Rule2024-13190
Current Good Manufacturing Practice, Certification, Postmarketing Safety Reporting, and Labeling Requirements for Certain Medical Gases
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
June 18, 2024
Effective
December 18, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is issuing a final rule revising the requirements concerning current good manufacturing practice (CGMP), postmarketing safety reporting, and labeling that apply to certain medical gases. This final rule also establishes regulations regarding certification of designated medical gases. This final rule satisfies the medical gas rulemaking requirements of the Consolidated Appropriations Act, 2017.
Full Text
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[Federal Register Volume 89, Number 118 (Tuesday, June 18, 2024)]
[Rules and Regulations]
[Pages 51738-51783]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-13190]
[[Page 51737]]
Vol. 89
Tuesday,
No. 118
June 18, 2024
Part V
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 4, 16, 201, et al.
Current Good Manufacturing Practice, Certification, Postmarketing
Safety Reporting, and Labeling Requirements for Certain Medical Gases;
Final Rule
Federal Register / Vol. 89 , No. 118 / Tuesday, June 18, 2024 / Rules
and Regulations
[[Page 51738]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 4, 16, 201, 210, 211, 213, 230, 314, and 514
[Docket No. FDA-2021-N-1333]
RIN 0910-AH96
Current Good Manufacturing Practice, Certification, Postmarketing
Safety Reporting, and Labeling Requirements for Certain Medical Gases
AGENCY: Food and Drug Administration, Department of Health and Human
Services (HHS).
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing a final rule revising the requirements concerning current good
manufacturing practice (CGMP), postmarketing safety reporting, and
labeling that apply to certain medical gases. This final rule also
establishes regulations regarding certification of designated medical
gases. This final rule satisfies the medical gas rulemaking
requirements of the Consolidated Appropriations Act, 2017.
DATES: This rule is effective December 18, 2025, except for the
amendments to Sec. Sec. 4.2 (amendatory instruction 2), 4.3
(amendatory instruction 3), and 4.4 (amendatory instruction 4) (21 CFR
4.2, 4.3, and 4.4), which are effective February 2, 2026. The
incorporation by reference of certain material listed in this rule has
been approved by the Director of the Federal Register as of February 2,
2026.
ADDRESSES: For access to the docket to read background documents or
comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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,
240-402-7500.
FOR FURTHER INFORMATION CONTACT:
With regard to the final rule: David Faranda, Center for Drug
Evaluation and Research (CDER), Food and Drug Administration, 10903 New
Hampshire Ave., Silver Spring, MD 20993, 301-796-8767,
<a href="/cdn-cgi/l/email-protection#074366716e63294166756669636647616366296f6f7429606871"><span class="__cf_email__" data-cfemail="fabe9b8c939ed4bc9b889b949e9bba9c9e9bd4929289d49d958c">[email protected]</span></a>.
With regard to the information collection: Domini Bean, Office of
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852,
<a href="/cdn-cgi/l/email-protection#bceceefdefc8dddadafcdad8dd92d4d4cf92dbd3ca"><span class="__cf_email__" data-cfemail="cb9b998a98bfaaadad8badafaae5a3a3b8e5aca4bd">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Final Rule
B. Summary of the Four Major Provisions of the Final Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. Need for the Regulation/History of the Rulemaking
B. Summary of Comments to the Proposed Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
A. Introduction
B. Description of General Comments and FDA Response
C. Description of Part 4 Comments and FDA Response
D. Part 16
E. Description of Part 201 Comments and FDA Response
F. Part 210
G. Part 211
H. Description of Part 213 Comments and FDA Response
I. Description of Part 230 Comments and FDA Response
J. Description of Part 314 Comments and FDA Response
K. Part 514
VI. Effective Date
VII. Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References
I. Executive Summary
A. Purpose of the Final Rule
On May 23, 2022, FDA issued a proposed rule to amend requirements
concerning CGMP, postmarketing safety reporting, and labeling that
apply to certain medical gases, and to establish regulations regarding
certification of designated medical gases (87 FR 31302). This rule
satisfies the requirement in section 756 of the Consolidated
Appropriations Act, 2017 (Pub. L. 115-31) that FDA issue final
regulations revising the Federal drug regulations with respect to
medical gases by July 15, 2017.
By tailoring certain labeling, CGMP, certification, and
postmarketing safety reporting requirements more narrowly to medical
gases, FDA intends to better address the unique characteristics of
medical gases. Specifically, the final rule is intended to provide
clarity and consistency regarding how information is presented in the
labeling of certain medical gases, as well as to ensure important
safety information is included. The CGMP requirements in this final
rule are intended to reflect appropriate requirements for the
manufacturing, processing, packing, and holding of such products. The
certification requirements in this final rule implement and clarify the
certification process for designated medical gases described in section
576 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C.
360ddd-1). Lastly, the new postmarketing safety reporting regulations
for designated medical gases address human and animal use and better
reflect the development, manufacturing, and distribution of designated
medical gases. Independently and collectively, FDA anticipates that
these four categories of regulatory changes will promote greater
efficiency in the regulation of medical gases while helping to ensure
that they adhere to all applicable safety and quality standards.
Following consideration of comments received and further internal
deliberation, we are finalizing this rule as described in this
document.
B. Summary of the Four Major Provisions of the Final Rule
We received fewer than 25 comments on the proposed rule. The most
detailed comments were from industry trade associations and
consultants. The other comments were from individuals. Comments
addressed many of the labeling, CGMP, certification, and safety
reporting provisions, as well as general considerations, including
general support, definitions, timing of the rule, and the effective
date.
The remainder of this subsection includes a brief description of
the four major provisions of this rule.
1. Labeling Provisions
This rule includes several changes to FDA's drug labeling
regulations, including the addition of certain operations required to
produce a medical gas to the list of operations that are performed by
its manufacturer. We are revising the requirements for stating the
ingredients in the labeling of a designated medical gas or medically
appropriate combination of designated medical gases (referred to
hereafter in this preamble as ``medically appropriate
combination'').\1\ We also specify
[[Page 51739]]
requirements for the declaration of net quantity of contents in the
labeling of designated medical gases and medically appropriate
combinations.
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\1\ Section 576(a)(3)(A)(i) of the FD&C Act provides that ``[a]
designated medical gas for which a certification is granted under
paragraph (2) is deemed, alone or in combination, as medically
appropriate, with another designated medical gas or gases for which
a certification or certifications have been granted, to have in
effect an approved application under section [505 or 512], subject
to all applicable postapproval requirements,'' for certain
indications for use. FDA interprets the term ``combination'' in this
section to mean two or more distinct designated medical gases that
are mixed together. For example, a mixture of oxygen and nitrous
oxide that each meet the standards set forth in an official
compendium could constitute a medically appropriate combination of
designated medical gases. However, the addition of oxygen to a
container that already contains oxygen would not result in a
medically appropriate combination of designated medical gases
because only one kind of designated medical gas would be present in
the container.
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We are requiring that all designated medical gases--whether
certified for human use, animal use, or both--and medically appropriate
combinations bear labeling that is in a standardized format.
FDA is revising the requirements for warning statements for certain
medical gases including that the labeling of medical air and carbon
monoxide bear certain warning statements. We are including different
labeling requirements for final use containers and bulk or transport
containers. We also are requiring a new oxygen warning statement and
graphic warning symbol to alert users of the risks of smoking, vaping,
and open flames near an oxygen container.
FDA is revising the medical gas container labeling regulations to
clarify that the owner of a designated medical gas container or a
container of a medically appropriate combination can be mentioned on
the container to facilitate return of the container to the owner, and
to ensure that product quality issues are directed to the appropriate
entity. This rule also includes clarifying revisions to the definition
of ``portable cryogenic medical gas container'' for purposes of FDA's
labeling regulations.
2. CGMP Provisions
FDA is issuing new CGMP regulations specific to medical gases.
These regulations include many of the same categories of provisions as
the general drug CGMP regulations but reflect differences in how
medical gases are manufactured, processed, packed, and held. These
regulations represent the minimum CGMP for medical gases. Of note, we
include different cleaning requirements for medical gases because these
gases are generally manufactured in a sealed, closed system, and
because cleaning at inappropriate times can introduce contaminants.
FDA is including requirements for medical gas containers and
closures that are similar to the general drug CGMP regulations, with an
additional requirement that portable cryogenic medical gas containers
and small cryogenic gas containers for use by individual patients have
a working gauge to assist the user in determining whether the container
contains an adequate supply of medical gas for continued use (minor
revisions were made to the version of this provision in the proposed
rule). This will help users determine when a container must be refilled
or replaced and when a leaking or venting container is empty. We are
not including time limitations on production because medical gases are
generally not expected to expire or degrade. Additionally, unlike the
salvaging requirements under the general drug CGMP regulations, medical
gases that have been stored improperly may be salvaged unless their
containers have been subjected to adverse conditions that negatively
impact the identity, strength, quality, or purity of the product or the
integrity of the product's container closure.
3. Certification Provisions
FDA is issuing new regulations regarding the certification process
for designated medical gases that are intended to codify the
certification process and provide additional clarity where necessary.
These requirements govern the process for applicants to file a
certification request and supplements as well as the contents of such a
request. The regulations also set forth requirements concerning the
transfer of ownership of a certification from one entity to another.
We are requiring the submission of a streamlined annual report, to
include certain required contents and submission timing. Changes to the
proposed rule include requiring submission on a calendar year basis,
rather than based on the anniversary of the date the certification
request was deemed granted, and clarifying revisions to the list of
facilities to be included in the annual report.
These regulations set forth requirements that are similar to the
recommendations described in the November 2015 draft guidance for
industry ``Certification Process for Designated Medical Gases''
(November 25, 2015, 80 FR 73771) (Ref. 1).
4. Postmarketing Quality and Safety Reporting Provisions
FDA is issuing new postmarketing quality and safety reporting
requirements for designated medical gases.
We are including requirements for submitting field alert reports
(FARs), including revised submission timelines to allow applicants time
to compile sufficient information to complete their FAR.
We are including adverse event reporting requirements related to
the use of designated medical gases in humans and animals. For
designated medical gases that are certified for human use and deemed to
have in effect an approved application under section 505 of the FD&C
Act (21 U.S.C. 355), we are requiring that applicants and nonapplicants
report serious adverse events within 15 calendar days from when the
applicant or nonapplicant has met certain reporting criteria and
acquired certain minimum data.
We are issuing requirements for the contents and format of
submissions, including an electronic submission requirement, the
process for requesting a waiver of the electronic submission
requirement, recordkeeping requirements, written procedures
requirements, and patient privacy provisions.
For designated medical gases that are certified for animal use and
deemed to have in effect an approved application under section 512 of
the FD&C Act (21 U.S.C. 360b), we are requiring that applicants and
nonapplicants submit serious adverse event reports to FDA within 15
calendar days from when the applicant or nonapplicant has met certain
reporting criteria and that recordkeeping requirements related to
adverse events are maintained.
C. Legal Authority
Sections 501, 502, 505, 512, 575, 576, and 704 of the FD&C Act (21
U.S.C. 351, 352, 355, 360b, 360ddd, 360ddd-1, and 374), in conjunction
with our general rulemaking authority in section 701(a) of the FD&C Act
(21 U.S.C. 371(a)), serve as our principal legal authority for this
final rule.
D. Costs and Benefits
This final rule establishes CGMP regulations specific to medical
gases. These regulations include many of the same categories of
requirements as the general drug product CGMP regulations but are
tailored to reflect differences in how medical gases are manufactured,
packaged, labeled, stored, and distributed. We quantify benefits to
industry from removing CGMP requirements that would not apply to
medical gases, such as removing certain building and facility
requirements, including more limited equipment maintenance and cleaning
requirements, and codifying some existing practices, which may
streamline inspections. Additional benefits will include a potentially
small reduction in fires from
[[Page 51740]]
graphic warning labels on oxygen containers, and clarification that
adverse events generally are not required to be submitted for reports
of the death of a patient or animal who was administered oxygen, nor
when fires associated with the administration of oxygen occur but do
not include an adverse event experienced by the patient or animal.
We quantify costs to industry from new labeling requirements,
regulatory clarification leading to firms becoming compliant with
existing requirements, and added CGMP requirements including a
requirement for portable cryogenic containers to have a working gauge.
Additional costs will include maintaining resumes for consultants, and
potential cost of relabeling medical air containers. We estimate that
the annualized benefits over 10 years will range from $0.00 million to
$7.02 million at a 7 percent discount rate, with a primary estimate of
$3.51 million, and from $0.00 million to $7.43 million at a 3 percent
discount rate, with a primary estimate of $3.72 million. The annualized
costs will range from $1.52 million to $5.30 million at a 7 percent
discount rate, with a primary estimate of $3.24 million, and from $1.36
million to $5.11 million at a 3 percent discount rate, with a primary
estimate of $3.07 million.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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ANDA......................... Abbreviated New Drug Application.
CDER......................... Center for Drug Evaluation and Research.
CFR.......................... Code of Federal Regulations.
CGMP......................... Current Good Manufacturing Practice.
COA.......................... Certificate of Analysis.
CVM.......................... Center for Veterinary Medicine.
FAR.......................... Field Alert Report.
FD&C Act..................... Federal Food, Drug, and Cosmetic Act.
FDA or Agency................ Food and Drug Administration.
FR........................... Federal Register.
ICSR......................... Individual Case Safety Report.
NADA......................... New Animal Drug Application.
NDA.......................... New Drug Application.
NDC.......................... National Drug Code.
OMB.......................... Office of Management and Budget.
PET.......................... Positron Emission Tomography.
PRIA......................... Preliminary Regulatory Impact Analysis.
USP.......................... United States Pharmacopeia.
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III. Background
A. Need for the Regulation/History of the Rulemaking
Medical gases have historically been manufactured, labeled, and
distributed in a manner different than most other drugs. Under section
576 of the FD&C Act, the process for obtaining marketing authorization
for a designated medical gas also differs from the process for
obtaining marketing authorization for other human and animal drugs.
Moreover, because of these differences, FDA believes that the
likelihood of identifying new safety issues for medical gases is low.
Thus, some existing regulations are not well-tailored to addressing
designated medical gases and other medical gases. FDA undertook this
rulemaking to address these differences, and to decrease regulatory
burden where appropriate. On May 23, 2022, FDA issued a proposed rule
to amend requirements concerning CGMP, postmarketing safety reporting,
and labeling that apply to certain medical gases, and to establish
regulations regarding certification of designated medical gases.
Although we believe that these four categories of regulatory
changes will best help to address the unique characteristics of medical
gases when implemented collectively, each provision independently
improves the clarity of the regulations and requirements applicable to
medical gases. In the event of a stay or invalidation of any major
provision(s), those that remain in effect would continue to function
sensibly \2\ to advance the statutory requirements applicable to
medical gases and provide useful, clear standards for firms to meet
their existing statutory obligations. For example, invalidation of the
major provisions related to certification of a designated medical gas
would have no effect on those addressing CGMP for medical gases.
Likewise, in the absence of new provisions specific to postmarketing
safety reporting for medical gases, each of the other major provisions
would continue to contribute to greater clarity and efficiency for the
medical gas industry, while helping to maintain a high standard of
safety and quality. Finally, because medical gases have historically
been regulated as drugs rather than as a specialized subset thereof,
were any major provision in this regulation invalidated, medical gases
would continue to be regulated under the existing general regulatory
regime corresponding to that provision (e.g., if medical gas CGMP
requirements are invalidated, medical gases would remain subject to the
general drug CGMP requirements in parts 210 and 211 (21 CFR parts 210
and 211)). Therefore, it is FDA's intent to preserve each of the rule's
four major provisions to the fullest possible extent, to help address
the unique aspects of medical gases that set them apart from most other
drugs.
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\2\ See, e.g., Belmont Mun. Light Dep't v. FERC, 38 F.4th 173,
188 (D.C. Cir. 2022) (finding severability of a portion of an
administrative action, applying the principle that severability is
appropriate where ``the agency prefers severability to overturning
the entire regulation'' and where the remainder of the regulation
``could function sensibly without the stricken provision'')
(citations omitted).
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B. Summary of Comments to the Proposed Rule
We received fewer than 25 comments on the proposed rule. The most
detailed comments were from industry trade associations and
consultants. The other comments were from individuals. Comments covered
many aspects of the proposed rule, including:
<bullet> General considerations, including general support,
definitions, timing of the rule, and the effective date;
<bullet> Labeling requirements, including labeling statements and
the applicability of labeling provisions to different types of
containers;
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<bullet> CGMP requirements, including buildings and facilities,
equipment, control of incoming products, packaging and labeling
control, holding and distribution, laboratory controls, records, and
returned medical gases;
<bullet> Certification requirements, including annual reporting,
withdrawal, and the applicability of current requirements in part 314
(21 CFR part 314); and
<bullet> Postmarketing quality and safety reporting requirements,
including submitting FARs, reporting of individual case safety reports
(ICSRs) related to human use, and reporting of adverse events related
to animal use.
IV. Legal Authority
We are issuing this final rule under sections 501, 502, 505, 512,
575, 576, 701, and 704 of the FD&C Act. Medical gases are generally
regulated as prescription drugs under sections 201(g)(1) and 503(b)(1)
of the FD&C Act (21 U.S.C. 321(g)(1) and 353(b)(1)) (although oxygen
may be provided without a prescription for certain uses specified at
section 576(b)(2) of the FD&C Act).
Section 501 of the FD&C Act describes the circumstances under which
a drug is deemed to be adulterated. Under section 501(a)(2)(B) of the
FD&C Act, a drug is deemed to be adulterated if the methods used in, or
the facilities or controls used for, its manufacture, processing,
packing, or holding do not conform to or are not operated or
administered in conformity with current good manufacturing practice.
For purposes of section 501(a)(2)(B), ``current good manufacturing
practice'' includes the implementation of oversight and controls over
the manufacture of drugs to ensure quality, including managing the risk
of and establishing the safety of raw materials, materials used in the
manufacturing of drugs, and finished drug products.
Section 502 of the FD&C Act describes the circumstances under which
a drug is deemed to be misbranded. Under section 502(f) of the FD&C
Act, a drug is deemed to be misbranded unless its labeling bears
adequate directions for use and such adequate warnings against use
where its use may be dangerous to health, or against unsafe dosage or
methods or duration of administration, in such manner and form, as are
necessary for the protection of users. Under section 704 of the FD&C
Act, FDA is authorized to inspect, among other things, records in any
establishment in which prescription drugs or nonprescription drugs
intended for human use are manufactured, processed, packed, or held
bearing on whether such products are in violation of the FD&C Act.
Section 576 of the FD&C Act describes the certification process for
designated medical gases (as defined in section 575 of the FD&C Act)
and the effect of certification, the applicability of FDA's
prescription requirements, and certain labeling requirements. Under
section 576(a)(3)(A)(i) of the FD&C Act, a certified designated medical
gas is subject to all applicable postapproval requirements. Under
section 505(k) of the FD&C Act, FDA has the authority to establish
certain postmarketing safety reporting regulations for human drugs to
enable FDA to determine or facilitate a determination as to whether
there are or may be grounds to invoke section 505(e) of the FD&C Act,
which concerns the withdrawal or suspension of approval of a new drug
application (NDA) or abbreviated new drug application (ANDA). Section
512(l) of the FD&C Act authorizes FDA to establish postmarketing safety
reporting regulations for new animal drugs to enable FDA to determine
or facilitate a determination as to whether there are or may be grounds
to withdraw approval of an application pursuant to section 512(e) or
512(m)(4) of the FD&C Act.
Thus, sections 501, 502, 505, 512, 575, 576, and 704 of the FD&C
Act, in conjunction with our general authority in section 701(a) of the
FD&C Act to issue regulations for the efficient enforcement of the FD&C
Act, serve as our principal legal authority for this final rule.
V. Comments on the Proposed Rule and FDA Response
A. Introduction
We received fewer than 25 comment letters on the proposed rule by
the close of the comment period, each containing one or more comments
on one or more issues. We received comments from individuals, trade
organizations, and industry consultants.
We describe and respond to the comments in sections V.B. through
V.G. of this document. 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.
Additionally, on its own initiative, FDA is making minor technical
and grammatical changes to the rule to improve clarity.
B. Description of General Comments and FDA Response
(Comment 1) Some comments make general remarks supporting the
proposed rule without focusing on a particular proposed provision. One
comment also notes that the COVID-19 pandemic highlighted the need for
updated medical gas regulations.
(Response 1) We appreciate these comments of support and agree that
this rulemaking is needed.
(Comment 2) One comment encourages FDA to publish this rule widely
to ensure that all affected entities access it.
(Response 2) FDA is publishing this final rule publicly consistent
with requirements under the Administrative Procedure Act and Agency
practice. We believe this sufficiently addresses the need to make
regulatory changes widely accessible to the public.
(Comment 3) One comment discusses when to publish the final rule,
urging FDA to issue the final rule swiftly.
(Response 3) FDA acknowledges the public interest in finalizing
this rule promptly. The Agency works within its defined processes to
draft, clear, and issue regulations. During the rulemaking process, FDA
published in the Unified Agenda of Federal Regulatory and Deregulatory
Actions (Unified Agenda) its estimated timeline for completion of the
final rule.
C. Description of Part 4 Comments and FDA Response
FDA proposed changes to part 4, subpart A (21 CFR part 4, subpart
A) to reflect the new CGMP requirements for medical gases proposed in
part 213 (21 CFR part 213). FDA proposed definitions of ``medical gas''
and ``medical gas CGMPs'' in Sec. 4.2, and conforming changes to
account for combination products that contain a medical gas in Sec.
4.3. FDA also proposed in Sec. 4.4 conforming changes to account for
combination products that contain a medical gas, as well as a list of
CGMP provisions from part 213 that must be satisfied if the CGMP
operating system for a combination product containing a medical gas has
been shown to comply with the device quality system regulations. We
received one comment on these provisions, which we discuss below.
(Comment 4) One comment notes that some manufacturers of designated
medical gases will not know whether their product will ultimately be
used as
[[Page 51742]]
a drug constituent part of a combination product. As such, the comment
asks whether such designated medical gases are subject to the CGMP
regulations in part 4.
(Response 4) In the example in the comment, if the entities are
manufacturing only the gas, they would not be subject to the CGMP
regulations in part 4, which only apply to combination product
manufacturers (Sec. 4.1). Such original manufacturers of designated
medical gases only have to comply with part 213. However, for example,
a third party manufacturing a combination product that includes such a
designated medical gas would be subject to these part 4 CGMP
requirements.
D. Part 16
FDA proposed to revise Sec. 16.1(b)(2) (21 CFR 16.1(b)(2)) to
broaden the scope of regulatory hearings to include hearings relating
to revocation of a grant of a certification for a designated medical
gas. We did not receive comments on the proposed revision and are
finalizing the provision as proposed with minor technical changes made
on our own initiative.
E. Description of Part 201 Comments and FDA Response
1. General Comments
(Comment 5) One comment makes general remarks supporting the
proposed revisions to the labeling regulations in part 201 (21 CFR part
201) without focusing on a particular proposed provision.
(Response 5) We appreciate this comment of support.
2. Manufacturer Definition (Proposed Sec. 201.1)
FDA proposed revisions to the ``manufacturer'' definition in Sec.
201.1(b), adding proposed paragraph (11) to address medical gas
manufacturing activities for purposes of part 201 and section 502(a)
and (b)(1) of the FD&C Act. We proposed to specify that, with respect
to a medical gas, the manufacturer is the person fabricating the gas by
chemical reaction, physical separation, compression of atmospheric air,
purification (e.g., reprocessing an industrial gas into a medical gas),
by combining two or more distinct medical gases, or by other process.
(Comment 6) One comment recommends that FDA remove the catchall
``other processes'' and include filling a medical gas container in the
list of manufacturing operations. The comment expresses that this
change would capture operations performed post-fabrication.
(Response 6) FDA does not agree with this recommendation. The
operations listed in Sec. 201.1(b)(11) focus on methods of
``fabricating the gas,'' rather than downstream processes. While
certain downstream processes will be subject to the CGMP requirements
in part 213 when in effect, the purpose of Sec. 201.1(b) is to capture
the primary activities conducted to initially produce a drug product.
3. Adequate Directions for Use (Sec. 201.100)
Although FDA did not propose revisions to Sec. 201.100, the Agency
received comments proposing revisions to the current text.
(Comment 7) One comment proposes a new Sec. 201.100(a)(1)(iv) to
specify that a designated medical gas used to clean or purge medical
gas containers, including medical gas pipelines, is exempt from the
requirement in section 502(f)(1) of the FD&C Act that its labeling bear
adequate directions for use. The comment adds that this would allow
individuals to obtain designated medical gases for such use (for
example, nitrogen for purging medical pipelines).
(Response 7) FDA does not agree with this comment. Revisions to
Sec. 201.100(a)(1) are not necessary because gases used for the
purposes described in the comment do not meet the definition of a drug
under section 201(g)(1) of the FD&C Act. Therefore FDA's drug labeling
requirements, including the requirement to bear adequate directions for
use, would not apply to a gas intended only for these uses.
(Comment 8) One comment proposes revisions to Sec. 201.100(b)
exempting designated medical gases in compliance with Sec. 201.161
from the labeling requirements in Sec. 201.100(b) because Sec.
201.161 as revised by this rulemaking includes specific requirements
for designated medical gas labeling.
(Response 8) FDA does not believe these revisions are needed. The
purpose of Sec. 201.100 is to exempt prescription drugs from the
requirements in section 502(f)(1) of the FD&C Act if certain
requirements are met. For designated medical gases, section
576(a)(3)(A)(ii) of the FD&C Act already addresses this requirement by
stating that, for such gases, the requirements of sections 503(b)(4)
and 502(f) of the FD&C Act are deemed to have been met for a designated
medical gas if the labeling on its final use container bears the
information required by section 503(b)(4), a warning statement
concerning the use of the medical gas (as determined by the Secretary
by regulation), and appropriate directions and warnings concerning
storage and handling.
The revisions to Sec. 201.161 in this rulemaking further satisfy
this requirement, as sections 503(b)(4) and 502(f) of the FD&C Act are
deemed to have been met for a designated medical gas if the final use
container bears the information required in Sec. 201.161(a).
4. Medical Gas Labeling Statements (Proposed Sec. 201.161)
FDA proposed several changes to the medical gas labeling
requirements in Sec. 201.161. We proposed moving the warning statement
requirements for oxygen in Sec. 201.161(a)(1)(i) to Sec.
201.161(a)(1), without proposing any changes to the requirements. We
also proposed moving the warning statement requirements for nitrogen,
carbon dioxide, helium, nitrous oxide, and medically appropriate
combinations of oxygen, nitrogen, carbon dioxide, helium, and nitrous
oxide in Sec. 201.161(a)(1)(ii) to Sec. 201.161(a)(2) and proposed
expanding their scope to all designated medical gases other than oxygen
as well as medically appropriate combinations of any medical gases. We
also proposed adding a requirement that the final use container bears
the symbol ``Rx only.'' In proposed Sec. 201.161(a)(3), we proposed
requiring that the final use container bears appropriate directions and
warnings concerning storage and handling.
In proposed Sec. 201.161(b), we proposed requirements that a
designated medical gas or medically appropriate combination of
designated medical gases in a bulk or transport container be identified
with the name of the product contained therein and accompanied by
documentation identifying the product as meeting applicable compendial
standards.
Lastly, proposed Sec. 201.161(c) included several definitions. We
received no comments on the proposed definitions of ``designated
medical gas'' (proposed Sec. 201.161(c)(1)) or ``bulk or transport
container'' (proposed Sec. 201.161(c)(3)) and are finalizing these
definitions as proposed with minor technical changes made on our own
initiative. We proposed to define ``final use container'' as a
container that is for direct use or access by a patient or healthcare
provider to administer a designated medical gas or medically
appropriate combination of designated medical gases, not including bulk
or transport containers or containers that are described in Sec.
868.5655 (21 CFR 868.5655).
We respond to the comments on proposed Sec. 201.161 in the
following paragraphs.
[[Page 51743]]
(Comment 9) One comment recommends that the oxygen warning
statement in proposed Sec. 201.161(a)(1)(i) include additional
instances in which oxygen may be provided without a prescription aside
from depressurization or environmental oxygen deficiency, or emergency
resuscitation. As an example of such an additional use, the comment
suggests the emergency use of oxygen for hyperbaric oxygen therapy for
decompression sickness.
(Response 9) FDA disagrees. The uses described in Sec.
201.161(a)(1)(i) of the proposed rule are consistent with the
circumstances described in section 576(b)(2)(A) of the FD&C Act under
which oxygen may be provided without a prescription. FDA does not
believe it would be appropriate to include additional uses in this
provision.
(Comment 10) Regarding FDA's proposed requirement in Sec.
201.161(a)(1)(ii) that final use containers bear a ``No Smoking'' and
``No Vaping'' warning statement and a graphic symbol conveying that
smoking, vaping, and open flames near oxygen are dangerous, one comment
notes that industry may need time to develop graphic symbols and text.
(Response 10) FDA recognizes the concerns expressed in this
comment, and we note, as stated in section VI of this document, that
firms will have 18 months to develop the required warning statement and
graphic symbol. The Agency is happy to discuss the matter further with
industry as firms develop graphics to address this requirement.
(Comment 11) One comment proposes adding a new Sec.
201.161(a)(1)(iii) to state that, if oxygen is provided as a designated
medical gas in the form of a cryogenic liquid in a cryogenic final use
container meeting the definition of a device, the warning statements in
Sec. 201.161 are not required. The comment conditions this on the
device label providing adequate directions for use in accordance with
the device approval. The comment notes that this would reflect the
current labeling appearing on home oxygen units.
(Response 11) FDA does not agree that this revision is needed. The
definition of ``final use container'' in Sec. 201.161(c)(2) already
makes clear that the term does not include containers meeting the
definition of a medical device and classified under Sec. 868.5655. As
devices, these containers have separate labeling requirements.
Therefore, further clarification in Sec. 201.161 is not necessary.
(Comment 12) In response to FDA's request for feedback regarding
the inclusion in Sec. 201.161(a)(2) of medical air in the proposed
labeling requirements for designated medical gases other than oxygen
and medically appropriate combinations of designated medical gases, one
comment responds that they do not oppose this.
(Response 12) FDA appreciates the feedback on this request.
(Comment 13) One comment requests that FDA add language to Sec.
201.161(a)(2) explaining that the required statements in Sec. 201.161
are not required for cryogenic nitrogen in an open top dewar. The
comment notes that certain uses of cryogenic nitrogen, such as
dermatological use, are device uses rather than drug uses.
(Response 13) While FDA agrees that cryogenic nitrogen being used
for certain dermatological purposes is a device use, and therefore not
subject to Sec. 201.161, the Agency declines to add the requested
language. As revised by this rule, Sec. 201.161(a) states that section
503(b)(4) of the FD&C Act, which only applies to drugs, is deemed to
have been met if a designated medical gas is in compliance with Sec.
201.161(a). Therefore, it is clear that the requirements in Sec.
201.161 only apply to medical gases that are drugs, and that if a gas
is a device, it is subject to applicable device labeling requirements.
This position is consistent with FDA's draft guidance for industry
entitled ``Certification Process for Designated Medical Gases'' \3\
(Ref. 1).
---------------------------------------------------------------------------
\3\ ``Gases not intended for human or animal drug use . . . do
not fall within the definition of `medical gas' provided in section
575(2) of the FD&C Act, and are not subject to the certification
process described in this guidance.''
---------------------------------------------------------------------------
(Comment 14) One comment requests that FDA revise Sec. 201.161(b)
to require that a designated medical gas or medically appropriate
combination of designated medical gases in a bulk or transport
container must be ``provided with'' documentation identifying the
product as meeting applicable compendial standards, rather than
``accompanied by'' such documentation. This comment is intended to
allow for current industry practices of electronic delivery of such
documentation.
(Response 14) FDA believes that this change is unnecessary.
Information promptly transmitted electronically would be considered to
accompany a drug. Therefore, revisions are not necessary to address the
concern expressed in this comment.
(Comment 15) One comment recommends that the definition of ``final
use container'' in Sec. 201.161(c)(2) be revised to mean a container
that is ``labeled'' for direct use, rather than a container that is
``for'' direct use. The comment notes that the proposed definition of
``bulk or transport container'' includes cylinders that are connected
to a medical gas supply system, such as a hospital's oxygen system.
However, the comment asserts that cylinder banks may contain individual
labeled cylinders.
(Response 15) FDA disagrees with the proposed revision. First,
specifying that a container is a final use container if it is
``labeled'' for direct use would be circular, and a firm could avoid
being regulated as a final use container simply by not labeling its
containers accordingly. Second, FDA believes that the purpose of the
container should determine the appropriate labeling. If the container
is intended to be used as a final use container, it must be labeled in
compliance with Sec. 201.161(a), and if a container is intended to be
used as a bulk or transport container, it must be labeled in compliance
with Sec. 201.161(b).
5. Labeling of Medical Gas Containers (Proposed Sec. 201.328)
FDA proposed changes to Sec. 201.328(a)(1) to reference Sec.
213.94(e)(3) instead of Sec. 211.94(e)(2). We also proposed to add
Sec. 201.328(d) to clarify that a container filled with a designated
medical gas or medically appropriate combination of designated medical
gases may bear a statement identifying the name of the owner of the
container or the address to which the container should be returned
after use, noting that this statement may appear on a separate sticker
or decal. We further proposed that if the owner of the container is not
the manufacturer, packer, or distributor of the designated medical gas
or medically appropriate combination of designated medical gases, that
shall be clearly stated on the container. Proposed Sec. 201.328(d)
further notes that the addition of such statement shall not cause the
owner of the cylinder to be a ``relabeler'' for purposes of FDA's
registration and listing requirements.
(Comment 16) Although FDA did not propose changes to the definition
of ``portable cryogenic medical gas container'' in Sec. 201.328(a),
one comment did suggest changes. This provision refers to a container
that is capable of being transported and is intended to be attached to
a medical gas supply system within a hospital, health care entity,
nursing home, other facility, or home health care setting, or is a base
unit used to fill small cryogenic gas containers for use by individual
patients. The term does not include cryogenic containers that are not
designed to be connected to a medical gas supply system, including
portable liquid oxygen units as defined in Sec. 868.5655. First, the
comment requests to remove the term ``base unit''
[[Page 51744]]
because the term is commonly used to refer to the device maintained at
a patient's home that is filled with oxygen. The comment notes that
these containers are not typically moved. Second, the comment suggests
removing ``small'' before ``cryogenic gas containers'' in the
exclusionary language, as well as including language clarifying that
cryogenic gas containers utilize proprietary connections. Third, the
comment suggests removing from the exclusionary language the reference
to devices defined in Sec. 868.5655.
(Response 16) FDA agrees that the term ``base unit'' should be
removed from the definition. Because there may be confusion over what a
``base unit'' includes, we believe it is more appropriate to focus on
the purpose of the container. As such, we are revising the definition
to include, among other things, a container that ``is used to fill
small cryogenic gas containers for use by individual patients.''
However, we disagree with the other requested changes. Because
portable cryogenic medical gas containers can be in patients' homes, we
believe that it is critical that they include proper labeling. Removing
``small'' before ``cryogenic gas containers'' would unnecessarily
expand the exclusionary language and limit the scope of products
subject to the labeling requirements described in part 201. We also do
not believe adding the qualifier that cryogenic gas containers utilize
proprietary connections to the exclusionary language is appropriate, as
it is not clear why the exclusion should depend on the type of
connections used. We also note that these requested revisions are not
consistent with similar revisions proposed for Sec. 213.94(e)(1)
(concerning requirements for medical gas containers and closures) (see
response 30).
We do not believe it is appropriate to remove the reference to
Sec. 868.5655 from the exclusionary language. It is unclear why the
comment suggests removing this language while also noting that base
units are considered devices; if the reference to Sec. 868.5655 were
removed from the exclusionary language, the definition might arguably
be read to consider such devices to be portable cryogenic medical gas
containers subject to the wraparound labeling requirement. This
distinction between containers that are devices, and those that are
not, is important, and FDA believes that the definition as revised
makes clear which containers are devices subject to applicable device
requirements, and which are portable cryogenic medical gas containers
subject to applicable drug requirements.
Lastly, we are revising ``does not include'' to ``exclude,''
consistent with the revisions discussed in response 31 below. As
finalized, the term ``portable cryogenic medical gas containers''
excludes cryogenic containers that are not designed to be connected to
a medical gas supply system.
(Comment 17) One comment requests that Sec. 201.328(d) be revised
to clarify that, if information identifying the name of the owner of
the container or the address to which the container should be returned
after use appears on a separate sticker or decal, such sticker or decal
should not cover up other language on the label.
(Response 17) FDA appreciates the concern that labeling information
should be clearly displayed and not covered up, but the Agency does not
believe the proposed revisions are necessary because other provisions
address this issue. In particular, section 502(c) of the FD&C Act
states that a drug shall be misbranded if any word, statement, or other
information required by or under authority of the FD&C Act to appear on
the label or labeling is not prominently placed thereon with such
conspicuousness and in such terms as to render it likely to be read and
understood by the ordinary individual under customary conditions of
purchase and use.
Additionally, Sec. 201.15(a)(6) of FDA's labeling regulations
makes clear that ``obscuring designs or vignettes'' may cause required
information to lack the prominence and conspicuousness required by
section 502(c) of the FD&C Act.
F. Part 210
FDA proposed conforming edits to the general provisions concerning
drug CGMP requirements in part 210 to reflect the proposed
establishment of medical gas CGMP requirements in part 213. We did not
receive comments on the proposed revisions and are finalizing the
provisions as proposed with minor technical changes made on our own
initiative.
G. Part 211
FDA proposed conforming edits to the drug CGMP requirements in part
211 to reflect that medical gases would no longer be subject to this
part. We did not receive comments on the proposed revisions and are
finalizing the provisions as proposed.
H. Description of Part 213 Comments and FDA Response
1. General Comments
(Comment 18) Some comments make general remarks supporting the
proposed CGMP regulations without focusing on a particular proposed
provision.
(Response 18) We appreciate these comments of support.
2. Definitions (Proposed Sec. 213.3)
FDA proposed definitions of several terms used in part 213. We
received comments on several of those proposed definitions, as
discussed below. We are finalizing as proposed (with minor technical
and grammatical changes made on our own initiative) those definitions
for which we received no comments.
a. Acceptance Criteria (Proposed Sec. 213.3(b)(1))
We proposed to define ``acceptance criteria'' as the product
specifications and acceptance/rejection criteria, such as acceptable
quality level and unacceptable quality level, with an associated
sampling plan, that are necessary for making a decision to accept or
reject a lot or batch (or any other convenient subgroups of
manufactured units).
(Comment 19) One comment requests that the ``acceptance criteria''
definition in proposed Sec. 213.3(b)(1) be consistent not only with
the acceptance criteria definition in part 210, but also the
corresponding definitions in other regulations and guidance. For
example, the comment notes that the ``acceptance criteria'' definition
in part 212 (21 CFR part 212) concerning positron emission tomography
(PET) drugs differs from the proposed definition for medical gases.
(Response 19) FDA does not believe that revisions are necessary.
The proposed ``acceptance criteria'' definition in Sec. 213.3(b)(1) is
identical to the current ``acceptance criteria'' definition in Sec.
210.3(b)(20), and FDA further believes that it is generally consistent
with the ``acceptance criteria'' definition in Sec. 212.1. In any
case, PET drugs are outside the scope of this rulemaking, as FDA did
not propose any revisions to part 212 in the proposed rule.
b. Batch (Proposed Sec. 213.3(b)(2))
We proposed to define ``batch'' as a specific quantity of a medical
gas or other material that is intended to have uniform character and
quality, within specified limits, and is produced according to a single
manufacturing order during the same cycle of manufacture.
(Comment 20) One comment suggests that batches, as defined in
proposed Sec. 213.3(b)(2), and lot numbers, as defined in Sec.
213.3(b)(10), be defined per day. The comment argues that this
[[Page 51745]]
would provide sufficient information for downstream tracking and
reporting.
(Response 20) FDA disagrees. As discussed in the proposed rule, we
believe the proposed ``batch'' definition allows for significant
flexibility in defining a batch to address considerations raised by
different types of firms and different manufacturing, processing,
packing, and holding activities (87 FR 31302 at 31310). We do not
believe the term should restrict batches to a quantity produced in a
single day. As such, we also do not believe that any revisions to the
definition in Sec. 213.3(b)(10) for ``lot number, control number, or
batch number'' are necessary.
c. Commingling or Commingled (Proposed Sec. 213.3(b)(3))
We proposed to define ``commingling or commingled'' as the act of
combining one lot of designated medical gas or component with another
lot or lots of the same designated medical gas or component.
(Comment 21) One comment concurs with the definition of
``commingling or commingled'' in proposed Sec. 213.3(b)(3), but notes
that, in the event lots are combined, firms should maintain tracking
information at the container level to record which lots are included in
the combined product and when they were added.
(Response 21) We believe that the tracking requirements established
in this final rule sufficiently address any risks associated with the
receipt of gases from multiple suppliers. Specifically, Sec. 213.82
contains requirements for the receipt of incoming designated medical
gases, including that either a signed certificate of analysis (COA)
must accompany the gas or that the receiving firm must conduct full
compendial testing (all tests necessary to ensure compliance with an
official compendium), and that an identity test must be performed (see
response 26 below for more information regarding revisions to Sec.
213.82). Additionally, Sec. 213.101(b) requires that in-process and
final product containers of components and incoming designated medical
gases shall identify the name of the component or designated medical
gas or the name and percentage of each component or designated medical
gas if they contain multiple components or designated medical gases,
and the unique lot number assigned.
d. Original Manufacturer (Proposed Sec. 213.3(b)(13))
We proposed to define ``original manufacturer'' as the person or
entity that initially produces a designated medical gas by chemical
reaction, physical separation, compression of atmospheric air,
purification (e.g., re-processing an industrial gas into a medical
gas), or other means.
(Comment 22) One comment suggests that the ``original
manufacturer'' definition in Sec. 213.3(b)(13) be revised to exclude
processing agents such as nitrogen used in bottle purging and product
overlay because these gases are not a part of the drug product and are
not considered medical gases.
(Response 22) FDA does not believe that revisions are necessary to
address this concern. We agree that gases used in the production of
drugs that are not medical gases are not subject to part 213. Such
gases may be subject to part 211 if the drug product is subject to
those regulations depending on the use of the gas, but that is outside
the scope of this rulemaking. We also note that, as discussed below in
response 45, we do not believe it is necessary for the definition to
include ``or entity'' because the word ``person'' captures all relevant
entities. As such, we have revised the definition to remove ``or
entity.''
(Comment 23) One comment proposes adding a definition of
``subsequent manufacturer'' in Sec. 213.3(b) to resolve regulatory
uncertainty that may exist without distinguishing between subsequent
manufacturers and original manufacturers.
(Response 23) FDA does not believe that this definition is
necessary. We understand ``subsequent manufacturer'' to refer to a
person that performs manufacturing operations after the initial
production of a designated medical gas, such as transfilling and
curbside filling. We agree that subsequent manufacturers that are not
engaged in the activities described in Sec. 213.3(b)(13) are not
original manufacturers. However, the proposed rule preamble clarified
what kinds of entities would not be considered an original manufacturer
(87 FR 31302 at 31311). If a provision does not specify that it applies
only to original manufacturers, then subsequent manufacturers subject
to part 213 would need to comply as applicable. Moreover, part 213 does
not use the term ``subsequent manufacturer,'' and the comment's
proposed revisions would only use the term in the definition section.
3. Buildings and Facilities (Proposed Part 213, Subpart C)
FDA proposed to establish requirements for the design and
construction features of buildings and facilities for the manufacture,
processing, packing, or holding of medical gases (proposed Sec.
213.42). We received one comment on these provisions, which we discuss
below.
(Comment 24) One comment asks for clarification regarding what FDA
considers to be ``adequate space'' in proposed Sec. 213.42(a), which
would require that buildings and facilities used in the manufacture,
processing, packing, or holding of a medical gas be of adequate design,
including adequate space, for the orderly placement of equipment and
materials to prevent mix-ups and allow for adequate cleaning,
maintenance, and proper operations. The comment asserts that the term
is ambiguous and proper equipment, operations, and labeling should
allow firms to mitigate the risk of mix-ups.
(Response 24) The use of the term ``adequate space'' is intended to
allow for flexibility in designing a manufacturing facility that
prevents mix-ups and allows for adequate cleaning, maintenance, and
proper operations. We agree that there are not necessarily size
restrictions and that using proper equipment and processes are key to
ensuring that the space is appropriate for the operations. We do not
believe that revisions to Sec. 213.42(a) are necessary.
4. Equipment (Proposed Part 213, Subpart D)
FDA proposed to establish several requirements concerning equipment
used in the manufacture, processing, packing, or holding of medical
gases (proposed Sec. Sec. 213.63, 213.65, 213.67, and 213.68). We
received no comments on proposed Sec. Sec. 213.63, 213.65, and 213.67
and are finalizing them as proposed with a minor technical change made
on our own initiative. We received comment only on proposed Sec.
213.68(a), which specified that automatic, mechanical, and electronic
equipment used in the manufacture of medical gases shall be routinely
calibrated, inspected, and checked according to a written program
designed to ensure proper performance, and that written procedures and
records of calibration, inspections, and checks shall be maintained.
(Comment 25) One comment suggests that proposed Sec. 213.68(a) be
revised to include a minimum frequency for calibration, inspection, and
checking of automatic, mechanical, and electronic equipment.
(Response 25) FDA does not believe it is necessary to include
specific frequency requirements for such calibration, inspection, and
checking of equipment. This is also consistent with Sec. 211.68(a) and
affords flexibility to
[[Page 51746]]
firms to take steps that will ensure proper performance based on the
operations conducted and equipment used.
5. Control of Incoming Designated Medical Gas, Components, and Medical
Gas Containers and Closures (Proposed Part 213, Subpart E)
FDA proposed to establish several requirements concerning the
control of incoming designated medical gas, components, and medical gas
containers and closures (proposed Sec. Sec. 213.80, 213.82, 213.84,
213.89, and 213.94). We received no comments on proposed Sec. Sec.
213.80 and 213.89 and are finalizing them as proposed. We respond to
the comments on proposed Sec. Sec. 213.82, 213.84, and 213.94 below.
a. Receipt and Storage of Incoming Designated Medical Gases (Proposed
Sec. 213.82)
FDA proposed that, upon receipt of an incoming designated medical
gas, the firm shall verify and record that a signed certificate of
analysis from the supplier accompanies each different designated
medical gas in a shipment, including the supplier's name; name of the
incoming designated medical gas; lot number or other unique
identification number; actual analytical result obtained for strength,
as well as the results of other tests performed; identification of the
test method(s) used for analysis; NDA or new animal drug application
(NADA) number of the incoming designated medical gas; and the supplier
representative's signature and the date of signature (proposed Sec.
213.82(a)(1)). If the incoming designated medical gas is obtained from
a supplier other than the original manufacturer, FDA proposed requiring
the shipment to include complete information from the original
manufacturer's COA, and that the firm establish and maintain a program
to ensure the reliability of the supplier's capabilities through
appropriate assessment and testing procedures (proposed Sec.
213.82(a)(2)). Lastly, FDA proposed requiring that an identity test be
performed upon receipt (proposed Sec. 213.82(b)).
(Comment 26) One comment asks that Sec. 213.82(a)(1) be revised to
allow receiving firms to conduct full compendial testing on the
commingled product as an alternative to verifying that a COA
accompanies the shipment. The comment maintains that this is consistent
with industry practice.
(Response 26) FDA generally agrees with this comment. The Agency
believes that both proposed approaches are appropriate for ensuring
that each shipment of each incoming designated medical gas is verified
as meeting relevant standards and is appropriate for use. However, FDA
does not believe it is appropriate to specify that the full compendial
testing be of the commingled product because testing of the gas before
it is commingled would also confirm that it meets compendial standards.
Further, Sec. 213.82(a)(2) requires that, for incoming designated
medical gas from a supplier other than the original manufacturer, each
shipment shall also include complete information from the original
manufacturer's COA. We are revising Sec. 213.82(a)(1) accordingly to
state that, upon receipt of each shipment of each incoming designated
medical gas, the firm shall either perform full compendial testing on
the gas and record the results, or verify and record that a signed COA
from the supplier accompanies each different designated medical gas in
a shipment.
(Comment 27) One comment requests that, instead of requiring that
``a signed certificate of analysis from the supplier accompanies each
different designated medical gas,'' Sec. 213.82(a)(1) should state
that ``a signed document from the supplier is provided for each
different designated medical gas . . . .'' The comment suggests
additional edits, including that the document must identify the product
as meeting compendial standards, that a COA may be used to satisfy
these requirements, and that only if a COA is used would paragraphs
(a)(1)(i) through (vii) apply.
(Response 27) FDA does not agree that the term ``certificate of
analysis'' should be replaced with the term ``document.'' First, by
retaining the term ``certificate of analysis'' after using the more
general term ``document,'' the suggested revisions would create
ambiguity concerning what requirements would apply to a ``document''
that is not a COA. Second, our intent is that the entity providing this
documentation certify the information accompanying the shipment.
Therefore, ``document'' is less clear than the term ``certificate of
analysis.'' We similarly disagree with including a statement that a COA
may be used to satisfy these requirements because FDA is already using
that term to refer to the applicable documentation.
FDA disagrees with revising ``accompanies'' to read ``is provided
for.'' In general, we believe the terms can be read similarly, and FDA
generally intends to interpret ``accompany'' broadly enough to include
prompt electronic transmission, as discussed above in response 14.
FDA does not agree that it is necessary to add that the COA
identifies the product as meeting applicable compendial standards. This
is already covered by Sec. 213.82(a)(1)(ii), (iv), and (vii), which
require that the COA identify the name of the designated medical gas,
its analytical test results, and a signature from the supplier's
representative. For example, a supplier of Oxygen, USP (United States
Pharmacopeia) would be certifying that the gas meets compendial
standards for Oxygen, USP by identifying the gas by its compendial name
and including test results demonstrating that the gas meets applicable
standards.
(Comment 28) One comment asks that FDA delete proposed Sec.
213.82(a)(1)(vi) because the inclusion of NDA or NADA information does
not provide support for the quality or traceability of the product in
addition to the other information provided. The comment maintains that
NDA or NADA information may not be accurate in the case of commingled
or combined gases, or gases from subsequent manufacturers.
(Response 28) FDA disagrees with the requested deletion. The
Agency's intent in Sec. 213.82 is to ensure that adequate information
accompanies incoming designated medical gases shipped from original
manufacturers to downstream entities, not combined or commingled gases
from one subsequent manufacturer to another. However, we recognize that
there may be confusion regarding the proposed definition of ``incoming
designated medical gas.'' Therefore, we are revising that definition in
Sec. 213.3(b)(8) to state that an ``incoming designated medical gas''
is a designated medical gas received from one source that, after
receipt, is commingled with the same gas from another source, used in a
medically appropriate combination of designated medical gases or in the
production of another medical gas, or further distributed.
b. Testing and Approval or Rejection of Components, Containers, and
Closures (Proposed Sec. 213.84)
FDA proposed requirements for testing and approval or rejection of
components, containers, and closures. Proposed Sec. 213.84(a) included
requirements either to examine components, containers, and closures
prior to manufacturing or filling, or ensure that a statement of
verification is provided from the supplier, provided that the firm
establishes and maintains a program to ensure the reliability of the
supplier's capabilities. Under proposed Sec. 213.84(b), firms shall
take appropriate actions to protect against container and closure
leaks, including performing leak
[[Page 51747]]
tests on containers and closures at the time of fill and after fill but
prior to release. Under proposed Sec. 213.84(c), each component shall
be sampled, tested, and approved or rejected as appropriate prior to
use, either by performing testing for conformance with written
specifications or by an identity test on the component accompanied by
an acceptable COA from the supplier, provided that the firm establishes
and maintains a program to ensure the reliability of the supplier's
capabilities through appropriate assessment and testing procedures.
(Comment 29) FDA specifically sought comments on the proposed
requirement in Sec. 213.84(b) that firms take appropriate actions to
protect against container and closure leaks, including performing leak
tests on containers and closures at the time of fill and after fill but
prior to release. One comment maintains that FDA's proposed
requirements would be sufficient. However, one comment asserts that
leak testing upon pickup of a container would not be appropriate, both
because of staffing and due to the varied timing at which the container
is returned.
(Response 29) FDA appreciates this feedback and agrees that, unless
an establishment is in receipt of a complaint or complaints of leaking
or empty containers, the proposed language and associated testing
described in Sec. 213.84(b) is sufficient. Regarding the comment
concerning leak testing upon pickup, FDA did not propose to require
such testing, but rather noted in the preamble to the proposed rule
that such testing may be needed to further protect against container
and closure leaks to provide sufficient assurance of the durability of
the container closure system throughout its period of use (87 FR 31302
at 31314). FDA does not believe that such testing will always be
necessary, and other testing (or no additional testing) could be
appropriate depending on the manufacturer's circumstances.
However, we continue to believe that leaking and empty container
complaints is a serious concern, in light of the numerous instances of
leaking and empty containers described in the proposed rule (87 FR
31302 at 31314) (see also Ref. 2). In several instances, firms did not
appropriately evaluate the complaints in that the investigation
conducted was inadequate, even when similar complaints were received,
lacking steps such as evaluating the durability and suitability of
containers and closures to identify a root cause. Therefore, we are
adding to the complaint files provision at Sec. 213.198(a) a
requirement that all complaints involving leaking containers or
closures be reviewed, evaluated, and investigated in accordance with
Sec. 213.192.
The level of effort, formality, and documentation of the
investigation of complaints should be commensurate with the level of
risk. For complaints of leaking and empty containers, an appropriate
investigation should include a review of production and testing
procedures and records, and will often include additional testing and
actions, such as use of more sensitive leak testing methods and use of
mechanisms that allow for identification of containers that are the
subject of a complaint. Based on the result of the investigation, the
firm must take appropriate corrective action under Sec. 213.192 (e.g.,
additional leak testing, removal of container or closure from
circulation, addition of periodic leak testing to support container and
closure durability). When there are no complaints of leaking or empty
containers, we do not anticipate the need for additional leak testing.
But in the event a firm becomes aware of repeated or trending leaks or
empty containers, or other information indicating a production issue or
container or closure issue that may result in leaking or empty
containers, it is important that root causes are identified and
corrective actions are taken that result in product and process
improvements to ensure that the container closure system operates
correctly, and that the gas will be available to the patient when
needed.
c. Medical Gas Containers and Closures (Proposed Sec. 213.94)
FDA proposed that medical gas containers and closures shall not be
reactive, additive, or absorptive so as to alter the safety, identity,
strength, quality, or purity of the gas beyond the official or
established requirements (proposed Sec. 213.94(a)). We also proposed
to require that container closure systems provide adequate protection
against foreseeable external factors in storage and use that can cause
deterioration or contamination of the gas (proposed Sec. 213.94(b)).
Under proposed Sec. 213.94(c), medical gas containers and closures
shall be clean to assure that they are suitable for their intended use.
Additionally, we proposed that standards or specifications, testing
methods, and where indicated, cleaning methods shall be written and
followed (proposed Sec. 213.94(d)).
Proposed Sec. 213.94(e) included revisions to the requirements in
Sec. 211.94(e), including new proposed requirements. Under proposed
Sec. 213.94(e)(1), portable cryogenic medical gas containers that are
not manufactured with permanent gas use outlet connections (e.g., those
that have been silver-brazed) must have gas-specific use outlet
connections that are attached to the valve body so that they cannot be
readily removed or replaced (without making the valve inoperable and
preventing the container's use) except by the manufacturer. FDA
proposed to define ``manufacturer'' for purposes of Sec. 213.94(e)(1)
to include any individual or firm that fills high-pressure medical gas
cylinders or cryogenic medical gas containers. FDA proposed to define
``portable cryogenic medical gas container'' for purposes of Sec.
213.94(e)(1) as one that is capable of being transported and is
intended to be attached to a medical gas supply system within a
hospital, healthcare entity, nursing home, other facility, or home
healthcare setting, or is a base unit used to fill small cryogenic gas
containers for use by individual patients. The term would not include
cryogenic containers that are not designed to be connected to a medical
gas supply system, e.g., tank trucks, trailers, rail cars, or small
cryogenic gas containers for use by individual patients (including
portable liquid oxygen units as defined in Sec. 868.5655).
Under proposed Sec. 213.94(e)(2), portable cryogenic medical gas
containers as defined in proposed Sec. 213.94(e)(1) as well as small
cryogenic gas containers for use by individual patients (including
portable liquid oxygen units as defined in Sec. 868.5655) must have a
working gauge sufficient to indicate whether the container has an
adequate supply of medical gas for continued use.
Finally, proposed Sec. 213.94(e)(3) required that the labeling
specified at Sec. 201.328(a) be affixed to the container in a manner
that does not interfere with other labeling, and each label as well as
materials used for coloring medical gas containers must be reasonably
resistant to fading, durable when exposed to atmospheric conditions,
and not readily soluble in water.
(Comment 30) Regarding the proposed requirements for gas-specific
use outlet connections in Sec. 213.94(e)(1), one comment recommends
adding ``home healthcare'' before ``base unit'' in the definition of
``portable cryogenic medical gas container.'' The comment intends for
this to clarify the term ``base unit'' and to achieve consistency with
current safe practices.
(Response 30) FDA does not agree. As discussed above in response
16, although the proposed language for the
[[Page 51748]]
definition of ``portable cryogenic medical gas container'' in Sec.
213.94(e)(1) is identical to the current definition in Sec. Sec.
201.328(a) and 211.94(e)(1), different revisions were proposed for
Sec. Sec. 201.328(a) and 213.94(e)(1). Rather than adding ``home
healthcare'' before ``base unit,'' FDA believes that it is most
appropriate to remove ``base unit'' to focus on the purpose of the
container.
(Comment 31) One comment recommends that the exclusionary language
in the last sentence in Sec. 213.94(e)(1) be revised such that ``does
not include'' would be revised to ``exclude'' and that ``not'' would be
removed before ``designed.'' The comment's requested revisions would
read ``[t]he term excludes cryogenic containers that are designed to be
connected to a medical gas supply system . . . .'' The comment asserts
that these changes would remove the double negative and provide
clarity.
(Response 31) FDA agrees that revising ``does not include'' to
``exclude'' is clearer and has made that change in the final rule.
However, FDA does not agree with removing ``not'' before ``designed,''
as that revision would change the meaning of the sentence. The first
revision is sufficient to remove the double negative. We are also
making this change in Sec. 201.328(a). As finalized, the term
``portable cryogenic medical gas container'' excludes cryogenic
containers that are not designed to be connected to a medical gas
supply system.
(Comment 32) Multiple comments discuss the proposed requirement in
Sec. 213.94(e)(2) that portable cryogenic medical gas containers and
small cryogenic gas containers for use by individual patients have a
working gauge sufficient to indicate whether the container contains an
adequate supply of medical gas for continued use. One comment expresses
general support but maintains that the gauge should be subject to the
testing provisions for components in Sec. 213.84(c). Another comment
suggests deleting the phrase ``sufficient to indicate whether the
container contains an adequate supply of medical gas for continued
use'' because patient use is subjective and determined on an individual
basis. Instead, the comment requests that the gauge should indicate
container pressure or the amount of liquid in the container.
(Response 32) We appreciate the comment of support and agree that
the gauge would be subject to the testing provisions for components, as
the gauge is part of the container closure system. Regarding the
comment recommending that we revise proposed Sec. 213.94(e)(2), FDA
would like to clarify that the intent of this language is to ensure
that the gauge allows the user to understand how much of the medical
gas remains in the tank. We recognize that it is not possible for a
gauge to display patient-specific information. To help clarify this we
are revising the codified to read, in pertinent part, that portable
cryogenic medical gas containers and small cryogenic gas containers for
use by individual patients have a working gauge sufficient to assist
the user in determining whether the container contains an adequate
supply of medical gas for continued use. We agree with the comment that
a gauge capable of displaying container pressure or liquid level would
satisfy this requirement.
6. Production and Process Controls (Proposed Part 213, Subpart F)
FDA proposed to establish several requirements concerning
production and process controls for medical gases (proposed Sec. Sec.
213.100, 213.101, and 213.110). We received no comments on the proposed
provisions and are finalizing them as proposed.
7. Packaging and Labeling Control (Proposed Part 213, Subpart G)
FDA proposed to establish several requirements concerning packaging
and labeling controls for medical gases (proposed Sec. Sec. 213.122,
213.125, and 213.130). We received no comments on proposed Sec. Sec.
213.122 and 213.130 and are finalizing them as proposed.
In proposed Sec. 213.125(a), we proposed that labeling and
packaging operations must be controlled to prevent labeling and product
mix-ups, and that procedures shall be written and followed describing
in sufficient detail the control procedures employed for the issuance
of labeling. In proposed Sec. 213.125(b), we proposed requiring that
procedures be used to reconcile the quantities of labeling issued,
used, and returned, and that procedures require evaluation of
discrepancies when such discrepancies are outside narrow preset limits
based on historical operating data (FDA proposed that labeling
reconciliation be waived for cut or roll labeling if a 100-percent
examination is performed in accordance with Sec. 213.122(f)(2), and
for 360[deg] wraparound labels on portable cryogenic medical gas
containers). Proposed Sec. 213.125(c) states that all excess lot
number stickers or decals bearing lot or control numbers shall be
discarded. Lastly, proposed Sec. 213.125(d) exempted bulk or transport
containers from Sec. 213.125. We respond to the comments on proposed
Sec. 213.125 below.
(Comment 33) Regarding proposed Sec. 213.125(c), one comment
requests clarification regarding what constitutes excess lot number
stickers or decals. The comment asserts that, if the intent is for a
container to only have one label, the wear and tear of medical gas
labels may justify multiple labels including the same content.
(Response 33) FDA's intent in proposed Sec. 213.125(c) is to
address the risks of excess labeling materials that are unused. FDA
does not object to including lot number information in more than one
location on the container closure. Rather, our concern is that extra
stickers will be inadvertently used for another batch, which would lead
to mix-ups. We believe the provision as drafted addresses this concern
and do not believe that changes are needed.
8. Holding and Distribution (Proposed Part 213, Subpart H)
FDA proposed to establish warehousing and distribution procedure
requirements. Specifically, FDA proposed that written procedures be
established and followed describing the distribution of medical gases,
including a system by which the distribution of each lot can be readily
determined to facilitate its recall (proposed Sec. 213.150(a)).
Additionally, FDA proposed that written procedures be established and
followed describing the warehousing of medical gases, including
quarantine before release by the quality unit (proposed Sec.
213.150(b)).
(Comment 34) Although not directed at a specific provision, one
comment discusses the transfilling process and the information that
should be tracked. The comment maintains that transfillers should
record which lots of medical gas were added as well as the date. The
comment further asserts that once transfilling occurs, this information
can no longer be tracked.
(Response 34) FDA does not believe that changes are needed to
address this issue. Although tracking this information upon adding gas
to a transfilling container may enhance traceability to some degree,
FDA expects that the benefits would be minimal while the added burden
of tracking this information would be significant. Moreover, it would
be unclear in the long term what lots are in the cylinder because the
gases from multiple batches would commingle and the transfiller would
not be able to determine when a lot is no longer present in the
container. Therefore, the list of lots could become quite long and
unmanageable over time.
[[Page 51749]]
9. Laboratory Controls (Proposed Part 213, Subpart I)
FDA proposed to establish several laboratory control requirements
(proposed Sec. Sec. 213.160, 213.165, and 213.166). We received no
comments on proposed Sec. Sec. 213.160 and 213.166 and are finalizing
them as proposed.
FDA proposed testing and release requirements in Sec. 213.165.
Under proposed Sec. 213.165(a), for each batch of medical gas, there
shall be appropriate laboratory determination of satisfactory
conformance to final specifications for the gas, including the identity
and strength, prior to release. Additionally, FDA proposed that any
sampling and testing plans shall be described in written procedures
that shall be followed, including the method of sampling, the number of
units per batch to be tested, and acceptance criteria (proposed Sec.
213.165(b)). Under proposed Sec. 213.165(c), the accuracy,
sensitivity, specificity, and reproducibility of test methods employed
by the firm shall be established and documented, and such validation
and documentation may be accomplished in accordance with Sec.
213.194(a)(2). Also under proposed Sec. 213.165(c), the suitability of
all testing methods shall be verified under actual conditions of use.
Proposed Sec. 213.165(d) would require rejection of medical gases that
fail to meet established standards or specifications and any other
relevant quality criteria. This proposal is generally consistent with
the requirements described in Sec. 211.165(f), but FDA did not propose
to include in Sec. 213.165(d) the provision stating that reprocessing
may be performed or the requirements for using reprocessed material
because the Agency is not aware of reprocessing that occurs for medical
gases. FDA solicited comment on this issue, including any example
scenarios in which medical gases are reprocessed. Finally, proposed
Sec. 213.165(e) would exempt from this section filling of designated
medical gases and medically appropriate combinations of medical gases
via liquid to liquid into a container at a delivery site.
(Comment 35) Regarding Sec. 213.165(d)'s proposed requirement to
reject medical gases that fail to meet established standards or
specifications, one comment notes that they are not aware of any
reprocessing of medical gases.
(Response 35) FDA appreciates the additional information. In light
of the response received, we do not believe revisions to Sec.
213.165(d) are necessary.
10. Records (Proposed Part 213, Subpart J)
FDA proposed to establish records requirements (proposed Sec. Sec.
213.180, 213.182, 213.184, 213.186, 213.189, 213.192, 213.194, 213.196,
and 213.198). We received no comments on proposed Sec. Sec. 213.180,
213.184, 213.186, 213.192, 213.194, and 213.198 and are finalizing them
as proposed with minor technical and grammatical changes made on our
own initiative. We respond to the comments on proposed Sec. Sec.
213.182, 213.189, and 213.196 below.
a. Equipment Cleaning and Use Log (Proposed Sec. 213.182)
We proposed that a written record of major equipment cleaning,
maintenance (except routine maintenance), and use shall be included in
individual equipment logs that show the date, time, product, and lot
number of each batch processed (proposed Sec. 213.182). If equipment
is dedicated to manufacture of one product, then individual equipment
logs would not be required, provided that lots or batches of such
product follow in numerical order and are manufactured in numerical
sequence. In cases where dedicated equipment is employed, we proposed
that the records of cleaning, maintenance, and use shall be part of the
batch record. We proposed that the persons performing and double-
checking the cleaning and maintenance (or, if using automated equipment
under Sec. 213.68, just the person verifying the cleaning and
maintenance done by the automated equipment) shall date and sign or
initial the log indicating that the work was performed. Lastly, we
proposed that entries in the log shall be in chronological order.
(Comment 36) One comment suggests revising Sec. 213.182 to state
that cleaning and maintenance is performed on a periodic basis or when
there is suspected contamination and is not associated with a batch or
lot process. The comment further requests that this provision state
that equipment cleaning and non-routine maintenance is documented on
separate cleaning or maintenance records. While the comment agrees that
keeping a record of maintenance performed on production equipment is
necessary, the comment maintains that, because these gases are
manufactured and filled in a closed, pressurized system, equipment
should not be cleaned between batches and lots. Otherwise, the comment
asserts, contaminants could be introduced. Additionally, the comment
states that the requirement to keep a use log of production equipment
is not needed because this information is included on batch production
records and would only increase manufacturers' burden.
(Response 36) FDA disagrees with this comment. The comment's
suggested revisions go beyond recordkeeping requirements. The
underlying cleaning and maintenance requirements are already addressed
in Sec. Sec. 213.42(c) and 213.67. Additionally, FDA does not believe
that this provision as originally proposed suggests or requires
cleaning at inappropriate times.
We also do not believe that the proposed requirements in Sec.
213.182 are overly burdensome. Because the requirements in Sec.
213.182 are intended to support good recordkeeping practices, such as
the ability to locate records related to the equipment used in medical
gas production (without needing to review one or more batch records),
we decline to make the suggested revisions.
b. Batch Production and Control Records (Proposed Sec. 213.189)
We proposed to require that batch production and control records be
prepared for each batch of medical gas produced (proposed Sec.
213.189(a)). We further proposed in Sec. 213.189(b) that these records
shall include documentation that each significant step in the
manufacture, processing, packing, or holding of the medical gas
produced was accomplished, including dates and times of each
significant step, including in-process and laboratory tests as
applicable; a description of the container for the medical gas,
including the number and size of the containers filled as applicable;
specific identification of each component and its source or in-process
material used as applicable; measures of components used in the course
of processing as applicable; testing results, including any in-process
test results and finished product test results; dated signature or
initials of the persons performing and directly supervising or checking
each significant event in the operation; inspection of the packaging
and labeling area before and after use; complete labeling control
records, including specimens or copies of all labeling used and label
application and reconciliation records as appropriate; and any
investigation made according to Sec. 213.192.
(Comment 37) One comment requests that the Agency revise Sec.
213.189(b)(1) by deleting the words ``and times'' from the provision
requiring that batch production and control records include ``[d]ates
and times of each significant step, including in-process and laboratory
tests as applicable.'' The
[[Page 51750]]
comment asserts that recording the time of production would not improve
medical gas safety in light of the manufacturing processes used for
medical gases.
(Response 37) FDA agrees with this comment. The Agency also notes
that, considering the long, continuous production processes associated
with many of these gases (for example, air separation used to produce
oxygen and nitrogen), recording time as part of a firm's batch
production and control records may be challenging. Therefore, the
Agency is revising Sec. 213.189(b)(1) to delete the reference to the
time of significant steps. The finalized language requires that batch
production records include the dates of each significant step,
including in-process and laboratory tests as applicable.
(Comment 38) One comment asks that we delete Sec. 213.189(b)(8),
which would require batch production and control records to include
complete labeling control records, including specimens or copies of all
labeling used and label application and reconciliation records as
appropriate. The comment maintains that the inclusion of labeling
information would not provide added safety assurance, as would be the
case for other drugs. Additionally, the comment notes that labels are
reused, and industry performs a 100 percent inspection of cylinder
labels during production.
(Response 38) We decline to delete Sec. 213.189(b)(8). As
discussed in the preamble to the proposed rule, because labeling does
not always need to be applied due to the reuse of labels, documentation
of these labeling control activities is important to help prevent mix-
ups and the incorrect application of labeling (87 FR 31302 at 31319).
Moreover, the inclusion of labeling control records can help facilitate
investigations of complaints and other post-market activities. Due to
the industry practice of the reuse of the labels, it is possible that
no labels are applied during the manufacturing of a batch. In these
instances, a copy of the label or a reproduction of the label is
reasonable to include as part of the labeling control activities.
c. Distribution Records (Proposed Sec. 213.196)
We proposed in Sec. 213.196 to require that distribution records
contain the name of the product, lot or batch number, name and address
of the consignee, and date and quantity shipped, and that, for medical
air and medically appropriate combinations of designated medical gases,
the distribution record include the percentage of each gas.
(Comment 39) Multiple comments discuss the proposed requirement to
include lot or batch number information in distribution records in
Sec. 213.196. One comment expresses concern that the exemption in
Sec. 211.196 (stating that compressed medical gas products do not need
to include lot or control numbers in distribution records) would limit
the ability to track a safety event. Another comment requests that
``lot or batch number'' be removed from Sec. 213.196 to be consistent
with the current requirements in Sec. 211.196.
(Response 39) FDA declines to revise Sec. 213.196. Regarding the
concern about handling safety events, FDA proposed deletion of the
exemption in Sec. 211.196 for compressed medical gas products
specifically because Sec. 213.196 would fully address this requirement
for medical gases. Regarding the proposed revision to Sec. 213.196 to
remove ``lot or batch number,'' FDA continues to believe that including
the lot or batch number is essential to properly tracking and tracing
product in the event a safety issue is discovered (see proposed rule
discussion, 87 FR 31302 at 31320).
(Comment 40) One comment requests that FDA revise Sec. 213.196 to
explain that distribution records shall contain the required
information (the name of the product, lot or batch number, name and
address of the consignee, and date and quantity shipped) ``to
facilitate a recall if needed.'' The comment asserts this would help
achieve FDA's objective of improved traceability.
(Response 40) FDA does not agree. Because distribution records can
serve many purposes aside from facilitating a recall, the suggested
revision would unduly narrow the provision. As proposed (and
finalized), Sec. 213.196 can help a firm facilitate a recall and
address other safety concerns that arise.
(Comment 41) One comment maintains that distribution records for
medical air should not be required to include the percentage of each
gas. The comment contends that, because the compendial standard for
medical air specifies the range for the quantity of oxygen in nitrogen,
including the specific percentage of oxygen for a shipment would not
provide a benefit.
(Response 41) FDA agrees. Because medical air must be shown to meet
compendial standards in order to be released, it is not necessary to
state the amount of oxygen within the allowable range in the
distribution records. Therefore, we have deleted ``medical air and''
from the second sentence of Sec. 213.196 such that the requirement
that the distribution record include the percentage of each gas only
applies to medically appropriate combinations of designated medical
gases.
11. Returned and Salvaged Medical Gases (Proposed Part 213, Subpart K)
FDA proposed to establish requirements for returned and salvaged
medical gases (proposed Sec. Sec. 213.204 and 213.208). We received no
comments on proposed Sec. 213.208 and are finalizing it as proposed
with a minor grammatical change made on our own initiative.
FDA proposed in Sec. 213.204 to require that returned medical
gases be identified as such and held, and that, if the conditions under
which the returned gases have been held, stored, or shipped before or
during their return, or if the condition of the gas, its container,
carton, or labeling, as a result of storage or shipping, cast doubt on
its safety, identity, strength, quality, or purity, the returned
medical gas shall be destroyed unless examination, testing, or other
investigations prove the gas meets appropriate standards of safety,
identity, strength, quality, or purity. Moreover, FDA proposed to
require that firms maintain certain records of returned medical gases,
and if the reason for a medical gas being returned implicates
associated batches, an appropriate investigation pursuant to proposed
Sec. 213.192 shall be conducted. Procedures for holding, testing, and
use of returned medical gases would need to be in writing and followed.
FDA proposed that Sec. 213.204 would not apply to the routine
refilling of cryogenic medical gas containers in the normal course of
business unless the container was returned for a quality issue.
(Comment 42) One comment requests that FDA exempt containers that
assure the quality of the residual product prior to refill from the
returned medical gases requirements in proposed Sec. 213.204. The
comment maintains that certain cylinders have residual pressure valves
that prevent backflow.
(Response 42) FDA does not believe this change is necessary to
address the comment's concern. As noted in the proposed rule, Sec.
213.204 would apply to situations in which a distributed medical gas is
sent back to a firm due to a quality issue (87 FR 31302 at 31321).
Proposed Sec. 213.204 included an exception for the routine refilling
of cryogenic medical gas containers in the normal course of business
because we understand that small amounts of gas are expected to remain
in a returned container that will be reused (Id.). In the event a
cylinder with a residual pressure valve is returned in the normal
course of business for refilling and
[[Page 51751]]
redistribution, the requirements in Sec. 213.204 would not apply. We
note, however, that such valves could nonetheless fail, and if, for any
reason, a cylinder with such a valve were returned and any of the
conditions in the second sentence of Sec. 213.204 are present, then
the returned gas must be destroyed unless examination, testing, or
other investigations prove the gas meets appropriate standards of
safety, identity, strength, quality, or purity.
I. Description of Part 230 Comments and FDA Response
1. General Comments
We proposed a new part 230 (21 CFR part 230) to include
requirements concerning the certification of designated medical gases
and postmarketing safety reporting.
(Comment 43) Some comments make general remarks supporting the
proposed certification and safety reporting regulations without
focusing on a particular proposed provision.
(Response 43) We appreciate these comments of support.
2. Definitions (Proposed Sec. 230.3)
FDA proposed definitions of several terms used in part 230. We
received comments on several of those proposed definitions, as
discussed below. We are finalizing as proposed those definitions for
which we received no comments with minor technical changes made on our
own initiative.
a. Applicant (Proposed Sec. 230.3(b)(2))
We proposed to define ``applicant'' as any person or entity who
submits a certification request for a designated medical gas under part
230, including a supplement, and any person or entity who owns a
granted certification for a designated medical gas under part 230
(proposed Sec. 230.3(b)(2)).
(Comment 44) One comment asks that we add language to clarify that
the applicant is a person or entity who submits a certification request
``as an original manufacturer'' as defined in the medical gas CGMP
regulations at Sec. 213.3(b)(13). The comment asserts that this would
be consistent with parts 201 and 213 and account for applicants that
are both original manufacturers and subsequent manufacturers.
(Response 44) FDA does not agree with these requested revisions.
Consistent with section 576(a)(1) of the FD&C Act, Sec. 230.50(a)(1)
of the designated medical gas certification regulations makes clear
that any person who seeks to initially introduce or deliver for
introduction a designated medical gas into interstate commerce is the
entity that shall file a certification request. We agree that
subsequent manufacturers are not required to submit certification
requests, but revising the ``applicant'' definition is unnecessary
because the applicant is any person or entity who submits a
certification request. If a subsequent manufacturer erroneously
submitted a certification request, FDA may determine that the request
was unnecessary and not grant it, but the subsequent manufacturer would
still be considered the applicant for purposes of all interactions with
the Agency related to the certification request. Moreover, as stated in
response 45, FDA does believe it is appropriate to remove ``or entity''
from the definition of ``applicant,'' as the word ``person'' captures
all relevant entities.
b. Nonapplicant (Proposed Sec. 230.3(b)(9))
We proposed to define ``nonapplicant'' as any person other than the
applicant whose name appears on the label of a designated medical gas
container as a manufacturer, packer, or distributor (proposed Sec.
230.3(b)(9)).
(Comment 45) One comment suggests revisions to the proposed
``nonapplicant'' definition in Sec. 230.3(b)(9) for consistency across
the regulations applicable to designated medical gases. First, the
comment asks that the definition be revised to include any person or
entity, rather than just any person, meeting the criteria in the
definition. This suggested revision is intended to be consistent with
the ``applicant'' definition in Sec. 230.3(b)(2). Second, the comment
asks that the definition be revised to refer to entities that appear on
the label of a designated medical gas container as a subsequent
manufacturer or distributor, rather than as a manufacturer, packer, or
distributor. The comment asserts that these revisions are intended to
account for nonapplicants that are also original manufacturers. The
comment maintains that removal of the term ``packer'' would be
consistent with industry terminology.
(Response 45) We do not believe that changes are necessary to the
``nonapplicant'' definition. First, FDA routinely uses the word
``person'' to include entities and organizations that are not
individuals. The term ``person'' as defined in section 201(e) of the
FD&C Act includes an individual, partnership, corporation, and
association. Additionally, the definition of ``applicant'' in Sec.
314.3 ``is any person who submits an NDA . . . or ANDA . . . .'' As
discussed in response 44 above, FDA also concludes it is not necessary
to include ``or entity'' in the definition of ``applicant'' in Sec.
230.3(b)(2). Section 230.50(b)(1) has also been revised to refer to
``person'' and not ``entity.''
Second, we do not agree with the use of the term ``subsequent
manufacturer'' or the removal of the term ``packer.'' If an entity is
an original manufacturer of a designated medical gas, FDA expects that
it would be the applicant as opposed to a nonapplicant. Nonetheless,
for a given designated medical gas, whether a firm is the applicant or
a nonapplicant will depend on the activities performed for that
product. We also note that the terminology used in the proposed
definition is consistent with existing Sec. 314.80(c)(1)(iii). While
the medical gas industry may not ordinarily use the term ``packing'' to
refer to its operations, the activities that subsequent manufacturers
perform (such as transfilling, mixing, or filling at a delivery site)
are expected to fall within the term ``manufacturer, packer, or
distributor.''
3. General Requirements for All Submission Types (Proposed Sec.
230.50)
FDA proposed requirements for all types of certification
submissions (proposed Sec. 230.50). We received no comments on the
proposed requirements and are finalizing them as proposed with minor
technical edits made on our own initiative for clarity.
4. Withdrawal by the Applicant of a Certification Request Before It Is
Deemed Granted (Proposed Sec. 230.65)
FDA proposed requirements regarding withdrawal of a certification
request prior to it being deemed granted (proposed Sec. 230.65). We
received no comments on the proposed requirements and are finalizing
them as proposed.
5. Supplements and Other Changes to a Granted Certification (Proposed
Sec. 230.70)
FDA proposed requirements regarding supplements and other changes
to a granted certification (proposed Sec. 230.70). We received no
comments on the proposed requirements and are finalizing them as
proposed.
6. Change in Ownership of a Granted Certification (Proposed Sec.
230.72)
FDA proposed requirements regarding the change in ownership of a
granted certification (proposed Sec. 230.72). We received no comments
on the proposed requirements and are finalizing them as proposed.
[[Page 51752]]
7. Annual Report (Proposed Sec. 230.80)
FDA proposed to establish annual report requirements in proposed
Sec. 230.80. First, FDA proposed that applicants must submit an annual
report each year within 60 calendar days of the anniversary of the date
the certification was granted, and that the annual report form must be
signed and completed and submitted in an electronic format that FDA can
process, review, and archive, or in hard copy by submitting two paper
copies to CDER's Central Document Room (proposed Sec. 213.80(a)).
Under proposed Sec. 213.80(b), the annual report would contain, for
the prior 12 months, a brief summary of significant new information
that might affect the safety, effectiveness, or labeling of the
designated medical gas, including any actions the applicant has taken
or intends to take as a result of this new information; information
about the quantity of the designated medical gas distributed by the
applicant, including the National Drug Code (NDC) numbers and
quantities distributed for domestic use and the quantities distributed
for foreign use; any changes to the applicant's name or contact
information; and a list of current facilities, as well as a list of
facilities that are no longer in use.
(Comment 46) One comment requests that annual reports be submitted
after the start of the new calendar year, rather than on the
anniversary of the date the certification request was deemed granted.
The comment asserts that this would align the annual reporting
requirements with reporting requirements stemming from the Coronavirus
Aid, Relief, and Economic Security Act (CARES Act) (Pub. L. 116-136).
The comment also states that annual reports are provided for activities
related to the original manufacturing operations of the applicant, and
not for subsequent manufacturing activities.
(Response 46) FDA agrees with this comment. In particular, section
3112(e) of the CARES Act established new section 510(j)(3) of the FD&C
Act (21 U.S.C. 360(j)(3)), which requires all drug registrants to
report annually on the amount of each listed drug manufactured,
prepared, propagated, compounded, or processed for commercial
distribution. We recognize that it may create efficiencies for firms to
track information across multiple reports if the reports are submitted
on the same reporting schedule. Therefore, we have revised Sec.
230.80(a) to require annual reports to be submitted within 60 calendar
days of the new calendar year. We also agree that annual reports cover
activities related to the original manufacture of the designated
medical gas.
(Comment 47) One comment requests deletion of the requirement in
proposed Sec. 230.80(b)(2) that annual reports include distribution
data because, as required by the CARES Act, section 510(j)(3) of the
FD&C Act requires similar distribution data. Specifically, section
510(j)(3)(A) requires that each person who registers with FDA under
section 510 of the FD&C Act with regard to a drug must report annually
to FDA on the amount of each drug listed that was manufactured,
prepared, propagated, compounded, or processed by such person for
commercial distribution.
(Response 47) FDA appreciates the need to avoid duplicate
submissions of information. However, we conclude it is appropriate to
retain the proposed requirement that distribution data be included in
designated medical gas annual reports. Certain information, such as the
NDC number and quantities of gas distributed for domestic and foreign
use, is important to retain.
FDA considers the requirement to submit distribution data in annual
reports under Sec. 230.80(b)(2) to have been met if: (1) the
registrant of establishments identified in the application submits a
timely and complete report under section 510(j)(3) of the FD&C Act; (2)
the registrant of establishments identified in the application includes
in its section 510(j)(3) report the amount of listed drug product
(organized by NDC number) that was distributed for foreign use during
the reporting period (in addition to the amount distributed in the
United States); (3) the applicant's annual report provides the date(s)
of the report(s) submitted under section 510(j)(3) of the FD&C Act that
includes the domestic and foreign distribution information; and (4) the
applicant's annual report submitted under Sec. 230.80 contains all
other information required in Sec. 230.80(b). FDA believes that this
would maintain the Agency's access to information that would enhance
the Agency's ability to assess, prevent, and mitigate possible drug
shortages, and would also address the potential reporting burden for
applicants that are subject to both Sec. 230.80 and section 510(j)(3)
of the FD&C Act.
(Comment 48) One comment requests that the proposed requirement in
Sec. 230.80(b)(4) that the annual report contain a list of ``current
facilities'' be revised to require a list of ``the applicant's current
original manufacturing facilities'' because only original manufacturing
locations are required to be listed.
(Response 48) Our intent in Sec. 230.80(b)(4) is for applicants to
submit information regarding their original manufacturing facilities,
as opposed to any subsequent manufacturing facilities they operate. In
light of the comment received, we have revised Sec. 230.80(b)(4)
consistent with the requirement in section 576(a)(1)(C) of the FD&C Act
and what we proposed for Sec. 230.50(b)(4), which both address
information to be submitted as part of a certification request. Because
the purpose of Sec. 230.80(b)(4) is to receive updates of the same
information, we have revised the provision to require that the annual
report include a list of current facilities where the designated
medical gas is initially produced, and a list of facilities that are no
longer in use.
8. FDA Review of Submissions (Proposed Sec. 230.100)
FDA proposed requirements regarding FDA's review of submissions
(proposed Sec. 230.100). We received no comments on the proposed
requirements and are finalizing them as proposed with minor technical
edits made on our own initiative.
9. When a Submission Is Deemed Granted (Proposed Sec. 230.105)
FDA proposed requirements regarding when a submission is deemed
granted (proposed Sec. 230.105). We received no comments on the
proposed requirements and are finalizing them as proposed.
10. Withdrawal (Proposed Sec. 230.150)
FDA proposed withdrawal and revocation requirements in proposed
Sec. 230.150. We did not receive comments on the proposed revocation
requirements in Sec. 230.150(b) and are finalizing those requirements
as proposed with minor technical and grammatical changes made on our
own initiative.
FDA proposed in Sec. 230.150(a)(1) and (2) several grounds for
withdrawing approval of a designated medical gas application, subject
to FDA notifying the applicant and affording an opportunity for a
hearing. Under proposed Sec. 230.150(a)(3), FDA will withdraw approval
of an application if the applicant requests its withdrawal because the
designated medical gas subject to the application is no longer being
marketed, provided none of the conditions listed in Sec. 230.150(a)(1)
and (2) apply. FDA would consider such a written request to be a waiver
of an opportunity for hearing, and such withdrawal would be without
prejudice
[[Page 51753]]
to refiling. FDA proposed in Sec. 230.150(a)(4) that we may notify an
applicant that we believe a potential problem associated with a
designated medical gas is sufficiently serious that the designated
medical gas should be removed from the market and may ask the applicant
to waive the opportunity for hearing otherwise provided for under this
section, to permit FDA to withdraw approval of the application for the
product, and to remove voluntarily the product from the market. Lastly,
FDA proposed under Sec. 230.150(a)(5) that, if FDA withdraws an
approval, FDA will publish a notice in the Federal Register announcing
the withdrawal.
(Comment 49) Regarding the proposed withdrawal requirements in
Sec. 230.150, one comment states that FDA should include a reason for
voluntary withdrawals to clarify whether the designated medical gas was
withdrawn for safety reasons. The comment asserts that, without such
information, an applicant's reputation may be harmed.
(Response 49) FDA does not believe that posting a withdrawal
notification without a rationale would necessarily be interpreted as a
statement that the designated medical gas was withdrawn for safety or
effectiveness reasons. Because designated medical gases are generally
considered appropriate for the uses stated in the statute, many of the
considerations relevant to drugs approved under section 505 of the FD&C
Act are not applicable. Moreover, the withdrawal of a designated
medical gas does not create the same follow-on considerations that the
withdrawal of an NDA approved under section 505 of the FD&C Act would
create for current and future ANDAs that reference the withdrawn NDA.
Therefore, we decline to make the suggested revisions to Sec. 230.150.
However, as discussed in response 61 below, FDA is revising Sec.
230.150(a)(2)(i) to include failure to submit reports under Sec.
314.81(b)(3). Because of this revision, it is unnecessary for Sec.
314.81(d) to continue to apply to designated medical gases.
11. Field Alert Report (Proposed Sec. 230.205)
We proposed field alert reporting requirements for designated
medical gases in Sec. 230.205. Specifically, FDA proposed that
applicants be required to submit FARs to the FDA district office
responsible for the facility involved within 3 working days of receipt
by the applicant, and that the information may be provided by telephone
or other rapid communication, with prompt written followup. FDA also
proposed formatting requirements for the FAR and its mailing cover. In
proposed Sec. 230.205(a), FDA proposed that a FAR is required for
information concerning any incident that causes the designated medical
gas or its labeling to be mistaken for, or applied to, another article.
In proposed Sec. 230.205(b), FDA proposed that a FAR is required for
information concerning any bacteriological contamination, or any
significant chemical, physical, or other change or deterioration in the
distributed designated medical gas, or any failure of one or more
distributed batches of the designated medical gas to meet established
specifications.
(Comment 50) One comment requests that the field alert reporting
requirements apply to nonapplicants as well as applicants. The comment
asserts that downstream entities are more directly linked to the end
user and would have the most current and detailed information about any
issues that might require a FAR.
(Response 50) FDA disagrees. We note that the proposed field alert
reporting requirements are drafted for designated medical gases, as
opposed to combinations of designated medical gases. This scope is also
consistent with the field alert reporting requirements in Sec.
314.81(b)(1), which require that applicants submit reports to the
Agency. It is worth noting that the field alert reporting requirements
in Sec. 514.80(b)(1) (21 CFR 514.80(b)(1)) require the applicant, or
the nonapplicant through the applicant, to report, so in either case
the applicant would submit the FAR to FDA.
(Comment 51) One comment expresses support for the proposed 3-
working-day reporting period, but asserts that FARs may still be
incomplete at that timepoint.
(Response 51) FDA acknowledges the concern that more information
may be available after 3 working days, and thus, under the proposed
reporting timeframe, FARs may be incomplete in some instances. FDA
believes that a 45-day reporting deadline for certain FARs for
designated medical gases is appropriate. The 3-working-day reporting
period originally proposed would apply if the information suggests that
the reportable incident may require a rapid response to address a
public health risk. Therefore, as finalized, Sec. 230.205 requires
that an applicant submit a FAR as soon as possible but no later than 45
calendar days from the date the applicant, or its agent or contractor,
obtained information suggesting that a reportable incident has
occurred, and if the information suggests that the reportable incident
may require a rapid response to address a public health risk, the
applicant must submit the FAR as soon as possible, but no later than 3
working days from obtaining the information. Reporting as soon as
possible but no later than 45 calendar days from the date the
applicant, or its agent or contractor, obtained information suggesting
that a reportable incident has occurred appropriately balances the need
to report quickly with helping to ensure that the applicant collects
sufficient information to enable an appropriate response.
FDA is not making further revisions to the field alert reporting
requirements for designated medical gases to reflect the proposed
changes to part 314. The Agency has not received many FARs for
designated medical gases. Considering certain characteristics of these
drug products (including that they are generally manufactured in a
sealed, closed system, which makes contamination and stability less of
a concern), we conclude that further revisions are unnecessary.
However, as we gain more experience with designated medical gases and
with any future revisions to the field alert reporting requirements in
part 314, we will consider whether revisions to Sec. 230.205 are
needed.
12. General Reporting Requirements for Designated Medical Gas Adverse
Events (Proposed Sec. 230.210)
FDA proposed general reporting requirements for designated medical
gas adverse events (proposed Sec. 230.210). We received no comments on
the proposed requirements and are finalizing them as proposed.
13. Human Postmarketing Safety Reporting (Proposed Sec. 230.220)
FDA proposed human postmarketing safety reporting requirements in
Sec. 230.220. Under proposed Sec. 230.220(a)(1), applicants and
nonapplicants must submit each ICSR associated with the use of a
designated medical gas in humans described in Sec. 230.220(b) as soon
as possible but no later than 15 calendar days from the date the
applicant or nonapplicant met the reporting criteria and acquired a
minimum data set for an ICSR for that adverse event. FDA further
proposed that applicants and nonapplicants should not resubmit any
ICSRs obtained from FDA's adverse event reporting database or forwarded
to the applicant or nonapplicant by FDA (proposed Sec. 230.220(a)(2)).
Additionally, FDA proposed that applicants and nonapplicants must
submit new information related to a previously submitted ICSR or an
ICSR sent to the
[[Page 51754]]
applicant by FDA no later than 15 calendar days after the information
is received or otherwise obtained (proposed Sec. 230.220(a)(3)).
FDA proposed in Sec. 230.220(b) to specify which adverse events
must be reported in an ICSR. FDA proposed that applicants and
nonapplicants must submit ICSRs for serious adverse events reported to
the applicant or nonapplicant spontaneously (such as a report initiated
by a patient, consumer, or healthcare provider) or obtained from
published scientific and medical journals (either as case reports or as
the result of a formal clinical trial) (proposed Sec. 230.220(b)(1)(i)
and (ii)). Proposed Sec. 230.220(b)(1)(iii) explains that ICSRs are
not required for reports of the death of a patient who was administered
oxygen, unless the applicant or nonapplicant is aware of evidence to
suggest that the death was caused by the administration of oxygen. In
addition, under proposed Sec. 230.220(b)(2), upon notification by FDA,
applicants and nonapplicants must submit, in a timeframe established by
FDA, ICSRs for any adverse event that are not required under Sec.
230.220(b)(1).
Under proposed Sec. 230.220(c), FDA proposed to specify how to
complete and submit ICSRs required under Sec. 230.220. FDA proposed to
require that ICSRs and ICSR attachments be submitted in an electronic
format that FDA can process, review, and archive, though applicants and
nonapplicants may request, in writing, a temporary waiver of this
requirement (proposed Sec. 230.220(c)(1)). FDA further proposed to
require that each ICSR be submitted only once, that separate ICSRs be
submitted for each patient who experiences a reportable adverse event,
that adverse event terms must be coded using standardized medical
terminology, that all ICSRs must contain at least the minimum data set
for an ICSR, that the applicant or nonapplicant must complete all
known, available elements of an ICSR as specified in Sec. 230.220(d),
and that an applicant must submit autopsy reports, hospital discharge
summaries, or published articles as specified (proposed Sec.
230.220(c)(2)).
Proposed Sec. 230.220(d) sets forth the information that must be
included in an ICSR, including patient information, adverse event
information, information about the suspect designated medical gas(es),
information about the initial reporter, and applicant or nonapplicant
information.
Under proposed Sec. 230.220(e), FDA proposed recordkeeping
requirements, including that applicants and nonapplicants maintain
records of information relating to adverse events for 10 years, whether
or not submitted to FDA (proposed Sec. 230.220(e)(1)). FDA further
proposed that such records must include raw data, correspondence, and
any other information relating to the evaluation and reporting of
adverse event information that is received or otherwise obtained by the
applicant or nonapplicant (proposed Sec. 230.220(e)(2)). Lastly, FDA
proposed that, upon written notice by FDA, the applicant or
nonapplicant must submit any or all of these records to FDA within 5
calendar days after receipt of the notice, and the applicant or
nonapplicant must permit any authorized FDA employee, at reasonable
times, to access, copy, and verify these established and maintained
records (proposed Sec. 230.220(e)(3)).
Proposed Sec. 230.220(f) specified that applicants and
nonapplicants must develop written procedures needed to fulfill the
requirements of Sec. 230.220 for the surveillance, receipt,
evaluation, and reporting to FDA of adverse event information.
Proposed Sec. 230.220(g) would establish requirements concerning
patient privacy. Specifically, FDA proposed that an applicant or
nonapplicant should not include in reports under Sec. 230.220 the
names and addresses of individual patients; instead, the applicant or
nonapplicant should assign a unique code for identification of the
patient. FDA further proposed that the applicant or nonapplicant should
include the name of the reporter from whom the information was received
as part of the initial reporter information, even when the reporter is
the patient. Proposed Sec. 230.220(g) further states that as set forth
in FDA's public information regulations in 21 CFR part 20, the Agency
generally may not disclose the names of patients, individual reporters,
healthcare professionals, hospitals, and geographical identifiers
submitted to FDA in adverse event reports.
Before discussing the comments received regarding FDA's proposed
human postmarketing safety reporting requirements, the Agency notes an
additional set of revisions we are making to Sec. 230.220 on our own
initiative. We are revising proposed Sec. 230.220(b)(1)(i) to describe
more clearly the requirement that applicants and nonapplicants must
submit ICSRs for serious adverse events reported to or otherwise
received by the applicant or nonapplicant. This revision aligns with
the requirement in Sec. 230.210(a) for prompt review of all safety
information that the applicant or nonapplicant receives or otherwise
obtains from any source and is intended to help ensure that reports of
serious adverse events otherwise received (or obtained) by the
applicant or nonapplicant are submitted to the Agency. Accordingly,
this requirement includes, for example, serious adverse event reports
received at the request of the applicant or nonapplicant (such as
reports received as part of a patient support program), in addition to
unsolicited communications such as reports initiated by a patient,
consumer, or healthcare professional.
In the proposed rule, FDA proposed that Sec. 314.80(g) would
continue to apply to designated medical gases, and proposed Sec.
230.220(c)(1)(i) and (ii) included cross-references to Sec. 314.80(g).
After further consideration, the Agency believes that it would be most
helpful and efficient to set forth the electronic format requirements
in Sec. 230.220 rather than referencing Sec. 314.80(g). Therefore, we
have revised Sec. 230.220(c)(1)(i) to directly include the requirement
that ICSRs and ICSR attachments be in an electronic format that FDA can
process, review, and archive, rather than cross-reference Sec.
314.80(g)(1). FDA intends to issue guidance on how to provide the
electronic submission (e.g., method of transmission, media, file
formats, preparation and organization of files). We have also revised
Sec. 230.220(c)(1)(ii) to directly state that an applicant or
nonapplicant may request, in writing, a temporary waiver of the
electronic reporting requirements, and that these waivers will be
granted on a limited basis for good cause shown, rather than cross-
reference Sec. 314.80(g)(2). FDA intends to issue guidance on
requesting a waiver of the requirements in Sec. 230.220(c)(1)(i).
Furthermore, we have revised Sec. 314.1(c) to state that Sec.
314.80, as a whole, does not apply to designated medical gases. These
revisions have the same regulatory effect as the language included in
the proposed rule on this issue.
(Comment 52) One comment maintains that some nonapplicants may be
unable to comply with the proposed ICSR requirements.
(Response 52) FDA believes it is appropriate to apply the proposed
ICSR requirements to nonapplicants. We note that nonapplicants are
currently required to comply with the postmarketing safety reporting
requirements in Sec. 314.80(c)(1)(i) and (ii), although nonapplicants
may comply by submitting all reports of serious adverse drug
experiences to the applicant. Under Sec. 230.220, the only difference
will be that nonapplicants for designated medical gases must report to
FDA, rather than the applicant.
[[Page 51755]]
Therefore, we do not believe that revisions are necessary.
(Comment 53) Regarding the proposed exception to the ICSR
requirements for serious adverse events in proposed Sec.
230.220(b)(1)(iii), one comment recommends expanding the exception to
serious injuries of patients administered oxygen, unless the applicant
or nonapplicant is aware of evidence to suggest that the serious injury
was caused by the administration of oxygen. The comment references the
proposed ``no smoking'' and ``no vaping'' warning statements in Sec.
201.161(a)(1)(ii) and maintains that its suggested changes would be
consistent with the warning statements.
(Response 53) FDA does not agree that this change is necessary. The
purpose of the exception in Sec. 230.220(b)(1)(iii) is to address
cases where a patient being administered oxygen dies and there is no
reason to believe that the oxygen contributed to the patient's death.
This is very common because, as discussed in the proposed rule, oxygen
is commonly administered during end-of-life care or to patients with a
life-threatening disease or who are otherwise in critical condition (87
FR 31302 at 31329). This provision is not intended to address fire-
related injuries.
(Comment 54) One comment expresses support for the proposed minimum
data set requirements for human postmarketing safety reporting but
asserts that the burden could be significant for firms. The comment
maintains that, for purposes of complying with Sec. 230.220(c)(2) or
Sec. 230.220 more generally, firms may need to hire or contract with
medical professionals to evaluate potential ICSRs.
(Response 54) FDA appreciates the feedback regarding the proposed
minimum data set requirements and acknowledges the concern regarding
compliance burden. (Section VII below discusses the economic burden of
compliance with Sec. 230.220, including Sec. 230.220(c)(2).)
Nonetheless, FDA does not believe that firms will need to hire medical
professionals. We further note that applicants (and nonapplicants by
way of applicants) are currently required to submit adverse event
reports to FDA under Sec. Sec. 314.80 and 514.80 for human adverse
drug experiences and animal adverse drug events, respectively. In both
cases, this requires determining whether the event is unexpected,
something that generally would not be required under Sec. 230.220 or
Sec. 230.230. Required reports of serious adverse events must be
submitted regardless of expectedness, and a causality assessment is
only required in the event there is evidence to suggest that the death
of a patient being administered oxygen was caused by such
administration of oxygen.
(Comment 55) Regarding the proposed requirement in Sec.
230.220(c)(2)(iii) that event terms in ICSRs be coded using
standardized medical terminology, one comment requests that the word
``must'' be revised to ``should.'' The comment also requests that the
recommendation that standardized medical terminology be used should
only apply if the terminology is provided by the reporter. The comment
maintains that medical gas firms do not necessarily have medical
expertise available to code ICSR events.
(Response 55) FDA disagrees with these suggested revisions. We do
not believe that coding using standardized medical terminology is a
significant burden, nor do we believe that medical professionals are
needed to code an event correctly. Standardized medical terminology
generally includes terms commonly used by laypersons when describing
adverse events. Moreover, because the reporter may be the patient or a
relative, and thus not necessarily familiar with ICSR reporting or FDA
regulation more broadly, it would be unreasonable to rely on the
original reporter to properly code an event. Because the use of
standardized medical terminology helps FDA track, evaluate, and respond
to safety signals, we do not believe the requested revisions are
appropriate.
(Comment 56) FDA received one comment concerning proposed Sec.
230.220(c)(2)(vi)(B). The comment states that applicants and
nonapplicants should be required to submit a reference to published
articles, rather than the articles themselves, due to copyright
restrictions. As an alternative, the comment suggests that FDA could
require that the article be provided upon request, subject to
copyright.
In light of these recommendations, the comment also requests
deletion of the provisions requiring translation of the abstract of
foreign language articles and describing the requirements for
submitting more than one ICSR from the same published article. The
comment maintains that the burden of these requirements would be
significant, as firms would need to hire medical professionals to
evaluate ICSRs.
(Response 56) FDA does not agree with these suggested changes.
First, it is unclear why medical professionals would be needed to help
an applicant or nonapplicant comply with the requirements in Sec.
230.220(c)(2)(vi)(B). Additionally, we note that Sec. 314.80(d)
currently requires that a 15-day Alert report based on information in
the scientific literature be accompanied by a copy of the published
article.
Regarding the submission of foreign language articles, FDA
recognizes that there may be additional burden associated with
translating foreign language documents, but we proposed that only the
abstract be translated and expect that the burden associated with this
activity would be minimal. As such, we believe that requiring
translation of only the abstract of a foreign language article is
appropriate.
Because we are requiring in this final rule that the applicant or
nonapplicant provide a copy of published articles as an attachment, we
believe it is important to retain the language concerning the
submission of multiple ICSRs from the same article.
(Comment 57) One comment asks that proposed Sec. 230.220(g) be
revised to create an exception to the recommendation that the applicant
or nonapplicant should include the name of the reporter from whom the
information was received as part of the initial reporter information,
even when the reporter is the patient. Specifically, the comment
requests an exception for when the reporter is the patient out of
concern for disclosing the patient's personal information.
(Response 57) FDA disagrees. As noted in the sentence that
immediately follows the referenced provision in Sec. 230.220(g), FDA
acknowledges that, as addressed in the Agency's public information
regulations, FDA generally may not disclose the names of patients,
individual reporters, healthcare professionals, hospitals, and
geographical identifiers submitted to FDA in adverse event reports.
Moreover, in situations in which the reporter is the patient, nothing
in the submission necessarily makes that fact evident to the reader.
Lastly, the language at issue is consistent with the current text of
Sec. 314.80(i) indicating that the name of the reporter be included
even when the reporter is the patient.
(Comment 58) FDA sought comment on the Agency's decision not to
propose periodic safety reporting requirements for designated medical
gases and received comments in support and in opposition. Some comments
maintain that this decision is consistent with FDA's March 2015
Compliance Program Guidance Manual 7356.002E (Ref. 3), while other
comments assert that periodic safety reporting enables cumulative
review of safety information.
(Response 58) After considering the comments, FDA does not believe
it is necessary to include a periodic safety reporting requirement in
this
[[Page 51756]]
rulemaking. Medical gases have historically been manufactured, labeled,
and distributed in a manner different than most other drugs. Because of
these differences, FDA believes that the likelihood of identifying new
safety issues for medical gases is low, and that ICSRs are an adequate
and efficient means of identifying any new safety issues for these
products.
14. Animal Postmarketing Safety Reporting (Proposed Sec. 230.230)
FDA proposed animal postmarketing safety reporting requirements in
Sec. 230.230. Under proposed Sec. 230.230(a), applicants and
nonapplicants must submit serious adverse events to FDA as soon as
possible but no later than within 15 calendar days of first receiving
the information. FDA proposed that applicants and nonapplicants must
submit reports for each serious adverse event reported to the applicant
or nonapplicant spontaneously (such as reports initiated by a patient,
consumer, veterinarian, or other healthcare professional), regardless
of whether the applicant or nonapplicant believes the events are
related to the designated medical gas (proposed Sec.
230.230(a)(1)(i)). FDA also proposed that applicants and nonapplicants
must submit reports for each serious adverse event obtained from
published scientific and medical literature regardless of whether the
applicant or nonapplicant believes the events are related to the
designated medical gas (proposed Sec. 230.230(a)(1)(ii)). FDA proposed
that adverse event reports not be required for reports of the death of
an animal who was administered oxygen, unless the applicant or
nonapplicant is aware of evidence to suggest that the death was caused
by the administration of oxygen (proposed Sec. 230.230(a)(1)(iii)).
Under proposed Sec. 230.230(a)(2), upon notification by FDA,
applicants and nonapplicants must submit reports of adverse events
associated with the use of a designated medical gas in animals that do
not qualify for reporting under Sec. 230.230(a)(1). FDA proposed under
Sec. 230.230(a)(3) that applicants and nonapplicants should not
resubmit adverse event reports obtained from FDA's adverse event
reporting database or forwarded to the applicant or nonapplicant by
FDA.
FDA proposed in Sec. 230.230(b) to require that adverse event
reports be submitted in an electronic format that FDA can process,
review, and archive, and that data provided in electronic submissions
must be in conformance with the data elements in Form FDA 1932 and FDA
technical documents describing transmission (proposed Sec.
230.230(b)(1)). FDA further proposed that applicants and nonapplicants
may request, in writing, a temporary waiver of this requirement
(proposed Sec. 230.230(b)(2)).
Under proposed Sec. 230.230(c), FDA proposed recordkeeping
requirements, including that applicants and nonapplicants maintain
records of information relating to adverse event reports for 5 years,
whether or not submitted to FDA (proposed Sec. 230.230(c)(1)). FDA
further proposed that such records must include raw data,
correspondence, and any other information relating to the evaluation
and reporting of adverse event information that is received or
otherwise obtained by the applicant or nonapplicant (proposed Sec.
230.230(c)(2)). Lastly, FDA proposed that, upon written notice by FDA,
the applicant or nonapplicant must submit any or all of these records
to FDA within 5 calendar days after receipt of the notice, and the
applicant or nonapplicant must permit any authorized FDA employee, at
reasonable times, to access, copy, and verify these established and
maintained records (proposed Sec. 230.230(c)(3)).
Before responding to a comment we received regarding the proposed
animal postmarketing safety reporting requirements, the Agency notes a
revision we have made on our own initiative. We have revised Sec.
230.230(a)(1)(i) to more clearly specify that applicants and
nonapplicants must submit reports for serious adverse events reported
to or otherwise received by the applicant or nonapplicant. This
revision aligns Sec. 230.230(a)(1)(i) with the requirement in Sec.
230.210(a) for prompt review of all safety information that the
applicant or nonapplicant receives or otherwise obtains from any
source, and helps ensure that reports of serious adverse events
otherwise received (or obtained) by the applicant or nonapplicant are
submitted to the Agency. Accordingly, Sec. 230.230(a)(1)(i) includes,
for example, serious adverse event reports received at the request of
the applicant or nonapplicant, in addition to unsolicited
communications such as reports initiated by a patient, consumer,
veterinarian, or other healthcare professional.
(Comment 59) Regarding the proposed exception to the reporting
requirements for serious adverse events in proposed Sec.
230.230(a)(1)(iii), one comment recommends expanding the exception to
serious injuries of animals administered oxygen, unless the applicant
or nonapplicant is aware of evidence to suggest that the serious injury
was caused by the administration of oxygen. The comment references the
``no smoking'' and ``no vaping'' warning statements in proposed Sec.
201.161(a)(1)(ii) and maintains that the suggested changes would be
consistent with the warning statements.
(Response 59) As discussed above, FDA does not agree that this
change is necessary. The purpose of the exception in Sec.
230.230(a)(1)(iii) is to address cases where an animal being
administered oxygen dies and there is no reason to believe that the
oxygen contributed to the animal's death. This is very common because,
as discussed in the proposed rule, we expect that oxygen will be
administered to animals that are in critical condition, and death is
expected to be a common outcome (87 FR 31302 at 31331). This provision
is not intended to address fire-related injuries.
J. Description of Part 314 Comments and FDA Response
FDA proposed carving out designated medical gases from certain
provisions in part 314, either because a corresponding provision
specific to designated medical gases was proposed to be added to part
230, or because the provision is not relevant to designated medical
gases. Specifically, FDA proposed exempting designated medical gases
from Sec. Sec. 314.50 through 314.72 (concerning certain information
required in NDAs); Sec. 314.80, except paragraph (g) (concerning
certain postmarketing reporting requirements); Sec. 314.81(a) and
(b)(1) and (2) (concerning certain other postmarketing reports); Sec.
314.90 (concerning waivers); subpart C (concerning ANDAs); Sec. Sec.
314.100 through 314.162 (concerning certain requirements related to FDA
action on NDAs and ANDAs; subpart H (concerning accelerated approval);
and subpart I (concerning approval of new drugs when human efficacy
studies are not ethical or feasible). FDA received comments related to
some of these proposed changes, to which we respond below.
(Comment 60) One comment requests that designated medical gases be
exempted from Sec. 314.81(b)(3), which includes requirements for
submitting advertisements and promotional labeling, special reports
requested by the Agency, the process for notifying FDA of a permanent
discontinuance of manufacture of a drug product, and withdrawal of an
approved drug product from sale. The comment asserts that, in light of
the proposed revisions to the labeling requirements in part 201, it is
not necessary for these provisions to apply to designated medical
gases.
(Response 60) FDA does not agree that designated medical gases
should be exempted from Sec. 314.81(b)(3). The
[[Page 51757]]
Agency assumes that the comment is primarily focused on Sec.
314.81(b)(3)(i), which concerns the submission of advertisements and
promotional labeling, because of the comment's discussion of part 201.
The other provisions in Sec. 314.81(b)(3) are unrelated to labeling,
and it is not clear how the changes FDA proposed to part 201 would
address these requirements. Furthermore, we do not believe that the
changes FDA is making to part 201 address the requirements in Sec.
314.81(b)(3)(i), as part 201 does not include requirements for
promotional labeling. Because FDA believes it is still important for
promotional materials to be submitted to the Agency, we believe it is
important to retain this provision.
(Comment 61) One comment requests that designated medical gases be
exempted from Sec. 314.81(c) because an original manufacturer will
only have one application for each designated medical gas.
(Response 61) We assume the comment concerns only Sec.
314.81(c)(1), regarding the submission of information common to more
than one application, as the comment does not discuss the requirements
of Sec. 314.81(c)(2). FDA does not expect that designated medical gas
applicants will have information common to more than one application.
In addition, upon further consideration, FDA concludes it is not
necessary to retain the requirements in Sec. 314.81(c)(2) for
designated medical gases because patient privacy information is not
expected to be included in reports for designated medical gases
submitted under Sec. 314.81. For these reasons, we are revising the
codified at Sec. 314.1(c) such that Sec. 314.81(c) no longer applies
to designated medical gases.
In addition, because Sec. 230.150 now provides for withdrawal of
an application for a designated medical gas based on failure to submit
reports required under Sec. 314.81(b)(3) (see section V.I.11), it is
not necessary for Sec. 314.81(d) (which concerns withdrawal of
approval for failure to make required reports) to continue to apply to
designated medical gases. Accordingly, FDA has revised Sec.
314.1(c)(3) to read ``Section 314.81, except paragraph (b)(3)''.
K. Part 514
FDA proposed carving out designated medical gases from provisions
in part 514 (21 CFR part 514) to align with the provisions specific to
designated medical gases that we proposed to add to part 230. We did
not receive comments on the proposed revisions and are finalizing the
provisions as proposed with minor technical changes made on our own
initiative.
VI. Effective Date
This rule is effective December 18, 2025, except for Sec. Sec.
4.2, 4.3, and 4.4. The effective date for Sec. Sec. 4.2, 4.3, and 4.4
will be February 2, 2026.
(Comment 62) One comment supports the proposed effective date of 18
months after publication of the final rule. The comment notes that
firms will need time to update labeling information to ensure
compliance with the new requirements.
(Response 62) FDA acknowledges this comment, and we believe that 18
months is an appropriate time after publication of the final rule to
enable firms to comply with these requirements. However, we note that
the recently published final rule ``Medical Devices; Quality System
Regulation Amendments'' (the QSRA rule), which will become effective on
February 2, 2026,\4\ amends provisions of part 4 that are further
revised by this rule. To prevent any confusion that may result from
multiple amendments to part 4 occurring so close in time, FDA has
determined that this rule's amendments to Sec. Sec. 4.2, 4.3, and 4.4
will be effective on February 2, 2026, the same date the QSRA rule
becomes effective.
---------------------------------------------------------------------------
\4\ See 89 FR 7496 (February 2, 2024).
---------------------------------------------------------------------------
VII. Economic Analysis of Impacts
We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, Executive Order 14094, the
Regulatory Flexibility Act (5 U.S.C. 601-612), the Congressional Review
Act/Small Business Regulatory Enforcement Fairness Act (5 U.S.C. 801,
Pub. L. 104-121), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4).
Executive Orders 12866, 13563, and 14094 direct us to assess all
benefits, costs, and transfers 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). Rules are ``significant'' under Executive Order 12866
Section 3(f)(1) (as amended by Executive Order 14094) if they ``have an
annual effect on the economy of $200 million or more (adjusted every 3
years by the Administrator of [the Office of Information and Regulatory
Affairs (OIRA)] for changes in gross domestic product); or adversely
affect in a material way the economy, a sector of the economy,
productivity, competition, jobs, the environment, public health or
safety, or State, local, territorial, or tribal governments or
communities.'' OIRA has determined that this final rule is not a
significant regulatory action under Executive Order 12866, section
3(f)(1).
Because this rule is not likely to result in an annual effect on
the economy of $100 million or more or meets other criteria specified
in the Congressional Review Act/Small Business Regulatory Enforcement
Fairness Act, OIRA has determined that this rule does not fall within
the scope of 5 U.S.C. 804(2).
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because this final rule will better tailor the current good
manufacturing practice requirements for medical gases and medically
appropriate combinations of such gases and creates small net cost
savings for small entities, 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 estimates of
anticipated impacts, 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 2022 threshold after adjustment for inflation is $177
million, using the (2022) Implicit Price Deflator for the Gross
Domestic Product. This final rule will not result in an expenditure in
any year that meets or exceeds this amount.
This final rule establishes, within part 213, CGMP regulations
specific to medical gases. These regulations include many of the same
categories of requirements as the general drug product CGMP regulations
but are tailored to reflect differences in how medical gases are
manufactured, packaged, labeled, stored, and distributed. This rule
makes limited changes to the labeling requirements of part 201,
including requiring that a ``no smoking'' statement, a ``no vaping''
statement, and graphic warning symbol be added to oxygen containers to
reduce the risk of fire. This rule codifies and clarifies the process
for obtaining a certification to market designated medical gases.
Recommendations for how to request a certification for designated
medical gases are currently included in a draft guidance. This rule
makes changes to postmarketing safety reporting regulations for
designated medical gases that address human and animal use and more
specifically reflect
[[Page 51758]]
the development, manufacturing, and distribution of designated medical
gases.
The costs of this final rule are primarily driven by new labeling
requirements, clarification leading to firms becoming compliant with
existing requirements, and added CGMP requirements, including a
requirement for portable cryogenic containers to have a working gauge.
The cost savings of this final rule are primarily driven by
removing or relaxing CGMP requirements that do not apply to medical
gases, such as removing certain building and facility requirements,
which may streamline inspections for industry and FDA.
Table 1 summarizes the estimated benefits and costs of the final
rule. The annualized benefits will range from $0.00 million to $7.02
million with a primary estimate of $3.51 million over a 10-year span at
a 7 percent discount rate. Annualized at a 3 percent discount rate
these benefits will range from $0.00 million to $7.43 million with a
primary estimate of $3.72 million. The annualized costs will range from
$1.52 million to $5.30 million with a primary estimate of $3.24 million
at a 7 percent discount rate. Annualized at a 3 percent discount rate
these costs will range from $1.36 million to $5.11 million with a
primary estimate of $3.07 million.
The present value of the estimated benefits will range from $0.00
million to $56.33 million with a primary estimate of $28.17 million at
a 7 percent discount rate and from $0.00 million to $59.64 million with
a primary estimate of $29.82 million at a 3 percent discount rate. The
present value of the estimated costs will range from $12.23 million to
$42.49 million with a primary estimate of $25.96 million at a 7 percent
discount rate and from $12.98 million to $48.72 million with a primary
estimate of $29.28 million at a 3 percent discount rate.
Table 1--Summary of Benefits, Costs, and Distributional Effects of the Final Rule
[Millions of 2022 dollars]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------
Category Primary Low High Period Notes
estimate estimate estimate Year Discount covered
dollars rate (%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $millions/ $3.51 $0.00 $7.02 2022 7 10 Most benefits are cost savings to
year. 3.72 0.00 7.43 2022 3 10 industry while the remaining are cost
savings for FDA due to a more
streamlined inspection process.
Annualized Quantified............. .......... .......... .......... .......... 7 .......... ........................................
.......... .......... .......... .......... 3 ..........
------------------------------------------------------------------------
Qualitative....................... Potential small increase in safety from a reduction in fire risk from
graphic warning labels on oxygen containers; flexibility in testing of
components, containers, and closures; clarifies calculations of yield
requirement does not apply to medical gases; clarifies medical gas
salvage is allowed under certain conditions; removes requirement that
labels not be susceptible to becoming worn or detached; outlines the
certification request process; and clarifies adverse event reports are
generally not required for reports of the death of a patient or animal
who was administered oxygen and fires associated with the
administration of oxygen that do not include an adverse event
experienced by the patient or animal.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized millions/year 3.24 1.52 5.30 2022 7 10
3.07 1.36 5.11 2022 3 10
Annualized Quantified............. .......... .......... .......... .......... 7 .......... ........................................
.......... .......... .......... .......... 3 .......... ........................................
------------------------------------------------------------------------
Qualitative....................... Maintaining resumes for consultants, and potential cost of relabeling ........................................
medical air containers.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized .......... .......... .......... .......... 7 ..........
millions/year. .......... .......... .......... .......... 3 ..........
-----------------------------------------------------------------------------------------------------------------
From/To........................... From:
To:
Other Annualized Monetized .......... .......... .......... .......... 7 .......... ........................................
millions/year. .......... .......... .......... .......... 3 .......... ........................................
-----------------------------------------------------------------------------------------------------------------
From/To........................... From:
To:
-----------------------------------------------------------------------------------------------------------------
Effects:
State, Local or Tribal Government: None.............................................................................................................
Small Business: Not significant.....................................................................................................................
Wages: None.........................................................................................................................................
Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
FDA conducted a regulatory flexibility analysis of the impact of
the final rule on small entities. Approximately 41 percent of domestic
entities that would be affected by the final rule are small according
to Small Business Administration size standards. We estimate that the
highest single year cost for a firm could be as high as 0.860 percent,
while the average costs to receipts ratio is 0.007 percent. Therefore,
our analysis of the impact of the final rule on small entities suggests
that small firms will not be significantly affected by the final
regulation.
[[Page 51759]]
We received one comment directed at the preliminary regulatory
impact analysis (PRIA) and a few comments on the rule that we
considered to be relevant to the economic analysis. The number assigned
to each comment is purely for organizational purposes and does not
signify the comment's value, importance, or the order in which it was
received.
(Comment 63) One comment maintains that entering a specific
percentage of oxygen in the distribution records for each medical air
cylinder is not necessary, because medical air contains a range of
oxygen in nitrogen.
(Response 63) FDA agrees. We removed ``medical air and'' from the
distribution records section to clarify. This clarification ensures no
additional burden for distribution records.
(Comment 64) One comment suggests that transfilling be included in
the distribution records and tracked, including which lots of gas
material were added and on which date.
(Response 64) FDA declines to make this change. Including
transfilling in the distribution records would be burdensome, and the
tracking information might be of limited use for traceability due to
the use of multiple batches and commingling.
(Comment 65) One comment states that the potential burden
associated with the proposed minimum data set requirements for human
postmarketing safety reporting on medical gas firms could be
significant based on the number of adverse event reports received and
the specific information required for individual case safety reports.
The comment asserts that adverse event reporting would require all
registered medical gas firms to hire or have available medical
professionals or contractors to evaluate potential adverse events.
(Response 65) Adverse event reporting is already required for
applicants and nonapplicants. This final rule requires nonapplicants to
report adverse events directly to FDA rather than reporting to the
applicant who in turn would report the adverse event to FDA. The Agency
believes this will be less burdensome in the context of medical gases.
Our analysis does anticipate a small increase in adverse event
reporting for animals as a result of clarification of the requirements
applicable to industry. However, because this is not a new requirement,
we believe that the small increase is an accurate estimate of the
additional burden for adverse event reports.
We do not anticipate an additional burden per adverse event report
as a result of the minimum data set requirements established in the
final rule. Collection of the minimum data set is already included in
FDA's July 2009 guidance for industry ``Postmarketing Adverse Event
Reporting for Nonprescription Human Drug Products Marketed Without an
Approved Application,'' and the March 2001 draft guidance for industry
``Postmarketing Safety Reporting for Human Drug and Biological Products
Including Vaccines'' (Refs. 4 and 5), and is industry practice.
FDA does not believe that firms will need to hire medical
professionals. Reporters are not required to determine causality but
only to report that an adverse event did occur. Additionally, adverse
event reporting is not a new requirement.
(Comment 66) One comment maintains that the requirements do not
reflect current industry practice and there may be additional economic
burden on the industry that is not included in FDA's summary.
(Response 66) We appreciate the comment, but we believe we have
sufficiently estimated all direct additional costs for new requirements
not determined to be de minimis. We also acknowledged additional
potential costs and possible sensitivities in the sensitivity analysis
of the PRIA.
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. 6) and at
<a href="https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria">https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria</a>.
VIII. Analysis of Environmental Impact
We have determined under 21 CFR 25.30(h), (j), and (k) 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. Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The title,
description, and respondent description of the information collection
provisions are shown in the following paragraphs with an estimate of
the annual reporting, recordkeeping, and third-party disclosure burden.
Included in the burden estimate is the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.
Title: Information Collection for Rulemaking of Current Good
Manufacturing Practice, Certification, Postmarketing Safety Reporting,
and Labeling Requirements for Certain Medical Gases.
Description: This rulemaking is amending existing regulations and
establishing new regulatory requirements pertaining to medical gases.
Description of Respondents: Respondents to this information
collection are entities who manufacture, process, pack, label, or
distribute certain medical gases.
1. Product Jurisdiction and Combination Products; OMB Control No. 0910-
0523--Revision
FDA recognizes that some medical gases are marketed as part of a
combination product. For example, a medical gas may be marketed with a
device constituent part (for example, a portable liquid oxygen unit or
a pressure regulator). Combination products are subject to information
collection provisions found in parts 3 and 4, which prescribe content
and format requirements associated with marketing applications,
together with applicable recordkeeping and reporting requirements.
FDA is revising provisions in part 4 to account for combination
products that contain a medical gas, as FDA is requiring medical gases
to be subject to new part 213, and to clarify (where appropriate)
applicable medical gases requirements throughout part 4. We believe
that the new regulations impose no new burden associated with
information collection currently approved under OMB control number
0910-0523.
2. Labeling Requirements for Prescription Drugs; OMB Control No. 0910-
0572--Revision
Regulations in part 201 govern the statement of ingredients and
declaration of net quantity of contents with regard to prescription
drug product labeling.
The new regulations require that firms identify bulk or transport
containers with the name of the product contained therein and that
containers be accompanied by documentation that identifies the product
as meeting applicable compendial standards. Bulk or transport
containers are excluded from the definition of final use containers.
Because these large containers are removed from the point of care and
we do not expect that patients and healthcare practitioners
[[Page 51760]]
will use them directly to administer a designated medical gas, FDA does
not believe that firms' bulk or transport containers need to bear the
information required under Sec. 201.161(a). However, to prevent mix-
ups, it is essential that the identity of the gas inside such
containers is evident to individuals who handle and transport the
containers. FDA expects that these requirements will help prevent mix-
ups and ensure that recipients of medical gases in bulk or transport
containers are provided information indicating that such gases meet
applicable compendial standards.
We estimate that 1,696 firms will label 4,000 containers and
anticipate firms will expend 6 minutes (0.1 hours) to identify the
containers with the name of the product and place documentation that
identifies the product as meeting applicable compendial standards,
totaling 400 hours annually.
Section 201.328(d) provides that the owner of a designated medical
gas container or a container of a medically appropriate combination of
designated medical gases may be identified on the container. This
statement may appear on a separate sticker or decal on the container
(that is, it need not be contiguous with other labeling on the
container), but if the container owner is not the manufacturer, packer,
or distributor of the gas, that information shall be clearly stated.
FDA recognizes the complex distribution system for designated medical
gases and medically appropriate combinations of designated medical
gases and the importance of each entity in the distribution chain being
clearly identified so that patients and healthcare professionals can
contact the appropriate entity if necessary. We intend for this
provision to help ensure that appropriate entities can be contacted
about quality issues or adverse events. In addition, the labeling
requirement facilitates the return of cylinders to owners who may not
also be medical gas manufacturers. FDA believes that including the
container owner's information will not cause the container owner to be
a ``relabeler'' for purposes of FDA's registration and listing
requirements.
We estimate that 1,696 firms will identify on a designated medical
gas container or a container of a medically appropriate combination of
designated medical gases the name of the container owner who may not
also be the manufacturer, packer, or distributor of the gas. We
estimate firms would include this label on 4,000 containers and will
expend 6 minutes (0.1 hours) to perform this activity, totaling 400
hours annually.
We estimate the burden of the information collection as follows:
Table 2--Estimated Annual Third-Party Disclosure Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of
Activity; 21 CFR Section Number of disclosures per Total annual Average burden per Total
respondents respondent disclosures disclosure (hours) hours
----------------------------------------------------------------------------------------------------------------
Labeling of bulk or transport 1,696 2.36 4,000 0.1 (6 minutes)...... 400
containers used to hold
designated medical gases;
Sec. 201.161(b).
Identify the owner of a 1,696 2.36 4,000 0.1 (6 minutes)...... 400
designated medical gas
container or a container of
a medically appropriate
combination of designated
medical gases on the
container label. If the
container owner is not the
manufacturer, packer, or
distributor of the gas,
identify that information on
the label; Sec. 201.328(d).
----------------------------------------------------------------------------------
Total.................... .............. ................. 8,000 ..................... 800
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with the information collection.
3. Current Good Manufacturing Practice for Medical Gases; OMB Control
No. 0910-0906
FDA is establishing new part 213 setting forth CGMP requirements
applicable to medical gases. Part 213 applies to firms that manufacture
a medical gas and establishes requirements applicable to firms that
subsequently combine, commingle, refill, or distribute medical gases.
The regulations also include recordkeeping requirements pertaining
to personnel qualifications and responsibilities of persons who are
engaged in the manufacturing, processing, packing, or holding of a
medical gas.
Provisions under Sec. 213.42(c) include recordkeeping to document
the development and implementation of written procedures to ensure that
firms maintain a clean condition for any building used to manufacture,
process, pack, or hold a medical gas so as to ensure the safety,
identity, strength, quality, and purity of the gas. Firms also need to
develop written procedures that apply to recordkeeping for cleaning and
maintaining buildings. Based on available data, we estimate 1,696 firms
will each develop and implement written procedures to maintain and
clean buildings. We estimate it will take 13 hours to perform this
activity, totaling 22,048 hours initially. Firms will also update these
written procedures annually. Based on available data, we estimate 1,696
firms would each update written procedures to maintain and clean
buildings and that it will take 39 minutes (0.65 hours) to perform this
activity, totaling 1,102 hours annually.
Provisions under Sec. 213.100 include development and maintenance
of written procedures to ensure that production and process controls
are designed to assure that medical gases have the appropriate
qualities (identity, strength, quality, and purity) they are purported
to possess. Based on available data, we estimate 1,696 firms will each
develop and implement written procedures. We estimate it will take 13
hours to perform this activity, totaling 22,048 hours. Firms will also
update these written procedures annually. Based on available data, we
estimate 1,696 firms would each update written procedures to maintain
and clean buildings and that it will take 39 minutes (0.65 hours) to
perform this activity, totaling 1,102 hours annually.
In concert with Sec. Sec. 213.42 and 213.80, under Sec. 213.150,
firms are required to establish and follow written procedures regarding
warehousing and distribution of medical gases, including procedures for
the quarantine of such gases before release by the quality unit. The
distribution procedures are also required to include a system by which
the distribution of each lot can be readily determined, to facilitate
any necessary recalls. Based on available data, we estimate 1,696 firms
will each develop and implement written procedures for warehousing and
distribution of medical gases. We anticipate it will take approximately
13 hours to perform this activity totaling 22,048 hours initially.
Firms will also update these written procedures annually. Based on
available data, we estimate 1,696 firms would each update these written
procedures annually and
[[Page 51761]]
that it will take 39 minutes (0.65 hours) to perform this activity,
totaling 1,102 hours annually.
Similarly, under Sec. 213.208, firms are required to develop and
implement written procedures for the holding, testing, and use of
salvaged medical gases. Based on available data, we estimate 1,696
firms will develop and implement written procedures for the holding,
testing, and use of salvaged medical gases. We estimate it will take 13
hours for firms to perform this activity, totaling 22,048 hours. In
addition, based on available data, we estimate that 1,696 firms will
update their written procedures (1 procedure each) for the holding,
testing, and use of salvaged medical gases. We estimate it takes 0.65
hours to perform the updates, totaling 1,102 hours annually.
The regulations under Sec. 213.25 provide that employee training
be included in the firm operations. Recordkeeping would be established
to demonstrate that qualified individuals conduct training on a
continuing basis and with sufficient frequency to allow employees to
remain familiar with applicable requirements. Based on available data,
we estimate that 1,696 firms will prepare written documentation
pertaining to employee training. We estimate that 10 employees per firm
will create 16,960 records (10 records per firm) and that it will take
5 minutes (0.083 hours) to prepare each record, for a total of 1,408
hours annually.
Under Sec. 213.34, records demonstrating that consultants have
sufficient education, training, and experience, or any combination
thereof, to advise on the subject for which they are retained will be
required. Based on available data, we estimate that 1,696 firms will
maintain 571 records of consultants' education, training, and
experience, or any combination thereof and expect that it will take 30
minutes (0.5 hours) to perform this activity, totaling 286 hours
annually.
In addition, under Sec. 213.67(c), we estimate that 1,696 firms
will maintain 74,230 records of equipment maintenance and cleaning and
anticipate it will take 15 minutes (0.25 hours) to perform this
activity, totaling 18,557 hours annually. We also anticipate that,
under Sec. 213.68(d), 1,696 firms will develop and implement 11,420
written procedures for automatic, mechanical, and electronic equipment
and that firms will expend 15 minutes (0.25 hours) to perform this
activity, totaling 2,855 hours annually.
As provided in the new regulation under Sec. 213.82, once a
shipment of an incoming designated medical gas is received, the firm
will perform full compendial testing on the gas and record the results
or verify and record that a signed certificate of analysis accompanies
the shipment. If an incoming designated medical gas is obtained from a
supplier other than the original manufacturer, the shipment would also
need to include specific information. To ensure the reliability of
appropriate assessment and testing, firms will be required to establish
and maintain a program to ensure the reliability of the supplier's
capabilities through appropriate assessment and testing procedures. We
estimate that 1,380 firms would verify and document records upon
receipt of a designated medical gas. We anticipate that firms will
maintain 575,460 records (417 records each (1 delivery per week of
oxygen for 1 year (52 deliveries) plus 1 delivery per day of nitrogen
for 1 year (365 deliveries)). We further estimate firms will expend 15
minutes (0.25 hours) each (104 hours in total for each firm) to perform
this activity, totaling approximately 143,865 hours annually.
Section 213.89 requires that firms identify and control rejected
components, containers, and closures under a quarantine system designed
to prevent their use in operations for which they are unsuitable.
Section 213.89 also applies to incoming designated medical gases.
Quarantine systems would not need to include physical quarantining
because other methods can adequately ensure that unsuitable products
are not used. We estimate that 1,380 downstream firms would need to
assess and document 33.4 million medical gas components, containers,
and closures annually. We estimate that firms would reject 0 to 0.1
percent of all containers. These firms will maintain a total of 33,400
records of rejected components and we estimate they will expend 5
minutes (0.083 hours) to perform this activity, totaling 2,772 hours
annually.
Under Sec. 213.122(c), firms need to maintain records for each
shipment received of each different labeling and packaging material
indicating receipt, examination, and whether accepted or rejected.
Based on available data, we estimate 1,696 firms will prepare 74,230
records to document each shipment received of each different labeling
and packaging material indicating receipt, examination, and whether
accepted or rejected. We estimate it will take 15 minutes (0.25 hours)
to perform this activity, totaling 18,558 hours annually.
Under Sec. 213.130(e), firms are required to document results of
inspections concerning packaging and labeling in the batch production
records. Based on available data, we estimate 1,696 firms will document
results of inspections in the batch production records in approximately
114,200 records. We estimate it will take 15 minutes (0.25 hours) per
record to perform this activity, totaling 28,550 hours annually.
Under Sec. 213.180(d), firms are required to maintain written
records so that data therein can be used for evaluating, at least
annually, the quality standards of each medical gas to determine the
need for changes in specifications or manufacturing or control
procedures. Based on available data, we estimate 1,696 firms will
prepare 457 records. We estimate it will take 15 minutes (0.25 hours)
to perform this activity, totaling 114 hours annually.
Under Sec. 213.182, firms are required to maintain a written
record of major equipment cleaning, maintenance (except routine
maintenance such as lubrication and adjustments), and use. Based on
available data, we estimate 1,696 firms will prepare 2,969 records
documenting major equipment cleaning, maintenance (except routine
maintenance such as lubrication and adjustments), and use. We estimate
it will take 10 minutes (0.16 hours) to perform this activity, totaling
475 hours annually.
Under Sec. 213.184, firms are required to maintain certain records
concerning components, medical gas containers and closures, and
labeling. We estimate 1,696 firms will prepare 4,454 records for
components, medical gas containers and closures, and labeling. We
estimate firms will expend 19.8 minutes (0.33 hours) to perform this
activity, totaling 1,470 hours annually.
Under Sec. 213.186, to ensure uniformity from batch to batch,
firms are required to prepare, date, and sign master production and
control records for each medical gas. We estimate 1,696 firms will
prepare and maintain approximately 22,840 master production and control
records and estimate that it will require 2 hours for firms to perform
this activity, totaling 45,680 hours annually.
Under Sec. 213.189, firms are required to maintain batch
production and control records. These records would need to include
documentation that the firm has accomplished each significant step in
the manufacturing, processing, packing, or holding of the medical gas
produced, including in-process and laboratory tests. We estimate 1,696
firms will prepare and maintain 37,115 batch production and control
records. We anticipate it will require 78 minutes (1.3 hours) for firms
to perform this activity, totaling 48,250 hours annually.
[[Page 51762]]
Section 213.192(a) describes production record review. Per
paragraph (a), firms are required to maintain a written record of any
investigation of errors, unexplained discrepancies in production, or
failure of a batch or any component of a batch to meet specifications
and include the conclusions and followup. We estimate 1,696 firms will
prepare and maintain 4,568 laboratory records and that it will require
1 hour for firms to perform this activity, totaling 4,568 hours
annually.
Under Sec. 213.194(b) through (e), firms are required to maintain
certain laboratory records. Based on available data, we estimate 1,696
firms will prepare and maintain 57,100 laboratory records and estimate
it will require 30 minutes (0.5 hours) for firms to perform this
activity, totaling 28,550 hours annually.
Section 213.196 describes certain requirements for distribution
records. Based on available data, we estimate 1,696 firms will prepare
and maintain 57,100 distribution records and estimate it will require
15 minutes (0.25 hours) for firms to perform this activity, totaling
14,275 hours annually.
Under Sec. 213.198, firms are required to maintain written records
of each complaint regarding medical gases. We estimate 1,696 firms will
maintain 11,420 records of complaints. We estimate it will require
approximately 1 hour for firms to perform this activity, totaling
11,420 hours annually.
We estimate the burden of the information collection as follows:
Table 3--Estimated One-Time Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Average burden
Number of Number of Total annual per
Activity; 21 CFR section recordkeepers records per records recordkeeping Total hours
recordkeeper (hours)
--------------------------------------------------------------------------------------------------------------------------------------------------------
New Start Up SOP--Cleaning, Maintenance and Operation; Sec. 1,696 1 1,696 13 22,048
213.42...........................................................
New Start Up SOP--Medical Gases Production and Process Controls; 1,696 1 1,696 13 22,048
Sec. 213.100...................................................
New Start Up SOP--Warehousing and Distribution; Sec. 213.150.... 1,696 1 1,696 13 22,048
New Start Up SOP--Salvaging of Medical Gases; Sec. 213.208...... 1,696 1 1,696 13 22,048
-------------------------------------------------------------------------------------
Total......................................................... .............. ................. 6,784 ................. 88,192
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 4--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average burden per
Activity; 21 CFR section Number of records per Total annual recordkeeping Total
recordkeepers recordkeeper records (hours) hours
----------------------------------------------------------------------------------------------------------------
SOP Maintenance--cleaning, 1,696 1 1,696 0.65 (39 minutes)... 1,102
maintenance, and operation;
Sec. 213.42.
SOP Maintenance--Medical 1,696 1 1,696 0.65 (39 minutes)... 1,102
Gases Production and Process
Controls; Sec. 213.100.
SOP Maintenance--salvaging of 1,696 1 1,696 0.65 (39 minutes)... 1,102
medical gases; Sec.
213.208.
SOP Maintenance--Medical 1,696 1 1,696 0.65 (39 minutes)... 1,102
Gases Warehousing and
distribution; Sec. 213.150.
Documentation of completion 1,696 10 16,960 0.083 (5 minutes)... 1,408
of training; Sec.
213.25(a).
Consultants' records of 1,696 0.34 571 0.5 (30 minutes).... 286
sufficient education,
training, and experience, or
any combination thereof;
Sec. 213.34.
Firms' records of equipment 1,696 43.77 74,230 0.25 (15 minutes)... 18,558
maintenance and cleaning;
Sec. 213.67(c).
Maintain records for 1,696 6.73 11,420 0.25 (15 minutes)... 2,855
modifications to automatic,
mechanical, and electronic
equipment; Sec. 213.68(d).
Receipt and storage of 1,380 417 575,460 0.25 (15 minutes)... 143,865
incoming designated medical
gases; Sec. 213.82(a).
Records of rejected 1,380 24.2 33,400 0.083 (5 minutes)... 2,772
components; Sec. 213.89.
Maintain records for each 1,696 43.77 74,230 0.25 (15 minutes)... 18,558
shipment received of each
different labeling and
packaging material
indicating receipt,
examination, and whether
accepted or rejected; Sec.
213.122(c).
Document results of 1,696 67.33 114,200 0.25 (15 minutes)... 28,550
inspections in the batch
production records; Sec.
213.130(e).
Maintain written records so 1,696 0.27 457 0.25 (15 minutes)... 114
that data therein can be
used for evaluating, at
least annually, the quality
standards of each medical
gas to determine the need
for changes in
specifications or
manufacturing or control
procedures; Sec.
213.180(d).
Maintain record of equipment 1,696 1.76 2,969 0.16 (10 minutes)... 475
cleaning and use log
maintenance; Sec. 213.182.
Maintain records for 1,696 2.63 4,454 0.33 (19.8 minutes). 1,470
components, medical gas
containers and closures, and
labeling; Sec. 213.184.
Maintain master production 1,696 13.47 22,840 2 hours............. 45,680
and control records; Sec.
213.186.
Maintain batch production and 1,696 21.88 37,115 1.3 hours........... 48,250
control records; Sec.
213.189.
Maintain record of the 1,696 2.69 4,568 1 hour.............. 4,568
investigation; Sec.
213.192(a).
Maintain laboratory records; 1,696 33.67 57,100 0.5 (30 minutes).... 28,550
Sec. 213.194(b) through
(e).
Maintain distribution 1,696 33.67 57,100 0.25 (15 minutes)... 14,275
records; Sec. 213.196.
Maintain written records of 1,696 6.73 11,420 1 hour.............. 11,420
each complaint; Sec.
213.198.
----------------------------------------------------------------------------------
Total.................... .............. ................. 1,105,278 .................... 376,061
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with the information collection.
4. Certification and Postmarketing Reporting for Designated Medical
Gases; OMB Control No. 0910-0906
Section 230.50 establishes the general requirements for requesting
a designated medical gas certification for all submission types and
outlines the information that must be included in certification request
submissions (Form FDA 3864). The new regulations require applicants to
include facility information in certification requests. Such
information would include, among others, name and address of the
original manufacturing facility or facilities where the gas is or will
be manufactured.
Section 230.50 also provides for the submission of additional
information if FDA deems it appropriate to determine
[[Page 51763]]
whether a medical gas meets the definition of a designated medical gas.
This information would generally be in the form of a written request by
FDA for the additional information. We estimate that five respondents
will submit a total of five certification requests annually, including
certification forms for original and resubmissions, and each
certification request will require 3 hours to prepare and submit,
totaling 15 hours annually.
Under Sec. 230.65, applicants will be allowed to withdraw a
certification request that has not been deemed granted. An applicant
may notify FDA that it withdraws its certification request at any time
before the certification is granted. Upon an applicant's withdrawal of
a certification request, FDA will retain the certification request, and
if the applicant requests a copy via a Freedom of Information Act
request, FDA will provide it pursuant to the fee schedule in FDA's
public information regulations. Since the passage of the Food and Drug
Administration Safety and Innovation Act, FDA has received several
certification requests but has not received any withdrawal requests.
FDA has no other data on which to provide a burden estimate. Therefore,
the Agency does not expect to receive withdrawal requests except in
exceedingly rare situations.
Section 230.70 requires applicants to submit a supplement if any
information in the granted certification has changed. The regulation
prescribes information to be included in a supplement to the marketing
application. We estimate four applicants will submit supplements, and
each submission will require 3 hours to prepare, totaling 12 hours
annually.
Section 230.72 governs changes in ownership of a granted
certification. An example of when a change in ownership could occur is
during a merger or acquisition. Upon a change in ownership, the
regulations require that both the new and previous owner notify FDA.
Based on related submissions received by FDA over the last few years
and averaged accordingly, we estimate two respondents will submit four
letters or other supporting documents, requiring 2 hours to complete
each of the tasks, totaling 8 hours annually.
To assist respondents with the requirements associated with Sec.
230.80 (annual reports), we are developing an annual report form (Form
FDA 5025). We estimate that 57 applicants will submit 123 annual
reports to FDA. We estimate firms will expend 2 hours per report to
perform this activity, totaling 246 hours annually.
Our estimate associated with requirements in Sec. 230.205 for
field alert reporting for designated medical gases is based on our
prior experience with similar reports that FDA receives. We estimate
that FDA will receive a total of 3 field alert reports from the pool of
1,380 applicants and nonapplicants. We anticipate the respondents will
each expend approximately 8 hours to perform this activity, totaling 24
hours annually.
Section 230.210 requires that applicants and nonapplicants promptly
review all safety information that the applicant or nonapplicant
receives or otherwise obtains from any source (including both foreign
and domestic sources). Applicants and nonapplicants will generate
reports from review of the safety information and will submit the
reports under Sec. Sec. 230.220 and 230.230. As described in Sec.
230.220(a) through (d), firms are required to submit ICSRs associated
with the use of a designated medical gas in humans.
Section 230.220 contains requirements for submission of ICSRs
associated with the use of a designated medical gas in humans. Under
Sec. 230.220(a)(1), applicants and nonapplicants are required to
submit each ICSR as soon as possible, but no later than 15 calendar
days from the date the applicant or nonapplicant meets the reporting
criteria under Sec. 230.220(b) and acquires a minimum data set for an
ICSR for that adverse event.
Under Sec. 230.220(a)(3), applicants and nonapplicants will submit
new information they receive or otherwise obtain about an ICSR
previously submitted to FDA. The regulation prescribes reporting
schedules to ensure FDA becomes aware of any new information about the
adverse event in a timely manner.
Section 230.220(b) describes the types of ICSRs that applicants and
nonapplicants are required to report for human use. Under Sec.
230.220(b)(1), applicants and nonapplicants would be required to submit
ICSRs for serious adverse events. Under Sec. 230.220(b)(2), upon
notification by FDA, an applicant is required to report to FDA, in a
timeframe established by FDA, ICSRs for any adverse events that would
not be required under Sec. 230.220(b)(1).
Section 230.220(c) and (d) include additional requirements for the
content and format of human designated medical gas ICSRs. Under Sec.
230.220(a) through (d), we estimate that 1,430 applicants and
nonapplicants will submit to FDA 172 ICSRs annually. We previously
estimated it would take 6 hours for respondents to perform this
activity. Upon considering recent estimates for safety reporting that
describe a lower time burden (Ref. 6), we estimate it will be less
burdensome than we previously expected in the proposed rule for
designated medical gas applicants and nonapplicants to comply with ICSR
reporting requirements. Moreover, we do not anticipate that safety
reporting compliance will be more burdensome for human reports than for
animal reports. Therefore, we estimate that it will take 4 hours for
respondents to perform this activity, totaling 688 hours annually.
Under Sec. 230.230(a)(1), an applicant or nonapplicant will submit
serious adverse events related to the use of a designated medical gas
in animals to FDA as soon as possible but no later than 15 calendar
days from first receiving the information. The applicant or
nonapplicant will submit the report to FDA in electronic format as
described under Sec. 230.230(b)(1), unless the applicant or
nonapplicant obtains a waiver under Sec. 230.230(b)(2) or FDA requests
the report in an alternate format.
Under Sec. 230.230(a)(2), upon notification by FDA, applicants and
nonapplicants will submit reports of adverse events associated with the
use of a designated medical gas in animals that do not qualify for
reporting under Sec. 230.230(a)(1). The notice will specify the
adverse events to be reported and the reason for requiring the reports.
We anticipate that eight records will be submitted per year. We
previously estimated that it will take approximately 5 hours to perform
this activity. Upon considering recent estimates for safety reporting
that describe a lower time burden (Ref. 6; see also 84 FR 24798, May
29, 2019), we estimate it will be less burdensome than we previously
expected in the proposed rule for designated medical gas applicants and
nonapplicants to comply with adverse event reporting requirements.
Therefore, we estimate that it will take 4 hours for respondents to
perform this activity, totaling 32 hours annually.
Under Sec. 230.230(b)(2), an applicant or nonapplicant may
request, in writing, a temporary waiver of the electronic submission
requirements under Sec. 230.230(b)(1). An applicant or nonapplicant
will provide the initial request by telephone or email to Center for
Veterinary Medicine's (CVM's) Division of Pharmacovigilance and
Surveillance, with prompt written followup submitted as a letter to the
granted certification or certifications. FDA will grant waivers on a
limited basis for good cause shown. If FDA
[[Page 51764]]
grants a waiver, the applicant or nonapplicant is required to comply
with the conditions for reporting specified by FDA upon granting the
waiver. We estimate eight waiver requests will be submitted annually
and anticipate it will take 5 hours to prepare and submit the request
totaling 40 hours annually.
Table 5--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
[…truncated; see source link]Indexed from Federal Register on June 18, 2024.
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