Document ID: FDA-2014-N-1110-0001
Agency: fda
Document Type: Proposed Rule
Title: Revocation of General Safety Test Regulations That Are Duplicative of
Requirements in Biological License Applications
Posted Date: 2014-08-22T04:00Z

[Federal Register Volume 79, Number 163 (Friday, August 22, 2014)]
[Proposed Rules]
[Pages 49727-49731]
From the Federal Register Online via the Government Printing 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

[[Page 49731]]

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