[Federal Register Volume 84, Number 63 (Tuesday, April 2, 2019)]
[Rules and Regulations]
[Pages 12505-12508]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-06187]



[[Page 12505]]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 600

[Docket No. FDA-2017-N-7007]
RIN 0910-AH49


Removal of Certain Time of Inspection and Duties of Inspector 
Regulations for Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
issuing a final rule amending the general biologics regulations 
relating to time of inspection requirements and also removing duties of 
inspector requirements. FDA is taking this action to remove outdated 
requirements and accommodate new approaches, such as a risk-based 
inspection frequency for drug and device establishments, thereby 
providing flexibility without diminishing public health protections. 
This action is part of FDA's implementation of Executive Orders (E.O.s) 
13771 and 13777. Under these E.O.s, 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 May 2, 2019.

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: Jenifer Stach, 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. Need for This Regulation
    B. Summary of Comments to the Proposed Rule
    C. General Overview of the Final Rule
III. Legal Authority
IV. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Description of Comments Regarding Proposed Revisions to 
Sec. Sec.  600.21 and 600.22
    C. Description of Comments Outside the Scope of This Rulemaking
V. Economic Analysis of Impacts
VI. Analysis of Environmental Impact
VII. Paperwork Reduction Act of 1995
VIII. Federalism
IX. Consultation and Coordination With Indian Tribal Governments

I. Executive Summary

A. Purpose of the Final Rule

    FDA is issuing this final rule to amend the general biologics 
regulations relating to time of inspection requirements and to remove 
duties of inspector requirements. FDA is taking this action to remove 
outdated requirements and accommodate new approaches, such as a risk-
based inspection frequency for drug and device establishments, thereby 
providing flexibility without diminishing public health protections.

B. Summary of the Major Provisions of the Final Rule

    This final rule revises the time of inspection requirements 
contained in Sec.  [thinsp]600.21 (21 CFR 600.21) and also removes the 
duties of inspector requirements contained in Sec.  [thinsp]600.22 (21 
CFR 600.22). These changes to the biological product regulations 
eliminate outdated requirements and accommodate new approaches, such as 
a risk-based inspection frequency for drug and device establishments, 
thereby providing flexibility without diminishing public health 
protections. Revision and removal of these regulations does not change 
the biological product establishment inspection requirements and duties 
of an investigator requirements that apply under sections 704 and 
510(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 
U.S.C. 374 and 360(h)) and section 351(c) of the Public Health Service 
Act (PHS Act) (42 U.S.C. 262(c)).

C. Legal Authority

    FDA is taking this action under the biological product provisions 
of the PHS Act, and the drugs and general administrative provisions of 
the FD&C Act, including sections 704 and 510(h) of the FD&C Act and 
section 351(c) of the PHS Act.

D. Costs and Benefits

    Because this final rule does 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. Need for This Rulemaking

    In the Federal Register on January 26, 2018, FDA published a 
proposed rule entitled ``Removal of Certain Time of Inspection and 
Duties of Inspector Regulations for Biological Products; Companion to 
Direct Final Rule'' (83 FR 3631), as well as a companion direct final 
rule entitled ``Removal of Certain Time of Inspection and Duties of 
Inspector Regulations for Biological Products'' (83 FR 3586). To allow 
for consideration of the issues raised in the comments to the proposed 
rule, FDA withdrew the direct final rule in the Federal Register of May 
7, 2018 (83 FR 19936). After careful consideration of these issues, FDA 
is issuing this final rule to revise the time of inspection 
requirements contained in Sec.  [thinsp]600.21 and to remove the duties 
of inspector requirements contained in Sec.  [thinsp]600.22. As 
discussed in the proposed rule, on February 24, 2017, President Donald 
Trump issued E.O. 13777, ``Enforcing the Regulatory Reform Agenda'' (82 
FR 12285, March 1, 2017). One of the provisions in the E.O. requires 
Agencies to evaluate existing regulations and make recommendations to 
the Agency head regarding their repeal, replacement, or modification, 
consistent with applicable law. As one step in implementing the E.O., 
FDA published a notice in the Federal Register of September 8, 2017 (82 
FR 42492) entitled ``Review of Existing Center for Biologics Evaluation 
and Research Regulatory and Information Collection Requirements.'' 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 updating 
outdated regulations as specified in this rule.

[[Page 12506]]

    FDA's general biological products regulations in part 600 (21 CFR 
part 600) are intended to help ensure the safety, purity, and potency 
of biological products administered to humans. The revision and removal 
of certain general biological products regulations are designed to 
eliminate outdated requirements and accommodate new approaches, such as 
a risk-based inspection frequency for drug and device establishments, 
and provide flexibility without diminishing public health protections. 
Specifically, this final rule revises Sec.  [thinsp]600.21 and removes 
Sec.  600.22.

B. Summary of Comments to the Proposed Rule

    We received five comments on the proposed rule from individual 
submitters. We received comments both in support of the proposed rule 
and comments raising concerns over the proposed revisions to Sec. Sec.  
[thinsp]600.21 and 600.22. These comments are further summarized in 
section IV.

C. General Overview of the Final Rule

    As discussed in the proposed rule (83 FR 3631 at 3633), FDA's 
authority to conduct establishment inspections is included in both the 
FD&C Act and the PHS Act. Specifically, section 704 of the FD&C Act and 
section 351(c) of the PHS Act authorize the Agency to inspect 
establishments that manufacture biological products. Following 
enactment of the Food and Drug Administration Safety and Innovation Act 
(FDASIA) (Pub. L. 112-144) on July 9, 2012, and as provided under the 
provisions in E.O. 13777, FDA is revising Sec.  [thinsp]600.21 and 
removing Sec.  [thinsp]600.22.
    FDA is revising Sec.  [thinsp]600.21 to remove the biennial 
inspection requirement for biological product establishments that are 
registered as drug establishments and for those that are registered as 
device establishments. Before FDASIA was signed into law, section 
510(h) of the FD&C Act provided, among other things, that drug and 
device establishments registered with FDA must be inspected on a 
biennial basis. Section 510(h) of the FD&C Act applies to biological 
product establishments because all biological products are subject to 
regulation under the drug or device provisions of the FD&C Act (in 
addition to the biological product provisions of the PHS Act). Since 
1983, FDA's biological product regulation at Sec.  600.21 has also 
included a biennial inspection requirement, which was consistent with 
the pre-FDASIA biennial inspection requirement in section 510(h) of the 
FD&C Act.
    With the enactment of FDASIA, however, the biennial inspection 
requirement for drug establishments in section 510(h) of the FD&C Act 
was replaced with a requirement that FDA inspect drug establishments in 
accordance with a risk-based schedule established by FDA. Additionally, 
the FDA Reauthorization Act of 2017 (FDARA) was signed into law on 
August 18, 2017, and substantively amended the FD&C Act to, among other 
things, revise section 510(h)(2) such that the biennial inspection 
schedule for device establishments was also replaced by a risk-based 
schedule. FDA has determined that the biennial inspection requirement 
in Sec.  600.21 regarding the frequency of inspections is outdated and 
no longer consistent with the FD&C Act (e.g., the risk-based inspection 
schedule for drug and device establishments may result in scheduling 
inspections at intervals of greater or less than 2 years for certain 
biological product establishments).
    FDA is also removing provisions in Sec.  [thinsp]600.21 concerning 
inspectional notice and the timing of pre-licensure reinspections of 
biological product establishments, as these provisions are outdated and 
unnecessary. As discussed in the proposed rule (83 FR 3631 at 3634), 
inspectional notice is addressed in the Agency's practices for 
inspections in its Standard Operating Procedures and Policies and in 
the Investigations Operations Manual (IOM). With respect to the timing 
of a reinspection of a biological product establishment following the 
denial of a biologics license application, the general biologics 
licensing provision at 21 CFR 601.4, which was issued subsequent to 
Sec.  600.21, sets forth the administrative procedures following the 
denial of a license; accordingly, the specific provision in Sec.  
600.21 regarding timing of a reinspection following denial of a license 
is unnecessary.
    FDA has further decided that current Sec.  [thinsp]600.22, which 
requires specific duties of an FDA inspector, is unnecessary because 
the requirements in Sec.  [thinsp]600.22(a) through (h) are duplicative 
of statutory requirements that apply to biological product inspections 
under section 704 of the FD&C Act. Specifically, the inspection 
requirements in section 704 of the FD&C Act encompass all of the 
requirements outlined in Sec.  [thinsp]600.22. Thus, we are removing 
Sec.  [thinsp]600.22(a) through (h).
    The removal of these regulations, however, does not change the 
establishment inspection requirements and duties of investigator 
requirements specified in sections 704 and 510(h) of the FD&C Act, 
section 351(c) of the PHS Act, or the procedures described in the IOM. 
Additionally, it does not change the established process for risk-based 
inspection planning and work planning.

III. Legal Authority

    FDA is issuing this 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, 
351, 352, 353, 355, 356c, 356e, 360, 360i, 371, 374, and 379k-l). 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 to prevent the introduction, 
transmission, and spread of communicable disease.

IV. Comments on the Proposed Rule and FDA Response

A. Introduction

    We received five comments on the proposed rule from individual 
submitters. We describe and respond to the comments in sections IV. B 
through IV. C. We have numbered each comment to help distinguish 
between different comments. We have grouped similar comments together 
under the same number and, in some cases, we have separated different 
issues discussed in the same comment and designated them as distinct 
comments for purposes of our responses. 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. Description of Comments Regarding Revisions to Sec. Sec.  
[thinsp]600.21 and 600.22

    (Comment 1) One comment supported the proposed rule.
    (Response 1) We acknowledge and appreciate the supportive comment.
    (Comment 2) One comment expressed concern that the risk-based 
inspection frequency will not be without negative health consequences. 
The comment also stated that ``[R]isk Management is an identified known 
weak element to a majority of biological and medical device companies'' 
and that the management and mitigation of risk without FDA oversight 
for a number of years is going to be a high-risk endeavor.
    (Response 2) We disagree that the risk-based inspection frequency 
will have negative health consequences. The purpose of this rule is to 
remove outdated requirements and accommodate new approaches, such as a 
risk-based inspection frequency for

[[Page 12507]]

device and drug establishments. We believe this final rule will provide 
flexibility without diminishing public health protections. Furthermore, 
as discussed in the preamble to the proposed rule (83 FR 3633), 
establishing a risk-based schedule for inspections of drug 
establishments registered with FDA was mandated with the enactment of 
the FDASIA that was signed into law on July 9, 2012. In August 2017, 
FDARA mandated a risk-based schedule for inspections of device 
establishments registered with FDA. As a result of these amendments to 
the FD&C Act, sections 510(h)(2) and (3) of the FD&C Act now include 
requirements to establish a risk-based schedule for the inspection of 
drug and device establishments. In accordance with section 510(h)(4) of 
the FD&C Act, the risk-based schedule must consider, among other 
things, the known safety risks of such establishments, including the 
compliance history of the establishment; the record, history, and 
nature of recalls linked to the establishment; the inherent risk of the 
drug or device manufactured, prepared, propagated, compounded, or 
processed at the establishment; the inspection frequency and history of 
the establishment; and any other criteria deemed necessary and 
appropriate by FDA. While we agree that application of the risk-based 
inspection frequency may result in some establishments being inspected 
less frequently than every 2 years, these establishments will have been 
determined to be at a lower risk based on the Agency's evaluation of 
the above factors. In addition, the resources saved by performing less 
frequent inspections at lower risk establishments will allow FDA to 
inspect those establishments deemed higher risk more frequently if 
needed. Therefore, we believe the comment's concerns about negative 
health consequences are addressed during FDA's review of the known 
safety risks of drug and device establishments. The known safety risks 
that FDA must consider in establishing a risk-based schedule are 
outlined in section 510(h)(4) of the FD&C Act. With regard to ``[R]isk 
Management,'' we note that any such discussion is outside the scope of 
this rule.
    (Comment 3) One comment expressed concern with FDA's implementation 
and process for the review of existing regulations under E.O. 13771.
    (Response 3) We reiterate that the purpose of this rule is to 
remove outdated requirements and accommodate new approaches, such as 
the risk-based inspection frequency for drug and device establishments 
required by the FD&C Act, and to provide flexibility without 
diminishing public health protections. With regard to FDA's 
implementation and process for the review of existing regulations under 
E.O. 13771, we note that any such discussion is outside the scope of 
this rule.
    (Comment 4) One comment expressed concern with respect to 
determining the frequency of inspections and asserted that any revised 
risk-based inspection schedule should provide for ``both more relaxed 
and more frequent forms of inspection, if indicated by the conditions 
and risks that are assessed.'' The comment also asserted that FDA must 
``recognize that for products or processes for which quality is 
important and significant failures of quality are unacceptable, there 
may be a need for inspection more frequently than every two years, and 
with the degree of inspection and discussion now contained in the 
inspector duties under 600.20.''
    (Response 4) As discussed in the preamble to the proposed rule (83 
FR 3633), the risk-based inspection schedule for drug and device 
establishments may result in scheduling inspections at intervals of 
greater than 2 years for certain biological product establishments. 
However, those establishments will have been determined to be at a 
lower risk based on evaluation of the factors included in section 
510(h)(4) of the FD&C Act. In addition, the resources saved by 
performing less frequent inspections at lower risk establishments will 
allow FDA to inspect those establishments deemed higher risk more 
frequently when needed. We reiterate that the removal of these 
regulations will not change the establishment inspection requirements 
and duties of an investigator requirements specified in sections 704 
and 510(h) of the FD&C Act and section 351(c) of the PHS Act. 
Additionally, it will not change the established process for risk-based 
inspection planning and work planning. Furthermore, this revision will 
not change FDA's authority to inspect an establishment for special 
cause, such as when FDA becomes aware of consumer complaints or adverse 
event reports, signaling a possible product quality issue for which a 
prompt inspection may be useful in investigating the matter. Therefore, 
while we agree, in part, with the comment, we believe the concerns 
expressed in the comment are addressed through FDA's review of the 
known safety risks of drug and device establishments and by FDA's 
ability to inspect as needed in the interest of patient safety. The 
known safety risks that FDA must consider in establishing a risk-based 
schedule are outlined in section 510(h)(4) of the FD&C Act.

C. Description of Comments Outside the Scope of This Rulemaking

    (Comment 5) One comment requested an exemption to newly created 
Occupational Safety and Health Administration (OSHA) requirements.
    (Response 5) We decline to respond because the request is outside 
the scope of this rule.

V. Economic Analysis of Impacts

    We have examined the impacts of the final rule under E.O. 12866, 
E.O. 13563, E.O. 13771, the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). 
E.O. 12866 and E.O. 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). E.O. 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 E.O. 
12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because the final rule does not impose any additional 
regulatory burdens, we certify that this 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 $150 
million, using the most current (2017) 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.
    This rule is being issued to amend the general biologics 
regulations by removing certain time of inspection requirements and the 
duties of inspector requirements. This action is being taken

[[Page 12508]]

to remove outdated requirements, accommodate new approaches, and 
provide flexibility without diminishing public health protections. 
Because this rulemaking would remove regulations to be consistent with 
updated practice and does not impose any additional regulatory burdens, 
this rulemaking is not anticipated to result in any compliance costs 
and the economic impact is expected to be minimal.

VI. 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.

VII. 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.

VIII. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in E.O. 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.

IX. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this rule in accordance with the principles set 
forth in E.O. 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.

List of Subjects in 21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 600 is amended as follows:

PART 600--BIOLOGICAL PRODUCTS: GENERAL

0
1. The authority citation for part 600 is revised to read as follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356c, 356e, 360, 
360i, 371, 374, 379k-l; 42 U.S.C. 216, 262, 263, 263a, 264.


Sec.  [thinsp]600.21   [Amended]

0
2. Amend Sec.  [thinsp]600.21 by removing the last three sentences.


Sec.  [thinsp]600.22  [Removed and Reserved]

0
3. Remove and reserve Sec.  [thinsp]600.22.

    Dated: March 25, 2019.
Scott Gottlieb,
Commissioner of Food and Drugs.
[FR Doc. 2019-06187 Filed 4-1-19; 8:45 am]
 BILLING CODE 4164-01-P