[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]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 610
[Docket No. 97N-0449]
RIN 0910-ZA08
Revisions to the General Safety Requirements for Biological
Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Direct final rule.
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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,
1998.
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.
SUPPLEMENTARY INFORMATION:
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
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-
[[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
Act
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
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 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
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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 10 40 400
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
[[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
rule.
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:
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, 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]
BILLING CODE 4160-01-F
