Current Good Manufacturing Practice, Certification, Postmarketing Safety Reporting, and Labeling Requirements for Certain Medical Gases

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.

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 §§ 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,

David.Faranda@fda.hhs.gov.

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,

PRAStaff@fda.hhs.gov.

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

requirements for the declaration of net quantity of contents in the labeling of designated medical gases and medically appropriate combinations.

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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.

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

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

Abbreviation/acronym

What it means

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.

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

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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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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).

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;

• 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 § 4.2, and conforming changes to account for combination products that contain a medical gas in § 4.3. FDA also proposed in § 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

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 (§ 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 § 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 § 201.1)

FDA proposed revisions to the “manufacturer” definition in § 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 § 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 § 201.1(b) is to capture the primary activities conducted to initially produce a drug product.

3. Adequate Directions for Use (§ 201.100)

Although FDA did not propose revisions to § 201.100, the Agency received comments proposing revisions to the current text.

(Comment 7) One comment proposes a new § 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 § 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 § 201.100(b) exempting designated medical gases in compliance with § 201.161 from the labeling requirements in § 201.100(b) because § 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 § 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 § 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 § 201.161(a).

4. Medical Gas Labeling Statements (Proposed § 201.161)

FDA proposed several changes to the medical gas labeling requirements in § 201.161. We proposed moving the warning statement requirements for oxygen in § 201.161(a)(1)(i) to § 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 § 201.161(a)(1)(ii) to § 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 § 201.161(a)(3), we proposed requiring that the final use container bears appropriate directions and warnings concerning storage and handling.

In proposed § 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 § 201.161(c) included several definitions. We received no comments on the proposed definitions of “designated medical gas” (proposed § 201.161(c)(1)) or “bulk or transport container” (proposed § 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 §  868.5655 (21 CFR 868.5655).

We respond to the comments on proposed § 201.161 in the following paragraphs.

(Comment 9) One comment recommends that the oxygen warning statement in proposed § 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 § 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 § 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 § 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 § 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 § 201.161(c)(2) already makes clear that the term does not include containers meeting the definition of a medical device and classified under § 868.5655. As devices, these containers have separate labeling requirements. Therefore, further clarification in § 201.161 is not necessary.

(Comment 12) In response to FDA's request for feedback regarding the inclusion in § 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 § 201.161(a)(2) explaining that the required statements in § 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 § 201.161, the Agency declines to add the requested language. As revised by this rule, § 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 § 201.161(a). Therefore, it is clear that the requirements in § 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”

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(Ref. 1).

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“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 § 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 § 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 § 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 § 201.161(b).

5. Labeling of Medical Gas Containers (Proposed § 201.328)

FDA proposed changes to § 201.328(a)(1) to reference § 213.94(e)(3) instead of § 211.94(e)(2). We also proposed to add § 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 § 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 § 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 § 868.5655. First, the comment requests to remove the term “base unit”

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 § 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 § 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 § 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 § 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 § 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, § 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 § 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 § 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 § 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 § 213.3(b)(1) is identical to the current “acceptance criteria” definition in § 210.3(b)(20), and FDA further believes that it is generally consistent with the “acceptance criteria” definition in § 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 § 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 § 213.3(b)(2), and lot numbers, as defined in § 213.3(b)(10), be defined per day. The comment argues that this

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 § 213.3(b)(10) for “lot number, control number, or batch number” are necessary.

c. Commingling or Commingled (Proposed § 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 § 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, § 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 § 213.82). Additionally, § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 §§ 213.63, 213.65, 213.67, and 213.68). We received no comments on proposed §§ 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 § 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 § 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 § 211.68(a) and affords flexibility to

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 §§ 213.80, 213.82, 213.84, 213.89, and 213.94). We received no comments on proposed §§ 213.80 and 213.89 and are finalizing them as proposed. We respond to the comments on proposed §§ 213.82, 213.84, and 213.94 below.

a. Receipt and Storage of Incoming Designated Medical Gases (Proposed § 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 § 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 § 213.82(a)(2)). Lastly, FDA proposed requiring that an identity test be performed upon receipt (proposed § 213.82(b)).

(Comment 26) One comment asks that § 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, § 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 § 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,” § 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 § 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 § 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 § 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 § 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 § 213.84)

FDA proposed requirements for testing and approval or rejection of components, containers, and closures. Proposed § 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 § 213.84(b), firms shall 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. Under proposed § 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 § 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 § 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 § 213.198(a) a requirement that all complaints involving leaking containers or closures be reviewed, evaluated, and investigated in accordance with § 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 § 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 § 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 § 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 § 213.94(b)). Under proposed § 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 § 213.94(d)).

Proposed § 213.94(e) included revisions to the requirements in § 211.94(e), including new proposed requirements. Under proposed § 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 §  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 §  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 §  868.5655).

Under proposed § 213.94(e)(2), portable cryogenic medical gas containers as defined in proposed §  213.94(e)(1) as well as small cryogenic gas containers for use by individual patients (including portable liquid oxygen units as defined in §  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 § 213.94(e)(3) required that the labeling specified at § 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 § 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

definition of “portable cryogenic medical gas container” in § 213.94(e)(1) is identical to the current definition in §§ 201.328(a) and 211.94(e)(1), different revisions were proposed for §§ 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 § 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 § 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 § 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 § 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 § 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 §§ 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 §§ 213.122, 213.125, and 213.130). We received no comments on proposed §§ 213.122 and 213.130 and are finalizing them as proposed.

In proposed § 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 § 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 § 213.122(f)(2), and for 360° wraparound labels on portable cryogenic medical gas containers). Proposed § 213.125(c) states that all excess lot number stickers or decals bearing lot or control numbers shall be discarded. Lastly, proposed § 213.125(d) exempted bulk or transport containers from § 213.125. We respond to the comments on proposed § 213.125 below.

(Comment 33) Regarding proposed § 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 § 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 § 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 § 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.

9. Laboratory Controls (Proposed Part 213, Subpart I)

FDA proposed to establish several laboratory control requirements (proposed §§ 213.160, 213.165, and 213.166). We received no comments on proposed §§ 213.160 and 213.166 and are finalizing them as proposed.

FDA proposed testing and release requirements in § 213.165. Under proposed § 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 § 213.165(b)). Under proposed § 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 §  213.194(a)(2). Also under proposed § 213.165(c), the suitability of all testing methods shall be verified under actual conditions of use. Proposed § 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 § 211.165(f), but FDA did not propose to include in § 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 § 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 § 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 § 213.165(d) are necessary.

10. Records (Proposed Part 213, Subpart J)

FDA proposed to establish records requirements (proposed §§ 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 §§ 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 §§ 213.182, 213.189, and 213.196 below.

a. Equipment Cleaning and Use Log (Proposed § 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 § 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 §  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 § 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 §§ 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 § 213.182 are overly burdensome. Because the requirements in § 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 § 213.189)

We proposed to require that batch production and control records be prepared for each batch of medical gas produced (proposed § 213.189(a)). We further proposed in § 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 §  213.192.

(Comment 37) One comment requests that the Agency revise § 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

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 § 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 § 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 § 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 § 213.196)

We proposed in § 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 § 213.196. One comment expresses concern that the exemption in § 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 § 213.196 to be consistent with the current requirements in § 211.196.

(Response 39) FDA declines to revise § 213.196. Regarding the concern about handling safety events, FDA proposed deletion of the exemption in § 211.196 for compressed medical gas products specifically because § 213.196 would fully address this requirement for medical gases. Regarding the proposed revision to § 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 § 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), § 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 § 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 §§ 213.204 and 213.208). We received no comments on proposed § 213.208 and are finalizing it as proposed with a minor grammatical change made on our own initiative.

FDA proposed in § 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 §  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 §  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 § 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, § 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 § 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

redistribution, the requirements in § 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 § 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 § 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 § 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 § 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 § 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, § 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 § 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 § 230.3(b)(9)).

(Comment 45) One comment suggests revisions to the proposed “nonapplicant” definition in § 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 § 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 § 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 § 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 § 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 § 230.50)

FDA proposed requirements for all types of certification submissions (proposed § 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 § 230.65)

FDA proposed requirements regarding withdrawal of a certification request prior to it being deemed granted (proposed § 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 § 230.70)

FDA proposed requirements regarding supplements and other changes to a granted certification (proposed § 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 § 230.72)

FDA proposed requirements regarding the change in ownership of a granted certification (proposed § 230.72). We received no comments on the proposed requirements and are finalizing them as proposed.

7. Annual Report (Proposed § 230.80)

FDA proposed to establish annual report requirements in proposed § 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 § 213.80(a)). Under proposed § 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 § 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 § 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 § 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 § 230.80 contains all other information required in § 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 § 230.80 and section 510(j)(3) of the FD&C Act.

(Comment 48) One comment requests that the proposed requirement in § 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 § 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 § 230.80(b)(4) consistent with the requirement in section 576(a)(1)(C) of the FD&C Act and what we proposed for § 230.50(b)(4), which both address information to be submitted as part of a certification request. Because the purpose of § 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 § 230.100)

FDA proposed requirements regarding FDA's review of submissions (proposed § 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 § 230.105)

FDA proposed requirements regarding when a submission is deemed granted (proposed § 230.105). We received no comments on the proposed requirements and are finalizing them as proposed.

10. Withdrawal (Proposed § 230.150)

FDA proposed withdrawal and revocation requirements in proposed § 230.150. We did not receive comments on the proposed revocation requirements in § 230.150(b) and are finalizing those requirements as proposed with minor technical and grammatical changes made on our own initiative.

FDA proposed in § 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 § 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 § 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

to refiling. FDA proposed in § 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 § 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 § 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 § 230.150.

However, as discussed in response 61 below, FDA is revising § 230.150(a)(2)(i) to include failure to submit reports under § 314.81(b)(3). Because of this revision, it is unnecessary for § 314.81(d) to continue to apply to designated medical gases.

11. Field Alert Report (Proposed § 230.205)

We proposed field alert reporting requirements for designated medical gases in § 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 § 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 § 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 § 314.81(b)(1), which require that applicants submit reports to the Agency. It is worth noting that the field alert reporting requirements in § 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, § 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 § 230.205 are needed.

12. General Reporting Requirements for Designated Medical Gas Adverse Events (Proposed § 230.210)

FDA proposed general reporting requirements for designated medical gas adverse events (proposed § 230.210). We received no comments on the proposed requirements and are finalizing them as proposed.

13. Human Postmarketing Safety Reporting (Proposed § 230.220)

FDA proposed human postmarketing safety reporting requirements in § 230.220. Under proposed § 230.220(a)(1), applicants and nonapplicants must submit each ICSR associated with the use of a designated medical gas in humans described in § 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 § 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

applicant by FDA no later than 15 calendar days after the information is received or otherwise obtained (proposed § 230.220(a)(3)).

FDA proposed in § 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 § 230.220(b)(1)(i) and (ii)). Proposed § 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 § 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 § 230.220(b)(1).

Under proposed § 230.220(c), FDA proposed to specify how to complete and submit ICSRs required under § 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 § 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 § 230.220(d), and that an applicant must submit autopsy reports, hospital discharge summaries, or published articles as specified (proposed § 230.220(c)(2)).

Proposed § 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 § 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 § 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 § 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 § 230.220(e)(3)).

Proposed § 230.220(f) specified that applicants and nonapplicants must develop written procedures needed to fulfill the requirements of § 230.220 for the surveillance, receipt, evaluation, and reporting to FDA of adverse event information.

Proposed § 230.220(g) would establish requirements concerning patient privacy. Specifically, FDA proposed that an applicant or nonapplicant should not include in reports under § 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 § 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 § 230.220 on our own initiative. We are revising proposed § 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 § 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 § 314.80(g) would continue to apply to designated medical gases, and proposed § 230.220(c)(1)(i) and (ii) included cross-references to § 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 § 230.220 rather than referencing § 314.80(g). Therefore, we have revised § 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 § 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 § 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 § 314.80(g)(2). FDA intends to issue guidance on requesting a waiver of the requirements in § 230.220(c)(1)(i).

Furthermore, we have revised § 314.1(c) to state that § 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 § 314.80(c)(1)(i) and (ii), although nonapplicants may comply by submitting all reports of serious adverse drug experiences to the applicant. Under § 230.220, the only difference will be that nonapplicants for designated medical gases must report to FDA, rather than the applicant.

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 § 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 § 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 § 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 § 230.220(c)(2) or § 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 § 230.220, including § 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 §§ 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 § 230.220 or § 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 § 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 § 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 § 230.220(c)(2)(vi)(B). Additionally, we note that § 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 § 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 § 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 § 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

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 § 230.230)

FDA proposed animal postmarketing safety reporting requirements in § 230.230. Under proposed § 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 § 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 § 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 § 230.230(a)(1)(iii)). Under proposed § 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 § 230.230(a)(1). FDA proposed under § 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 § 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 § 230.230(b)(1)). FDA further proposed that applicants and nonapplicants may request, in writing, a temporary waiver of this requirement (proposed § 230.230(b)(2)).

Under proposed § 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 § 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 § 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 § 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 § 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 § 230.230(a)(1)(i) with the requirement in § 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, § 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 § 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 § 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 § 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 §§  314.50 through 314.72 (concerning certain information required in NDAs); §  314.80, except paragraph (g) (concerning certain postmarketing reporting requirements); §  314.81(a) and (b)(1) and (2) (concerning certain other postmarketing reports); §  314.90 (concerning waivers); subpart C (concerning ANDAs); §§  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 § 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 § 314.81(b)(3). The

Agency assumes that the comment is primarily focused on § 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 § 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 § 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 § 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 § 314.81(c)(1), regarding the submission of information common to more than one application, as the comment does not discuss the requirements of § 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 § 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 § 314.81. For these reasons, we are revising the codified at § 314.1(c) such that § 314.81(c) no longer applies to designated medical gases.

In addition, because § 230.150 now provides for withdrawal of an application for a designated medical gas based on failure to submit reports required under § 314.81(b)(3) (see section V.I.11), it is not necessary for § 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 § 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 §§ 4.2, 4.3, and 4.4. The effective date for §§ 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 §§ 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

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]

Category

Primary

estimate

Low

estimate

High

estimate

Units

Year

dollars

Discount

rate

(%)

Period

covered

(years)

Notes

Benefits:

Annualized Monetized $millions/year

$3.51

3.72

$0.00

0.00

$7.02

7.43

2022

2022

7

3

10

10

Most benefits are cost savings to 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

3.07

1.52

1.36

5.30

5.11

2022

2022

7

3

10

10

Annualized Quantified

7

3

Qualitative

Maintaining resumes for consultants, and potential cost of relabeling medical air containers.

Transfers:

Federal Annualized Monetized millions/year

7

3

From/To

From:

To:

Other Annualized Monetized millions/year

7

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.

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

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 § 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

Activity; 21 CFR

Section

Number of

respondents

Number of

disclosures per

respondent

Total annual

disclosures

Average burden per disclosure

(hours)

Total hours

Labeling of bulk or transport containers used to hold designated medical gases; § 201.161(b)

1,696

2.36

4,000

0.1 (6 minutes)

400

Identify the owner of a 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; § 201.328(d)

1,696

2.36

4,000

0.1 (6 minutes)

400

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 § 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 d

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