[Federal Register Volume 79, Number 163 (Friday, August 22, 2014)]
[Proposed Rules]
[Pages 49727-49731]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-19888]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 610 and 680
[Docket No. FDA-2014-N-1110]
Revocation of General Safety Test Regulations That Are
Duplicative of Requirements in Biological License Applications
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 removing the general safety test (GST)
requirements for biological products. FDA is proposing this action
because the existing codified GST regulations are duplicative of
requirements that are also specified in biologics licenses, or are no
longer necessary or appropriate to help ensure the safety, purity, and
potency of licensed biological products. FDA is taking this action as
part of its retrospective review of its regulations to promote
improvement and innovation, in response to an Executive order.
DATES: Submit either electronic or written comments on this proposed
rule by November 20, 2014. See section V of this document for the
proposed effective date of any final rule that may publish based on
this proposal.
ADDRESSES: You may submit comments by any of the following methods:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions
Submit written submissions in the following ways:
Mail/Hand Delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include Docket No. FDA-
2014-N-
[[Page 49728]]
1110 for this rulemaking. All comments received may be posted without
change to http://www.regulations.gov, including any personal
information provided. For additional information on submitting
comments, see the ``Request for Comments'' heading in section X of the
SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Lori J. Churchyard, Center for
Biologics Evaluation and Research, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002,
240-402-7911.
SUPPLEMENTARY INFORMATION:
Executive Summary
Purpose and Coverage of the Proposed Rule
The proposed rule would eliminate the codified GST \1\ regulations
for biological products. FDA is proposing this action because the
existing codified GST regulations are duplicative of requirements that
are also specified in biologics license applications (BLAs) or are no
longer necessary or appropriate to help ensure the safety, purity, and
potency of licensed biological products. FDA is taking this action as
part of its retrospective review of its regulations to promote
improvement and innovation, in response to Executive Order (E.O.) 13563
of January 18, 2011.
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\1\ For purposes of this proposed rulemaking, the terms
``general safety test'' or ``GST'' refer to the requirements found
under Title 21 of the Code of Federal Regulations (CFR), subchapter
F, parts 600 through 680 (21 CFR parts 600 through 680),
specifically 21 CFR 610.11, 21 CFR 610.11a and 21 CFR 680.3(b).
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Summary of the Major Provisions of the Proposed Rule
The proposed rule would remove the requirements contained in 21 CFR
610.11, 610.11a, and 680.3(b) from the regulations. Section 610.11
concerns a GST for the detection of extraneous toxic contaminants in
biological products intended for administration to humans. Section
610.11a concerns the GST regulations for inactivated influenza vaccine.
Section 680.3(b) concerns GST regulations for allergenic products.
Removal of these regulations would not remove GST requirements
specified in individual BLAs, however. A biological product
manufacturer would continue to be required to follow the GST
requirements specified in its BLA unless the BLA were revised to
eliminate or modify the test through a supplement in accordance with 21
CFR 601.12(c). FDA would review proposed changes to a manufacturer's
approved biologics license on a case-by-case basis so that we could
ensure that any such action is appropriate.
Costs and Benefits
FDA is proposing this action because the existing codified GST
regulations are duplicative of requirements that are also specified in
BLAs, or are no longer necessary or appropriate to help ensure the
safety, purity, and potency of licensed biological products. Because
this proposed rule would impose no additional regulatory burdens, this
regulation is not anticipated to result in any compliance costs and the
economic impact is expected to be minimal.
I. Background
On January 18, 2011, President Barack Obama issued E.O. 13563,
``Improving Regulation and Regulatory Review'' (76 FR 3821, January 21,
2011). One of the provisions in the E.O. is the affirmation of
retrospective reviews of existing significant regulations. As one step
in implementing the new E.O., FDA published a notice in the Federal
Register on April 27, 2011 (76 FR 23520), entitled ``Periodic Review of
Existing Regulations; Retrospective Review Under E.O. 13563.'' In that
notice, FDA announced that it was conducting a review of existing
regulations to determine, in part, whether they can be made more
effective in light of current public health needs and to take advantage
of, and support, advances in innovation that have occurred since those
regulations took effect. As part of this initiative, FDA is proposing
to eliminate the codified GST regulations as specified in this rule. We
believe this action is appropriate because in many instances, the GST
regulations duplicate requirements that are also specified in the BLA
required for biological products intended for human use under section
351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262), or they
are outmoded or otherwise unnecessary to help ensure the continued
safety, purity, and potency of biological products. For a number of
years, FDA has not codified specific requirements for licensed
biological products, in part because codifying specific requirements
for biological products can diminish the ability of the Agency and
industry to respond to technological developments. Instead the Agency
has described the required tests for particular products in
manufacturers' BLAs.
The GST is one of several tests listed in part 610, General
Biological Product Standards, that is intended to help ensure the
safety, purity, and potency of biological products administered to
humans. Manufacturers of biological products are currently required to
perform this test for general safety on biological products intended
for administration to humans under Sec. 610.11, on inactivated
influenza vaccines under Sec. 610.11a, and on allergenic products
under Sec. 680.3(b), unless exempted by regulation or an exemption is
granted under Sec. 610.11(g)(2).
The GST was intended to be a final check designed to detect any
toxic contaminants present in the final product. The test was cited as
early as 1909 (Ref. 1), and appeared in the first Code of Federal
Regulations in 1938, before the establishment of Current Good
Manufacturing Practices (cGMPs) for drug manufacture in the CFR, which
occurred in 1963. The GST was subsequently revised to, among other
things, ``reflect the best current testing procedures established by
the scientific community as well as to promote uniformity and
specificity in the safety testing of licensed biological products''
(March 15, 1976, 41 FR 10888).
A product that meets the requirements for general safety will
comply with the criteria found in Sec. 610.11(d) of the GST
regulation, i.e., injected animals survive the test period; they do not
exhibit any response that is not specific for or expected from the
product and which 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.
While originally a useful approach, as time has passed, the Agency
has periodically explored the utility and efficiency of this approach.
In the Federal Register of May 14, 1996 (61 FR 24227), FDA published a
final rule exempting certain biotechnology-derived and synthetic
biological products from a number of regulations applicable to
biological products, including the GST (see Sec. 601.2(c)). This
action was in response to technical advances that greatly increased the
ability of manufacturers to control the manufacture of, and to more
fully analyze the physical and biological characteristics of, many
biotechnology-derived biological products.
[[Page 49729]]
Approximately 2 years later, in the Federal Register of April 20,
1998, FDA issued a direct final rule (DFR) and a companion proposed
rule (63 FR 19399 and 19431, respectively) to expand the exceptions in
Sec. 610.11(g) to include ``cellular therapy products'' because, among
other reasons, the Agency believed that the procedures and materials
used to manufacture these products are stringently controlled and
monitored. In addition, FDA provided for in the DFR and the companion
proposed rule an administrative procedure for manufacturers of other
biological products to request and obtain exemptions from conducting
the GST. FDA took this action ``. . . because the GST may not be
relevant or necessary for biological products . . . currently in
various stages of development'' and as part of FDA's continuing efforts
at that time ``to reduce the burden of unnecessary regulations on
biological products without diminishing the protection of the public
health'' (63 FR 19399 at 19400) (FDA refers readers to the preamble of
the April 20, 1998, proposed rule should they wish to obtain additional
details on the history of this rulemaking).
In the Federal Register of August 5, 1998 (63 FR 41718) (August
1998 Notice), FDA published a DFR confirming in part, and withdrawing
in part, the provisions in the DFR that published April 20, 1998.
Specifically, FDA confirmed a revision to Sec. 610.11(g)(1) to add
``cellular therapy products'' to the list of products exempted from the
GST. However, because the Agency received significant adverse comments
concerning Sec. 610.11(g)(2), the provision of the rule that required
administrative procedures for requesting an exemption from the GST
regulations, Sec. 610.11(g)(2) was withdrawn. As discussed in the
August 1998 Notice, the comments were applied to the corresponding
portion of the companion proposed rule and considered in developing the
final rule.
After considering the comments to the DFR and companion proposed
rule, in the Federal Register of March 4, 2003 (68 FR 10157 at 10158)
(March 2003 Final Rule), FDA again provided for an administrative
procedure under which manufacturers of biological products may request
and obtain exemptions from conducting the GST (Sec. 610.11(g)(2)). In
the preamble to the March 2003 Final Rule, FDA again noted that the GST
may not be relevant or necessary for certain biological products (68 FR
10157).
Accordingly, Sec. 610.11 currently includes a provision allowing
manufacturers to request an exemption from the GST. Note that this
exemption provision requires manufacturers to provide supporting
documentation when making their request (see 68 FR 10157 through
10159). Specifically, when requesting such an exemption, manufacturers
must submit information as part of a BLA or supplement to an approved
BLA establishing that because of the mode of administration, the method
of preparation, or the special nature of the product, a test for
general safety is unnecessary to assure the safety, purity, and potency
of the product, or cannot be performed (Sec. 610.11(g)(2)).
Since FDA issued the March 2003 Final Rule, it has become
increasingly clear that the codified GST regulations are too
restrictive for certain additional biological products because they
specify particular methodologies or requirements when alternatives may
be available that provide the same or greater level of assurance of
safety. Thus, the Agency believes that the regulations may no longer
reflect the best current testing procedures established by the
scientific community as a general matter (although the testing
procedures may still be appropriate in certain circumstances) and that
the more efficient way of prescribing testing requirements for
particular products would be to allow such requirements to be specified
in the BLA to enhance flexibility to make appropriate changes to
testing methods.
II. Appropriate Controls Would Remain in Place
FDA believes that if this rulemaking becomes finalized as proposed,
we would be able to continue to ensure that appropriate controls remain
in place. For example, manufacturers of all products derived from
inherently toxic substances would be required to continue to use the
safety tests that are prescribed in their BLAs to control and monitor
toxicity. These product-specific tests (performed in animals, cell
cultures, or other systems) in conjunction with physical, chemical, and
biological characterization tests define and monitor the production
process and alert manufacturers to potential problems. Because these
tests are tailored to the proprietary manufacturing process and are
appropriate for the detection of intrinsic or extraneous toxic
contaminants for a particular product or product class, they are more
appropriately specified in the manufacturer's BLA or BLA supplement
than codified as regulations.
Furthermore, we anticipate that the proposal to eliminate the
codified GST regulations would encourage the implementation of the
principles of the ``3Rs,'' to reduce, refine, and replace animal use in
testing, thus addressing the need to minimize the use of animals in
such testing and promoting more humane, appropriate, and specific test
methods for assuring the safety of biological products.\2\
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\2\ Interagency Coordinating Committee on the Validation of
Alternative Methods (ICCVAM) Authorization Act of 2000 (42 U.S.C.
2851-3). Additional information on the Federal Government's
implementation of the principles of the 3Rs may be found at the
ICCVAM Web site at http://ntp.niehs.nih.gov/go/iccvam.
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If the proposed rule is finalized and the GST regulations are
eliminated, manufacturers would continue to be required to perform a
particular safety test for certain products that present specific
safety concerns, for example, testing for a specific toxicity, as set
forth in an approved BLA or BLA supplement. As discussed previously,
although this rulemaking proposes to eliminate the codified GST from
the biologics regulations, FDA recognizes that all manufacturers that
currently conduct a GST have this test described in their BLAs for
their licensed products. As a result, if this proposed rule is
finalized, these manufacturers would continue to be required to perform
the GST unless the manufacturer's BLA were revised through a supplement
to eliminate or modify the test. FDA would review these proposed
changes to a manufacturer's approved BLA on a case-by-case basis so
that we could ensure that any such action is appropriate. Thus, the
removal of these biologics regulations, should this proposed rule be
finalized, would not automatically revise a manufacturer's BLA or BLA
supplement.
The requirements for a licensed biological product manufacturer to
report changes in its product, product labeling, production process,
quality controls, equipment, facilities, or responsible personnel, as
established in its approved BLA, are detailed in Sec. 601.12. Under
this regulation, manufacturers must report each change to the Agency in
one of several different types of submissions. The applicable
submission category depends on the potential for the change(s) at issue
to have an adverse effect on the identity, strength, quality, purity,
or potency of the particular biological product as it may relate to the
safety or effectiveness of the product. A BLA supplement for a change
that has a moderate potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the product as it
may relate to the safety
[[Page 49730]]
or effectiveness of the product must be submitted under Sec. 601.12(c)
(Changes requiring supplement submission at least 30 days prior to
distribution of the product made using the change).
As a general matter, should a manufacturer wish to no longer
perform the GST described in its BLA, the Agency would consider the
discontinuation of the GST to have a moderate potential to have an
adverse effect on the identity, strength, quality, purity, or potency
of the product as it may relate to the safety or effectiveness of the
product. Accordingly, a manufacturer who desires to discontinue the GST
in the approved BLA or utilize an alternative method other than the GST
approved in its BLA must submit a BLA supplement reporting the change
in accordance with Sec. 601.12(c). Within 30 days of the date FDA
receives the submission, FDA will determine if the change has been
reported in the proper category and will notify the manufacturer if it
has not. If FDA has not notified the manufacturer otherwise within 30
days after FDA receives the supplement, the manufacturer may distribute
its product using the change described in the supplement. If, however,
FDA determines that the information submitted in the supplement fails
to demonstrate the continued safety or effectiveness of the product
made using the change, FDA will try to resolve the problems with the
manufacturer. For example, in the event that the Agency determines that
for a particular manufacturer's unique product a GST is still necessary
to assure the continued safety or effectiveness of the product (e.g.,
for products with concerns related to residual toxin activity/reversion
to toxicity, or if the alternative method proposed is unacceptable),
the Agency would notify the manufacturer of its decision within 30 days
following receipt of the supplement and would work with the
manufacturer to resolve the issue.
III. Highlights of the Proposed Rule
The proposed rule would remove Sec. Sec. 610.11, 610.11a, and
680.3(b), the regulations that require that manufacturers of biological
products perform a specified test for general safety of biological
products. FDA is taking this action because the existing codified GST
regulations are duplicative, outmoded, or are otherwise unnecessary to
help ensure the continued safety, purity, and potency of licensed
biological products.
IV. Legal Authority
FDA is issuing this regulation under the biological products
provisions of the PHS Act (42 U.S.C. 262 and 264), and the drugs and
general administrative provisions of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 U.S.C. 321 et seq.). Under these provisions
of the PHS Act and the FD&C Act, we have the authority to issue and
enforce regulations designed to ensure that biological products are
safe, effective, pure, and potent, and to prevent the introduction,
transmission, and spread of communicable disease.
V. Proposed Effective Date
FDA is proposing that any final rule that may issue based on this
proposal be effective 90 days after the date of its publication in the
Federal Register.
VI. Analysis of Impacts
FDA has examined the impacts of the proposed rule under E.O. 12866,
E.O. 13563, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders
12866 and 13563 direct 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 proposed rule is not a significant regulatory action as defined by
E.O. 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because this proposed rule generally increases
flexibility for safety testing and would result in the reduction of
certain regulatory burdens and does not add any new regulatory
responsibilities, the Agency proposes to certify that the final rule
will not have a significant economic impact on a substantial number of
small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141 million, using the most current (2013) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.
This rule proposes to amend the biologics regulations by removing
GST regulations for biological products found in Sec. Sec. 610.11,
610.11a and 680.3(b). FDA is proposing this action because the current
codified GST regulations are duplicative of requirements that are also
specified in biologics licenses, or are no longer necessary or
appropriate to help ensure the safety, purity, and potency of licensed
biological products. The removal of the GST regulations for biological
products would not remove GST requirements specified in individual
biologics license applications, however. All manufacturers that
currently conduct a GST are already required, as part of the
requirements specified in their biologics license applications, to
perform the GST and would thus continue to be required perform the GST
unless the BLA were revised to eliminate or modify the test through a
supplement in accordance with Sec. 601.12(c). Because this proposed
rule would impose no additional regulatory burdens, this regulation is
not anticipated to result in any compliance costs and the economic
impact is expected to be minimal.
VII. The Paperwork Reduction Act of 1995
This proposed rule refers to previously approved collections of
information that are subject to review by the Office of Management and
Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C.
3501-3520). The collections of information in Sec. 601.12 have been
approved under OMB control number 0910-0338. Therefore, FDA tentatively
concludes that the proposed requirements in this document are not
subject to review by OMB because they do not constitute a ``new
collection of information'' under the PRA.
VIII. Environmental Impact
The Agency has determined under 21 CFR 25.30(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.
IX. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in E.O. 13132. FDA has
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determined that the proposed rule, if finalized, would not contain
policies that would 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 tentatively concludes that the
proposed rule does not contain policies that have federalism
implications as defined in the E.O. and, consequently, a federalism
summary impact statement is not required.
X. Request for Comments
Interested persons may submit either electronic comments regarding
this document to http://www.regulations.gov or written comments to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of comments. Identify comments with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.
XI. Reference
FDA has placed the following reference on display in the Division
of Dockets Management (see ADDRESSES) and may be seen by interested
persons between 9 a.m. and 4 p.m., Monday through Friday and are
available electronically at http://www.regulations.gov.
1. Anderson, J. F., ``The Influence of Concentration (Gibson's
Method) On the Presence of Tetanus Toxin in Blood Serum,'' Journal
of Experimental Medicine: 1909 September 2; 11(5): 656-658.
List of Subjects
21 CFR Part 610
Biologics, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 680
Biologics, Blood, 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, it is proposed that 21 CFR parts 610
and 680 be amended as follows:
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
0
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.
Sec. 610.11 [Removed and Reserved]
0
2. Remove and reserve Sec. 610.11.
Sec. 610.11a [Removed and Reserved]
0
3. Remove and reserve Sec. 610.11a.
PART 680--ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS
0
4. The authority citation for 21 CFR part 680 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.
Sec. 680.3 [Amended]
0
5. Remove and reserve paragraph (b).
Dated: August 18, 2014.
Peter Lurie,
Associate Commissioner for Policy and Planning.
[FR Doc. 2014-19888 Filed 8-21-14; 8:45 am]
BILLING CODE 4164-01-P