[Federal Register Volume 68, Number 42 (Tuesday, March 4, 2003)]
[Rules and Regulations]
[Pages 10157-10160]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-4973]
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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
Revision to the General Safety Requirements for Biological
Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the
biologics regulations regarding general biological products standards
by adding an administrative procedure for obtaining exemptions from the
general safety test (GST) requirements. We are taking this action
because the GST may not be relevant or necessary for certain biological
products. The rule will permit manufacturers of biological products to
apply for an exemption from the GST requirement provided they submit
information to demonstrate that they use appropriate production
controls and quality assurance safeguards.
DATES: This rule is effective May 5, 2003.
FOR FURTHER INFORMATION CONTACT: Stephen M. Ripley, Center for
Biologics
[[Page 10158]]
Evaluation and Research (HFM-17), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852-1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Background
Under Sec. 610.11 (21 CFR 610.11), manufacturers of biological
products must perform a test for general safety on biological products
intended for administration to humans. The GST is one of several tests
listed 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 the product
in the final container from every final filling of each lot of the
biological product.
The source of such toxic contaminants may be bacterial and fungal
by-products that persist after the bacteria are removed by filtration
or killed by sterilization, or formulation errors that result in
harmful levels of certain substances, e.g., preservatives. The test
serves as a safety net to detect harmful contaminants.
Technological advances have increased the ability of manufacturers
to control and analyze the manufacture of many biotechnology derived
biological products. After more then a decade of experience with these
products, we found that we 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 a number of regulations applicable to biological
products, including the GST (see 21 CFR 601.2(c)).
In the Federal Register of April 20, 1998, we published a direct
final rule and a companion proposed rule (63 FR 19399 and 19431,
respectively) to revise the general safety requirements for biological
products. The direct final rule amended the regulations to exempt
cellular therapy products from the GST requirement and added an
administrative procedure for manufacturers of other biological products
to request exemptions from performing the GST. We published a companion
proposed rule to provide a procedural framework within which the rule
could be finalized in the event we received any significant adverse
comments regarding the direct final rule and we withdrew or severed the
direct final rule.
We received six comments. We did not receive any significant
adverse comments to the amendment to specifically exempt ``cellular
therapy products'' in Sec. 610.11(g)(1). We received significant
adverse comments on the administrative procedure provision Sec.
610.11(g)(2). In this rulemaking, we respond to all comments received.
Accordingly, we published a notice in the Federal Register of
August 5, 1998 (63 FR 41718), confirming in part and withdrawing in
part the direct final rule amending the GST requirements. We confirmed
a revision to Sec. 610.11(g)(1) to add ``cellular therapy products''
to the list of products excepted from the GST. Based on receipt of
adverse comments, we withdrew the revision of Sec. 610.11(g)(2) that
provided a general administrative procedure for requesting and
obtaining exemptions from the GST. We applied the comments regarding
the withdrawn portion of the rule to the companion proposed rule and
considered them in developing this final rule.
II. Highlights of the Final Rule
The final rule codifies, at Sec. 610.11(g)(2), an administrative
procedure under which manufacturers of biological products may 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
Sec. 610.11(g)(2) we will permit biological product manufacturers who
employ appropriate production and final filling controls and quality
assurance safeguards to apply for an exemption from the GST
requirement. Manufacturers who request an exemption must provide
supporting documentation to the Director, Center for Biologics
Evaluation and Research (CBER), as to why a product should not be
subject to the GST requirement. The request must 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 must describe alternate procedures, if any, to be employed.
The Director of CBER may grant an exemption if he/she finds that the
manufacturer's submission justifies an exemption.
Manufacturers wishing to obtain an exemption to the GST for a
particular product should contact the appropriate CBER product division
for specific information regarding how to apply and what information
should be included in the application or supplemental application.
III. Comments on the Proposed Rule
(Comment 1) Proposed Sec. 610.11(g)(1) would add ``cellular
therapy products'' to the list of products excepted from the GST.
One comment supported the amendment, and none of the comments
objected to the amendment to add ``cellular therapy products'' to the
list of exceptions.
We confirmed a revision to Sec. 610.11(g)(1) in the Federal
Register of August 5, 1998, notice to add ``cellular therapy products''
to the list of products excepted from the GST.
(Comment 2) Proposed Sec. 610.11(g)(2) would add an administrative
procedure for manufacturers to request and obtain an exemption from the
GST. The proposal would require manufacturers to submit information as
part of a biologics license application submission or a supplement to
an approved biologics license application.
One comment opposed proposed Sec. 610.11(g)(2) because the
mechanism for requiring each licensed manufacturer to submit a license
supplement to gain an exemption from the GST was too restrictive and
alternative mechanisms should be available by which all manufacturers
of a specific product or a group of products could be exempted.
We disagree with this comment. The comment did not suggest an
alternate mechanism for our consideration. We believe such changes
should be addressed on a case-by-case basis through a biologics license
application or supplement so that we can ensure appropriate controls
are in place to detect contaminants ordinarily found by the GST.
(Comment 3) One comment specifically objected that the
administrative procedure in proposed Sec. 610.11(g)(2) would codify
FDA's use of the biologics licensure process to achieve the regulatory
objectives that should be achieved instead only through notice and
comment rulemaking.
We intend to revise our regulations only when a group of products
which can be defined as a product type, such as ``cellular therapy
products,'' can be excepted from a regulatory provision. Rulemaking is
not an efficient vehicle for exempting specific or individual products
or specific manufacturers, or when there are limitations to the
exemptions, which should be outlined in some detail. We believe the
biologics licensure process is a more efficient
[[Page 10159]]
process than rulemaking for granting exemptions to the GST.
(Comment 4) Proposed Sec. 610.11(g)(2) would allow manufacturers
to request an exemption from the GST; it would not allow other entities
to request such exemptions.
One comment argued that a letter from a trade association should
suffice to obtain such an exemption.
We disagree with this comment. The request for exemption represents
an alternative to the regulations to establish a firm, enforceable
commitment by the manufacturer to FDA as to specific obligations.
Submissions by an association would not be suitable because it is the
manufacturer that must follow the regulations. Trade associations
cannot compel specific actions by their member manufacturers. In
addition, trade associations do not have the authority to change an
applicant's submission.
However, anyone may submit a request to FDA, with supporting
information, to revise the regulations to provide for exceptions from
GST requirements.
(Comment 5) One comment noted that the proposal did not create a
procedural mechanism to allow for partial exemptions. The comment
explained that partial exemptions could be appropriate for specific
subclasses of products.
We decline to amend the rule as suggested by the comment. The
comment did not provide enough information that would allow us to
determine the merits of or need for partial exemptions. However, under
Sec. 610.11(g)(2), we may accept a request for an exemption in the
form of a biologics license supplement for a limited group of products
after a case-by-case evaluation. Section 610.11(g)(2) gives
manufacturers a mechanism for obtaining exemptions for specific
biological products on an individual basis, rather than for whole
``classes'' of products, such as are excepted in Sec. 610.11(g)(1). We
believe such exemptions should be addressed on a case-by-case basis
through a biologics license application or supplement.
(Comment 6) Two comments would revise the proposal to exempt
allergenic products if each lot of stock concentrates of allergenic
extracts and each lot of diluent contained in the final product
satisfies the GST requirements. The comments requested that we modify
21 CFR 680.3(b)(1) to exempt allergenic extracts from the requirement
to perform the repeat GST on final products when a GST is performed on
a stock concentrate. The comments explained that the suggested
amendment would eliminate an unnecessary burden on the allergenic
product industry that would result from separate rulemaking procedures.
The issue of exempting allergenic products is outside the scope of
this rulemaking. Consequently, we decline to amend the rule as
suggested by the comment.
IV. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 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 impacts; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
principles set forth in the Executive order. OMB has determined that
the final rule is a significant regulatory action as defined by the
Executive order and is subject to review under the Executive order.
In accordance with the principles of Executive Order 12866, the
final rule will provide increased flexibility for applications with
approved biological products and may substantially reduce the burdens
on some applicants seeking 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 the final rule has no compliance
costs and does not result in any new requirements, the agency certifies
that the 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.
V. Environmental Impact
This agency has determined under 21 CFR 25.31(h) 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.
VI. Paperwork Reduction Act of 1995
This 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.
Title: Request for Exemptions from the General Safety Testing
Requirements for Biological Products.
Description: FDA is revising the requirements for GST set forth in
Sec. 610.11. The test may detect harmful contaminants that may enter
or be introduced through undetected failures in the manufacture of
biological products. The revision would add an administrative procedure
for obtaining exemptions from the GST requirements for biological
products not already excepted under Sec. 610.11(g)(1). FDA is
codifying the new administrative procedure because alternatives to the
GST may be feasible or appropriate for some biological products. FDA
anticipates that manufacturers requesting exemptions would have
demonstrated a record of the GST compliance, well-documented in-process
safety controls, and use sophisticated analytical techniques to
adequately characterize the product and validate its safety.
Manufacturers would submit their requests and documentation to the
Director, CBER, who may grant the exemption if it is determined that
the manufacturer's submission justifies such an action.
Description of Respondents: Manufacturers of biological products.
This final rule requires only those manufacturers requesting an
exemption from the GST under Sec. 610.11(g)(2) to submit additional
information as part of a biologics license application or supplement to
an approved biologics license application. Based on our experience, we
estimate that we will receive approximately 10 requests for
administrative exemption from the GST under Sec. 610.11(g)(2)
annually. We also estimate that an applicant will take 40 hours to
complete and submit the appropriate information for the exemption
request. Since the applicant
[[Page 10160]]
ordinarily compiles and organizes the information while performing the
GST, we anticipate that the additional time needed to submit an
exemption request will be minimal.
Table 1.--Estimated Annual Reporting Burden \1\
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Annual Frequency Total Annual
21 CFR Section No. of Respondents per Response Responses Hours per Response Total Hours
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610.11(g)(2) 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.
The direct final rule and companion proposed rule of April 20, 1998
(63 FR 19399 and 19431, respectively) provided a 60-day public comment
period on the information collection provisions reflected in this final
rule. Although some comments objected to the license supplement
mechanism of gaining approval for an exemption as being too burdensome,
we received no comments on the actual burden estimates for submitting
such supplements.
VII. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in that the Executive order and, consequently,
a federalism summary impact statement is not required.
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 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, 331, 351, 352, 353, 355, 360, 360c,
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a,
264.
2. Section 610.11 is amended by adding paragraph (g)(2) to read as
follows:
Sec. 610.11 General safety.
* * * * *
(g) * * *
(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 must submit information as part of a biologics
license application submission or supplement to an approved biologics
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
must include 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: February 26, 2003.
William K. Hubbard,
Associate Commissioner for Policy and Planning.
[FR Doc. 03-4973 Filed 3-3-03; 8:45 am]
BILLING CODE 4160-01-S