Current Good Manufacturing Practice, Certification, Postmarketing Safety Reporting, and Labeling Requirements for Certain Medical Gases, 51738-51783 [2024-13190]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[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 [www.gpo.gov]
[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 https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule into 
the ``Search'' box and follow the prompts, and/or go to the Dockets 
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 
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, 
[email protected].
    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, 
[email protected].

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

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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

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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:
     General considerations, including general support, 
definitions, timing of the rule, and the effective date;
     Labeling requirements, including labeling statements and 
the applicability of labeling provisions to different types of 
containers;

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     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;
     Certification requirements, including annual reporting, 
withdrawal, and the applicability of current requirements in part 314 
(21 CFR part 314); and
     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

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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 
https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria.

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\
----------------------------------------------------------------------------------------------------------------
                                                                                            Average
                                                 Number of      Number of       Total      burden per    Total
           Activity; 21 CFR section             respondents   responses per     annual      response     hours
                                                               respondent     responses     (hours)
----------------------------------------------------------------------------------------------------------------
Submission of certification requests and                  5               1            5            3         15
 certification form (Form FDA 3864) that
 includes any resubmissions and amendments to
 pending requests; Sec.   230.50..............
Submission of supplements to certification                4               1            4            3         12
 requests and other changes; Sec.   230.70....
Submission of requests to transfer ownership              2               2            4            2          8
 of certification, including new address and
 the owner's submission of any change in the
 conditions in the granted certification; Sec.
   230.72.....................................
Submission of annual reports (Form FDA 5025);            57            2.15          123            2        246
 Sec.   230.80................................
Submission of field alert reports; Sec.               1,380           0.002            3            8         24
 230.205......................................
CDER: Submission of ICSRs (Sec.   230.220(a)          1,430            0.12          172            4        688
 through (d)).................................
CVM: Submission of adverse event reports; Sec.        1,696          0.0044            8            4         32
   230.230(a).................................
CVM: Waiver request from electronic submission        1,696          0.0044            8            5         40
 requirement; Sec.   230.230(b)...............
                                               -----------------------------------------------------------------
    Total.....................................  ...........  ..............          327  ...........      1,065
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    Section 230.220(e) prescribes requirements for keeping records 
pertaining to human designated medical gas adverse events. For a period 
of 10 years from the initial receipt of information, each applicant or 
nonapplicant is required to maintain records of information relating to 
adverse events, whether or not submitted to FDA. These records must 
include raw data, correspondence, and any other information relating to 
evaluating and reporting adverse event information that is received or 
otherwise obtained by the applicant or nonapplicant. Upon written 
notice by FDA, the applicant or nonapplicant will submit any and all of 
these records to FDA within 5 calendar days after receipt of the 
notice. The applicant or nonapplicant will permit any authorized FDA 
employee, at reasonable times, to access, copy, and verify the 
established and maintained records described in this section. We 
anticipate that 1,430 manufacturers will create 686 records pertaining 
to human designated medical gas requirements and it will take 
approximately 16 hours to perform this activity, totaling 10,976 hours 
annually.
    Section 230.230(c) prescribes requirements for records to be 
maintained for animal designated medical gas adverse events. For a 
period of 5 years from the initial receipt of information, each 
applicant or nonapplicant is required to maintain records of 
information relating to adverse events, whether or not submitted to 
FDA. These records must include raw data, correspondence, and any other 
information relating to evaluating and reporting adverse event 
information that is received or otherwise obtained by the applicant or 
nonapplicant. Upon written notice by FDA, the applicant or nonapplicant 
will submit any and all of these records to FDA within 5 calendar days 
after receipt of the notice. The applicant or nonapplicant will permit 
any authorized FDA employee, at reasonable times, to access, copy, and 
verify the established and maintained records described in this 
section. We anticipate that 1,696 manufacturers will create eight 
records pertaining to animal designated medical gas requirements and it 
will take approximately 5 hours to perform this activity, totaling 40 
hours annually.

                               Table 6--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                                                            Average
                                                Number of       Number of       Total      burden per    Total
          Activity; 21 CFR section            recordkeepers    records per      annual      response     hours
                                                              recordkeeper     records      (hours)
----------------------------------------------------------------------------------------------------------------
CDER's maintenance of records for human              1,430             0.48          686           16     10,976
 designated medical gas ICSR requirements;
 Sec.   230.220(e)..........................
CVM's recordkeeping requirements related to          1,696           0.0044            8            5         40
 adverse event reports; Sec.   230.230(c)...
                                             -------------------------------------------------------------------
    Total...................................  .............  ..............          694  ...........     11,016
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    The information collection provisions in this final rule have been 
submitted to OMB for review as required by section 3507(d) of the 
Paperwork Reduction Act of 1995. Before the effective date of this 
final rule, FDA will publish a notice in the Federal Register 
announcing OMB's decision to approve, modify, or disapprove the 
information collection provisions in this final rule. An Agency may not 
conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB 
control number.

X. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We have determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we conclude that the rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

[[Page 51765]]

XI. Consultation and Coordination With Indian Tribal Governments

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

XII. References

    The following references are on display at the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m. Monday through Friday; they are also 
available electronically at https://www.regulations.gov. Although FDA 
has verified the website addresses in this document, please note that 
websites are subject to change over time.

1. FDA draft guidance for industry ``Certification Process for 
Designated Medical Gases,'' November 2015, available at https://www.fda.gov/media/85013/download.
2. Kreiter, P., T.G. Bizjak, and R.L. Friedman, ``Preventing 
Patients From Receiving Leaking or Empty Containers of Medical Gas: 
A Review of Inspectional Findings From 2003 to 2021,'' CDER Office 
of Manufacturing Quality, December 2021, U.S. Food and Drug 
Administration.
3. FDA, Compliance Program Guidance Manual 7356.002E, ``Compressed 
Medical Gases,'' March 15, 2015, available at https://www.fda.gov/media/75194/download.
4. FDA guidance for industry ``Postmarketing Adverse Event Reporting 
for Nonprescription Human Drug Products Marketed Without an Approved 
Application,'' July 2009; available at https://www.fda.gov/media/77193/download.
5. FDA draft guidance for industry ``Postmarketing Safety Reporting 
for Human Drug and Biological Products Including Vaccines,'' March 
2001, available at https://www.fda.gov/media/73593/download.
6. FDA, Final Regulatory Impact Analysis: Current Good Manufacturing 
Practice, Certification, Postmarketing Safety Reporting, and 
Labeling Requirements for Certain Medical Gases, available at 
https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-riahttps://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-riahttps://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria.

    The following standards appear in the amendatory text of this 
document and were approved for Sec.  4.4 in the final rule published at 
89 FR 7496 (which will be effective February 2, 2026): ISO 13485 and 
ISO 9000. No changes are proposed to the incorporation by reference 
(IBR) material.

List of Subjects

21 CFR Part 4

    Biologics, Drugs, Human cells and tissue-based products, 
Incorporation by reference, Medical devices.

21 CFR Part 16

    Administrative practice and procedure.

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 210

    Drugs, Packaging and containers.

21 CFR Part 211

    Drugs, Labeling, Laboratories, Packaging and containers, 
Prescription drugs, Reporting and recordkeeping requirements, 
Warehouses.

21 CFR Part 213

    Drugs, Labeling, Laboratories, Packaging and containers, 
Prescription drugs, Reporting and recordkeeping requirements, 
Warehouses.

21 CFR Part 230

    Administrative practice and procedure, Animal drugs, Drugs, 
Reporting and recordkeeping requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 514

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, 
chapter I of title 21 of the Code of Federal Regulations is amended as 
follows:

PART 4--REGULATION OF COMBINATION PRODUCTS

0
1. The authority citation for part 4 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360b-
360f, 360h-360j, 360l, 360hh-360ss, 360aaa-360bbb, 360ddd, 360ddd-1, 
371(a), 372-374, 379e, 381, 383, 394; 42 U.S.C. 216, 262, 263a, 264, 
271.


0
2. Effective February 2, 2026, revise Sec.  4.2 to read as follows:


Sec.  4.2   How does FDA define key terms and phrases in this subpart?

    The terms listed in this section have the following meanings for 
purposes of this subpart:
    Biological product has the meaning set forth in Sec.  3.2(d) of 
this chapter. A biological product also meets the definitions of either 
a drug or device as these terms are defined under this section.
    Combination product has the meaning set forth in Sec.  3.2(e) of 
this chapter.
    Constituent part is a drug, device, or biological product that is 
part of a combination product.
    Co-packaged combination product has the meaning set forth in Sec.  
3.2(e)(2) of this chapter.
    Current good manufacturing practice operating system means the 
operating system within an establishment that is designed and 
implemented to address and meet the current good manufacturing practice 
requirements for a combination product.
    Current good manufacturing practice requirements means the 
requirements set forth under Sec.  4.3(a) through (e).
    Device has the meaning set forth in Sec.  3.2(f) of this chapter. A 
device that is a constituent part of a combination product is 
considered a finished device within the meaning of the Quality 
Management System Regulation (QMSR).
    Drug has the meaning set forth in Sec.  3.2(g) of this chapter and 
includes medical gas as defined in section 575(2) of the Federal Food, 
Drug, and Cosmetic Act. Medical gas includes designated medical gases 
as defined in section 575(1) of the Federal Food, Drug, and Cosmetic 
Act and medical gases approved under section 505 of the Federal Food, 
Drug, and Cosmetic Act. A drug other than a medical gas that is a 
constituent part of a combination product is considered a drug product 
within the meaning of the drug current good manufacturing practice 
(CGMP) requirements. A drug that is a medical gas that is a constituent 
part of a combination product is considered a medical gas within the 
meaning of the medical gas CGMP requirements.
    Drug CGMP requirements refers to the current good manufacturing 
practice regulations set forth in parts 210 and 211 of this chapter.
    HCT/Ps refers to human cell, tissue, and cellular and tissue-based 
products,

[[Page 51766]]

as defined in Sec.  1271.3(d) of this chapter. An HCT/P that is not 
regulated solely under section 361 of the Public Health Service Act may 
be a constituent part of a combination product. Such an HCT/P is 
subject to part 1271 of this chapter and is also regulated as a drug, 
device, and/or biological product.
    Manufacture includes, but is not limited to, designing, 
fabricating, assembling, filling, processing, testing, labeling, 
packaging, repackaging, holding, and storage.
    Medical gas CGMP requirements refers to the current good 
manufacturing practice regulations set forth in part 213 of this 
chapter.
    QMSR refers to the requirements under part 820 of this chapter.
    Single-entity combination product has the meaning set forth in 
Sec.  3.2(e)(1) of this chapter.
    Type of constituent part refers to the category of the constituent 
part, which can be either a biological product, a device, or a drug, as 
these terms are defined under this section.


0
3. Effective February 2, 2026, amend Sec.  4.3 by revising paragraphs 
(a), (c), and (d) and adding paragraph (e) to read as follows:


Sec.  4.3   What current good manufacturing practice requirements apply 
to my combination product?

* * * * *
    (a) The current good manufacturing practice requirements in parts 
210 and 211 of this chapter apply to a combination product that 
includes a drug constituent part other than a medical gas;
* * * * *
    (c) The current good manufacturing practice requirements among the 
requirements (including standards) for biological products in parts 600 
through 680 of this chapter apply to a combination product that 
includes a biological product constituent part to which those 
requirements would apply if that constituent part were not part of a 
combination product;
    (d) The current good tissue practice requirements including donor 
eligibility requirements for HCT/Ps in part 1271 of this chapter apply 
to a combination product that includes an HCT/P; and
    (e) The current good manufacturing practice requirements in part 
213 of this chapter apply to a combination product that includes a drug 
constituent part that is a medical gas.


0
4. Effective February 2, 2026, amend Sec.  4.4 by:
0
a. Revising paragraphs (b)(1) introductory text and (b)(2) introductory 
text;
0
b. Redesignating paragraphs (b)(3) and (4) as paragraphs (b)(4) and 
(5), respectively;
0
c. Adding new paragraph (b)(3); and
0
d. Revising paragraph (e).
    The revisions and addition read as follows:


Sec.  4.4   How can I comply with these current good manufacturing 
practice requirements for a co-packaged or single-entity combination 
product?

* * * * *
    (b) * * *
    (1) If the combination product includes a device constituent part 
and a drug constituent part, and the current good manufacturing 
practice operating system has been shown to comply with the drug CGMP 
requirements or the medical gas CGMP requirements, as applicable, the 
following clauses of ISO 13485 (together with the definitions in Clause 
3 of ISO 9000), which is incorporated by reference into the QMSR under 
Sec.  820.7 of this chapter, and certain other provisions within the 
QMSR must also be shown to have been satisfied; upon demonstration that 
these requirements have been satisfied, no additional showing of 
compliance with respect to the QMSR need be made:
* * * * *
    (2) If the combination product includes a device constituent part 
and a drug constituent part other than a medical gas, and the current 
good manufacturing practice operating system has been shown to comply 
with the QMSR requirements for devices, the following provisions of the 
drug CGMP requirements must also be shown to have been satisfied; upon 
demonstration that these requirements have been satisfied, no 
additional showing of compliance with respect to the drug CGMP 
requirements need be made:
* * * * *
    (3) If the combination product includes a device constituent part 
and a drug constituent part that is a medical gas, and the current good 
manufacturing practice operating system has been shown to comply with 
the QMSR regulation, the following provisions of the medical gas CGMP 
requirements must also be shown to have been satisfied; upon 
demonstration that these requirements have been satisfied, no 
additional showing of compliance with respect to the medical gas CGMP 
requirements need be made:
    (i) Section 213.84 of this chapter. Testing and approval or 
rejection of components, containers, and closures.
    (ii) Section 213.94 of this chapter. Medical gas containers and 
closures.
    (iii) Section 213.122 of this chapter. Materials examination and 
usage criteria.
    (iv) Section 213.165 of this chapter. Testing and release for 
distribution.
    (v) Section 213.166 of this chapter. Stability testing and 
expiration dating for medical gases marketed under applications 
submitted under section 505 or section 512 of the Federal Food, Drug, 
and Cosmetic Act.
    (vi) Section 213.204 of this chapter. Returned medical gases.
    (vii) Section 213.208 of this chapter. Salvaging of medical gases.
* * * * *
    (e) The requirements set forth in this subpart and in parts 210, 
211, 213, 820, 600 through 680, and 1271 of this chapter listed in 
Sec.  4.3, supplement, and do not supersede, each other unless the 
regulations explicitly provide otherwise. In the event of a conflict 
between regulations applicable under this subpart to combination 
products, including their constituent parts, the regulations most 
specifically applicable to the constituent part in question shall 
supersede the more general.
* * * * *

PART 16--REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION

0
5. The authority citation for part 16 continues to read as follows:

    Authority:  15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394, 
467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.


0
6. Amend Sec.  16.1 by revising paragraph (b)(2) to read as follows:


Sec.  16.1   Scope.

* * * * *
    (b) * * *
    (2) The regulatory provisions are as follows:

                       Table 1 to Paragraph (b)(2)
------------------------------------------------------------------------
 
-------------------------------------------------------------------------
Sections 1.634 and 1.664, relating to revocation of recognition of an
 accreditation body and withdrawal of accreditation of third-party
 certification bodies that conduct food safety audits of eligible
 entities in the food import supply chain and issue food and facility
 certifications.
Section 1.1173, relating to the revocation of recognition of an
 accreditation body, and the disqualification of a laboratory, with
 respect to food testing conducted under part 1, subpart R of this
 chapter.

[[Page 51767]]

 
Section 1.1174, relating to the issuance of a directed food laboratory
 order by FDA pursuant to Sec.   1.1108.
Section 56.121(a), relating to disqualifying an institutional review
 board or an institution.
Section 58.204(b), relating to disqualifying a testing facility.
Section 71.37(a), relating to use of food containing a color additive.
Section 80.31(b), relating to refusal to certify a batch of a color
 additive.
Section 80.34(b), relating to suspension of certification service for a
 color additive.
Section 99.401(c), relating to a due diligence determination concerning
 the conduct of studies necessary for a supplemental application for a
 new use of a drug or device.
Sections 112.201 through 112.213, (see part 112, subpart R of this
 chapter), relating to withdrawal of a qualified exemption.
Sections 117.251 through 117.287 (part 117, subpart E of this chapter),
 relating to withdrawal of a qualified facility exemption.
Section 130.17(1), relating to a temporary permit to vary from a food
 standard.
Section 170.17(b), relating to use of food containing an investigational
 food additive.
Section 202.1(j)(5), relating to approval of prescription drug
 advertisements.
Section 230.150(b), relating to revocation of the grant of a
 certification for a designated medical gas.
Section 312.70, relating to whether an investigator is eligible to
 receive test articles under part 312 of this chapter and eligible to
 conduct any clinical investigation that supports an application for a
 research or marketing permit for products regulated by FDA, including
 drugs, biologics, devices, new animal drugs, foods, including dietary
 supplements, that bear a nutrient content claim or a health claim,
 infant formulas, food and color additives, and tobacco products.
Sections 312.70(d) and 312.44, relating to termination of an IND for a
 sponsor.
Section 312.160(b), relating to termination of an IND for tests in vitro
 and in laboratory research animals for a sponsor.
Section 507.60 through 507.85 (part 507, subpart D of this chapter)
 relating to withdrawal of a qualified facility exemption.
Section 511.1(b)(5), relating to use of food containing an
 investigational new animal drug.
Section 511.1(c)(1), relating to whether an investigator is eligible to
 receive test articles under part 511 of this chapter and eligible to
 conduct any clinical investigation that supports an application for a
 research or marketing permit for products regulated by FDA including
 drugs, biologics, devices, new animal drugs, foods, including dietary
 supplements, that bear a nutrient content claim or a health claim,
 infant formulas, food and color additives, and tobacco products; and
 any nonclinical laboratory study intended to support an application for
 a research or marketing permit for a new animal drug.
Section 511.1(c)(4) and (d), relating to termination of an INAD for a
 sponsor.
Section 812.119, relating to whether an investigator is eligible to
 receive test articles under part 812 of this chapter and eligible to
 conduct any clinical investigation that supports an application for a
 research or marketing permit for products regulated by FDA including
 drugs, biologics, devices, new animal drugs, foods, including dietary
 supplements, that bear a nutrient content claim or a health claim,
 infant formulas, food and color additives, and tobacco products.
Section 814.46(c) relating to withdrawal of approval of a device
 premarket approval application.
Section 822.7(a)(3), relating to an order to conduct postmarket
 surveillance of a medical device under section 522 of the act.
Section 830.130, relating to suspension or revocation of the
 accreditation of an issuing agency.
Section 895.30(c), regarding a proposed regulation to ban a medical
 device with a special effective date.
Section 900.7, relating to approval, reapproval, or withdrawal of
 approval of mammography accreditation bodies or rejection of a proposed
 fee for accreditation.
Section 900.14, relating to suspension or revocation of a mammography
 certificate.
Section 900.25, relating to approval or withdrawal of approval of
 certification agencies.
Section 1003.11(a)(3), relating to the failure of an electronic product
 to comply with an applicable standard or to a defect in an electronic
 product.
Section 1003.31(d), relating to denial of an exemption from notification
 requirements for an electronic product which fails to comply with an
 applicable standard or has a defect.
Section 1004.6, relating to plan for repurchase, repair, or replacement
 of an electronic product.
Section 1107.1(d), relating to rescission of an exemption from the
 requirement of demonstrating substantial equivalence for a tobacco
 product.
Section 1107.50, relating to rescission of an order finding a tobacco
 product substantially equivalent.
Section 1210.30, relating to denial, suspension, or revocation of a
 permit under the Federal Import Milk Act.
Section 1270.43(e), relating to the retention, recall, and destruction
 of human tissue.
Section 1271.440(e) relating to the retention, recall, and destruction
 of human cells, tissues, and cellular and tissue-based products (HCT/
 Ps), and/or the cessation of manufacturing HCT/Ps.
------------------------------------------------------------------------

PART 201--LABELING

0
7. The authority citation for part 201 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 343, 351, 352, 353, 355, 358, 
360, 360b, 360ccc, 360ccc-1, 360ddd, 360ddd-1, 360ee, 360gg-360ss, 
371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.


0
8. Amend Sec.  201.1 by revising paragraph (b) to read as follows:


Sec.  201.1   Drugs; name and place of business of manufacturer, 
packer, or distributor.

* * * * *
    (b) As used in this section, and for purposes of section 502(a) and 
(b)(1) of the Federal Food, Drug, and Cosmetic Act, the manufacturer of 
a drug product is the person who performs all of the following 
operations that are required to produce the product:
    (1) Mixing;
    (2) Granulating;
    (3) Milling;
    (4) Molding;
    (5) Lyophilizing;
    (6) Tableting;
    (7) Encapsulating;
    (8) Coating;
    (9) Sterilizing;
    (10) Filling sterile or aerosol drugs into dispensing containers; 
and
    (11) With respect to a medical gas, fabricating the gas by chemical 
reaction, physical separation, compression of atmospheric air, 
purification (e.g., re-processing an industrial gas into a medical 
gas), combining two or more distinct medical gases, or other process.
* * * * *

0
9. Amend Sec.  201.10 by revising paragraph (d)(2) to read as follows:


Sec.  201.10   Drugs; statement of ingredients.

* * * * *
    (d) * * *
    (2) A statement of the percentage of an ingredient in a drug shall, 
if the term percent is used without qualification, mean percent weight-
in-weight, if the ingredient and the drug are both solids, or if the 
ingredient is a liquid and the drug is a solid; percent weight in

[[Page 51768]]

volume at 68 [deg]F (20 [deg]C), if the ingredient is a solid and the 
drug is a liquid; percent volume in volume at 68 [deg]F (20 [deg]C), if 
both the ingredient and the drug are liquids, except that alcohol shall 
be stated in terms of percent volume of absolute alcohol at 60 [deg]F 
(15.56 [deg]C); and percent volume in volume if the ingredient is a 
designated medical gas (as defined in Sec.  201.161(c)(1)).
* * * * *


0
10. Amend Sec.  201.51 by revising paragraphs (a) and (b) to read as 
follows:


Sec.  201.51   Declaration of net quantity of contents.

    (a) The label of a prescription or insulin-containing drug in 
package form shall bear a declaration of the net quantity of contents. 
This shall be expressed in the terms of weight, measure, numerical 
count, or a combination of numerical count and weight or measure. The 
statement of quantity of drugs in tablet, capsule, ampule, or other 
unit dosage form shall be expressed in terms of numerical count; the 
statement of quantity for drugs in other dosage forms shall be in terms 
of weight if the drug is solid, semi-solid, or viscous, in terms of 
fluid measure if the drug is liquid, or in terms of volume measure if 
the drug is a designated medical gas (as defined in Sec.  
201.161(c)(1)) or a medically appropriate combination of designated 
medical gases in a gaseous state. When the drug quantity statement is 
in terms of the numerical count of the drug units, it shall be 
augmented to give the weight or measure of the drug units or the 
quantity of each active ingredient in each drug unit or, when quantity 
does not accurately reflect drug potency, a statement of the drug 
potency.
    (b) Statements of weight of the contents shall in the case of 
prescription drugs be expressed in terms of avoirdupois pound, ounce, 
and grain or of kilogram, gram, and subdivisions thereof. A statement 
of liquid measure of the contents shall in the case of prescription 
drugs other than designated medical gases and medically appropriate 
combinations thereof be expressed in terms of the U.S. gallon of 231 
cubic inches and quart, pint, fluid-ounce, and fluid-dram subdivisions 
thereof, or of the liter and milliliter, or cubic centimeter, and shall 
express the volume at 68 [deg]F (20 [deg]C). A statement of the liquid 
measure of the contents in the case of insulin-containing drugs shall 
be expressed in terms of the liter and milliliter, or cubic centimeter, 
and shall express the volume at 68 [deg]F (20 [deg]C). A statement of 
the measure of the contents shall in the case of designated medical 
gases (as defined in Sec.  201.161(c)(1)) and medically appropriate 
combinations thereof be expressed as follows:
    (1) If in a gaseous state in a high-pressure container, it shall be 
expressed in liters or cubic feet based on the filled pressure at 70 
[deg]F (21 [deg]C);
    (2) If in a liquefied compressed gas state in a high-pressure 
container, it shall be expressed in gaseous liters or by an appropriate 
net weight statement;
    (3) If in a liquefied state in a portable cryogenic container, it 
shall be expressed in gaseous liters, liquid liters (if identified as a 
liquid measure), gallons, or by an appropriate net weight statement at 
the time of fill; and
    (4) If in a bulk or transport container (as defined in Sec.  
201.161(c)(3)), labeling for net quantity of contents is not required.
* * * * *


0
11. Amend Sec.  201.105 by revising the introductory text to read as 
follows:


Sec.  201.105   Veterinary drugs.

    A drug subject to the requirements of section 503(f)(1) of the act 
shall be exempt from section 502(f)(1) of the act if it is a designated 
medical gas (as defined in Sec.  201.161(c)(1)) or a medically 
appropriate combination of designated medical gases and is in 
compliance with Sec.  201.161, or if all the following conditions are 
met:
* * * * *


0
12. Revise Sec.  201.161 to read as follows:


Sec.  201.161   Medical gases.

    (a) The requirements of sections 503(b)(4) and 502(f) of the 
Federal Food, Drug, and Cosmetic Act are deemed to have been met for a 
designated medical gas or a medically appropriate combination of 
designated medical gases if the labeling on its final use container 
bears the following:
    (1) In the case of oxygen:
    (i) A warning statement providing that uninterrupted use of high 
concentrations of oxygen over a long duration, without monitoring its 
effect on oxygen content of arterial blood, may be harmful; that oxygen 
should not be used on patients who have stopped breathing unless used 
in conjunction with resuscitative equipment; and, in the case of oxygen 
that may be provided without a prescription for use in the event of 
depressurization or other environmental oxygen deficiency, or for 
oxygen deficiency or for use in emergency resuscitation when 
administered by properly trained personnel, a warning statement 
providing that oxygen may be used for emergency use only when 
administered by properly trained personnel for oxygen deficiency and 
resuscitation, and that for all other medical applications a 
prescription is required.
    (ii) A clear and prominent warning containing the statements ``No 
Smoking'' and ``No Vaping'' and a graphic symbol conveying that 
smoking, vaping, and open flames near oxygen are dangerous.
    (2) In the case of a designated medical gas other than oxygen, and 
in the case of medically appropriate combinations of any designated 
medical gases:
    (i) A warning statement providing that the administration of the 
gas or gas combination (as applicable) may be hazardous or 
contraindicated; and that the gas or gas combination (as applicable) 
should be used only by or under the supervision of a licensed 
practitioner who is experienced in the use and administration of the 
gas or gas combination (as applicable) and is familiar with the 
indications, effects, dosages, methods, and frequency and duration of 
administration, and with the hazards, contraindications, and side 
effects and the precautions to be taken.
    (ii) The symbol ``Rx only.''
    (3) Appropriate directions and warnings concerning storage and 
handling.
    (b) A designated medical gas or medically appropriate combination 
of designated medical gases in a bulk or transport container must be 
identified with the name of the product contained therein and 
accompanied by documentation identifying the product as meeting 
applicable compendial standards.
    (c) For purposes of this section:
    (1) A designated medical gas means a drug that:
    (i) Is manufactured or stored in a liquefied, nonliquefied, or 
cryogenic state;
    (ii) Is administered as a gas; and
    (iii) Meets the definition in section 575(1) of the Federal Food, 
Drug, and Cosmetic Act.
    (2) A final use container means 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. The term final use container does not include 
bulk or transport containers and does not include containers that are 
described in Sec.  868.5655 of this chapter.
    (3) A bulk or transport container means a container used to 
transport or store designated medical gases or medically appropriate 
combinations of designated medical gases and that is not used directly 
to administer such gases to a patient.


[[Page 51769]]



0
13. Amend Sec.  201.328 by revising paragraphs (a) introductory text 
and (a)(1) introductory text and adding paragraph (d) to read as 
follows:


Sec.  201.328   Labeling of medical gas containers.

    (a) Portable cryogenic medical gas containers. For the purposes of 
this section a portable cryogenic medical gas container is one 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 used 
to fill small cryogenic gas containers for use by individual patients. 
The term excludes 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 at Sec.  
868.5655 of this chapter).
    (1) Each portable cryogenic medical gas container must be 
conspicuously marked with a 360[deg] wraparound label identifying its 
contents. Such label must meet the requirements of Sec.  213.94(e)(3) 
of this chapter and the following additional requirements.
* * * * *
    (d) Statement identifying owner or return address of medical gas 
containers. Notwithstanding Sec.  201.1, a container filled with a 
designated medical gas (as defined in Sec.  201.161(c)(1)) 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. Such 
statement may appear on a separate sticker or decal. If the owner of 
the medical gas 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. The addition of such statement shall not cause the 
owner of the cylinder to be a ``relabeler'' for purposes of 
registration and listing under part 207 of this chapter.

PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, 
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

0
14. The authority citation for part 210 is revised to read as follows:

    Authority:  21 U.S.C. 321, 351, 352, 355, 360b, 360ddd, 360ddd-
1, 371, 374; 42 U.S.C. 216, 262, 263a, 264.


0
15. Amend Sec.  210.1 by revising paragraphs (a) and (b) to read as 
follows:


Sec.  210.1   Status of current good manufacturing practice 
regulations.

    (a) The regulations set forth in this part and in parts 211, 213, 
225, and 226 of this chapter contain the minimum current good 
manufacturing practice for methods to be used in, and the facilities or 
controls to be used for, the manufacture, processing, packing, or 
holding of a drug to assure that such drug meets the requirements of 
the act as to safety, and has the identity and strength and meets the 
quality and purity characteristics that it purports or is represented 
to possess.
    (b) The failure to comply with any regulation set forth in this 
part and in parts 211, 213, 225, and 226 of this chapter in the 
manufacture, processing, packing, or holding of a drug shall render 
such drug to be adulterated under section 501(a)(2)(B) of the act and 
such drug, as well as the person who is responsible for the failure to 
comply, shall be subject to regulatory action.
* * * * *


0
16. Amend Sec.  210.2 by revising paragraphs (a) and (b) to read as 
follows:


Sec.  210.2   Applicability of current good manufacturing practice 
regulations.

    (a) The regulations in this part and in parts 211, 213, 225, and 
226 of this chapter as they may pertain to a drug; in parts 600 through 
680 of this chapter as they may pertain to a biological product for 
human use; and in part 1271 of this chapter as they are applicable to a 
human cell, tissue, or cellular or tissue-based product (HCT/P) that is 
regulated as a drug (subject to premarket review under an application 
submitted under section 505 of the act or under a biologics license 
application under section 351 of the Public Health Service Act); shall 
be considered to supplement, not supersede, each other, unless the 
regulations explicitly provide otherwise. In the event of a conflict 
between applicable regulations in this part and in other parts of this 
chapter, the regulation specifically applicable to the drug product in 
question shall supersede the more general.
    (b) If a person engages in only some operations subject to the 
regulations in this part and in parts 211, 213, 225, 226, 600 through 
680, and 1271 of this chapter, and not in others, that person need only 
comply with those regulations applicable to the operations in which the 
person is engaged.
* * * * *

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED 
PHARMACEUTICALS

0
17. The authority citation for part 211 is revised to read as follows:

    Authority:  21 U.S.C. 321, 351, 352, 355, 360b, 360ddd, 360ddd-
1, 371, 374; 42 U.S.C. 216, 262, 263a, 264.


0
18. Amend Sec.  211.1 by revising paragraph (a) to read as follows:


Sec.  211.1   Scope.

    (a) The regulations in this part contain the minimum current good 
manufacturing practice for preparation of drug products (excluding 
positron emission tomography drugs and medical gases as defined in 
Sec.  213.3(b)(12) of this chapter) for administration to humans or 
animals.
* * * * *


Sec.  211.94   [Amended]

0
19. Amend Sec.  211.94 by removing paragraph (e).


0
20. Amend Sec.  211.125 by revising paragraph (c) to read as follows:


Sec.  211.125   Labeling issuance.

* * * * *
    (c) Procedures shall be used to reconcile the quantities of 
labeling issued, used, and returned, and shall require evaluation of 
discrepancies found between the quantity of drug product finished and 
the quantity of labeling issued when such discrepancies are outside 
narrow preset limits based on historical operating data. Such 
discrepancies shall be investigated in accordance with Sec.  211.192. 
Labeling reconciliation is waived for cut or roll labeling if a 100-
percent examination for correct labeling is performed in accordance 
with Sec.  211.122(g)(2).
* * * * *


0
21. Amend Sec.  211.132 by revising paragraph (c)(1) introductory text 
to read as follows:


Sec.  211.132   Tamper-evident packaging requirements for over-the-
counter (OTC) human drug products.

* * * * *
    (c) * * *
    (1) In order to alert consumers to the specific tamper-evident 
feature(s) used, each retail package of an OTC drug product covered by 
this section (except ammonia inhalant in crushable glass ampules or 
aerosol products that depend upon the power of a liquefied or 
compressed gas to expel the contents from the container) is required to 
bear a statement that:
* * * * *


[[Page 51770]]



0
22. Amend Sec.  211.170 by revising paragraph (b) introductory text to 
read as follows:


Sec.  211.170   Reserve samples.

* * * * *
    (b) An appropriately identified reserve sample that is 
representative of each lot or batch of drug product shall be retained 
and stored under conditions consistent with product labeling. The 
reserve sample shall be stored in the same immediate container-closure 
system in which the drug product is marketed or in one that has 
essentially the same characteristics. The reserve sample consists of at 
least twice the quantity necessary to perform all the required tests, 
except those for sterility and pyrogens. Except for those for drug 
products described in paragraph (b)(2) of this section, reserve samples 
from representative sample lots or batches selected by acceptable 
statistical procedures shall be examined visually at least once a year 
for evidence of deterioration unless visual examination would affect 
the integrity of the reserve sample. Any evidence of reserve sample 
deterioration shall be investigated in accordance with Sec.  211.192. 
The results of the examination shall be recorded and maintained with 
other stability data on the drug product. The retention time is as 
follows:
* * * * *


0
23. Revise Sec.  211.196 to read as follows:


Sec.  211.196   Distribution records.

    Distribution records shall contain the name and strength of the 
product and description of the dosage form, name and address of the 
consignee, date and quantity shipped, and lot or control number of the 
drug product.


0
24. Add part 213 to subchapter C to read as follows:

PART 213--CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICAL GASES

Subpart A--General Provisions
Sec.
213.1 Scope.
213.3 Definitions.
Subpart B--Organization and Personnel
213.22 Responsibilities of quality unit.
213.25 Personnel qualifications and responsibilities.
213.34 Consultants.
Subpart C--Buildings and Facilities
213.42 Design and construction features.
Subpart D--Equipment
213.63 Equipment design, size, and location.
213.65 Equipment construction.
213.67 Equipment maintenance and cleaning.
213.68 Automatic, mechanical, and electronic equipment.
Subpart E--Control of Incoming Designated Medical Gas, Components, and 
Medical Gas Containers and Closures
213.80 General requirements.
213.82 Receipt and storage of incoming designated medical gases.
213.84 Testing and approval or rejection of components, containers, 
and closures.
213.89 Rejected components, incoming designated medical gases, and 
medical gas containers and closures.
213.94 Medical gas containers and closures.
Subpart F--Production and Process Controls
213.100 Written procedures; deviations.
213.101 Charge-in of components and incoming designated medical 
gases.
213.110 Sampling and testing of in-process materials.
Subpart G--Packaging and Labeling Control
213.122 Materials examination and usage criteria.
213.125 Labeling issuance.
213.130 Packaging and labeling operations.
Subpart H--Holding and Distribution
213.150 Warehousing and distribution procedures.
Subpart I--Laboratory Controls
213.160 General requirements.
213.165 Testing and release for distribution.
213.166 Stability testing and expiration dating for medical gases 
marketed under applications submitted under section 505 or section 
512 of the Federal Food, Drug, and Cosmetic Act.
Subpart J--Records
213.180 General requirements.
213.182 Equipment cleaning and use log.
213.184 Records for components, medical gas containers and closures, 
and labeling.
213.186 Master production and control records.
213.189 Batch production and control records.
213.192 Production record review.
213.194 Laboratory records.
213.196 Distribution records.
213.198 Complaint files.
Subpart K--Returned and Salvaged Medical Gases
213.204 Returned medical gases.
213.208 Salvaging of medical gases.

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360b, 360ddd, 
360ddd-1, 371, 374.

Subpart A--General Provisions


Sec.  213.1   Scope.

    The regulations in this part contain the minimum current good 
manufacturing practice for preparation of medical gases for 
administration to humans or animals.


Sec.  213.3   Definitions.

    (a) The definitions and interpretations contained in section 201 of 
the Federal Food, Drug, and Cosmetic Act shall be applicable to such 
terms when used in this part.
    (b) The following definitions of terms apply to this part:
    (1) Acceptance criteria means 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).
    (2) Batch means 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.
    (3) Commingling or commingled refers to 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.
    (4) Component means any ingredient intended for use in the 
manufacture of a medical gas, including those that may not appear in 
such gas. It does not include an incoming designated medical gas.
    (5) Designated medical gas means a drug that is manufactured or 
stored in a liquefied, nonliquefied, or cryogenic state; is 
administered as a gas; and is defined in section 575(1) of the Federal 
Food, Drug, and Cosmetic Act.
    (6) FDA means the Food and Drug Administration.
    (7) In-process material means any material fabricated, compounded, 
blended, or derived by chemical reaction that is produced for, and used 
in, the preparation of the medical gas.
    (8) Incoming designated medical gas means 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.
    (9) Lot means a batch, or a specific identified portion of a batch, 
having uniform character and quality within specified limits; or, in 
the case of a medical gas produced by continuous process, it is a 
specific identified amount produced in a unit of time or quantity in a 
manner that assures its having uniform character and quality within 
specified limits.
    (10) Lot number, control number, or batch number means any 
distinctive

[[Page 51771]]

combination of letters, numbers, or symbols, or any combination of 
them, from which the complete history of the manufacture, processing, 
packing, holding, and distribution of a batch or lot of medical gas or 
other material can be determined.
    (11) Manufacture, processing, packing, or holding of medical gases 
includes packaging and labeling operations, testing, and quality 
control.
    (12) Medical gas has the meaning given the term in section 575(2) 
of the Federal Food, Drug, and Cosmetic Act.
    (13) Original manufacturer means the person 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.
    (14) Quality unit means any person or persons designated with the 
authority and responsibility for overall quality management and other 
responsibilities as defined in Sec.  213.22.
    (15) Strength means:
    (i) The concentration of the medical gas (for example, weight/
weight, weight/volume, or unit dose/volume basis); and/or
    (ii) The potency, that is, the therapeutic activity of the medical 
gas as indicated by appropriate laboratory tests or by adequately 
developed and controlled clinical data (expressed, for example, in 
terms of units by reference to a standard).

Subpart B--Organization and Personnel


Sec.  213.22   Responsibilities of quality unit.

    (a) There shall be a quality unit that shall have the 
responsibility and authority to approve or reject all components, 
medical gas containers and closures, in-process materials, packaging 
material, labeling, and medical gases, and the authority to review 
production records to assure that no errors have occurred or, if errors 
have occurred, that they have been fully investigated. The quality unit 
shall be responsible for approving or rejecting medical gases 
manufactured, processed, packed, or held under contract by another 
company.
    (b) Adequate laboratory facilities for the testing and approval (or 
rejection) of components, medical gas containers and closures, 
packaging materials, in-process materials, and medical gases shall be 
available to the quality unit.
    (c) The quality unit shall have the responsibility for approving or 
rejecting all procedures or specifications impacting on the identity, 
strength, quality, and purity of the medical gas.
    (d) The responsibilities and procedures applicable to the quality 
unit shall be in writing; such written procedures shall be followed.
    (e) Quality unit personnel may perform other functions provided 
appropriate written controls are in place to ensure any other functions 
are performed separately from quality unit responsibilities and such 
other functions do not interfere with the quality unit's 
responsibilities or subordinate the quality unit's responsibilities to 
any other unit.


Sec.  213.25   Personnel qualifications and responsibilities.

    (a) Each person engaged in the manufacture, processing, packing, or 
holding of a medical gas shall have education, training, and 
experience, or any combination thereof, to enable that person to 
perform the assigned functions. Training shall be in the particular 
operations that the employee performs and in current good manufacturing 
practice (including the current good manufacturing practice regulations 
in this chapter and written procedures required by these regulations) 
as they relate to the employee's functions. Training in current good 
manufacturing practice shall be conducted by qualified individuals on a 
continuing basis and with sufficient frequency to assure that employees 
remain familiar with current good manufacturing practice requirements 
applicable to them. Written documentation shall be maintained 
demonstrating the completion of employee training, and shall include 
the date of the training, the type of the training, and the results of 
any completion criteria, such as test results.
    (b) There shall be an adequate number of qualified personnel to 
perform the manufacture, processing, packing, or holding of each 
medical gas.
    (c) Only authorized personnel shall enter those areas of the 
buildings and facilities designated as limited-access areas.


Sec.  213.34   Consultants.

    Consultants advising on the manufacture, processing, packing, or 
holding of medical gases shall have sufficient education, training, and 
experience, or any combination thereof, to advise on the subject for 
which they are retained. Records shall be maintained stating the name, 
address, and qualifications of any consultants and the type of service 
they provide.

Subpart C--Buildings and Facilities


Sec.  213.42   Design and construction features.

    (a)(1) Any buildings and facilities used in the manufacture, 
processing, packing, or holding of a medical gas shall be of adequate 
design, including having adequate space, for the orderly placement of 
equipment and materials to prevent mix-ups between:
    (i) Components;
    (ii) Incoming designated medical gases;
    (iii) Medical gas containers and closures;
    (iv) Labeling;
    (v) In-process materials; or
    (vi) Medical gases.
    (2) Such buildings and facilities shall also allow for adequate 
cleaning, maintenance, and proper operations.
    (b)(1) Operations shall be performed within specifically defined 
areas of adequate size. There shall be separate or defined areas or 
such other control systems for the firm's operations as are necessary 
to prevent contamination or mix-ups during the course of the following 
procedures:
    (i) Receipt, identification, storage, and withholding from use of 
components, incoming designated medical gases, medical gas containers 
and closures, and labeling, pending the appropriate sampling, testing, 
or examination by the quality unit before release for manufacturing or 
packaging;
    (ii) Holding rejected components, incoming designated medical 
gases, medical gas containers and closures, and labeling before 
disposition;
    (iii) Storage of released components, incoming designated medical 
gases, medical gas containers and closures, and labeling;
    (iv) Storage of in-process materials;
    (v) Manufacturing and processing operations;
    (vi) Packaging and labeling operations;
    (vii) Quarantine storage before release of medical gases;
    (viii) Storage of medical gases after release; and
    (ix) Control and laboratory operations.
    (2) The flow of components, incoming designated medical gases, 
medical gas containers and closures, labeling, in-process materials, 
and medical gases through the buildings and facilities shall be 
designed to prevent contamination and mix-ups.
    (c) Any building or facility used in the manufacture, processing, 
packing, or holding of a medical gas shall be maintained in a clean 
condition so as to assure the safety, identity, strength, quality, and 
purity of the medical gas. Written procedures applicable to the

[[Page 51772]]

maintenance and cleaning of buildings and facilities shall be 
established and followed.

Subpart D--Equipment


Sec.  213.63   Equipment design, size, and location.

    Equipment used in the manufacture, processing, packing, or holding 
of a medical gas shall be of appropriate design and adequate size, and 
be suitably located to facilitate operations for its intended use and 
any necessary cleaning and maintenance.


Sec.  213.65   Equipment construction.

    (a) Equipment shall be constructed so that surfaces that contact 
components, in-process materials, or medical gases shall not be 
reactive, additive, or absorptive so as to alter the safety, identity, 
strength, quality, or purity of the medical gas beyond the official or 
other established requirements.
    (b) Any substances required for operation, such as lubricants or 
coolants, shall not come into contact with components, containers, 
closures, in-process materials, or medical gases so as to alter the 
safety, identity, strength, quality, or purity of the medical gas 
beyond the official or other established requirements.


Sec.  213.67   Equipment maintenance and cleaning.

    (a) Written procedures shall be established, maintained, and 
followed for adequate cleaning and maintenance of equipment used in the 
manufacture, processing, packing, or holding of medical gases. These 
procedures shall include, but are not necessarily limited to, the 
following:
    (1) Assignment of responsibility for cleaning and maintaining 
equipment;
    (2) Maintenance and cleaning schedules, including, where 
appropriate, sanitizing schedules;
    (3) A description in sufficient detail of the methods, equipment, 
and materials used in cleaning and maintenance operations, and the 
methods of disassembling and reassembling equipment as necessary to 
assure proper cleaning and maintenance;
    (4) Removal or obliteration of previous batch identification;
    (5) Protection of clean equipment from contamination prior to use; 
and
    (6) Inspection of equipment for cleanliness immediately before use.
    (b) The procedures described in paragraph (a) of this section shall 
not alter the safety, identity, strength, quality, or purity of the 
medical gas beyond the established requirements.
    (c) Records shall be kept of cleaning, maintenance, and inspection 
as specified in Sec. Sec.  213.180 and 213.182.


Sec.  213.68   Automatic, mechanical, and electronic equipment.

    (a) Automatic, mechanical, and electronic equipment used in the 
manufacture, processing, packing, and holding of medical gases shall be 
routinely calibrated, inspected, and checked according to a written 
program designed to ensure proper performance. Written procedures and 
records of calibration, inspections, and checks shall be maintained.
    (b) Computerized systems that record, store, or use data shall be 
appropriately validated.
    (c) A backup file of data entered into the computer system shall be 
maintained except where certain data, such as calculations performed in 
connection with laboratory analysis, are eliminated by computerization 
or other automated processes.
    (d) Appropriate change control shall be used whenever modifications 
are made to computer systems to assure that any changes do not 
adversely affect data integrity or product quality. Records of such 
modifications shall be maintained.

Subpart E--Control of Incoming Designated Medical Gas, Components, 
and Medical Gas Containers and Closures


Sec.  213.80   General requirements.

    (a) There shall be written procedures describing in sufficient 
detail the receipt, identification, storage, handling, sampling, 
testing, and approval or rejection of components, incoming designated 
medical gases, and medical gas containers and closures; such written 
procedures shall be followed.
    (b) Components, incoming designated medical gases, and medical gas 
containers and closures shall at all times be handled and stored in a 
manner to prevent contamination and mix-ups.
    (c) Lots of incoming designated medical gases or components, 
whether used directly as supply or commingled with an existing supply, 
shall be assigned a unique identification number.


Sec.  213.82  Receipt and storage of incoming designated medical gases.

    (a)(1) 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 
certificate of analysis from the supplier accompanies each different 
designated medical gas in a shipment. The certificate of analysis shall 
include the following:
    (i) Supplier's name;
    (ii) Name of the incoming designated medical gas;
    (iii) Lot number or other unique identification number;
    (iv) Actual analytical result obtained for strength, as well as the 
results of other tests performed;
    (v) Identification of the test method(s) used for analysis;
    (vi) New drug application and/or new animal drug application number 
of the incoming designated medical gas; and
    (vii) Supplier representative's signature and the date of 
signature.
    (2) If the incoming designated medical gas is obtained from a 
supplier other than the original manufacturer, the shipment shall also 
include complete information from the original manufacturer's 
certificate of analysis. The firm shall establish and maintain a 
program to ensure the reliability of the supplier's capabilities 
through appropriate assessment and testing procedures.
    (b) An identity test shall be performed upon receipt of the 
incoming designated medical gas.


Sec.  213.84   Testing and approval or rejection of components, 
containers, and closures.

    (a) Components, containers, and closures (including valves) shall 
be examined for conformance with appropriate written procedures and 
specifications, and approved or rejected, prior to the manufacturing or 
filling process. In lieu of such examination by the firm, a statement 
of verification that the component, container, or closure meets 
specifications may be accepted 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 
provisions. Any rejected items shall be handled in accordance with 
Sec.  213.89.
    (b) Firms shall take appropriate actions to protect against 
container and closure leaks, which shall include performing leak tests 
on containers and closures at the time of fill and after fill but prior 
to release.
    (c) Each component shall be sampled, tested, and approved or 
rejected as appropriate prior to use. This requirement can be met by 
performing testing for conformance with written specifications or by an 
identity test on the component accompanied by an acceptable certificate 
of analysis 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.

[[Page 51773]]

Sec.  213.89   Rejected components, incoming designated medical gases, 
and medical gas containers and closures.

    Rejected components, incoming designated medical gases, and medical 
gas containers and closures shall be identified and controlled under a 
quarantine system designed to prevent their use in manufacturing or 
processing operations for which they are unsuitable and shall be 
documented and assessed.


Sec.  213.94   Medical gas containers and closures.

    (a) 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.
    (b) Container closure systems shall provide adequate protection 
against foreseeable external factors in storage and use that can cause 
deterioration or contamination of the medical gas.
    (c) Medical gas containers and closures shall be clean to assure 
that they are suitable for their intended use.
    (d) Standards or specifications, methods of testing, and, where 
indicated, methods of cleaning shall be written and followed for 
medical gas containers and closures.
    (e) Medical gas containers and closures must meet the following 
requirements--
    (1) Gas-specific use outlet connections. 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 containers' use) except by the 
manufacturer. For the purposes of this paragraph (e)(1), the term 
manufacturer includes any individual or firm that fills high-pressure 
medical gas cylinders or cryogenic medical gas containers. For the 
purposes of this section, a portable cryogenic medical gas container is 
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 used to 
fill small cryogenic gas containers for use by individual patients. The 
term excludes 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 at Sec.  
868.5655 of this chapter).
    (2) Gauges for certain medical gas containers. Portable cryogenic 
medical gas containers as described in paragraph (e)(1) of this section 
and small cryogenic gas containers for use by individual patients 
(including portable liquid oxygen units as defined at Sec.  868.5655 of 
this chapter) must have a working gauge sufficient to assist the user 
in determining whether the container contains an adequate supply of 
medical gas for continued use.
    (3) Label and coloring requirements. The labeling specified at 
Sec.  201.328(a) of this chapter must be affixed to the container in a 
manner that does not interfere with other labeling. Each such 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.

Subpart F--Production and Process Controls


Sec.  213.100   Written procedures; deviations.

    (a) There shall be written procedures for production and process 
controls designed to assure that medical gases have the identity, 
strength, quality, and purity they purport or are represented to 
possess. Such procedures shall include all requirements in this 
subpart. These written procedures, including any changes, shall be 
drafted, reviewed, and approved by the appropriate organizational units 
and reviewed and approved by the quality unit.
    (b) Written production and process control procedures shall be 
followed in the execution of the various production and process control 
functions and shall be documented at the time of performance. Any 
deviation from the written procedures shall be recorded and justified.


Sec.  213.101  Charge-in of components and incoming designated medical 
gases.

    Written production and control procedures shall include the 
following, which are designed to assure that the medical gases produced 
have the identity, strength, quality, and purity they purport or are 
represented to possess:
    (a) Except when a monograph or formulary specifies a range, the 
batch shall be formulated with the intent to provide 100 percent of the 
labeled or established amount of each medical gas. When a monograph or 
formulary specifies a range for the contents of a medical gas, the 
batch shall be formulated with the intent to provide an amount of the 
medical gas within such specified range.
    (b) Components and incoming designated medical gases added to in-
process supply or final product containers shall be weighed or measured 
as appropriate. In-process and final product containers 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.


Sec.  213.110   Sampling and testing of in-process materials.

    (a) In-process materials shall be tested for identity, strength, 
quality, and purity as appropriate, and approved or rejected by the 
quality unit during the production process.
    (b) To assure batch uniformity and integrity of drug products, 
written procedures shall be established and followed that describe the 
in-process controls, and tests, or examinations to be conducted on 
appropriate samples of in-process materials of each batch. Such control 
procedures shall be established to monitor the output and to validate 
the performance of those manufacturing processes.
    (c) Rejected in-process materials shall be identified and 
controlled under a quarantine system designed to prevent their use in 
manufacturing or processing operations for which they are unsuitable.

Subpart G--Packaging and Labeling Control


Sec.  213.122   Materials examination and usage criteria.

    (a) There shall be written procedures describing in sufficient 
detail the receipt, identification, storage, handling, sampling, 
examination, and/or testing of labeling and packaging materials; such 
written procedures shall be followed. Labeling and packaging materials 
shall be representatively sampled, and examined or tested upon receipt 
and before use in packaging or labeling of a medical gas.
    (b) Any labeling or packaging materials meeting appropriate written 
specifications may be approved and released for use. Any labeling or 
packaging materials that do not meet such specifications shall be 
rejected to prevent their use in operations for which they are 
unsuitable.
    (c) Records shall be maintained for each shipment received of each 
different labeling and packaging material indicating receipt, 
examination, and whether accepted or rejected.
    (d) Labels and other labeling materials for each different medical 
gas, strength,

[[Page 51774]]

or quantity of contents shall be stored with suitable identification to 
avoid mix-ups. Access to the label storage area shall be limited to 
authorized personnel.
    (e) Labels, labeling, and other packaging materials that are 
obsolete, outdated, or that do not meet applicable requirements shall 
be destroyed.
    (f) Packaging and labeling operations shall include one of the 
following special control procedures:
    (1) Dedication of labeling and packaging lines to each different 
strength of each different medical gas;
    (2) Use of appropriate electronic or electromechanical equipment to 
conduct a 100-percent examination for correct labeling during or after 
completion of finishing operations; or
    (3) Use of visual inspection to conduct a 100-percent examination 
for correct labeling during or after completion of labeling operations 
for hand-applied labeling. Such examination shall be performed by one 
person and independently verified by a second person.
    (g) Printing devices on, or associated with, manufacturing lines 
used to imprint labeling upon the unit label or case shall be monitored 
to assure that all imprinting conforms to the print specified in the 
batch production record.
    (h) Labels may be reused if they are legible, properly affixed to 
the container, and otherwise meet all applicable requirements.


Sec.  213.125   Labeling issuance.

    (a) Labeling and packaging operations must be controlled to prevent 
labeling and product mix-ups. Procedures shall be written and followed 
describing in sufficient detail the control procedures employed for the 
issuance of labeling.
    (b) Procedures shall be used to reconcile the quantities of 
labeling issued, used, and returned, and shall require evaluation of 
discrepancies found between the quantity of medical gas and the 
quantity of labeling issued when such discrepancies are outside narrow 
preset limits based on historical operating data. Such discrepancies 
shall be investigated in accordance with Sec.  213.192. Labeling 
reconciliation is waived for cut or roll labeling if a 100-percent 
examination for correct labeling is performed in accordance with Sec.  
213.122(f)(2). Labeling reconciliation is also waived for 360[deg] 
wraparound labels on portable cryogenic medical gas containers.
    (c) All excess lot number stickers or decals bearing lot or control 
numbers shall be discarded.
    (d) Bulk or transport containers (as defined in Sec.  201.161(c)(3) 
of this chapter) are exempt from this section.


Sec.  213.130   Packaging and labeling operations.

    There shall be written procedures designed to assure that correct 
labels, labeling, and packaging materials are used for medical gases; 
such written procedures shall be followed. These procedures shall 
incorporate the following features:
    (a) Prevention of mix-ups by physical or spatial separation from 
operations on other products.
    (b) Identification and handling of filled containers of medical gas 
that are set aside and held in unlabeled condition for future labeling 
operations to preclude mislabeling of individual containers, lots, or 
portions of lots. Identification need not be applied to each individual 
container but shall be sufficient to determine name, strength, quantity 
of contents, and lot or control number of each container.
    (c) Identification of the medical gas with a lot or control number 
that permits determination of the history of the manufacture and 
control of the batch. The lot or control number of the medical gas may 
be identified by use of a separate identification sticker or decal.
    (d) Examination of packaging and labeling materials for suitability 
and correctness before packaging operations, and documentation of such 
examination in the batch production record. Product labels, including 
360[deg] wraparound labels, can be reused provided they meet all 
applicable labeling requirements, all information on the label is 
legible, and the label is in good condition.
    (e) Inspection of the packaging and labeling facilities immediately 
before use to assure that all medical gases have been removed from 
previous operations. Inspection shall also be made to assure that 
packaging and labeling materials not suitable for subsequent operations 
have been removed. Results of inspection shall be documented in the 
batch production records.
    (f) Bulk or transport containers (as defined in Sec.  201.161(c)(3) 
of this chapter) are exempt from this section provided they are 
identified with the name of the product contained therein and 
accompanied by documentation identifying the product as meeting 
applicable compendial standards.

Subpart H--Holding and Distribution


Sec.  213.150   Warehousing and distribution procedures.

    (a) Written procedures shall be established, and followed, 
describing the distribution of medical gases and including a system by 
which the distribution of each lot can be readily determined to 
facilitate its recall if necessary.
    (b) Written procedures shall be established, and followed, 
describing the warehousing of medical gases, including quarantine of 
such gases before release by the quality unit.

Subpart I--Laboratory Controls


Sec.  213.160   General requirements.

    (a) The establishment of any specifications, standards, sampling 
plans, test procedures, or other laboratory control mechanisms required 
by this subpart, including any change in such specifications, 
standards, sampling plans, test procedures, or other laboratory control 
mechanisms, shall be drafted by the appropriate organizational unit and 
reviewed and approved by the quality unit. The requirements in this 
subpart shall be followed and shall be documented at the time of 
performance. Any deviation from the written specifications, standards, 
sampling plans, test procedures, or other laboratory control mechanisms 
shall be recorded and justified.
    (b) Laboratory controls shall include the establishment of 
scientifically sound and appropriate specifications, standards, 
sampling plans, and test procedures designed to assure that components, 
medical gas containers and closures, in-process materials, labeling, 
and medical gases conform to appropriate standards of identity, 
strength, quality, and purity. Laboratory controls shall include:
    (1) Determination of conformity to applicable written 
specifications for the acceptance of each lot within each shipment of 
components, medical gas containers and closures, and labeling used in 
the manufacture, processing, packing, or holding of a medical gas. The 
specifications shall include a description of the sampling and testing 
procedures used. Samples shall be representative and adequately 
identified. Such procedures shall also require appropriate retesting of 
any component, container, or closure that is subject to deterioration.
    (2) Determination of conformance to written specifications and a 
description of sampling and testing procedures for in-process 
materials. Such samples shall be representative and properly 
identified.
    (3) Determination of conformance to written descriptions of 
sampling procedures and appropriate specifications for medical gases. 
Such

[[Page 51775]]

samples shall be representative and properly identified.
    (4) The calibration or verification of calibration for instruments, 
apparatus, gauges, and recording devices at suitable intervals in 
accordance with an established written program containing specific 
directions, schedules, limits for accuracy and precision, and 
provisions for remedial action in the event accuracy and/or precision 
limits are not met. Instruments, apparatus, gauges, and recording 
devices not meeting established specifications shall not be used.


Sec.  213.165  Testing and release for distribution.

    (a) For each batch of medical gas, there shall be appropriate 
laboratory determination of satisfactory conformance to final 
specifications for the medical gas, including the identity and 
strength, prior to release.
    (b) Any sampling and testing plans shall be described in written 
procedures that shall include the method of sampling, the number of 
units per batch to be tested, and acceptance criteria. Such written 
procedures shall be followed.
    (c) The accuracy, sensitivity, specificity, and reproducibility of 
test methods employed by the firm shall be established and documented. 
Such validation and documentation may be accomplished in accordance 
with Sec.  213.194(a)(2). The suitability of all testing methods shall 
be verified under actual conditions of use.
    (d) Medical gases failing to meet established standards or 
specifications and any other relevant quality criteria shall be 
rejected.
    (e) This section does not apply to the filling of a designated 
medical gas or medically appropriate combination of designated medical 
gases via liquid to liquid into a container at a delivery site.


Sec.  213.166   Stability testing and expiration dating for medical 
gases marketed under applications submitted under section 505 or 
section 512 of the Federal Food, Drug, and Cosmetic Act.

    (a) For medical gases marketed under applications submitted under 
section 505 or section 512 of the Federal Food, Drug, and Cosmetic Act, 
any stability testing performed and any expiration date established 
shall be in accordance with paragraph (b) of this section, subject to 
the conditions established in their approved applications, if any.
    (b) To assure that the medical gas described in paragraph (a) of 
this section meets applicable standards of identity, strength, quality, 
and purity at the time of use:
    (1) The stability testing program shall be designed to assess the 
stability characteristics of the medical gas and its container closure 
system. The results of stability testing shall be used in determining 
appropriate storage conditions and any expiration date included on the 
label. The stability program shall include the appropriate sample size, 
test intervals, container closure systems, and storage conditions for 
samples retained for testing.
    (2) Any expiration dates included on the label shall appear in 
accordance with the requirements of Sec.  201.17 of this chapter.
    (3) Stability shall be evaluated periodically to ensure that the 
medical gas continues to meet the standards for identity, strength, 
quality, and purity stated on the labeling to support the expiration 
date.

Subpart J--Records


Sec.  213.180   General requirements.

    (a) Record availability. All records required under this part, or 
copies of such records, shall be readily available for authorized 
inspection during the retention period at the establishment where the 
activities described in such records occurred and are subject to 
copying as part of such inspection. Records that can be immediately 
retrieved from another location by computer or other electronic means 
shall be considered as meeting the requirements of this paragraph (a).
    (b) Record requirements. All records must be legible, stored to 
prevent deterioration or loss, and original or accurate reproductions 
of the original records.
    (c) Record retention period. Except where otherwise provided, all 
records required to be maintained in compliance with this part must be 
maintained for a period of at least 3 years after the distribution of 
the batch of medical gas.
    (d) Maintenance of written records. Written records required by 
this part shall be maintained 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. Written procedures shall be 
established and followed for such evaluations and shall include 
provisions for:
    (1) A review of a representative number of batches, whether 
approved or rejected, and, where applicable, records associated with 
the batch; and
    (2) A review of complaints, recalls, returned or salvaged medical 
gases, and investigations conducted under Sec.  213.192 for each gas.
    (e) Written procedure requirements. A firm shall establish and 
follow written procedures to assure that responsible officials of the 
firm are notified in writing of any recalls, reports of inspectional 
observations by FDA, regulatory actions related to good manufacturing 
practices brought by FDA, or investigations resulting from adverse 
event complaints.


Sec.  213.182  Equipment cleaning and use log.

    A written record of major equipment cleaning, maintenance (except 
routine maintenance such as lubrication and adjustments), and use shall 
be included in individual equipment logs that show the date, time, 
product, and lot number of each batch processed. If equipment is 
dedicated to manufacture of one product, then individual equipment logs 
are not 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, the records of cleaning, 
maintenance, and use shall be part of the batch record. The persons 
performing and double-checking the cleaning and maintenance (or, if the 
cleaning and maintenance is performed 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. Entries in the log shall be in 
chronological order.


Sec.  213.184   Records for components, medical gas containers and 
closures, and labeling.

    Records for components, medical gas containers and closures, and 
labeling shall include the following:
    (a) The results of any test or examination performed (including 
those performed as required by Sec.  213.84 or Sec.  213.122) and the 
conclusions derived therefrom.
    (b) Documentation of the examination and review of labels and 
labeling for conformity with established specifications in accordance 
with Sec. Sec.  213.122 and 213.130.
    (c) The disposition of rejected components, medical gas containers 
and closures, and labeling.


Sec.  213.186   Master production and control records.

    (a) To assure uniformity from batch to batch, master production and 
control records for each medical gas shall be prepared, dated, and 
signed. The preparation of master production and control records shall 
be described in a

[[Page 51776]]

written procedure and such written procedure shall be followed.
    (b) Master production and control records shall include:
    (1) The name and strength of the medical gas;
    (2) A complete list of components and any incoming designated 
medical gases used in manufacturing designated by names or codes 
sufficiently specific to indicate any special quality characteristic;
    (3) A description of the medical gas containers and closures, 
packaging materials, and labels; and
    (4) Complete manufacturing and control instructions, sampling and 
testing procedures, specifications, special notations, and precautions 
to be followed.


Sec.  213.189   Batch production and control records.

    (a) Batch production and control records shall be prepared for each 
batch of medical gas produced.
    (b) These records shall include documentation that each significant 
step in the manufacture, processing, packing, or holding of the medical 
gas produced was accomplished, including:
    (1) Dates of each significant step, including in-process and 
laboratory tests as applicable;
    (2) A description of the container for the medical gas, including 
the number and size of the containers filled as applicable;
    (3) Specific identification of each component and its source or in-
process material used as applicable;
    (4) Measures of components used in the course of processing as 
applicable;
    (5) Testing results, including any in-process test results and 
finished product test results;
    (6) Dated signature or initials of the persons performing and 
directly supervising or checking each significant step in the 
operation;
    (7) Inspection of the packaging and labeling area before and after 
use;
    (8) Complete labeling control records, including specimens or 
copies of all labeling used and label application and reconciliation 
records as appropriate; and
    (9) Any investigation made according to Sec.  213.192.


Sec.  213.192   Production record review.

    (a) Manufacturing production and control records, including those 
for packaging and labeling, shall be reviewed and approved by the 
quality unit to determine compliance with all established, approved 
written procedures before a batch is released or distributed. The 
quality unit must review production records to determine whether errors 
or unexplained discrepancies have occurred prior to batch release. If 
errors or unexplained discrepancies have occurred, or a batch or any 
component of the batch fails to meet any of its specifications, the 
firm must thoroughly investigate and take appropriate corrective 
actions. A written record of the investigation shall be made and shall 
include the conclusions and followup.
    (b) For production and control records of filling at a delivery 
site, quality unit review as described in paragraph (a) of this section 
shall be within one business day after fill.


Sec.  213.194   Laboratory records.

    (a) Laboratory records related to the manufacture of a medical gas 
must include complete data derived from all tests necessary to assure 
compliance with established specifications and standards, including 
examinations and assays, as follows:
    (1) A description of the sample, the batch or lot number to be 
tested, the date the sample was taken, and the date the sample was 
tested.
    (2) The method used in the testing of the sample, the result of the 
test, how the results compare with established standards of identity, 
strength, quality, and purity for the component, container, closure, 
in-process materials (as applicable), and medical gas tested, a record 
of any calculations performed in connection with each test and any 
calculated results, and the unit of measurement of the result for each 
test. It is not necessary to provide the actual calculation where the 
result is evident through use of simple addition and subtraction.
    (3) Where applicable, any graphs, charts, and spectra from 
laboratory instrumentation, properly identified to show the specific 
component, in-process material, or medical gas for each lot tested.
    (4) The initials or signature of the person performing the test and 
the initials or signature of a second person showing that the original 
records have been reviewed for accuracy, completeness, and compliance 
with established standards.
    (b) Complete records shall be maintained of any modification of an 
established method employed in testing. Such records shall include the 
reason for the modification and data to verify that the modification 
produced results that are at least as accurate and reliable for the 
material being tested as the established method.
    (c) Complete records shall be maintained of any testing and 
standardization of laboratory reference standards, reagents, and 
standard solutions.
    (d) Complete records shall be maintained of the periodic 
calibration or verification of calibration of laboratory instruments, 
apparatus, gauges, and recording devices required by Sec.  
213.160(b)(4).
    (e) Complete records shall be maintained of all stability testing 
performed in accordance with Sec.  213.166.


Sec.  213.196   Distribution records.

    Distribution records shall contain the name of the medical gas, lot 
or batch number, name and address of the consignee, and date and 
quantity shipped. For medically appropriate combinations of designated 
medical gases, the distribution record shall include the percentage of 
each gas.


Sec.  213.198   Complaint files.

    (a) Written procedures shall be established and followed for the 
receipt and handling of all written or oral complaints concerning a 
medical gas. These procedures must include quality unit review of any 
complaint involving the possible failure of a medical gas to meet any 
of its specifications and provisions for determining the need for an 
investigation in accordance with Sec.  213.192 as well as determining 
whether the complaint represents an event that is required to be 
reported to FDA under part 230 of this chapter. Any complaint involving 
a possible leak of a container or closure must be reviewed, evaluated, 
and investigated in accordance with Sec.  213.192.
    (b) A written record of each complaint regarding a medical gas must 
be maintained. The record must include the name of the gas, the lot or 
batch number, the name of the complainant, the date the complaint was 
received, the nature of the complaint, and the response to the 
complaint. It must also include the findings of any investigation and 
followup. Where an investigation is not conducted, the written record 
shall include the reason that an investigation was found not to be 
necessary and the name of the responsible person making such a 
determination.
    (c) Complaint files shall be maintained in a manner such that they 
are readily available for inspection by the firm or by FDA during an 
inspection. Complaint files shall be maintained for at least 1 year 
after the date the complaint was received or for at least 3 years after 
distribution of the medical gas, whichever is longer.

[[Page 51777]]

Subpart K--Returned and Salvaged Medical Gases


Sec.  213.204   Returned medical gases.

    Returned medical gases shall be identified as such and held. If the 
conditions under which such 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, 
casts doubt on the safety, identity, strength, quality, or purity of 
the gas, the returned gas shall be destroyed unless examination, 
testing, or other investigations prove the gas meets appropriate 
standards of safety, identity, strength, quality, or purity. Records of 
returned medical gases shall be maintained and shall include the name, 
lot number (or control number or batch number), reason for the return, 
quantity returned, date of disposition, and ultimate disposition of the 
returned gas. If the reason for a medical gas being returned implicates 
associated batches, an appropriate investigation shall be conducted in 
accordance with the requirements of Sec.  213.192. Procedures for the 
holding, testing, and use of returned medical gases shall be in writing 
and shall be followed. This section is not applicable to the routine 
refilling of cryogenic medical gas containers in the normal course of 
business unless the cryogenic medical gas container was returned due to 
a quality issue.


Sec.  213.208   Salvaging of medical gases.

    Medical gases in containers that have been subjected to improper 
storage conditions may be salvaged unless their containers have been 
subjected to adverse conditions that impact the identity, strength, 
quality, and purity of the gas or integrity of the container closure. 
Whenever there is a question whether medical gases have been subjected 
to such conditions, salvaging operations may be conducted only if there 
is evidence from laboratory tests that such gases meet all applicable 
standards of identity, strength, quality, and purity, and the integrity 
of the container closure system is not compromised. Procedures for the 
holding, testing, and use of salvaged medical gases shall be in writing 
and shall be followed.

0
25. Add part 230 to subchapter C to read as follows:

PART 230--CERTIFICATION AND POSTMARKETING REPORTING FOR DESIGNATED 
MEDICAL GASES

Subpart A--General Provisions
Sec.
230.1 Scope of this part.
230.2 Purpose.
230.3 Definitions.
Subpart B--Certification of Designated Medical Gases
230.50 General requirements for all submission types.
230.65 Withdrawal by the applicant of a certification request before 
it is deemed granted.
230.70 Supplements and other changes to a granted certification.
230.72 Change in ownership of a granted certification.
230.80 Annual report.
230.100 FDA review of submissions.
230.105 When a submission is deemed granted.
230.150 Withdrawal or revocation of approval of an application.
Subpart C--Postmarketing Quality and Safety Reporting
230.205 Field alert reports.
230.210 General reporting requirements for designated medical gas 
adverse events.
230.220 Human designated medical gas ICSR requirements.
230.230 Animal designated medical gas adverse event reporting 
requirements.

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f, 
356, 356a, 356b, 356c, 356e, 360b, 360cc, 360ddd, 360ddd-1, 371, 
374, 379e, 379k-1, 381.

Subpart A--General Provisions


Sec.  230.1   Scope of this part.

    This part sets forth procedures and requirements for the submission 
to, and the review by, the Food and Drug Administration of 
certifications to market designated medical gases under sections 575 
and 576 of the Federal Food, Drug, and Cosmetic Act, as well as 
amendments and supplements to those certifications. This part also sets 
forth the postmarketing safety reporting requirements for designated 
medical gases.


Sec.  230.2   Purpose.

    The purpose of this part is to establish an efficient process for 
the certification of designated medical gases and to establish an 
effective system for surveillance of such gases.


Sec.  230.3   Definitions.

    (a) The definitions and interpretations contained in sections 201 
and 575 of the Federal Food, Drug, and Cosmetic Act apply to those 
terms when used in this part.
    (b) The following definitions of terms apply to this part:
    (1) Adverse event means any untoward medical occurrence associated 
with the use of a designated medical gas in humans or animals, whether 
or not it is considered related to the designated medical gas. An 
adverse event can occur in the course of the use of a designated 
medical gas; from overdose of a designated medical gas, whether 
accidental or intentional; from abuse of a designated medical gas; from 
discontinuation of the designated medical gas (e.g., physiological 
withdrawal); and it includes any failure of expected pharmacological 
action.
    (2) Applicant means any person who submits a certification request 
for a designated medical gas under this part, including a supplement, 
and any person who owns a granted certification for a designated 
medical gas under this part.
    (3) Certification request means a submission under section 576 of 
the Federal Food, Drug, and Cosmetic Act requesting certification of a 
medical gas as a designated medical gas.
    (4) FDA or Agency means the Food and Drug Administration.
    (5) Individual case safety report (ICSR) means a description of an 
adverse event related to an individual patient or subject.
    (6) ICSR attachments means documents related to the adverse event 
described in an ICSR, such as medical records, hospital discharge 
summaries, or other documentation.
    (7) Life-threatening adverse event means any adverse event that 
places the patient, in the view of the initial reporter, at immediate 
risk of death from the adverse event as it occurred, i.e., it does not 
include an adverse event that, had it occurred in a more severe form, 
might have caused death.
    (8) Minimum data set for an ICSR for an adverse event means the 
minimum four elements required for reporting an ICSR of an adverse 
event: An identifiable patient, an identifiable reporter, a suspect 
designated medical gas, and an adverse event.
    (9) Nonapplicant means any person other than the applicant whose 
name appears on the label of a designated medical gas container as a 
manufacturer, packer, or distributor.
    (10) Serious adverse event means:
    (i) An adverse event is considered ``serious'' if it results in any 
of the following outcomes:
    (A) Death;
    (B) A life-threatening adverse event;
    (C) Inpatient hospitalization or prolongation of existing 
hospitalization;
    (D) A persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; and/or
    (E) A congenital anomaly/birth defect.
    (ii) Other events that may be considered serious adverse events: 
Important medical events that may not result in one of the listed 
outcomes in this definition may be considered

[[Page 51778]]

serious adverse events when, based upon appropriate medical judgment, 
they may jeopardize the patient or study subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this paragraph (b)(10). Examples include: Allergic bronchospasm 
requiring intensive treatment in an emergency department or at home, 
blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of product dependency or product 
abuse. Additional examples in animals include: Severe hypersensitivity 
reactions or respiratory distress.

Subpart B--Certification of Designated Medical Gases


Sec.  230.50   General requirements for all submission types.

    (a) Who must submit a request for certification. (1) The 
certification process described in this subpart applies to designated 
medical gases for the indications described in section 576(a)(3)(A)(i) 
of the Federal Food, Drug, and Cosmetic Act. Any person who seeks to 
initially introduce or deliver for introduction a designated medical 
gas into interstate commerce shall file a request for certification. 
The certification process is the same for all designated medical gases, 
regardless of whether it is intended for human use, animal use, or 
both. The applicant must identify its intention to market its 
designated medical gas for human use, animal use, or both.
    (2) Any person that proposes to market a medical gas that is a new 
drug for human use must obtain approval under part 314 of this chapter, 
and any person that proposes to market a medical gas that is a new 
animal drug for animal use must obtain approval under part 514 of this 
chapter, unless--
    (i) The medical gas meets the definition of a designated medical 
gas; and
    (ii) The medical gas is proposed to be marketed alone or in 
combination (as medically appropriate) with another designated medical 
gas or other designated medical gases, for which a certification or 
certifications have been granted, for a use described under section 
576(a)(3)(A)(i) of the Federal Food, Drug, and Cosmetic Act.
    (b) The applicant must include the following information in its 
certification request--(1) Applicant information. The applicant must 
identify the name, address, telephone number, and email address of the 
person requesting certification. If the address of the person 
requesting certification is not in the United States, the certification 
request is required to contain the name and address of, and be 
countersigned by, an attorney, agent, or other authorized official who 
resides or maintains a place of business within the United States.
    (2) Type of submission. The applicant must indicate the type of 
submission as one of the following:
    (i) Original certification request. An initial request submitted by 
an applicant for certification of a medical gas as a designated medical 
gas.
    (ii) Amendment to a pending certification request. Any submission 
related to a pending submission that revises existing information or 
provides additional information, including responses to Information 
Request Letters.
    (iii) Resubmission. Any submission that has been revised and 
submitted again following a previous denial. If an applicant chooses to 
resubmit its submission, it must provide a written response to the 
deficiencies identified in FDA's denial letter, along with other 
information required for certification requests.
    (iv) Supplement to a granted certification. Any submission that 
contains a change to a granted certification.
    (v) Other. Any submission that does not fit in one of the other 
categories.
    (3) Description of medical gas. A separate certification request is 
required to be submitted for each designated medical gas for which 
certification is sought. Each designated medical gas certification 
request must include the name of the medical gas and a certification 
statement from the applicant that the designated medical gas meets the 
appropriate compendial standard.
    (4) Facility information. Each certification request must include 
the name and address of the facility or facilities where the designated 
medical gas will be initially produced. For each facility, include a 
brief description of the manufacturing or processing activities 
performed, the FDA Establishment Identifier, if one exists, and the 
Unique Facility Identifier in accordance with the requirements of part 
207 of this chapter and section 510 of the Federal Food, Drug, and 
Cosmetic Act. For amendments and supplements, only changes to the list 
of facilities are required to be included.
    (5) Certification of adequate manufacture, processing, packaging, 
and holding of designated medical gas. The applicant must certify that 
the applicant's methods, facilities, and controls used for the 
manufacture, processing, packing, and holding of the designated medical 
gas, as applicable, are adequate to ensure its safety, identity, 
strength, quality, and purity.
    (6) Additional information. The applicant must provide any other 
information which FDA deems appropriate to determine whether the 
medical gas is a designated medical gas. The applicant may also provide 
other information that the applicant believes will assist FDA in 
evaluating the request.
    (c) Where and how to submit a request for certification. The 
applicant must submit a signed, completed request for certification 
form either in an electronic format that FDA can process, review, and 
archive, or in hard copy by submitting two paper copies to the Central 
Document Room, Center for Drug Evaluation and Research, Food and Drug 
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705.


Sec.  230.65   Withdrawal by the applicant of a certification request 
before it is deemed granted.

    An applicant may at any time withdraw a certification request that 
is not yet deemed granted by notifying FDA in writing. A decision to 
withdraw the certification request is without prejudice to refiling. 
The Agency will retain the certification request and will provide a 
copy to the applicant on request under the fee schedule in Sec.  20.45 
of this chapter (FDA's public information regulations).


Sec.  230.70   Supplements and other changes to a granted 
certification.

    (a) The applicant must submit a supplement if any information in 
the certification request changes after the request has been deemed 
granted, including, but not limited to, the addition of a new facility 
manufacturing the designated medical gas, a change in contact 
information, or a change in the corporate name.
    (b) Each supplement must include a signed, completed request for 
certification form with the updated information in accordance with 
Sec.  230.50. The updated information must be submitted no later than 
30 calendar days after the date the change occurred.


Sec.  230.72   Change in ownership of a granted certification.

    An applicant may transfer ownership of its certification. At the 
time of transfer the new and former owners are required to submit 
information to FDA as follows:
    (a) The former owner must submit a letter or other document that 
states that all rights to the certification have been transferred to 
the new owner.

[[Page 51779]]

    (b) The new owner must submit a supplement under Sec.  230.70 
signed by the new owner describing any changes in the conditions in the 
granted certification and a letter or other document containing the 
date that the change in ownership is effective.


Sec.  230.80   Annual report.

    (a) The applicant must submit each year within 60 calendar days of 
the new calendar year an annual report containing the information 
described in paragraph (b) of this section. The applicant must submit a 
signed, completed annual report form either in an electronic format 
that FDA can process, review, and archive, or in hard copy by 
submitting two paper copies to the Central Document Room, Center for 
Drug Evaluation and Research, Food and Drug Administration, 5901-B 
Ammendale Rd., Beltsville, MD 20705.
    (b) The report must contain, for the prior calendar year, the 
following information in the order listed:
    (1) Summary. 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.
    (2) Distribution data. Information about the quantity of the 
designated medical gas distributed by the applicant. The information 
must include the National Drug Code (NDC) numbers, the quantities 
distributed for domestic use, and the quantities distributed for 
foreign use. Disclosure of financial or pricing data is not required.
    (3) Administrative changes. Any changes to the applicant's name or 
contact information.
    (4) Current facilities. A list of current facilities where the 
designated medical gas is initially produced, and a list of facilities 
that are no longer in use.


Sec.  230.100   FDA review of submissions.

    (a) In reviewing a submission pursuant to Sec.  230.50, FDA will 
consider information provided with the submission along with any other 
available, relevant information of which FDA becomes aware, including 
information obtained from State or Federal officials, FDA inspection 
reports, or any other source.
    (b) FDA will deny a submission if FDA finds that:
    (1) The medical gas that is the subject of the submission is not a 
designated medical gas;
    (2) The submission does not contain the required information or 
otherwise appears to lack sufficient information to determine that the 
medical gas is a designated medical gas;
    (3) The applicant's methods, facilities, and controls used for the 
manufacture, processing, and handling of the designated medical gas, as 
applicable, are not adequate to ensure its safety, identity, strength, 
quality, and purity; or
    (4) Denying the request is otherwise necessary to protect the 
public health.
    (c) Within 60 calendar days of filing of a submission, FDA may 
contact the applicant to request additional information regarding the 
submission if it determines that required information is not included 
in the submission, that FDA needs such information to determine whether 
the medical gas is a designated medical gas, or that FDA determines 
such information is necessary to protect the public health. Upon 
receipt of an amendment to a pending certification request, this 60-day 
review period will restart. If FDA is not able to contact the applicant 
to obtain and evaluate the information within the 60-day review period, 
FDA may find that the submission lacks sufficient information to permit 
a determination that the medical gas is a designated medical gas and 
deny the submission. If FDA is able to contact the applicant but is not 
provided with the additional information requested within the 60-day 
review period, FDA may find that the request lacks sufficient 
information to permit a determination that the medical gas is a 
designated medical gas and deny the submission.
    (d) Within 60 calendar days of filing of a submission, if FDA makes 
one of the findings described in paragraph (b) of this section, FDA 
will notify the applicant in writing that the submission is denied and 
provide the basis for FDA's determination.


Sec.  230.105   When a submission is deemed granted.

    Unless FDA makes one of the findings described in Sec.  230.100(b) 
and notifies the applicant within 60 calendar days of filing that the 
submission is denied, the certification is deemed to be granted and the 
designated medical gas will be deemed to have in effect an approved 
application under section 505 or section 512 of the Federal Food, Drug, 
and Cosmetic Act, or both, as applicable, for the indications described 
in section 576(a)(3)(A)(i) of the Federal Food, Drug, and Cosmetic Act. 
FDA will notify the applicant in writing.


Sec.  230.150   Withdrawal or revocation of approval of an application.

    (a) Withdrawal. (1) FDA will notify the applicant, and afford an 
opportunity for a hearing on a proposal to withdraw approval of the 
application under the procedure in Sec.  314.200 of this chapter, Sec.  
514.200 of this chapter, or both, as applicable, if any of the 
following apply:
    (i) The Secretary of Health and Human Services has suspended the 
approval of the application for a designated medical gas on a finding 
that there is an imminent hazard to the public health. FDA will 
promptly afford the applicant an expedited hearing following summary 
suspension on a finding of imminent hazard to health.
    (ii) FDA finds:
    (A) That clinical or other experience, tests, or other scientific 
data show that the designated medical gas is unsafe for use under the 
conditions of use upon the basis of which the application was approved; 
or
    (B) That new evidence of clinical experience not available to FDA 
until after the application was approved, or tests by new methods, or 
tests by methods not deemed reasonably applicable when the application 
was approved, evaluated together with the evidence available when the 
application was approved, reveal that the designated medical gas is not 
shown to be safe for use under the conditions of use upon the basis of 
which the application was approved; or
    (C) Upon the basis of new information before FDA with respect to 
the designated medical gas, evaluated together with the evidence 
available when the application was approved, that there is a lack of 
substantial evidence from adequate and well-controlled investigations 
as defined in Sec.  314.126 of this chapter, that the designated 
medical gas will have the effect it is purported or represented to have 
under the conditions of use prescribed, recommended, or suggested in 
its labeling; or
    (D) That the application contains any untrue statement of a 
material fact.
    (2) FDA may notify the applicant, and afford an opportunity for a 
hearing on a proposal to withdraw approval of the application under the 
procedure in Sec.  314.200 of this chapter, Sec.  514.200 of this 
chapter, or both, as applicable, if the Agency finds:
    (i) That the applicant has failed to establish a system for 
maintaining required records, or has repeatedly or deliberately failed 
to maintain required records or to make required reports applicable to 
designated medical gases, including under sections 505(k) and 512(l) of 
the Federal Food, Drug, and Cosmetic Act and this part, part 213 of 
this chapter, and Sec.  314.81(b)(3) of this chapter, or that the 
applicant has refused to permit access to, or copying or verification 
of, its records.

[[Page 51780]]

    (ii) That on the basis of new information before FDA, evaluated 
together with the evidence available when the application was approved, 
the methods used in, or the facilities and controls used for, the 
manufacture, processing, and packing of the designated medical gas are 
inadequate to ensure and preserve its identity, strength, quality, and 
purity and were not made adequate within a reasonable time after 
receipt of written notice from the Agency.
    (iii) That on the basis of new information before FDA, evaluated 
together with the evidence available when the application was approved, 
the labeling of the designated medical gas, based on a fair evaluation 
of all material facts, is false or misleading in any particular, and 
the labeling was not corrected by the applicant within a reasonable 
time after receipt of written notice from the Agency.
    (iv) That the applicant has failed to comply with the notice 
requirements of section 510(j)(2) of the Federal Food, Drug, and 
Cosmetic Act.
    (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 paragraphs (a)(1) and (2) of this section applies 
to the designated medical gas. FDA will consider a written request for 
a withdrawal under this paragraph (a)(3) to be a waiver of an 
opportunity for hearing otherwise provided for in this section. 
Withdrawal of approval of an application under this paragraph (a)(3) is 
without prejudice to refiling.
    (4) FDA may notify an applicant that it believes 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. If the applicant agrees, the Agency will 
not make a finding under paragraph (a)(1) or (2) of this section, but 
will withdraw approval of the application in a notice published in the 
Federal Register that contains a brief summary of the Agency's and the 
applicant's views of the reasons for withdrawal.
    (5) If FDA withdraws an approval, FDA will publish a notice in the 
Federal Register announcing the withdrawal of approval.
    (b) Revocation. FDA may revoke the grant of a certification if FDA 
determines, after providing the applicant with notice and opportunity 
for an informal hearing in accordance with part 16 of this chapter, 
that the request for certification contains any material omission or 
falsification.

Subpart C--Postmarketing Quality and Safety Reporting


Sec.  230.205   Field alert reports.

    The applicant shall submit a field alert report containing all 
information described in paragraphs (a) and (b) of this section about 
distributed designated medical gases and articles to the FDA district 
office that is responsible for the facility involved 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. If the information suggests 
that the reportable incident may require a rapid response to address a 
public health risk, the applicant must as soon as possible, but no 
later than 3 working days from obtaining the information, submit a 
field alert report. The information may be provided by telephone or 
other rapid communication means, with prompt written followup. The 
report and its mailing cover should be plainly marked: ``Designated 
Medical Gas--Field Alert Report.''
    (a) Information concerning any incident that causes the designated 
medical gas or its labeling to be mistaken for, or applied to, another 
article.
    (b) 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.


Sec.  230.210   General reporting requirements for designated medical 
gas adverse events.

    (a) Review of safety information. Each applicant and nonapplicant 
must promptly review all safety information that the applicant or 
nonapplicant receives or otherwise obtains from any source, foreign or 
domestic, such as information derived from commercial marketing 
experience, reports in the published scientific and medical literature, 
unpublished scientific papers, and reports from regulatory authorities.
    (b) Safety reporting disclaimer. (1) A report or information 
submitted by an applicant or nonapplicant (and any release by FDA of 
that report or information) under Sec.  230.220 or Sec.  230.230 does 
not necessarily reflect a conclusion by the applicant or nonapplicant 
or by FDA that the report or information constitutes an admission that 
the designated medical gas caused or contributed to an adverse effect.
    (2) An applicant or nonapplicant need not admit, and may deny, that 
the report or information submitted under Sec.  230.220 or Sec.  
230.230 constitutes an admission that the designated medical gas caused 
or contributed to an adverse effect.


Sec.  230.220   Human designated medical gas ICSR requirements.

    (a) ICSR reporting--(1) General. Except as provided in paragraph 
(c) of this section, applicants and nonapplicants must submit each ICSR 
associated with the use of a designated medical gas in humans described 
in paragraph (b) of this section to FDA as soon as possible but no 
later than 15 calendar days from the date when the applicant or 
nonapplicant has met the reporting criteria described in paragraph (b) 
of this section and acquired a minimum data set for an ICSR for an 
adverse event.
    (2) Copies of ICSRs obtained from FDA. An applicant or nonapplicant 
should not resubmit under this section any ICSRs obtained from FDA's 
adverse event reporting database or forwarded to the applicant or 
nonapplicant by FDA.
    (3) Followup information. Applicants and nonapplicants must submit 
any new information that is related to a previously submitted ICSR or 
an ICSR that was sent to the applicant or nonapplicant by FDA no later 
than 15 calendar days after the information is received or otherwise 
obtained.
    (b) Reporting requirements--(1) Serious adverse events--(i) 
Reported to or otherwise received by the applicant or nonapplicant. 
Applicants and nonapplicants must submit ICSRs for serious adverse 
events reported to or otherwise received by the applicant or 
nonapplicant (such as a report initiated by a patient, consumer, or 
healthcare professional, or received at the request of the applicant or 
nonapplicant).
    (ii) Reported from the scientific literature. Applicants and 
nonapplicants must submit ICSRs for serious adverse events obtained 
from published scientific and medical journals either as case reports 
or as the result of a formal clinical trial.
    (iii) Exception to reporting requirements for serious adverse 
events. Notwithstanding paragraphs (b)(1)(i) and (ii) of this section, 
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

[[Page 51781]]

death was caused by the administration of oxygen.
    (2) Other adverse event reports to be submitted upon notification 
by FDA. Upon notification by FDA, applicants and nonapplicants must 
submit, in a timeframe established by FDA, ICSRs for any adverse events 
that are not required under paragraph (b)(1) of this section. The 
notification will specify the adverse events to be reported and the 
reason for requiring the reports.
    (c) Completing and submitting ICSRs. This paragraph (c) describes 
how to complete and submit ICSRs required under this section.
    (1) Electronic format for submissions. (i) ICSRs and ICSR 
attachments must be in an electronic format that FDA can process, 
review, and archive.
    (ii) An applicant or nonapplicant may request, in writing, a 
temporary waiver of the requirements in paragraph (c)(1)(i) of this 
section. These waivers will be granted on a limited basis for good 
cause shown.
    (2) Submitting ICSRs--(i) Single submission of each ICSR. Submit 
each ICSR only once.
    (ii) Separate ICSR for each patient. The applicant or nonapplicant 
must submit a separate ICSR for each patient who experiences an adverse 
event reportable under paragraph (b) of this section.
    (iii) Coding terms. The adverse event terms described in the ICSR 
must be coded using standardized medical terminology.
    (iv) Minimum data set. All ICSRs submitted under this section must 
contain at least the minimum data set for an ICSR for an adverse event. 
The applicant or nonapplicant must actively seek the minimum data set 
in a manner consistent with the written procedures under paragraph (f) 
of this section. Applicants and nonapplicants must document and 
maintain records of their efforts to obtain the minimum data set.
    (v) ICSR elements. The applicant or nonapplicant must complete all 
known, available elements of an ICSR as specified in paragraph (d) of 
this section.
    (A) For adverse events, applicants and nonapplicants must actively 
seek any information needed to complete all applicable elements, 
consistent with their written procedures under paragraph (f) of this 
section.
    (B) Applicants and nonapplicants must document and maintain records 
of their efforts to obtain the missing information.
    (vi) Supporting documentation. An applicant or nonapplicant must 
submit the following types of supporting documentation in an ICSR, if 
available:
    (A) A copy of the autopsy report if the patient died, or a copy of 
the hospital discharge summary if the patient was hospitalized. The 
applicant or nonapplicant must submit each document as an ICSR 
attachment. The ICSR attachment must be submitted either with the 
initial ICSR or no later than 15 calendar days after obtaining the 
document. English translations of foreign language documents must be 
provided.
    (B) A copy of the published article as an ICSR attachment for each 
ICSR of an adverse event obtained from the published scientific and 
medical literature. Foreign language articles must be accompanied by an 
English translation of the abstract. When submitting more than one ICSR 
from the same published article, the applicant or nonapplicant must 
submit only one copy of the article with one of the ICSRs. For the 
remaining ICSRs not accompanied by a copy of the published article, the 
applicant or nonapplicant must include the cross-reference to the 
specific ICSR to which the article is attached.
    (d) Information reported on ICSRs. ICSRs must include the following 
information, subject to paragraph (c)(2)(v) of this section:
    (1) Patient information, which includes:
    (i) Patient identification code;
    (ii) Patient age at the time of adverse event, or date of birth;
    (iii) Patient sex; and
    (iv) Patient weight.
    (2) Adverse event, which includes:
    (i) Outcome attributed to adverse event;
    (ii) Date of adverse event;
    (iii) Date of ICSR submission;
    (iv) Description of adverse event;
    (v) Adverse event term(s);
    (vi) Description of relevant tests conducted, including dates and 
laboratory data; and
    (vii) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect designated medical gas(es), which includes:
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the adverse event abated after the use of the 
designated medical gas(es) stopped or the dose was reduced;
    (vi) Whether the adverse event reappeared after reintroduction of 
the designated medical gas(es);
    (vii) Lot number;
    (viii) National Drug Code (NDC) number; and
    (ix) Concomitant medical products and therapy dates.
    (4) Initial reporter information, which includes:
    (i) Name, address, email address, and telephone number;
    (ii) Whether the initial reporter is a healthcare professional; and
    (iii) Occupation, if a healthcare professional.
    (5) Applicant or nonapplicant information, which includes:
    (i) Applicant or nonapplicant name, address, email address, and 
telephone number;
    (ii) Report source, such as spontaneous, literature, or study;
    (iii) Date the report was received by applicant or nonapplicant;
    (iv) New drug application and/or new animal drug application 
number;
    (v) Whether the ICSR is an expedited report;
    (vi) Whether the ICSR is an initial report or followup report; and
    (vii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (e) Recordkeeping. (1) For a period of 10 years from the initial 
receipt of information, each applicant or nonapplicant must maintain 
records of information relating to adverse events under this section, 
whether or not submitted to FDA.
    (2) These 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.
    (3) 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. The applicant or nonapplicant must permit any 
authorized FDA employee, at reasonable times, to access, copy, and 
verify these established and maintained records described in this 
section.
    (f) Written procedures. The applicant or nonapplicant must develop 
written procedures needed to fulfill the requirements in this section 
for the surveillance, receipt, evaluation, and reporting to FDA of 
adverse event information, including procedures for employee training 
and for obtaining and processing adverse event information from other 
applicants and nonapplicants.
    (g) Patient privacy. An applicant or nonapplicant should not 
include in reports under this section the names and addresses of 
individual patients; instead, the applicant or nonapplicant

[[Page 51782]]

should assign a unique code for identification of the patient. 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. As set forth in 
FDA's public information regulations in part 20 of this chapter, FDA 
generally may not disclose the names of patients, individual reporters, 
healthcare professionals, hospitals, and geographical identifiers 
submitted to FDA in adverse event reports.


Sec.  230.230   Animal designated medical gas adverse event reporting 
requirements.

    (a) Report for adverse events. This report provides information on 
each adverse event associated with the use of a designated medical gas 
in animals, regardless of the source of the information.
    (1) Serious adverse events. The applicant or nonapplicant must 
submit serious adverse events to FDA as soon as possible but no later 
than within 15 calendar days of first receiving the information. The 
report must be submitted to the Agency in electronic format as 
described in paragraph (b)(1) of this section, unless the applicant or 
nonapplicant obtains a waiver under paragraph (b)(2) of this section or 
FDA requests the report in an alternate format.
    (i) Reported to or otherwise received by the applicant or 
nonapplicant. Applicants and nonapplicants must submit reports for each 
serious adverse event reported to or otherwise received by the 
applicant or nonapplicant (such as reports initiated by a patient, 
consumer, veterinarian, or other healthcare professional, or received 
at the request of the applicant or nonapplicant), regardless of whether 
the applicant or nonapplicant believes the events are related to the 
designated medical gas.
    (ii) Reported from the scientific and medical literature. 
Applicants and nonapplicants must submit reports for each serious 
adverse event obtained from the published scientific and medical 
literature regardless of whether the applicant or nonapplicant believes 
the events are related to the designated medical gas.
    (iii) Exception to reporting requirements for serious adverse 
events. Notwithstanding paragraphs (a)(1)(i) and (ii) of this section, 
reports are not required to be submitted for the death of an animal 
that was administered oxygen, unless the applicant or nonapplicant 
becomes aware of evidence to suggest that the death was caused by the 
administration of oxygen.
    (2) Other adverse event reports to be submitted upon notification 
by FDA. 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 paragraph (a)(1) of this section. The notice will specify the 
adverse events to be reported and the reason for requiring the reports.
    (3) Copies of adverse event reports obtained from FDA. An applicant 
or nonapplicant should not resubmit under this section any adverse 
event reports obtained from FDA's adverse event reporting database or 
forwarded to the applicant or nonapplicant by FDA.
    (b) Format for submissions--(1) Electronic submissions. Reports 
submitted to FDA under this section must be submitted in an electronic 
format that FDA can process, review, and archive. Data provided in 
electronic submissions must be in conformance with the data elements in 
Form FDA 1932 and FDA technical documents describing transmission. As 
necessary, FDA will issue updated technical documents on how to provide 
the electronic submission (e.g., method of transmission and processing, 
media, file formats, preparation and organization of files). Unless 
requested by FDA, paper copies of reports submitted electronically 
should not be submitted to FDA.
    (2) Waivers. An applicant or nonapplicant may request, in writing, 
a temporary waiver of the electronic submission requirements in 
paragraph (b)(1) of this section. The initial request may be provided 
by telephone or email to the Center for Veterinary Medicine's Division 
of Pharmacovigilance and Surveillance, with prompt written followup 
submitted as a letter to the granted certification(s). FDA will grant 
waivers on a limited basis for good cause shown. If FDA grants a 
waiver, the applicant or nonapplicant must comply with the conditions 
for reporting specified by FDA upon granting the waiver.
    (c) Records to be maintained. (1) For a period of 5 years from the 
initial receipt of information, each applicant or nonapplicant must 
maintain records of information relating to adverse event reports under 
this section, whether or not submitted to FDA.
    (2) These 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.
    (3) 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. The applicant or nonapplicant must permit any 
authorized FDA employee, at reasonable times, to access, copy, and 
verify these established and maintained records described in this 
section.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
26. The authority citation for part 314 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f, 
356, 356a, 356b, 356c, 356e, 360cc, 360ddd, 360ddd-1, 371, 374, 
379e, 379k-1.


0
27. Amend Sec.  314.1 by redesignating paragraph (c) as paragraph (d) 
and adding new paragraph (c) to read as follows:


Sec.  314.1   Scope of this part.

* * * * *
    (c) The following provisions do not apply to designated medical 
gases, which are subject to the certification and postmarketing 
reporting requirements under part 230 of this chapter:
    (1) Sections 314.50 through 314.72;
    (2) Section 314.80;
    (3) Section 314.81, except paragraph (b)(3);
    (4) Section 314.90;
    (5) Subpart C of this part;
    (6) Sections 314.100 through 314.162;
    (7) Subpart H of this part; and
    (8) Subpart I of this part.
* * * * *

PART 514--NEW ANIMAL DRUG APPLICATIONS

0
28. The authority citation for part 514 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 
360ccc, 360ddd, 360ddd-1, 371, 379e, 381.


0
29. Amend Sec.  514.1 by adding a sentence to the end of paragraph (a) 
to read as follows:


Sec.  514.1  Applications.

    (a) * * * The following provisions do not apply to designated 
medical gases, which are subject to the certification requirements 
under part 230 of this chapter: Sec. Sec.  514.1(b) and (c), 514.3 
through 514.8, 514.12, and 514.15, and subpart B of this part.
* * * * *


0
30. Amend Sec.  514.80 by:
0
a. In the introductory text table, adding an entry after the sixth 
entry; and

[[Page 51783]]

0
b. Adding paragraph (a)(6).
    The additions read as follows:


Sec.  514.80   Records and reports concerning experience with approved 
new animal drugs.

    The following table outlines the purpose for each paragraph of this 
section:

------------------------------------------------------------------------
                 Purpose                     21 CFR paragraph and title
------------------------------------------------------------------------
 
                              * * * * * * *
Does this section apply to designated                       514.80(a)(6)
 medical gases subject to the
 certification requirements under part
 230?....................................
 
                              * * * * * * *
------------------------------------------------------------------------

    (a) * * *
    (6) This section does not apply to designated medical gases, which 
are subject to the certification requirements under part 230 of this 
chapter. Part 230 of this chapter contains requirements related to 
records and reports concerning experience with the use of a designated 
medical gas in animals.
* * * * *

    Dated: June 10, 2024.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2024-13190 Filed 6-17-24; 8:45 am]
BILLING CODE 4164-01-P