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

<RULE> DEPARTMENT OF HEALTH AND HUMAN SERVICES <SUBAGY>Food and Drug Administration</SUBAGY> <CFR>21 CFR Parts 4, 16, 201, 210, 211, 213, 230, 314, and 514</CFR> <DEPDOC>[Docket No. FDA-2021-N-1333]</DEPDOC> <RIN>RIN 0910-AH96</RIN> <SUBJECT>Current Good Manufacturing Practice, Certification, Postmarketing Safety Reporting, and Labeling Requirements for Certain Medical Gases</SUBJECT> <HD SOURCE="HED">AGENCY:</HD> Food and Drug Administration, Department of Health and Human Services (HHS). <HD SOURCE="HED">ACTION:</HD> Final rule. <SUM> <HD SOURCE="HED">SUMMARY:</HD> 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. </SUM> <EFFDATE> <HD SOURCE="HED">DATES:</HD> 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. </EFFDATE> <HD SOURCE="HED">ADDRESSES:</HD> For access to the docket to read background documents or comments received, go to <E T="03">https://www.regulations.gov</E> 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. <FURINF> <HD SOURCE="HED">FOR FURTHER INFORMATION CONTACT:</HD> <E T="03">With regard to the final rule:</E> David Faranda, Center for Drug Evaluation and Research (CDER), Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, 301-796-8767, <E T="03">David.Faranda@fda.hhs.gov.</E> <E T="03">With regard to the information collection:</E> Domini Bean, Office of Operations, Food and Drug Administration, Three White Flint North, 10A-12M, 11601 Landsdown St., North Bethesda, MD 20852, <E T="03">PRAStaff@fda.hhs.gov.</E> </FURINF> <SUPLINF> <HD SOURCE="HED">SUPPLEMENTARY INFORMATION:</HD> <HD SOURCE="HD1">Table of Contents</HD> <EXTRACT> <FP SOURCE="FP-2">I. Executive Summary</FP> <FP SOURCE="FP1-2">A. Purpose of the Final Rule</FP> <FP SOURCE="FP1-2">B. Summary of the Four Major Provisions of the Final Rule</FP> <FP SOURCE="FP1-2">C. Legal Authority</FP> <FP SOURCE="FP1-2">D. Costs and Benefits</FP> <FP SOURCE="FP-2">II. Table of Abbreviations/Commonly Used Acronyms in This Document</FP> <FP SOURCE="FP-2">III. Background</FP> <FP SOURCE="FP1-2">A. Need for the Regulation/History of the Rulemaking</FP> <FP SOURCE="FP1-2">B. Summary of Comments to the Proposed Rule</FP> <FP SOURCE="FP-2">IV. Legal Authority</FP> <FP SOURCE="FP-2">V. Comments on the Proposed Rule and FDA Response</FP> <FP SOURCE="FP1-2">A. Introduction</FP> <FP SOURCE="FP1-2">B. Description of General Comments and FDA Response</FP> <FP SOURCE="FP1-2">C. Description of Part 4 Comments and FDA Response</FP> <FP SOURCE="FP1-2">D. Part 16</FP> <FP SOURCE="FP1-2">E. Description of Part 201 Comments and FDA Response</FP> <FP SOURCE="FP1-2">F. Part 210</FP> <FP SOURCE="FP1-2">G. Part 211</FP> <FP SOURCE="FP1-2">H. Description of Part 213 Comments and FDA Response</FP> <FP SOURCE="FP1-2">I. Description of Part 230 Comments and FDA Response</FP> <FP SOURCE="FP1-2">J. Description of Part 314 Comments and FDA Response</FP> <FP SOURCE="FP1-2">K. Part 514</FP> <FP SOURCE="FP-2">VI. Effective Date</FP> <FP SOURCE="FP-2">VII. Economic Analysis of Impacts</FP> <FP SOURCE="FP-2">VIII. Analysis of Environmental Impact</FP> <FP SOURCE="FP-2">IX. Paperwork Reduction Act of 1995</FP> <FP SOURCE="FP-2">X. Federalism</FP> <FP SOURCE="FP-2">XI. Consultation and Coordination With Indian Tribal Governments</FP> <FP SOURCE="FP-2">XII. References</FP> </EXTRACT> <HD SOURCE="HD1">I. Executive Summary</HD> <HD SOURCE="HD2">A. Purpose of the Final Rule</HD> 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. <HD SOURCE="HD2">B. Summary of the Four Major Provisions of the Final Rule</HD> 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. <HD SOURCE="HD3">1. Labeling Provisions </HD> 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”). <SU>1</SU> <FTREF/> We also specify requirements for the declaration of net quantity of contents in the labeling of designated medical gases and medically appropriate combinations. <FTNT> <SU>1</SU>  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. </FTNT> 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. <HD SOURCE="HD3">2. CGMP Provisions</HD> FDA is issuing new CGMP regulations specific to medical gases. 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