[Federal Register Volume 63, Number 75 (Monday, April 20, 1998)]
[Rules and Regulations]
[Pages 19399-19403]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-10314]



Food and Drug Administration

21 CFR Part 610

[Docket No. 97N-0449]
RIN 0910-ZA08

Revisions to the General Safety Requirements for Biological 

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule.


SUMMARY: The Food and Drug Administration (FDA) is amending the 
biologics regulations by adding ``cellular therapy products'' to the 
list of products excepted from the general safety test (GST) and by 
adding an administrative procedure for obtaining exemptions from the 
GST requirements for other biological products. FDA is taking this

[[Page 19400]]

action because the GST may not be relevant or necessary for biological 
products, including cellular therapy products, currently in various 
stages of development. This direct final rule 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. Elsewhere in this 
Federal Register, FDA is publishing a companion proposed rule under 
FDA's usual procedures for notice and comment to provide a procedural 
framework to finalize the rule in the event the agency receives any 
significant adverse comment and withdraws this direct final rule.

DATES: This regulation is effective September 2, 1998. Submit written 
comments on this direct final rule on or before July 6, 1998. Submit 
written comments on the information collection provisions by June 19, 

ADDRESSES: Submit written comments on the direct final 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.


I. Background

    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 nonspecific 
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 test was originally intended as a means 
by which harmful extraneous toxins could be detected (41 FR 10888, 
March 15, 1976). 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 on 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 (21 
CFR 601.2)).
    Recent scientific advances have dramatically increased the 
diversity of biological products regulated under section 351 of the 
Public Health Service 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.
    In the Federal Register of June 3, 1994 (59 FR 28821 at 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 
    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-

[[Page 19401]]

process safety controls, long-term compliance with current good 
manufacturing practices 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 Direct Final Rule

    FDA agrees with the comments received that cellular therapy 
products should be exempt from the GST requirement. FDA is issuing this 
direct final 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. 
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.

III. Rulemaking Action

    In the Federal Register of November 21, 1997 (62 FR 62466), FDA 
described its procedures on when and how FDA will employ direct final 
rulemaking. FDA believes that this rule is appropriate for direct final 
rulemaking because FDA views this rule as a noncontroversial amendment 
and anticipates no significant adverse comments. Consistent with FDA's 
procedures on direct final rulemaking, FDA is publishing elsewhere in 
this Federal Register issue, a companion proposed rule to amend the 
existing GST rule. The companion proposed rule provides a procedural 
framework within which the rule may be finalized in the event the 
direct final rule is withdrawn because of any significant adverse 
comment. The comment period for the direct final rule runs concurrently 
with the companion proposed rule. Any comments received under the 
companion proposed rule will be considered as comments regarding the 
direct final rule.
    FDA has provided a comment period on the direct final rule of 75 
days after April 20, 1998. If the agency receives any significant 
adverse comment, FDA intends to withdraw this direct final rule action 
by publication in the Federal Register within 30 days after the comment 
period ends. 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. 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.
    If any significant adverse comment is received during the comment 
period, FDA will publish, within 30 days after the comment period ends, 
a document withdrawing the direct final rule. If FDA withdraws the 
direct final rule, all comments received will be applied to the 
proposed rule and will be considered in developing a final rule using 
the usual Administrative Procedure Act notice-and-comment procedures.
    If FDA receives no significant adverse comments during the 
specified comment period, FDA intends to 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.

[[Page 19402]]

IV. Analysis of Impacts

A. Review Under Executive Order 12866 and the Regulatory Flexibility 

    FDA has examined the impact 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 (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). The agency believes that 
this direct final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. The direct final 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 direct final rule will be a substantial reduction in 
burdens on applicants filing for approval of certain biological 
    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 direct final rule will be a substantial reduction of the 
regulatory and reporting burdens, the agency certifies that the direct 
final rule will not have a significant negative economic impact on a 
substantial number of small entities. Therefore, under the Regulatory 
Flexibility Act, no further analysis is required. This rule also does 
not trigger the requirement for a written statement under section 
202(a) of the Unfunded Mandates Reform Act because it does not impose a 
mandate that results in an expenditure of $100 million or more by 
State, local, and tribal governments in the aggregate, or by the 
private sector in any one year.

B. Environmental Impact

    The agency has determined under 21 CFR 25.31(j) 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.

V. The Paperwork Reduction Act of 1995

    This direct final rule contains information collection provisions 
that are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (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 revising 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 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 direct final 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)(1) and 
thus, 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 Sec.  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                                  
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours 
                                    Respondents      Response        Responses       Response                   
610.11(g)(2)                           10               1              10              40             400       
Total                                  10                              10              40             400       
\1\ There are no capital costs or operating and maintenance costs associated with this collection of            

[[Page 19403]]

    As provided in 5 CFR 1320.5(c)(1), collections of information in a 
direct final rule are 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 (HFA-305), Food and 
Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
    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.

VI. 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 companion proposed 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 comments regarding the proposed rule and 
this direct final rule. In the event the direct final rule is 
withdrawn, all comments received regarding the companion proposed rule 
and the direct final rule will be considered comments on the proposed 

List of Subjects in 21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.
    Therefore under the Federal Food, Drug, and Cosmetic Act, and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
610 is amended as follows:


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

    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 

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, Center for 
Biologics Evaluation and Research, 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. The Director, Center for Biologics 
Evaluation and Research, 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. 98-10314 Filed 4-17-98; 8:45 am]