
[Federal Register Volume 80, Number 127 (Thursday, July 2, 2015)]
[Rules and Regulations]
[Pages 37971-37974]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-16366]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 601, 610, and 680

[Docket No. FDA-2014-N-1110]


Revocation of General Safety Test Regulations That Are 
Duplicative of Requirements in Biologics License Applications

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 by removing the general safety test (GST) 
requirements for biological products. FDA is finalizing 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 the 
Executive order.

DATES: This rule is effective August 3, 2015.

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 Final Rule

    The final rule removes the codified GST \1\ regulations for 
biological products which will update outdated requirements and 
accommodate new and evolving technology and testing capabilities 
without diminishing public health protections. FDA is finalizing

[[Page 37972]]

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. 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 final rule, 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, 610.11a, and 680.3(b).
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Summary of the Major Provisions of the Final Rule

    The final rule removes the requirements contained in Sec. Sec.  
610.11, 610.11a, and 680.3(b) (21 CFR 610.11, 610.11a, and 680.3(b)) 
from the regulations. Section 610.11 requires a GST for the detection 
of extraneous toxic contaminants in certain biological products 
intended for administration to humans. Section 610.11a concerns the GST 
requirements for inactivated influenza vaccine. Section 680.3(b) 
concerns GST requirements for allergenic products. Removal of these 
regulations, however, would not remove GST requirements specified in 
individual BLAs. A biological product manufacturer would continue to be 
required to follow the GST requirements specified in its BLA unless the 
manufacturer advised FDA of its elimination or modification of the test 
by a submission filed in accordance with Sec.  601.12 (21 CFR 601.12). 
FDA would review proposed changes to a manufacturer's approved 
biologics license on a case-by-case basis so that FDA can ensure that 
any such action is appropriate.

Costs and Benefits

    FDA is finalizing 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 final rule would impose no additional regulatory burdens, this 
rule is not anticipated to result in any compliance costs and the 
economic impact is expected to be minimal.

I. Background

    As part of FDA's retrospective review of its regulations to promote 
improvement and innovation under Executive Order 13563, FDA is removing 
the codified GST requirements 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 
requirements 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. FDA 
published the proposed rule ``Revocation of General Safety Test 
Regulations That Are Duplicative of Requirements in Biological License 
Applications'' in the Federal Register of August 22, 2014 (79 FR 
49727). FDA corrected the title of that proposed rule to ``Revocation 
of General Safety Test Regulations That Are Duplicative of Requirements 
in Biologics License Applications'' in the Federal Register of 
September 10, 2014 (79 FR 53670).
    For a number of years, FDA has not codified specific test methods 
as standards for licensed biological products, in part because 
codifying specific test methods as standards can diminish the ability 
of the Agency and industry to respond to technological developments. 
Instead the Agency has required manufacturers to provide a full 
description of manufacturing methods, including test methods, in 
manufacturers' BLAs (Sec.  601.2(a) (21 CFR 601.2(a))). Since FDA 
issued the March 2003 final rule ``Revision to the General Safety 
Requirements for Biological Products'' in the Federal Register of March 
4, 2003 (68 FR 10157), it has become increasingly clear that the 
codified GST regulations are too restrictive for certain biological 
products because alternatives may be available which provide the same 
or greater level of assurance of safety as the GST. Thus, the Agency 
believes that the GST regulations may not always reflect the scientific 
community's assessment of the best current testing procedures, although 
in certain circumstances the GST may still be appropriate. The Agency 
believes that a more efficient way of prescribing testing requirements 
for particular products would be to allow such requirements to be 
specified in the BLA, which will enhance flexibility to make 
appropriate changes to testing methods.

II. Summary of the Final Rule

    FDA is adopting as final, without material change, the proposed 
revocation of general safety test requirements that are duplicative of 
requirements in BLAs.
     The final rule is removing 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.
     As set forth in an approved BLA or BLA supplement, for 
products that present specific safety concerns, manufacturers will be 
required to perform appropriate safety test(s) to address those 
concerns. For example, the BLA may require testing for a specific 
toxicity.
     The appropriate tests will be specified in the 
manufacturer's BLA or BLA supplement rather than codified as 
regulations.
     Elimination of the codified GST regulations would 
encourage the implementation of the principles of the ``3Rs,'' to 
reduce, refine, and replace animal use in testing. This addresses the 
need to minimize the use of animals in such testing and promotes 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. 
285l-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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     The finalization of this rule does not automatically 
revise a manufacturer's BLA or BLA supplement.
     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 in accordance with Sec.  601.12.
     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 Sec.  601.12, 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.
     FDA anticipates that changes involving the discontinuance 
of the GST or the reliance on a test other than the GST would 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

[[Page 37973]]

or effectiveness of the product. Such changes must be identified in a 
supplement submitted under Sec.  601.12(c) (changes requiring 
supplement submission at least 30 days prior to distribution of the 
product made using the change).

III. Legal Authority

    FDA is issuing this regulation under the biological products and 
communicable disease provisions of the PHS Act (42 U.S.C. 262 and 264), 
and the provisions of the Federal Food, Drug, and Cosmetic Act (the 
FD&C Act) (21 U.S.C. 321 et seq.) applicable to drugs. Under these 
provisions of the PHS Act and the FD&C Act, we have the authority to 
issue and enforce regulations designed to ensure, among other things, 
that biological products are safe, pure, and potent and manufactured in 
accordance with current Good Manufacturing Practice, and to prevent the 
introduction, transmission, or spread of communicable disease.

IV. Comments on the Proposed Rule and FDA Response

    The Agency received two letters of comments on the proposed rule. 
Comments were received from a trade association, and an animal welfare 
organization.
    To make it easier to identify the comments and our responses, the 
word ``Comment'' and a comment number appear in parentheses before each 
comment's description, and the word ``Response'' in parentheses 
precedes each response. We have also numbered each comment to help 
distinguish between different comments. The number assigned to each 
comment is purely for organizational purposes and does not signify the 
comment's value or importance or the order in which it was received. 
Certain comments were grouped together because the subject matter of 
the comments was similar.

A. General Comments

    (Comment 1) Both letters of comments support the proposed rule.
    (Response) FDA acknowledges and appreciates that the comments we 
received agree with the need for this rulemaking. As stated previously, 
the rule removes the requirements contained in Sec. Sec.  610.11, 
610.11a, and 680.3(b) from the regulations 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. 
Removal of these regulations provides a more efficient way of 
prescribing testing requirements and enhances flexibility to make 
appropriate changes to testing methods.

B. Comments on Specific Topics

    (Comment 2) One comment requests that FDA encourage manufacturers 
who have a GST described in their BLAs for their licensed products to 
submit supplements to their BLAs to eliminate or modify the test and 
that FDA take additional steps to ensure that the final rule will have 
the intended effect of eliminating the use of animals in safety 
testing.
    (Response) As stated in the preamble of the proposed rule (79 FR 
49727 at 49729), we anticipate that the elimination of the codified GST 
regulations will encourage the implementation of the principles of the 
``3Rs,'' to reduce, refine, and replace animal use in testing. 
Moreover, on our own initiative, as discussed elsewhere in this 
document, we have determined that the effective date of the final rule 
will be 30 days after the date of its publication in the Federal 
Register to give manufacturers the flexibility to submit supplements to 
their BLAs for their licensed products as soon as possible.
    (Comment 3) One comment requests that we add language to Sec.  
601.2 or other relevant biologics regulation to clarify our intent to 
encourage the implementation of the principles of the 3Rs.
    (Response) FDA declines to adopt this recommended change because 
the request to add language to Sec.  601.2 or other relevant biologics 
regulations is outside the scope of this rulemaking.
    (Comment 4) One comment requests that FDA establish user fees with 
respect to the continued use of the GST after the effective date of 
this final rule, or that FDA establish other clear policies that will 
provide economic incentives to discontinue the use of the GST. Further, 
the comment refers to Executive Order 13563, which encourages Federal 
Agencies to ``. . . assess available alternatives to direct regulation, 
including providing economic incentives to encourage the desired 
behavior, such as user fees . . . .''
    (Response) We decline to adopt these suggested changes because they 
are beyond the scope of this rule. The proposed rule did not address 
user fees or economic incentives. This rule allows, but does not 
require, current BLA holders to submit to FDA supplements to their BLAs 
to eliminate or modify the GST.
    (Comment 5) One comment states that a manufacturer who submits a 
supplement to eliminate or modify a GST in its BLA will not be able to 
stop conducting the GST until FDA determines that the manufacturer has 
appropriately reported this change.
    (Response) We disagree in part. As stated in the preamble to the 
proposed rule (79 FR 49727 at 49730), a manufacturer who desires to 
discontinue the GST in its 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. Should 
a manufacturer wish to discontinue the GST described in the approved 
BLA, or to utilize an alternative method other than the GST approved in 
its BLA, FDA anticipates that the change would 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 make such a change 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 if any of the required information 
is missing, and will inform the applicant accordingly. If FDA does not 
so notify the applicant, distribution of the product made using the 
change may begin not less than 30 days after receipt of the supplement 
by FDA.

V. Conforming Amendments

    As part of this final rule, we need to make conforming changes when 
the removed provisions are referenced elsewhere in the CFR. The final 
rule removes ``Sec.  610.11'' from Sec.  601.2(c)(1) and 21 CFR 601.22.

VI. Effective Date

    We are making this rule effective 30 days after the date of 
publication in the Federal Register. We are making this change in the 
interest of reducing unnecessary regulatory burden to give 
manufacturers the flexibility to submit supplements right away, should 
they wish to do so.

VII. Economic Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, Executive Order 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

[[Page 37974]]

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 not a significant regulatory action as defined under 
Executive Order 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 final 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 certifies 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 $144 million, using the most current (2014) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    This final rule amends the biologics regulations by removing the 
GST requirements for biological products found in Sec. Sec.  610.11, 
610.11a and 680.3(b). FDA is finalizing 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, however, would not remove GST requirements specified in 
individual BLAs. All manufacturers that currently conduct a GST are 
already required, as part of the standards specified in their BLAs, to 
perform the GST and would thus continue to be required to perform the 
GST unless the BLA were revised to eliminate or modify the test through 
a supplement in accordance with Sec.  601.12. Because this 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.

VIII. The Paperwork Reduction Act of 1995

    This final 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 requirements in this document are not subject to 
review by OMB because they do not constitute a ``new collection of 
information'' under the PRA.

IX. 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.

X. 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 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 has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

List of Subjects

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

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, 21 CFR parts 601, 610, and 680 are 
amended as follows:

PART 601--LICENSING

0
1. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority:  15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).


Sec.  601.2  [Amended]

0
2. Section 601.2 is amended in paragraph (c)(1) by removing 
``610.11,''.


Sec.  601.22  [Amended]

0
3. Section 601.22 is amended in the third sentence by removing 
``610.11,''.

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

0
4. 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
5. Remove and reserve Sec.  610.11.


Sec.  610.11a  [Removed and Reserved]

0
6. Remove and reserve Sec.  610.11a.

PART 680--ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS

0
7. 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
8. In Sec.  680.3, remove and reserve paragraph (b).

    Dated: June 26, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-16366 Filed 7-1-15; 8:45 am]
BILLING CODE 4164-01-P


