reform Act of 19% (Public Law 10~4).

12866 directs agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory potential economic, approaches

that maximize

net benefits (including

environmental, impacts; and

public health and safety, and other advantages; distributive equity). We believe that this proposal is consistent philosophy and principles identified

with the regulatory order. In addition, the

in the Executive

proposed rule is not a significant


action as defined by the Executive order. a rule

order and is not subject to review under the Executive The Regulatory may have a significant Flexibility

Act requires agencies to analyze whether number of small

economic impact on a substantial

entities. Because the proposed rule allows for greater flexibility facilities and procedures for work with spore-forming

in production it


would not result in any increased burden or costs on small entities. Therefore,

9 FDA certifies that the proposed rule will not have a significant impact on a substantial required economic

number of small entities, and no further analysis is Flexibility Act.

under the Regulatory

The Unfunded written

Mandates Reform Act requires that agencies prepare a costs and benefits before by State, local

statement under section 202(a) of anticipated


any rule that may result in an annual expenditure

and tribal governments, million

in the aggregate, or by the private sector, of $100 for inflation). Because the rule does not impose or the private sector, that will or more, FDA is not

(adjusted annually

mandates on State, local, or tribal governments, result in an expenditure required to perform

in any one year of $100 million

a cost-benefit

analysis according to the Unfunded

Mandates Reform Act.

B. Environmental

Impact under 21 CFR 25.3 I(h) that this action is of a type or cumulatively have a significant effect on the assessment nor an

The agency determined that does not individually human environment. environmental C. Federalism

Therefore, neither an environmental

impact statement is required.

We have analyzed this proposed rule in accordance with the principles set forth in Executive not contain policies relationship distribution government. policies Order 13132. We have determined that have substantial that the rule does

direct effects on the States, on the and the States, or on the

between the National


of power and responsibilities Accordingly,

among the various levels of that the rule does not contain

we have concluded implications

that have federalism a federalism

as defined in the order and,


summary impact statement is not required.

10 IV. The Paperwork Reduction Act of 1995 of information. Therefore,

This proposed rule contains no collections clearance by the Office of Management Paperwork Reduction

and Budget (OMB) under the

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



or electronic


regarding this proposal.

Submit a

single copy of electronic


to except that individuals may

or two paper copies of any mailed comments, submit one paper copy. Comments

are to be identified

with the docket number

found in brackets in the heading of this document. be seen in the Division Monday through Friday. List of Subjects in 21 CFR Part 600 Biologics, Reporting and recordkeeping of Dockets Management

Received comments may

between 9 a.m. and 4 p.m.,


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 1. The authority

for 21 CFR part 600 continues to read as follows:




11 5 600.10 [Amended] (c)(3) by removing

2. Section 600.10 Personnel is amended in paragraph the words “spore-bearing” forming”.

and adding in their place the words “spore-

3. Section 600.11 is amended in paragraph (e)(l) by removing “spore-bearing” and adding in their place the words “spore-forming”; the words “spore-bearing”

the words in

paragraph (e)(Z) by removing

in the heading and and by revising

text, and adding in their place the words “spore-forming”; paragraph (e)(3) to read as follows: Q600.11 * * Physical establishment, * * *

equipment, animals, and care.

( e1 * * * (3) Work with spore-forming using spore-forming manufacturing contamination contamination microorganisms. conducted (i) Manufacturing in a multiproduct controls to prevent of spore or by processes


site must be performed of other products

under appropriate

and areas within

the site. Prevention

can be achieved by using a separate dedicated building if manufacturing is conducted

using process containment manufacturing building.

in a multiproduct between the and other

All product and personnel microorganisms


area where the spore-forming manufacturing introduction

are manufactured

areas must be conducted

under conditions

that will prevent the

of spores into other areas of the facility. is employed in a multiproduct manufacturing

(ii) If process containment area, procedures spore-forming manufacture

must be in place to demonstrate

adequate removal of the area for subsequent

microorganism(s) of other products.

from the manufacturing These procedures

must provide for adequate microorganisms on and

removal or decontamination

of the spore-forming

12 within manufacturing equipment, facilities, and ancillary room items as well

as the removal of disposable manufacturing

or product


items from the

area. Environmental


specific for the spore-forming

13 microorganism(s) operations must be conducted in adjacent areas during manufacturing area after completion of cleaning and

and in the manufacturing

* * * * *


/ 4;; /(-I ) i December 11, 2003.

[FR Dot. 03-????? Filed ??-??-03;