Revisions to the General Safety Requirements for Biological Products; Companion Document to Direct Final Rule

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 610

[Docket No. 97N-0449]

RIN 0910-AB51

Revisions to the General Safety Requirements for Biological

Products; Companion Document 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 adding cellular therapy products to the

list of products exempted from the general safety test (GST) and by

adding an administrative procedure for obtaining exemptions from the

GST requirements. This proposed rule is a companion document to the

direct final rule published elsewhere in this issue of the Federal

Register. FDA is taking this action because the GST may not be relevant

or necessary for many types of biological products, including cellular

therapy products, currently in various stages of development.

DATES: Comments must be received on July 6, 1998. Submit written

comments on the information collection provisions by June 19, 1998.

ADDRESSES: Submit written comments on the proposed rule to the Dockets

Management Branch (HFA-305), Food and Drug Administration, 12420

Parklawn Dr., rm. 1-23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Dano B. Murphy, Center for Biologics

Evaluation and Research (HFM-630), Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-594-3074.

SUPPLEMENTARY INFORMATION:

I. Background

n the proposed rule to the Dockets

Management Branch (HFA-305), Food and Drug Administration, 12420

Parklawn Dr., rm. 1-23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Dano B. Murphy, Center for Biologics

Evaluation and Research (HFM-630), Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-594-3074.

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 will provide the procedural

framework to finalize the rule in the event the direct final rule

receives any significant adverse comment and is withdrawn.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 proposed rule will also be considered as comments

regarding the direct final rule. FDA is publishing the direct final

rule because the rule contains noncontroversial changes, and FDA

anticipates that it will receive no significant adverse comment.

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 a significant adverse comment

is sufficient to terminate a direct final rulemaking, FDA 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. For example, a

comment requesting inclusion of additional product classes in the

exceptions paragraph of the GST (Sec. 610.11(g)) will not be considered

a significant adverse comment because it is outside the scope of this

rule

-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. For example, a

comment requesting inclusion of additional product classes in the

exceptions paragraph of the GST (Sec. 610.11(g)) will not be considered

a significant adverse comment because it is outside the scope of this

rule. 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 part

of a rule and that part can be severed form the remainder of the rule,

FDA may adopt as final those parts of the rule that are not subject of

a significant adverse comment.

A detailed rationale for the rule is set forth in the preamble to

the direct final rule and in section I of this document. 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, FDA will publish a confirmation document within 30 days after

the comment period ends confirming that the direct final rule will go

into effect on September 2, 1998. Additional information about FDA's

direct final rulemaking procedures is set forth in a guidance published

in the Federal Register of November 21, 1997 (62 FR 62466).

If FDA receives any significant adverse comment regarding this

rule, FDA will publish a document withdrawing the direct final rule

within 30 days after the comment period ends. FDA then will proceed to

respond to all of the comments received regarding this rule and, if

appropriate, the rule will be finalized under this proposed rule using

usual notice-and-comment procedures.

7 (62 FR 62466).

If FDA receives any significant adverse comment regarding this

rule, FDA will publish a document withdrawing the direct final rule

within 30 days after the comment period ends. FDA then will proceed to

respond to all of the comments received regarding this rule and, if

appropriate, the rule will be finalized under this proposed rule using

usual notice-and-comment procedures.

Requests to add other products to the named exceptions will be

considered separately by FDA. If FDA agrees that other products should

be excepted from the GST, it will propose those exceptions under other

independent rulemaking actions. Any parties interested in commenting on

this document should do so at this time. This action is part of FDA's

continuing effort to achieve the objectives of the President's

``Reinventing Government'' initiative, and is intended to reduce the

burden of unnecessary regulations on biological products without

diminishing the protection of the public health.

Under Sec. 610.11 (21 CFR 610.11), a test for general safety shall

be performed on biological products intended for administration to

humans. A GST is one of several tests in part 610, General Biological

Product Standards (21 CFR part 610), that are intended to help ensure

the safety, purity, and potency of biological products administered to

humans. The test is used to detect extraneous toxic contaminants that

may be present in a particular biological product. As outlined in

Sec. 610.11, an amount of the final container product is injected into

the peritoneum of guinea pigs and mice. The GST is satisfactory when

the criteria in Sec. 610.11(d) are met, i.e., injected animals survive

the test period, they do not exhibit an unexpected or non-specific

response that may indicate a difference in quality of the product, and

they weigh no less at the end of the test period than they did at the

time of injection. Section 610.11(g) identifies the biological products

for which the GST is not required

tory when

the criteria in Sec. 610.11(d) are met, i.e., injected animals survive

the test period, they do not exhibit an unexpected or non-specific

response that may indicate a difference in quality of the product, and

they weigh no less at the end of the test period than they did at the

time of injection. Section 610.11(g) identifies the biological products

for which the GST is not required.

The requirement for a GST was originally intended as a means by

which harmful extraneous toxins could be detected that published in a

document in the Federal Register of March 15, 1976 (41 FR 10888). The

source of such toxins may be bacterial toxins that persist even after

the bacteria producing the toxins had been removed by filtration or

killed by sterilization, or formulation errors that result in harmful

levels of certain substances, e.g., preservatives. The test continues

to serve as a safety net to detect harmful contaminants that may enter

or be introduced into the final container through undetected failures

in the manufacture of biological products.

In the last 15 years, technological advances have increased the

ability of manufacturers to control and analyze the manufacture of many

biotechnology derived biological products. After more than a decade of

experience with these products, FDA found that it could evaluate many

aspects of a biological product's safety, purity, or potency with tests

other than those prescribed in part 610. In response to these

developments, FDA published in the Federal Register of May 14, 1996 (61

FR 24227), a final rule exempting certain biotechnology and synthetic

biological products from, among other things, specified regulations

applicable to biological products, including the GST (Sec. 601.2).

Recent scientific advances have dramatically increased the

diversity of biological products regulated under section 351 of the

Public Health Service Act (the PHS Act)

er of May 14, 1996 (61

FR 24227), a final rule exempting certain biotechnology and synthetic

biological products from, among other things, specified regulations

applicable to biological products, including the GST (Sec. 601.2).

Recent scientific advances have dramatically increased the

diversity of biological products regulated under section 351 of the

Public Health Service Act (the PHS Act). In particular, cellular-based

therapies intended for the diagnosis, cure, mitigation, treatment, or

prevention of disease in man have been the subject of much biomedical

research and are used with increasing frequency. Typically, cellular

therapies use autologous or allogeneic cells, often lymphocyte

subpopulations, but other cell types may be used, obtained from a donor

and manipulated ex vivo to varying degrees before use in the recipient

patient. The ex vivo manipulation may consist of, for example, growing

a small number of cells to increase their number (cellular expansion),

selective enrichment of a specific cell subpopulation, or the addition

of specific cell factors or genetic sequences. A common characteristic

of cellular therapies is the need for a relatively short turn-around

time between first obtaining the cells and their final infusion as a

cellular therapy product into the patient. In many cases, cells used in

the final cellular therapeutic are obtained only hours before they must

be used and turn-around times of several days or less are presently

typical. A test, such as the GST, that requires 7 days to complete is

not compatible with such products and such a requirement would make it

impossible to use many of these products. Furthermore, because the

procedures and materials used to produce cellular therapy products are

stringently controlled and monitored, the likelihood of an extraneous

toxic component contaminating a final product is greatly reduced

uch as the GST, that requires 7 days to complete is

not compatible with such products and such a requirement would make it

impossible to use many of these products. Furthermore, because the

procedures and materials used to produce cellular therapy products are

stringently controlled and monitored, the likelihood of an extraneous

toxic component contaminating a final product is greatly reduced.

In the Federal Register of June 3, 1994 (59 FR 28821 and 28822),

FDA announced that the Center for Biologics Evaluation and Research

(CBER) would review certain biologics regulations to identify

regulations that are outdated, burdensome, inefficient, duplicative, or

otherwise unsuitable or unnecessary. FDA included Sec. 610.11 in the

review. On January 26, 1995, FDA held a public meeting to discuss the

retrospective review of regulations applicable to biological products

and to provide a forum for the public to voice its comments regarding

the retrospective review. At the meeting, only one comment addressed

whether Sec. 610.11 should be retained unchanged, modified, or deleted.

The comment acknowledged the utility of the GST for products that have

a high degree of intrinsic variability. However, despite its recognized

value in some specific cases, the comment questioned the rationale for

requiring the GST for all biological products intended for

administration to humans. The comment noted that the amount of final

container product administered to animals for the GST may not have any

correlation with the human dose, that some biological products possess

extensive documented histories of no GST failure, and that each run of

the test requires the use of at least four animals. The comment

suggested that FDA revise Sec. 610.11 to grant exemptions from the GST

when the test is unnecessary to evaluate the safety of a specific

product.

FDA received several comments from the public regarding issues

raised at the January 26, 1995, meeting

s possess

extensive documented histories of no GST failure, and that each run of

the test requires the use of at least four animals. The comment

suggested that FDA revise Sec. 610.11 to grant exemptions from the GST

when the test is unnecessary to evaluate the safety of a specific

product.

FDA received several comments from the public regarding issues

raised at the January 26, 1995, meeting. Two comments agreed with the

suggestion made at the public meeting that Sec. 610.11 be amended to

include a provision that would allow certain products to be exempted

from the GST upon approval of the Director, CBER. Another comment

suggested that exemptions be permitted for appropriate biological

products by the Director, CBER, after a suitable qualification period

was met without any failure of the GST, such as 1 year of production or

after 10 consecutive production lots pass the GST. The comment

suggested that a demonstrated record of GST compliance also be

supported by well-documented in-process safety controls, long-term

compliance with current good manufacturing practices (CGMP) regulations

(21 CFR parts 210 and 211), and the use of sophisticated analytical

techniques capable of adequately characterizing the final product and

validating its safety.

On March 17, 1997, FDA held a public meeting to discuss the

agency's proposed approach to the regulation of human cellular and

tissue-based products. The meeting was attended by FDA, members of

industry, representatives from accrediting organizations, and

interested members of the public. During the meeting, two attendees

addressed the use of the GST with cellular therapy products. The

comments regarded the 7-day incubation time of the test as an

unworkable requirement for many cellular therapy products and suggested

that such products be exempted from

the test, including allogeneic and autologous cell therapy products.

II. Highlights of the Proposed Rule

mbers of the public. During the meeting, two attendees

addressed the use of the GST with cellular therapy products. The

comments regarded the 7-day incubation time of the test as an

unworkable requirement for many cellular therapy products and suggested

that such products be exempted from

the test, including allogeneic and autologous cell therapy products.

II. Highlights of the Proposed Rule

FDA agrees with the comments received that cellular therapy

products should be exempt from the GST requirement. FDA is proposing

this rule to expand the exceptions in Sec. 610.11(g) to include

``cellular therapy products.'' In addition, FDA is adding an

administrative procedure for manufacturers of other biological products

to request and obtain exemptions from the GST. Many biological products

are currently manufactured, or will be manufactured in the future,

under highly controlled and rigorously monitored conditions. Therefore,

under the amended rule, manufacturers of biological products that

employ appropriate production controls and quality assurance safeguards

would be permitted to apply for an exemption from the GST requirement.

Such manufacturers will be required to provide supporting documentation

to the Director, CBER, as to why a product should not be subject to the

GST requirement. The request shall include an explanation of why the

GST is unnecessary or cannot be performed due to the mode of

administration, the method of preparation, or the special nature of the

product and shall describe alternate procedures, if any, to be

employed. The Director, CBER, may grant an exemption if she finds that

the manufacturer's submission justifies an exemption.

The value of the GST as a final assay for the presence of

extraneous toxins may be diminished for certain biological products,

such as vaccines containing recombinant or purified protein antigens

ure of the

product and shall describe alternate procedures, if any, to be

employed. The Director, CBER, may grant an exemption if she finds that

the manufacturer's submission justifies an exemption.

The value of the GST as a final assay for the presence of

extraneous toxins may be diminished for certain biological products,

such as vaccines containing recombinant or purified protein antigens.

Recombinant protein antigens are not produced from infectious bacteria

or virus and antigens derived from infectious pathogens may undergo

many production steps that kill or neutralize the pathogen or

inactivate toxic materials. Therefore, for these kinds of products, the

risk is extremely low that viable pathogenic or toxic materials will

persist through production to the final filling. The effectiveness of

such steps can be validated by specific in-process tests and controls

which can be used to alert manufacturers to potential problems. To

further reduce the possibility that an undetected extraneous toxin

could contaminate the product just before or during the final fill

stage, a manufacturer may use production facilities and final fill

equipment that can detect or enable the detection of any loss in the

integrity of the production and fill processes. In addition, a method

of production and detailed product characterization able to meet

requirements similar to those set out in Sec. 601.2(c) could be used to

demonstrate the safety, purity, and potency of a biological product

without the use of the GST. Each manufacturer will be responsible for

identifying the product or products that are produced in such a manner

that makes the GST unnecessary to ensure the safety, purity, and

potency of the biological product. Manufacturers wishing to obtain an

exemption to the GST for a particular product would contact the

appropriate product division of CBER for specific information regarding

how to apply and what information should be included in the application

or supplemental application.

duced in such a manner

that makes the GST unnecessary to ensure the safety, purity, and

potency of the biological product. Manufacturers wishing to obtain an

exemption to the GST for a particular product would contact the

appropriate product division of CBER for specific information regarding

how to apply and what information should be included in the application

or supplemental application.

III. Analysis of Impacts

A. Review Under Executive Order 12866 and the Regulatory Flexibility

Act

FDA has examined the impact 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 (Pub. L. 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 impact; and equity). This proposed rule is

consistent with the regulatory philosophy and principles identified in

the Executive Order. The proposed rule is a significant regulatory

action as defined by the Executive Order and is subject to review under

the Executive Order because it deals with a novel policy issue.

In accordance with the principles of Executive Order 12866, the

result of the proposed rule will be a substantial reduction in burdens

on applicants filing for approval of certain biological products.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small business entities. Because, as stated previously, the overall

result of the proposed rule will be a substantial reduction of the

regulatory and reporting burdens, the agency certifies that the

proposed rule will not have a significant negative economic impact on a

substantial number of small entities

(the PRA) (44 U.S.C. 3501-

3520). The title, description, and respondent description of the

information collection provisions are shown below with an estimate of

the annual reporting burden. Included in the estimate is the time for

reviewing the instructions, searching existing data sources, gathering

and maintaining the data needed, and completing and reviewing each

collection of information.

FDA invites comments on: (1) Whether the proposed collection of

information is necessary for the proper performance of FDA's functions,

including whether the information will have practical utility; (2) the

accuracy of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the

information to be collected; and (4) ways to minimize the burden of the

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

Title: Requests for Exemptions from the General Safety Testing

Requirements for Biological Products.

Description: FDA is proposing to revise the requirements for

general safety testing (GST) set forth in Sec. 610.11. The test serves

as a safety net to detect harmful contaminants that may enter or be

introduced into the final container through undetected failures in the

manufacture of biological products. The revision would add ``cellular

therapy products'' to the list of products excepted from the GST, and

add an administrative procedure for obtaining

general safety testing (GST) set forth in Sec. 610.11. The test serves

as a safety net to detect harmful contaminants that may enter or be

introduced into the final container through undetected failures in the

manufacture of biological products. The revision would add ``cellular

therapy products'' to the list of products excepted from the GST, and

add an administrative procedure for obtaining

exemptions from the GST requirements for other biological products. FDA

is proposing the new administrative procedure because the GST may not

be feasible or appropriate for some biological products. FDA

anticipates that manufacturers requesting exemptions would have a

demonstrated record of GST compliance supported by long-term compliance

with CGMP's, well-documented in-process safety controls, and use

sophisticated analytical techniques to adequately characterize the

final product and validate its safety. Manufacturers would submit their

request and documentation to the Director, CBER, who may grant the

exemption if it is determined that the manufacturer's submission

justifies an exemption.

Description of Respondents: Manufacturers of biological products.

The proposed rule would require only those manufacturers requesting

an exemption from the GST under Sec. 610.11(g)(2) to submit additional

information as part of a license application or supplement to an

approved license application. Manufacturers of ``cellular therapy

products'' would be excepted from the GST under Sec. 610.11(g)(2) and

thus, would not have to submit an exemption request. In fact,

manufacturers of cellular therapy products would be relieved of

significant burdens because they would no longer be required to perform

the GST and report the results to FDA. FDA estimates that annually it

will receive approximately 10 requests for administrative exemption

from the GST under 21 CFR 610.11(g)(2)

c. 610.11(g)(2) and

thus, would not have to submit an exemption request. In fact,

manufacturers of cellular therapy products would be relieved of

significant burdens because they would no longer be required to perform

the GST and report the results to FDA. FDA estimates that annually it

will receive approximately 10 requests for administrative exemption

from the GST under 21 CFR 610.11(g)(2). FDA estimates that 40 hours

will be required for an applicant to complete and submit the

appropriate information for the exemption request. Since that

information is ordinarily compiled and organized by the manufacturer

while performing the GST, FDA anticipates that the additional time

needed to submit an exemption request will be minimal.

Table 1.--Estimated Annual Reporting Burden1

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Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

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610.11(g)(2) 10 1 10 40 400

Total 10 1 10 40 400

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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

For consistency with the direct final rule to which this proposed

rule is a companion, FDA is following the PRA comment procedures for

direct final rules in this proposed rule. As provided in 5 CFR

1320.5(c)(1), collection of information in a direct final is subject to

the procedures set forth in 5 CFR 1320.10. Interested persons and

organizations may submit comments on the information collection

requirements of this direct final rule by June 19, 1998 to the Dockets

Management Branch (address above)

A comment procedures for

direct final rules in this proposed rule. As provided in 5 CFR

1320.5(c)(1), collection of information in a direct final is subject to

the procedures set forth in 5 CFR 1320.10. Interested persons and

organizations may submit comments on the information collection

requirements of this direct final rule by June 19, 1998 to the Dockets

Management Branch (address above).

At the close of the 60-day comment period, FDA will review the

comments received, revise the information collection provisions as

necessary, and submit these provisions to OMB for review. FDA will

publish a notice in the Federal Register when the information

collection provisions are submitted to OMB, and an opportunity for

public comment to OMB will be provided at that time. Prior to the

effective date of the direct final rule, FDA will publish a notice in

the Federal Register of OMB's decision to approve, modify, or

disapprove the information collection provisions. An agency may not

conduct or sponsor, and a person is not required to respond to, a

collection of information unless it displays a currently valid OMB

control number.

V. Request for Comments

Interested persons may, on or before July 6, 1998, submit to the

Docket Management Branch (address above) written comments regarding

this proposal. This comment period runs concurrently with the comment

period for the direct final rule. Two copies of any comments are to be

submitted, except that individuals may submit one 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 office above

between 9 a.m. and 4 p.m., Monday through Friday. All comments received

will be considered as comments regarding this companion proposed rule

and the direct final rule. In the event the direct final rule is

withdrawn, all comments received regarding the direct final rule and

this companion proposed rule, will be considered under this proposed

rule.

ed comments may be seen in the office above

between 9 a.m. and 4 p.m., Monday through Friday. All comments received

will be considered as comments regarding this companion proposed rule

and the direct final rule. In the event the direct final rule is

withdrawn, all comments received regarding the direct final rule and

this companion proposed rule, will be considered under this proposed

rule.

List of Subjects in 21 CFR Part 610

Biologics, Labeling, Reporting and recordkeeping requirements.

Therefore under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, and the authority delegated by the

Commissioner of Food and Drugs, 21 CFR part 610 is amended as follows:

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

1. The authority citation for 21 CFR part 610 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42

U.S.C. 216, 262, 263, 263a, 264.

2. Section 610.11 is amended by revising paragraph (g) to read as

follows:

Sec. 610.11 General safety.

* * * * *

(g) Exceptions--(1) The test prescribed in this section need not

be performed for Whole Blood, Red Blood Cells, Cryoprecipitated AHF,

Platelets, Plasma or Cellular Therapy Products.

(2) For products other than those identified in paragraph (g)(1) of

this section, a manufacturer may request from the Director, CBER, an

exemption from the general safety test. The manufacturer shall submit

information as part of a license application submission or supplement

to an approved license application establishing that because of the

mode of administration, the method of preparation, or the special

nature of the product a test of general safety is unnecessary to assure

the safety, purity, and potency of the product or cannot be performed.

The request shall include any alternate procedures, if any, to be

performed

ense application submission or supplement

to an approved license application establishing that because of the

mode of administration, the method of preparation, or the special

nature of the product a test of general safety is unnecessary to assure

the safety, purity, and potency of the product or cannot be performed.

The request shall include any alternate procedures, if any, to be

performed. The Director, CBER, upon finding that the manufacturer's

request justifies an exemption, may exempt the product from the general

safety test subject to any condition necessary to assure the safety,

purity, and potency of the product.

Dated: April 10, 1998.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 98-10313 Filed 4-17-98; 8:45 am]

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