[Federal Register Volume 63, Number 75 (Monday, April 20, 1998)]
[Proposed Rules]
[Pages 19431-19434]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-10313]


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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

    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receives any significant adverse comment and is withdrawn.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. 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.

[[Page 19432]]

    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.
    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). 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 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. 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

[[Page 19433]]

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. 
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. 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. Therefore, under the Regulatory 
Flexibility Act, no further analysis is required. This proposed 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.

IV. The Paperwork Reduction Act of 1995

    This proposed 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 (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

[[Page 19434]]

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). 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).
    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.

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. 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]
BILLING CODE 4160-01-F