[Federal Register Volume 85, Number 163 (Friday, August 21, 2020)]
[Rules and Regulations]
[Pages 51635-51639]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-17085]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 610

[Docket No. FDA-2018-N-4757]
RIN 0910-AH95


Revocation of the Test for Mycoplasma

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
issuing a final rule to remove the specified test for the presence of 
Mycoplasma for live virus vaccines and inactivated virus vaccines 
produced from in vitro living cell cultures. The rule is being 
finalized because the existing test for Mycoplasma is overly 
restrictive in that it identifies only one test method in detail to be 
used even though other methods also may be appropriate. More sensitive 
and specific methods exist and are currently being practiced, and 
removal of the specific method to test for Mycoplasma provides 
flexibility for accommodating new and evolving technology and 
capabilities without diminishing public health protections. This action 
is part of FDA's implementation of Executive Orders under which FDA is 
comprehensively reviewing existing regulations to identify 
opportunities for repeal, replacement, or modification that will result 
in meaningful burden reduction, while allowing the Agency to achieve 
our public health mission and fulfill statutory obligations.

DATES: This rule is effective September 21, 2020.

[[Page 51636]]


ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule into 
the ``Search'' box and follow the prompts, and/or go to the Dockets 
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Tami Belouin, 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:

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits
II. Background
    A. Introduction
    B. Need for the Regulation
    C. Summary of Comments to the Proposed Rule
III. Legal Authority
IV. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Comments and FDA Response
V. Effective Date
VI. Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
VII. Analysis of Environmental Impact
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. Consultation and Coordination With Indian Tribal Governments
XI. References

I. Executive Summary

A. Purpose of the Final Rule

    FDA is removing the regulation requiring a specified test for the 
presence of Mycoplasma for live virus vaccines produced from in vitro 
living cell cultures and inactivated virus vaccines produced from such 
living cell cultures because the regulation is overly restrictive in 
that it identifies only one test method in detail to be used even 
though other methods also may be appropriate. More sensitive and 
specific methods exist and are currently being practiced, and removal 
of the required test for Mycoplasma provides flexibility for 
accommodating new and evolving technology and capabilities without 
diminishing public health protections.

B. Summary of the Major Provisions of the Final Rule

    The final rule removes Sec.  610.30 (21 CFR 610.30), which details 
the method for Mycoplasma testing of samples of the virus harvest pool 
and control fluid pool of live virus vaccines and inactivated virus 
vaccines produced from in vitro living cell cultures.

C. Legal Authority

    FDA is taking this action under the biological products provisions 
of the Public Health Service Act (the PHS Act), and the drugs and 
general administrative provisions of the Federal Food, Drug, and 
Cosmetic Act (FD&C Act).

D. Costs and Benefits

    Because this final rule will not impose any additional regulatory 
burdens, this regulation is not anticipated to result in any compliance 
costs and the economic impact is expected to be minimal.

II. Background

A. Introduction

    On February 24, 2017, Executive Order 13777, ``Enforcing the 
Regulatory Reform Agenda'' (https://www.federalregister.gov/documents/2017/03/01/2017-04107/enforcing-the-regulatory-reform-agenda; 82 FR 
12285, March 1, 2017) was issued. One of the provisions in the 
Executive Order requires Agencies to evaluate existing regulations and 
make recommendations to the Agency head regarding their repeal, 
replacement, or modification, consistent with applicable law. As part 
of this initiative, FDA is revoking a regulation as specified in this 
final rule.

B. Need for the Regulation

    It has become increasingly clear that the requirement specifying a 
test for Mycoplasma is too restrictive for live virus vaccines and 
inactivated virus vaccines produced from in vitro living cell cultures 
because they specify particular methodologies when alternatives may be 
available that provide the same or greater level of assurance of 
safety. Modifications to Mycoplasma testing described in Sec.  610.30 
must meet the requirements of 21 CFR 610.9.
    Thus, the Agency believes that the regulation may no longer reflect 
the current testing procedures as a general matter and that it is more 
appropriate, flexible, and efficient to identify appropriate testing 
requirements for particular products in the biologics license 
application (BLA).
    This final rule removes the specified test for the presence of 
Mycoplasma to provide flexibility for accommodating new and evolving 
technology and capabilities without diminishing public health 
protections. Removal of this regulation allows manufacturers of live 
virus vaccines produced from in vitro living cell cultures and 
inactivated virus vaccines produced from such living cell cultures to 
select the most scientifically appropriate Mycoplasma testing method to 
assure the safety, purity, and potency of their vaccines.
    These newer technologies can result in higher sensitivity and 
specificity of Mycoplasma detection and could reduce the time required 
to complete testing for Mycoplasma. Removal of this regulation does not 
remove Mycoplasma testing requirements specified in individual BLAs. A 
manufacturer of a live virus vaccine produced from in vitro living cell 
cultures and inactivated virus vaccines produced from such living cell 
cultures will continue to be required to follow the Mycoplasma test 
requirements specified in its BLA, unless the BLA was revised to modify 
or replace the test through a supplement in accordance with Sec.  
601.12(c) (21 CFR 601.12(c)). FDA would review proposed changes to a 
manufacturer's approved biologics license in the context of that 
particular application to ensure that any such action is appropriate.
    Although the final rule removes the regulation, a manufacturer 
continues to be required to test for Mycoplasma as specified in its 
BLA. This action provides regulated industry with flexibility, as 
appropriate, to employ advances in science and technology as they 
become available, without diminishing public health protections. As 
appropriate, the Agency will describe the appropriate tests for 
particular products in manufacturers' BLAs.

C. Summary of Comments to the Proposed Rule

    We received comments on the proposed rule from individuals and 
industry submitters. The comments were generally supportive, with some 
comments suggesting new testing procedures be proposed. These comments 
are further summarized in section IV.

III. Legal Authority

    We are issuing this final rule under the biological products 
provisions of the PHS Act (42 U.S.C. 216, 262, 263, 263a, and 264) and 
the drugs and general administrative provisions of the FD&C Act (21 
U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 360h, 360i, 371, 
372, 374, and 381). 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, pure, and potent, and prevent 
the

[[Page 51637]]

introduction, transmission, and spread of communicable disease.

IV. Comments on the Proposed Rule and FDA Response

A. Introduction

    We received comments on the proposed rule from individuals and 
industry submitters. We describe and respond to the comments in section 
IV.B. We have combined comments on similar topics and have numbered 
each comment to help distinguish between different comments. The number 
assigned to each comment or comment topic is purely for organizational 
purposes and does not signify the comment's value or importance or the 
order in which comments were received.

B. Comments and FDA Response

    (Comment 1) One comment requested that FDA not finalize the rule, 
but instead amend the proposal to revoke the current test for 
Mycoplasma. The commenter proposed that FDA include methodologies on 
newer tests and how they are distinguishable from the present test; 
comparable data on the accuracy of Mycoplasma detection between the 
present and newer tests, and any other additional information that 
would support FDA's argument that the newer tests are more efficient.
    (Response 1) FDA interprets this comment to support the proposal to 
remove the currently described methodology and to amend the regulation 
to specify alternative acceptable tests. The purpose of this rulemaking 
is to permit manufacturers of live virus vaccines produced from in 
vitro living cell cultures and inactivated virus vaccines produced from 
such living cell cultures to select the most scientifically appropriate 
Mycoplasma testing method to assure the safety, purity, and potency of 
their vaccines. Thus, FDA declines to amend the regulation to specify 
alternative acceptable tests because this would not achieve the goal of 
allowing flexibility, as appropriate, to employ advances in science and 
technology as they become available without diminishing public health 
protections. However, FDA acknowledges that guidance is helpful to 
describe FDA's current thinking on alternative methods of testing for 
Mycoplasma in manufacturing samples of live virus vaccines and 
inactivated virus vaccines produced from in vitro living cell cultures. 
FDA notes that recommended alternative methods for Mycoplasma testing 
for viral vaccines are described in ``Guidance for Industry: 
Characterization and Qualification of Cell Substrates and Other 
Biological Materials Used in the Production of Viral Vaccines for 
Infectious Disease Indications'' (February 2010) (https://www.fda.gov/media/78428/download).
    (Comment 2) One comment supported the proposed rule.
    (Response 2) We acknowledge and appreciate the supportive comment.
    (Comment 3) One comment did not comment specifically on finalizing 
the rule, but stated that with changes to technology, it makes sense to 
update testing procedures. The comment stated that ``a list of the new 
proposed test methods would be beneficial to compare the overall 
benefits and disadvantages.'' Another comment suggested that if the 
rule is finalized, FDA should provide guidance for alternative methods 
of testing for Mycoplasma.
    (Response 3) While the comment states that it would be helpful to 
have a list of new proposed test methods, FDA does not believe the 
regulation should be amended to include such a list because that list 
could become outdated. License holders are welcome to discuss with FDA 
proposals to change their existing test methods and to submit proposals 
to FDA to revise the current test methods in use.
    FDA also acknowledges that guidance is helpful to describe FDA's 
current thinking on acceptable alternative methods of testing for 
Mycoplasma in manufacturing samples of live virus vaccines and 
inactivated virus vaccines produced from in vitro living cell cultures. 
FDA notes that recommended alternative methods for Mycoplasma testing 
for viral vaccines are described in ``Guidance for Industry: 
Characterization and Qualification of Cell Substrates and Other 
Biological Materials Used in the Production of Viral Vaccines for 
Infectious Disease Indications'' (February 2010) (https://www.fda.gov/media/78428/download).
    (Comment 4) One comment strongly supported removal of the 
regulation and agreed that more sensitive test methods exist; however, 
the commenter wanted the scope of the impact to be expanded to include 
all biological product manufacturers.
    (Response 4) We acknowledge and appreciate the supportive comment. 
The request to expand the revocation to include all biological product 
manufacturers is beyond the scope of this rule making because Sec.  
610.30 pertains to manufacturers of live virus vaccines and inactivated 
virus vaccines produced from in vitro living cell cultures.

V. Effective Date

    The final rule will become effective 30 days after the date of 
publication in the Federal Register.

VI. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, Executive Order 13771, 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 us 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). Executive Order 13771 
requires that the costs associated with significant new regulations 
``shall, to the extent permitted by law, be offset by the elimination 
of existing costs associated with at least two prior regulations.'' We 
believe that this final rule is not a significant regulatory action as 
defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because this rule would increase flexibility and does not add 
any new regulatory responsibilities, we certify that the final rule 
will not have a significant economic impact on a substantial number of 
small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before issuing ``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 $154 
million, using the most current (2018) Implicit Price Deflator for the 
Gross Domestic Product. This final rule would not result in an 
expenditure in any year that meets or exceeds this amount.

B. Summary of Costs and Benefits

    This final rule will amend the biologics regulations under Sec.  
610.30 by removing the specified test for Mycoplasma in the production 
of live virus vaccines produced from in vitro living cell cultures and 
inactivated virus

[[Page 51638]]

vaccines produced from such living cell cultures.
    Removing the Sec.  610.30 Test for Mycoplasma will provide 
manufacturers with the flexibility to determine the most appropriate 
and effective Mycoplasma testing methods. FDA guidance dated after 
Sec.  610.30, codified in 1973 (November 20, 1973, 38 FR 32056), 
outlines up-to-date scientific practices to identify Mycoplasma in 
production of live virus vaccines produced from in vitro living cell 
cultures and inactivated virus vaccines produced from in vitro living 
cell cultures. In practice, a vaccine manufacturer can change its 
procedures at any time with submission and prior approval of a 
supplement to its BLA. As a result, we do not expect the repeal of the 
Sec.  610.30 Test for Mycoplasma to significantly influence the 
behavior or procedures of vaccine manufacturers.
    Because manufacturers already have the ability to pursue 
alternative testing procedures, we anticipate no measurable change in 
industry or FDA behavior from this final rulemaking. We therefore 
expect the elimination of the Sec.  610.30 Test for Mycoplasma to be 
cost neutral. This final rule will therefore produce no quantifiable 
savings, costs, or transfers. We also expect no public health benefits 
to be lost as a result of this revocation. Finally, we note that this 
final rulemaking may drive some manufacturers to streamline their 
procedures and search for more efficient Mycoplasma testing methods. 
This optimization may produce some unquantifiable efficiencies.

                                      Table 1--Summary of Benefits, Costs and Distributional Effects of Final Rule
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                                                                                                  Units
                                             Primary        Low          High    ---------------------------------------
                 Category                    estimate     estimate     estimate       Year       Discount      Period                 Notes
                                                                                    dollars     rate  (%)     covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized...........................  ...........  ...........  ...........  ...........            7               ...............................
    Monetized $millions/year.............  ...........  ...........  ...........  ...........            3               ...............................
    Annualized...........................  ...........  ...........  ...........  ...........            7               ...............................
    Quantified...........................  ...........  ...........  ...........  ...........            3               ...............................
                                          --------------------------------------------------------------------------------------------------------------
    Qualitative..........................  Benefits to manufacturers from         ...........  ...........               ...............................
                                           flexibility to determine appropriate
                                           and effective Mycoplasma testing
                                           methods.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized...........................  ...........  ...........  ...........  ...........            7               ...............................
    Monetized $millions/year.............  ...........  ...........  ...........  ...........            3               ...............................
    Annualized...........................  ...........  ...........  ...........  ...........            7               ...............................
    Quantified...........................  ...........  ...........  ...........  ...........            3               ...............................
                                          --------------------------------------------------------------------------------------------------------------
    Qualitative..........................  Costs to manufacturers to change       ...........  ...........               ...............................
                                           Mycoplasma testing methods, if
                                           voluntarily pursued.
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Transfers:
    Federal..............................  ...........  ...........  ...........  ...........            7               ...............................
    Annualized...........................  ...........  ...........  ...........  ...........            3               ...............................
    Monetized $millions/year.............  ...........  ...........  ...........  ...........  ...........               ...............................
                                          --------------------------------------------------------------------------------------------------------------
    From/To..............................  From:
                                           To:
                                          --------------------------------------------------------------------------------------------------------------
    Other................................  ...........  ...........  ...........  ...........            7               ...............................
    Annualized...........................  ...........  ...........  ...........  ...........            3               ...............................
    Monetized $millions/year.............  ...........  ...........  ...........  ...........  ...........               ...............................
                                          --------------------------------------------------------------------------------------------------------------
    From/To..............................  From:
                                           To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: None.
    Small Business: None.
    Wages: None.
    Growth: None.
--------------------------------------------------------------------------------------------------------------------------------------------------------

    In line with Executive Order 13771, in table 2 we present 
annualized values of costs and cost savings over an infinite time 
horizon. There are no quantifiable costs or cost savings from this 
rule. This final rule would be considered a deregulatory action under 
Executive Order 13771.

[[Page 51639]]



                                  Table 2--Executive Order 13771 Summary Table
                           [in $ Millions 2016 Dollars, Over an Infinite Time Horizon]
----------------------------------------------------------------------------------------------------------------
                                                                      Primary          Lower           Upper
                              Item                                estimate  (7%)  estimate  (7%)  estimate  (7%)
----------------------------------------------------------------------------------------------------------------
Present Value of Costs..........................................  ..............  ..............  ..............
Present Value of Cost Savings...................................  ..............  ..............  ..............
Present Value of Net Costs......................................  ..............  ..............  ..............
Annualized Costs................................................  ..............  ..............  ..............
Annualized Cost Savings.........................................  ..............  ..............  ..............
Annualized Net Costs............................................  ..............  ..............  ..............
----------------------------------------------------------------------------------------------------------------

    We have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the final rule. The full analysis of economic 
impacts is available in the docket for this final rule (Ref. 1) and at 
https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

VII. Analysis of Environmental Impact

    We have 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.

VIII. Paperwork Reduction Act of 1995

    This final rule contains no collection of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

IX. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We have 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, we conclude 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.

X. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this rule in accordance with the principles set 
forth in Executive Order 13175. We have determined that the rule does 
not contain policies that have substantial direct effects on one or 
more Indian Tribes, on the relationship between the Federal Government 
and Indian Tribes, or on the distribution of power and responsibilities 
between the Federal Government and Indian Tribes. Accordingly, we 
conclude that the rule does not contain policies that have tribal 
implications as defined in the Executive Order and, consequently, a 
tribal summary impact statement is not required.

XI. Reference

    The following reference is on display at the Dockets Management 
Staff (see ADDRESSES) and is available for viewing by interested 
persons between 9 a.m. and 4 p.m. Monday through Friday; it is also 
available electronically at https://www.regulations.gov. FDA has 
verified the website address, as of the date this document publishes in 
the Federal Register, but websites are subject to change over time.

1. FDA/Economics Staff, ``Elimination of the 21 CFR 610.30 Test for 
Mycoplasma Preliminary Regulatory Impact Analysis, Preliminary 
Regulatory Flexibility Analysis, Unfunded Mandates Reform Act 
Analysis,'' 2018. (Available at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.)

List of Subjects in 21 CFR part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
610 is amended as follows:

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

0
1. The authority citation for 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.

Subpart D--[Removed and Reserved]

0
2. Remove and reserve subpart D, consisting of Sec.  610.30.

    Dated: July 29, 2020.
Stephen M. Hahn,
Commissioner of Food and Drugs.
[FR Doc. 2020-17085 Filed 8-20-20; 8:45 am]
BILLING CODE 4164-01-P


