Current Good Manufacturing Practice, Certification, Postmarketing Safety Reporting, and Labeling Requirements for Certain Medical Gases
Federal RegisterMay 23, 2022
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 4, 16, 201, 210, 211, 213, 230, 314, and 514
[Docket No. FDA-2021-N-1333]
RIN 0910-AH96
Current Good Manufacturing Practice, Certification, Postmarketing Safety Reporting, and Labeling Requirements for Certain Medical Gases
AGENCY:
Food and Drug Administration, HHS.
ACTION:
Proposed rule.
SUMMARY:
The Food and Drug Administration (FDA, the Agency, or we) is proposing new regulations that would amend the requirements concerning current good manufacturing practice (CGMP) and postmarketing safety reporting that apply to certain medical gases. FDA further proposes to establish regulations regarding certification of designated medical gases and amend the labeling regulations that apply to certain medical gases. This action, if finalized, will clarify the regulatory obligations of entities that manufacture, process, pack, label, or distribute certain medical gases, as well as reduce regulatory burden in this area. This proposed rule is intended to establish requirements that are more specifically tailored to the medical gas industry.
DATES:
Submit either electronic or written comments on the proposed rule by August 22, 2022. Submit written comments (including recommendations) on the collection of information under the Paperwork Reduction Act of 1995 by July 22, 2022.
ADDRESSES:
You may submit comments as follows. Please note that late, untimely filed comments will not be considered. Electronic comments must be submitted on or before August 22, 2022. The
https://www.regulations.gov
electronic filing system will accept comments until 11:59 p.m. Eastern Time at the end of August 22, 2022. Comments received by mail/hand delivery/courier (for written/paper submissions) will be considered timely if they are postmarked or the delivery service acceptance receipt is on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
•
Federal eRulemaking Portal:
https://www.regulations.gov
. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to
https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on
https://www.regulations.gov.
• If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see “Written/Paper Submissions” and “Instructions”).
Written/Paper Submissions
Submit written/paper submissions as follows:
•
Mail/Hand delivery/Courier (for written/paper submissions):
Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in “Instructions.”
Instructions:
All submissions received must include the Docket No. FDA-2021-N-1333 for “Current Good Manufacturing Practice, Certification, Postmarketing Safety Reporting, and Labeling Requirements for Certain Medical Gases.” Received comments, those filed in a timely manner (see
ADDRESSES
), will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at
https://www.regulations.gov
or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
• Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states “THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.” The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on
https://www.regulations.gov
. Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as “confidential.” Any information marked as “confidential” will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at:
https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf
.
Docket:
For access to the docket to read background documents or the electronic and written/paper comments received, go to
https://www.regulations.gov
and insert the docket number, found in brackets in the heading of this document, 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.
Submit comments on information collection issues under the Paperwork Reduction Act of 1995 to the Office of Management and Budget (OMB) at
https://www.reginfo.gov/public/do/PRAMain.
Find these particular information collections by selecting “Currently under Review—Open for Public Comments” or by using the search function. The titles of the proposed collections are:
• Current Good Manufacturing Practice (CGMP): Manufacturing, Processing, Packing, and Holding of Drugs; GMP for Finished Pharmaceuticals (Including Medical Gases and Active Pharmaceutical Ingredients); OMB control number 0910-0139—Revision
• Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products; OMB control number 0910-0572—Revision
• Current Good Manufacturing Practice for Medical Gases; OMB control number for 21 CFR part 213—New
• Certification and Postmarketing Reporting for Designated Medical Gases; OMB control number for 21 CFR part 230—New
FOR FURTHER INFORMATION CONTACT:
With regard to the proposed rule:
David Faranda, Center for Drug Evaluation and Research, 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, 301-796-5733,
PRAStaff@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. Introduction
B. Need for the Regulation
C. FDA's Current Regulatory Framework
D. History of the Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
A. Proposed Labeling Provisions
B. Proposed Current Good Manufacturing Practice Provisions
C. Proposed Certification and Annual Reporting Provisions
D. Proposed Postmarketing Quality and Safety Reporting Provisions
VI. Proposed Effective Date
VII. Preliminary 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 Proposed Rule
Section 756 of the Consolidated Appropriations Act, 2017 (Pub. L. 115-31) required FDA to issue final regulations revising the Federal drug regulations with respect to medical gases by July 15, 2017. These proposed regulations, if finalized, would satisfy that requirement and are intended to be more specifically tailored to the medical gas industry and decrease regulatory burden where appropriate.
FDA proposes revisions to its labeling regulations 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. FDA also proposes new CGMP regulations for medical gases to reflect appropriate requirements for the manufacturing, processing, packing, and holding of such products. These proposed regulations generally cover the same categories of provisions as the CGMP regulations in parts 210 and 211 (21 CFR parts 210 and 211) (hereafter the “general drug CGMP regulations”), revised as appropriate for medical gases. FDA also proposes regulations that would 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, FDA proposes new postmarketing safety reporting regulations for designated medical gases that would address human and animal use and would better reflect the development, manufacturing, and distribution of designated medical gases.
B. Summary of the Major Provisions of the Proposed Rule
1. Labeling Provisions
This proposed rule includes several proposed changes to FDA's drug labeling regulations including adding certain operations required to produce a medical gas to the list of operations that are performed by its manufacturer. We propose to revise 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”).
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We propose to 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 propose 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 further proposes revisions to warning statements for certain medical gases including that the labeling of medical air and carbon monoxide bear certain warning statements. We propose different labeling requirements for final use containers and bulk or transport containers. We also propose 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 proposes revisions to 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.
2. CGMP Provisions
FDA proposes CGMP regulations specific to medical gases. These proposed 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. If finalized as proposed, these regulations would represent the minimum CGMP for medical gases. Of note, we propose 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. Additionally, FDA proposes requirements for medical gas containers and closures that are similar to the general drug CGMP regulations, with an additional proposed requirement that portable cryogenic medical gas containers and small cryogenic gas containers for use by individual patients have a working gauge to indicate whether there is an adequate supply of gas for continued use. This would help users determine when a container must be refilled or replaced and when a leaking or venting container is empty. We are also not proposing to include time limitations on production because medical gases are generally not expected to expire or degrade. FDA also proposes that, 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 proposes regulations regarding the certification process for designated medical gases that are intended to codify the certification process and
provide additional clarity where necessary. These proposed requirements would govern the process for applicants to file a certification request and supplements as well as the contents of such a request. The regulations would set forth requirements concerning the transfer of ownership of a certification from one entity to another.
We are proposing to require the submission of a streamlined annual report, including the required contents and timing for submission.
These proposed regulations would 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 Safety Reporting Provisions
FDA is proposing new postmarketing safety reporting regulations for designated medical gases and general safety reporting requirements for all certified designated medical gases.
We also propose 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 proposing that applicants and nonapplicants be required to report serious adverse events within 15 calendar days from when the applicant or nonapplicant has both met certain reporting criteria and acquired certain minimum data.
We are also proposing 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 proposing that applicants and nonapplicants be required to 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 proposed rule.
D. Costs and Benefits
The costs of this proposed rule, if finalized, would be primarily driven by 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. The cost savings of this proposed rule, if finalized, would be primarily driven by removing CGMP requirements that would not apply to medical gases, such as removing certain building and facility requirements, or modifying CGMP requirements so that they would be more well-tailored to medical gases, which may streamline inspections. The annualized benefits are estimated to be $3.24 million at a 7 percent discount rate over 10 years. The annualized costs are estimated to be $3.03 million at a 7 percent discount rate over 10 years.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
Abbreviation/acronym
What it means
API
Active Pharmaceutical Ingredient.
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.
FDASIA
Food and Drug Administration Safety and Innovation Act.
FR
Federal Register.
ICSR
Individual Case Safety Report.
NDA
New Drug Application.
NADA
New Animal Drug Application.
NF
National Formulary.
OMB
Office of Management and Budget.
PRIA
Preliminary Regulatory Impact Analysis.
USP
United States Pharmacopeia.
III. Background
A. Introduction
On July 9, 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA, Pub. L. 112-144) was signed into law, establishing a new marketing pathway and specific requirements for the regulation of designated medical gases. Section 756 of the Consolidated Appropriations Act, 2017, required FDA to issue final regulations revising the Federal drug regulations with respect to medical gases by July 15, 2017.
The Agency has engaged with stakeholders and Congress to evaluate the need for changes to regulatory requirements for medical gases. This proposed rule is being published to address the areas for which FDA has determined regulatory changes are needed.
B. Need for the Regulation
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, sponsors of designated medical gases do
not generate the same safety information that sponsors of new drug applications (NDAs) and new animal drug applications (NADAs) would typically generate, including, for example, an understanding of expected adverse events based on clinical trial data. Thus, some existing regulations are not well-tailored to addressing designated medical gases and other medical gases. FDA is undertaking this rulemaking to address these differences, and to decrease regulatory burden where appropriate.
C. FDA's Current Regulatory Framework
Section 1111 of FDASIA established sections 575 through 577 of the FD&C Act (21 U.S.C. 360ddd through 360ddd-2) for medical gases. Section 575(2) of the FD&C Act defines a medical gas as a drug that is manufactured or stored in a liquefied, nonliquefied, or cryogenic state and administered as a gas. Section 575(1) of the FD&C Act defines a designated medical gas as any of the following gases that meet the standards set forth in an official compendium: Oxygen, nitrogen, nitrous oxide, carbon dioxide, helium, carbon monoxide, and medical air. Designated medical gases are also defined to include any other medical gas deemed appropriate by the Secretary of the Department of Health and Human Services (Secretary),
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after taking into account any investigational new drug application or investigational new animal drug file
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for the same medical gas submitted in accordance with applicable regulations, unless any period of exclusivity for a new drug under section 505(c)(3)(E)(ii) or (j)(5)(F)(ii) of the FD&C Act, or the extension of any such period under section 505A of the FD&C Act (21 U.S.C. 355a), or any period of exclusivity for a new animal drug under section 512(c)(2)(F) of the FD&C Act, applicable to such medical gas has not expired (section 575(1)(H) of the FD&C Act).
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The functions of the Secretary described herein have been delegated to FDA.
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We interpret the term “investigational new animal drug application” in FD&C Act section 575(1)(H) to refer to an “investigational new animal drug file” to reflect CVM's current administrative process for receiving data and information related to a new animal drug for investigational use. See 21 CFR part 511.
Any person who seeks to initially introduce or deliver for introduction into interstate commerce a designated medical gas may file with the Secretary a request for certification of a medical gas as a designated medical gas (FD&C Act section 576(a)(1)). Any such request shall contain a description of the medical gas, the sponsor's name and address, the name and address of the facility or facilities where the medical gas is or will be manufactured, and any other information the Secretary deems appropriate to determine whether the medical gas is a designated medical gas (Id.). The certification requested under section 576(a)(1) of the FD&C Act is deemed to be granted unless, within 60 days of filing of the request, the Secretary finds that the medical gas subject to the certification is not a designated medical gas, the request does not contain the information required under section 576(a)(1) of the FD&C Act or otherwise lacks sufficient information to permit the Secretary to determine that the medical gas is a designated medical gas, or denying the request is necessary to protect the public health (FD&C Act section 576(a)(2)). FDA interprets the period of 60 days in section 576(a)(2) to mean a period of 60 calendar days.
Section 576(a)(3)(A)(i) of the FD&C Act provides that a designated medical gas for which a certification is granted 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 of the FD&C Act, subject to all applicable postapproval requirements. The deemed approval is for certain indications specified in the statute or for any other indication for use for a designated medical gas or combination of designated medical gases deemed appropriate by the Secretary, unless any period of exclusivity under section 505(c)(3)(E)(iii) or (iv), 505(j)(5)(F)(iii) or (iv), or 527 of the FD&C Act (21 U.S.C. 360cc), or the extension of any such period under section 505A of the FD&C Act, applicable to such indication for use for such gas or combination of gases has not expired. Under section 576(a)(3)(A)(ii) of the FD&C Act, designated medical gases are deemed to have met the requirements of section 503(b)(4) of the FD&C Act (21 U.S.C. 353(b)(4); concerning the labeling of drugs with the symbol “Rx only”) and section 502(f) of the FD&C Act (concerning the labeling of drugs with adequate directions for use and adequate warnings against certain uses) if the labeling on the final use container bears:
• The information required by section 503(b)(4) of the FD&C Act;
• 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.
Designated medical gases that are deemed to have in effect an approved application under section 576(a)(3)(A)(i) of the FD&C Act are not eligible for any period of exclusivity for a new drug under section 505(c) or (j), or 527 of the FD&C Act, or the extension of any such period under section 505A of the FD&C Act, on the basis of such deemed approval (FD&C Act section 576(a)(3)(B)(i)). In addition, no period of exclusivity under section 505(c), 505(j), or 527 of the FD&C Act, or the extension of any such period under section 505A of the FD&C Act, with respect to an application for a drug product, shall prohibit, limit, or otherwise affect the submission, grant, or effect of a designated medical gas certification, except as provided in sections 575(1)(H) and 576(a)(3)(A)(i)(VIII) of the FD&C Act (FD&C Act 576(a)(3)(B)(ii)).
Section 576(a)(4)(A) of the FD&C Act affirms the Secretary's authority to withdraw or suspend approval of a drug product, including a designated medical gas deemed to have in effect an approved application under section 505 or 512 of the FD&C Act. The Secretary under section 576(a)(4)(B) of the FD&C Act may revoke the grant of a designated medical gas certification upon the determination that the certification request contains any material omission or falsification.
Under section 576(b)(1) of the FD&C Act, designated medical gases are subject to the requirements under section 503(b)(1) of the FD&C Act (concerning the dispensing of certain human drugs only pursuant to a prescription) except under the following circumstances:
• The Secretary exercises the authority provided in section 503(b)(3) of the FD&C Act to remove the designated medical gas from the requirements of section 503(b)(1) of the FD&C Act;
• The gas is approved for use without a prescription pursuant to an application under section 505 or 512 of the FD&C Act; or
• The use in question is authorized pursuant to another provision in the FD&C Act relating to the use of medical products in emergencies.
Notwithstanding section 576(b)(1), section 576(b)(2)(A) of the FD&C Act provides that oxygen may be provided without a prescription for use in the event of depressurization or other environmental oxygen deficiency, or for oxygen deficiency or for use in emergency resuscitation when administered by properly trained personnel. For oxygen provided without a prescription, section 576(b)(2)(B) provides that the requirements of section 503(b)(4) (concerning labeling of drugs with the symbol “Rx only”) are
deemed to have been met if its labeling bears a warning that it can only be used for emergency use, and that for all other medical applications a prescription is required.
Pursuant to section 577 of the FD&C Act, a designated medical gas, alone or in a medically appropriate combination with another designated medical gas or gases deemed under section 576 to have in effect an approved application, shall not be assessed prescription drug user fees under section 736(a) of the FD&C Act (21 U.S.C. 379h(a)) or animal drug user fees under section 740(a) of the FD&C Act (21 U.S.C. 379j-12(a)) on the basis of such deemed approval.
FDA's drug regulations also include several requirements specific to medical gases. FDA labeling regulations under part 201 (21 CFR part 201) that currently address the labeling of medical gases include the following:
• Section 201.25(b)(1)(i)(D), which exempts medical gases from bar code label requirements that otherwise apply to human prescription drug products;
• Section 201.161, which exempts certain medical gases from specified requirements if, among other things, applicable warning statements and information concerning storage and handling are included in the labeling; and
• Section 201.328, which describes certain labeling requirements for portable cryogenic medical gas containers and high-pressure medical gas cylinders, including a color coding system.
FDA's CGMP regulations under parts 210 and 211 that currently specifically address the manufacturing, labeling, and containers and closures for medical gases include the following:
• Section 211.94(e), which provides container and closure requirements for medical gases, including gas-specific outlet connections and label and coloring requirements;
• Section 211.125(c), which waives labeling reconciliation requirements for 360° wraparound labels on portable cryogenic medical gas containers;
• Section 211.170(b), which exempts compressed medical gases from the requirement to retain reserve samples; and
• Section 211.196, which exempts compressed medical gas products from the requirement that distribution records contain lot or control numbers.
D. History of the Rulemaking
In developing this proposed rule, FDA held three public workshops (Ref. 2), on December 15, 2017, February 9, 2018, and May 11, 2018, and opened a docket for public comment (FDA-2018-N-1214).
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The Agency received several comments from interested stakeholders during the public workshops and received more than a dozen comments through the docket. Additionally, FDA received one comment in relation to its regulatory reform efforts associated with Executive Orders 13771 and 13777 (FDA-2017-N-5093).
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Comments were submitted by industry groups, individual manufacturers, and private citizens. FDA has considered these comments in developing this proposed rule.
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The announcement for the first two workshops referenced Docket No. FDA-2017-N-0001 (82 FR 54353, November 17, 2017). In the announcement for the third workshop, FDA announced that the docket number would change to FDA-2018-N-1214 and that all comments submitted to the first docket would be transferred to the new docket number (83 FR 13440, March 29, 2018).
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These Executive Orders were revoked by Executive Order 13992.
FDA received comments recommending revisions to requirements that commenters believe are not well-tailored to medical gases. Other comments addressed safety and handling concerns for medical gases. Multiple comments discussed whether FDA should add additional gases to the list of designated medical gases. Finally, some comments addressed other uses for certain medical gases.
IV. Legal Authority
Sections 501, 502, 505, 512, 575, 576, 701, and 704 of the FD&C Act provide the principal legal authority for this proposed rule. Medical gases are generally regulated as prescription drugs under sections 201(g)(1) and 503(b)(1) of the FD&C Act (though 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), 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 an 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 promulgate regulations for the efficient enforcement of the FD&C Act, serve as our principal legal authority for this proposed rule.
V. Description of the Proposed Rule
We are proposing to establish new parts 213 and 230 (21 CFR parts 213 and 230) and amend parts 4, 16, 201, 210, 211, 314, and 514 (21 CFR parts 4, 16, 201, 210, 211, 314, and 514). The proposed rule would:
• Revise the labeling regulations specific to medical gases;
• Establish CGMP requirements specific to medical gases;
• Establish regulations governing the designated medical gas certification
process under section 576 of the FD&C Act, including certain postapproval requirements; and
• Establish postmarketing safety reporting requirements specific to designated medical gases.
A. Proposed Labeling Provisions
FDA proposes revisions to the labeling regulations in part 201 related to medical gases.
1. Definitions
Proposed § 201.161(c)(1) defines the term “designated medical gas.” This definition refers to the statutory definition found in section 575(1) of the FD&C Act and is intended to apply to the same gases described in section 575(1) of the FD&C Act.
The term “final use container” is defined in proposed § 201.161(c)(2) to mean a container that is for direct use or access by a patient or healthcare provider to administer a designated medical gas or medically appropriate combination of designated medical gases. The following would not be included in the proposed definition of “final use container”:
• Bulk or transport containers, or
• containers described in § 868.5655 (21 CFR 868.5655).
The Agency specifically requests comment on the scope of the proposed definition of “final use container” and how it relates to current labeling practice.
The term “bulk or transport container” is defined in proposed § 201.161(c)(3) to mean a container used to transport or store designated medical gases or medically appropriate combinations of designated medical gases and that is not used directly to administer such gases to a patient. This definition would cover storage tanks, storage banks, railcars, and tanker trucks. It would also include containers that are connected to medical gas supply systems (for example, cylinders connected to a hospital's oxygen system).
2. Description of Proposed Provisions
In § 201.1(b), FDA proposes to add certain operations that are required to produce a medical gas to the list of operations that are performed by its manufacturer for purposes of section 502(a) and (b)(1) of the FD&C Act and as used in the Agency's labeling regulations in part 201. FDA proposes that fabricating a medical 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, would constitute an operation performed by a manufacturer. Medical gases are produced via several different processes, including air separation, chemical synthesis, and compression, and FDA believes the proposed language would address all such processes. However, under the proposed language, repacking or filling operations in which a finished medical gas is transferred from one container to another, including a container that contains the same medical gas (sometimes referred to as transfilling or “curbside filling” activities at the point of use), would not be considered an operation performed by a manufacturer for purposes of the labeling regulations in part 201 (note that transfilling would be considered a manufacturing activity for purposes of the proposed CGMP regulations under part 213), so long as those operations are limited to transferring finished gas from one container to another without any change or transformation of the gas. FDA also notes that this provision refers to “medical gas” instead of “designated medical gas” because the processes used to produce designated medical gases and other types of medical gases generally fit within the broad categories of processes described in the proposed language. The Agency believes that clarification is needed for all medical gases, and as such, FDA proposes to list operations that are required to produce a medical gas as operations that are performed by its manufacturer, regardless of whether the medical gas is a designated medical gas.
FDA proposes to revise § 201.10(d)(2) to specify the format for a statement of ingredients for designated medical gases. FDA proposes that the statement of the percentage of a designated medical gas in a drug product be expressed in percent volume/volume. The intent of this provision is to better clarify and consistently display the amount of each designated medical gas present in a container.
FDA proposes to revise § 201.51, which requires the label of a prescription drug in package form to bear a declaration of net quantity of contents. In paragraph (a), FDA proposes to clarify that the statement of quantity of designated medical gases and medically appropriate combinations thereof in a gaseous state shall be in terms of volume measure. In paragraph (b), FDA proposes to clarify that the statement of liquid measure currently described in the regulation would not apply to designated medical gases or medically appropriate combinations thereof. Rather, FDA proposes separate requirements for the declaration of net quantity in the labels of designated medical gases or medically appropriate combinations thereof in a:
• Gaseous state in a high-pressure container;
• Liquefied compressed gas state in a high-pressure container; or
• Liquefied state in a portable cryogenic container.
FDA recognizes that some reasonable level of product loss due to venting or evaporation is expected during manufacture; thus, minor deviations between the stated net quantity and the actual net quantity that result from normal venting over time would not cause the product to be misbranded. FDA believes that the information in 201.51(b)(1) through (3) can be included on a separate sticker or decal on the container, and need not be contiguous with other portions of required labeling. Under proposed § 201.51(b)(4), labeling for net quantity of contents is not required for bulk or transport containers, as defined in § 201.161(c)(3). Examples of such containers include storage tanks, storage banks, railcars, and tanker trucks.
FDA proposes that designated medical gases and medically appropriate combinations for animal use utilize the same labeling information as designated medical gases and medically appropriate combinations for human use. Accordingly, FDA proposes to amend § 201.105 to exempt designated medical gases and medically appropriate combinations from the misbranding requirements of section 502(f)(1) of the FD&C Act if they are in compliance with the labeling requirements of § 201.161. This proposal is intended to allow manufacturers to have one set of labeling that can be utilized for both human and animal use of their designated medical gases. Manufacturers will not necessarily know at the time of manufacture, filling, or distribution how their gas will be used. Additionally, FDA expects that requiring two separate sets of labeling would create a significant burden on industry with little or no benefit to product safety or patient outcomes. Because FDA is not aware of any reason to require different information for animal use, the Agency believes utilization of the same labeling for both human and animal use is appropriate.
FDA proposes several revisions to § 201.161 in addition to the proposed definitions described above. Under proposed paragraph (a), the requirements of section 503(b)(4) (concerning when a drug's label must bear the symbol “Rx only”) and 502(f)
(requiring a drug's labeling to bear adequate directions for use and certain adequate warnings) of the FD&C Act are deemed to have been met for a designated medical gas or a medically appropriate combination of designated medical gases if the labeling on its final use container bears certain information depending on the specific gas or gases it contains. Each of the proposed revisions is described in turn below.
FDA proposes revisions to the statement describing the effect of compliance with this section. FDA proposes this revision to more closely align with section 576(a)(3)(A)(ii) of the FD&C Act. FDA does not believe it is necessary for § 201.161(a) to include exemptions from 21 CFR 201.100(b)(2), (3), and (c)(1), given that section 576(a)(3)(A)(ii) of the FD&C Act provides a separate way of satisfying the requirements of section 502(f) for designated medical gases.
FDA proposes to remove the list of gases in § 201.161(a) and instead refer to “designated medical gas.” FDA proposes these revisions to § 201.161 for consistency with section 576(a)(3)(A)(ii) of the FD&C Act. The proposed revisions would bring medical air and carbon monoxide that meet the definition of “designated medical gas” within the scope of § 201.161; these gases are not included in the list of gases in § 201.161 currently but are designated medical gases for which a certification can be granted under section 576 of the FD&C Act. Instead of adding medical air and carbon monoxide to the list of gases, FDA proposes to revise the first sentence to clarify that all designated medical gases and medically appropriate combinations thereof are within the scope of § 201.161(a). Should other medical gases be added to the definition of “designated medical gas” pursuant to section 575(1)(H) of the FD&C Act in the future, this proposed revision would make the provisions of § 201.161 applicable to such gases without the need to amend this regulation further. This proposed revision would also ensure that all designated medical gases other than oxygen, including medical air and carbon monoxide, and medically appropriate combinations of designated medical gases are required to bear the label statements in proposed § 201.161(a)(2) in order for sections 503(b)(4) and 502(f) to be deemed to be met for such gas or gases.
FDA proposes to remove the language in § 201.161 referencing §§ 201.328 and 211.94(e)(2). FDA believes it is unnecessary for § 201.161 to reference compliance with §§ 201.328 and 211.94(e)(2) as a condition for sections 503(b)(4) and 502(f) to be deemed to be met.
Additionally, FDA proposes to revise paragraph (a) to require that the final use container of a designated medical gas or medically appropriate combination of gases must bear the required information in order for sections 503(b)(4) and 502(f) to be deemed to be met for such gas or gases. This proposed revision is intended to clarify that the warnings, directions, and other information in § 201.161(a) must appear in the labeling of the final use container of a designated medical gas or medically appropriate combination of designated medical gases in order for the requirements of sections 503(b)(4) and 502(f) of the FD&C Act to be deemed to be met for such gas or gases, consistent with the requirements in section 576(a)(3)(A)(ii) of the FD&C Act.
In the case of oxygen, FDA proposes to require the final use container to bear a warning statement providing the following (§ 201.161(a)(1)(i)):
• Uninterrupted use of high concentrations of oxygen over a long duration, without monitoring its effect on oxygen content of arterial blood, may be harmful;
• oxygen should not be used on patients who have stopped breathing unless used in conjunction with resuscitative equipment; and
• in the case of oxygen that may be provided without a prescription for use in the event of depressurization or other environmental oxygen deficiency, or for oxygen deficiency or for use in emergency resuscitation when administered by properly trained personnel, a warning that the oxygen can be used for emergency use only when administered by properly trained personnel for oxygen deficiency and resuscitation, and that for all other medical applications a prescription is required.
This is the same information currently required in § 201.161(a)(1)(i) for oxygen. FDA believes this information is important to convey the risks of using oxygen and is consistent with the requirements in section 576(a)(3)(A)(ii) and (b)(2) of the FD&C Act.
FDA proposes § 201.161(a)(1)(ii), which would require clear and prominent “no smoking” and “no vaping” warning statements and a graphic warning symbol on the label of oxygen final use containers indicating that smoking, vaping, and open flames near oxygen are dangerous. Such a graphic symbol may be based on those created by standards development organizations. FDA is aware of numerous instances of fires related to the medical use of oxygen, most often related to individuals smoking in the vicinity of an oxygen tank in operation. Additionally, FDA has become aware of some reports that vaping products
6
have been linked to medical oxygen fires and explosions (Refs. 3 to 6). These events can cause death and serious injury to the patient, as well as cohabitants, neighbors, and first responders. Oxygen cylinders generally contain warnings regarding keeping oil, grease, combustibles, heat, sparks, and flame away from the product (though language varies from cylinder to cylinder). However, this language is generally in very fine print, is not expressed in a manner that is clear to lay users, and does not mention smoking or vaping directly. The purpose of this proposed provision is to include in product labeling a plain-language warning against smoking, vaping, or using open flames near an operating oxygen tank. Because many patients on oxygen therapy have smoking-related illnesses, and because some patients may continue to smoke or vape during treatment, FDA believes that the proposed warning will help mitigate the risk of fires during the administration of oxygen. The proposed “no smoking” and “no vaping” warning statements and graphic symbol may appear on a separate sticker or decal displaying the information on the container or be painted directly on the container. The Agency will continue to consider other risks of combustion as well.
6
The term “vaping products” includes vapes or vape pens, personal vaporizers, e-cigarettes, cigalikes, e-pens, e-hookahs, e-cigars, e-pipes and other battery-operated tobacco products in addition to other non-nicotine vape products.
In the case of all designated medical gases other than oxygen, and in the case of medically appropriate combinations of designated medical gases, FDA proposes to require the final use container to bear the following information (§ 201.161(a)(2)(i) and (ii)):
• A warning statement providing that the administration of the gas or gas combination (as applicable) may be hazardous or contraindicated; and
• a warning statement providing that the gas or gas combination (as applicable) should be used only by or under the supervision of a licensed practitioner who is experienced in the use and administration of the gas or gas combination (as applicable) and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken.
This is the same information currently required in § 201.161(a)(1)(ii) for the listed gases other than oxygen, as well
as for medically appropriate combinations of the listed gases. In addition, FDA proposes to require that the labeling on the final use container of designated medical gases other than oxygen and medically appropriate combinations of designated medical gases bear the symbol “Rx only.” FDA believes this information is important to convey the risks of using these gases and is consistent with the requirements in section 576(a)(3)(A)(ii) and (b)(1) of the FD&C Act.
Under proposed § 201.161(a)(3), the labeling on the final use container for all designated medical gases and medically appropriate combinations thereof would be required to bear appropriate directions and warnings concerning storage and handling. FDA believes this proposed revision is consistent with the current requirement in § 201.161(a)(2). The Agency proposes this revision to reflect the language in section 576(a)(3)(A)(ii)(III) of the FD&C Act on this issue.
The Agency has received comments recommending that it issue a separate warning statement requirement for medical air that states that medical air may be used without a prescription for breathing support when administered by properly trained personnel. FDA has decided not to propose a warning statement for medical air that is different from the warning statement proposed for designated medical gases other than oxygen, nor does FDA otherwise propose to exercise its authority under section 503(b)(3) of the FD&C Act to remove medical air from the requirements of section 503(b)(1). In the 2016 final rule entitled “Medical Gas Containers and Closures; Current Good Manufacturing Practice Requirements,” FDA responded to comments asserting that certain non-prescription uses of medical air are medically appropriate by deciding not to finalize its proposal to add medical air to the list of gases at § 201.161(a) and stating that it would continue to consider what would constitute an appropriate warning statement for medical air (81 FR 81685 at 81689; November 18, 2016). Since the publication of the 2016 final rule, FDA has continued to consider this issue, and the Agency remains unaware of any uses for medical air that would be appropriate for nonprescription use, and no new information supporting such uses has been provided since the Agency last addressed this issue in a citizen petition response to the Compressed Gas Association (Ref. 7). FDA believes that medical air intended for use by properly trained personnel in a healthcare setting should remain a prescription use subject to the requirements of section 503(b)(1) of the FD&C Act. The Agency specifically requests comment on this issue.
Proposed new § 201.161(b) would create separate labeling requirements for bulk or transport containers used for designated medical gases or medically appropriate combinations of designated medical gases. FDA proposes to require that such containers be identified with the name of the product contained therein and be accompanied by documentation identifying the product as meeting applicable compendial standards. As discussed in this section, bulk or transport containers are excluded from the proposed definition of final use containers. Because these large containers are generally removed from the point of care and are not expected to be used directly to administer a designated medical gas or medically appropriate combination of designated medical gases to a patient, FDA does not believe that such containers need to bear the information that would be required under proposed § 201.161(a). However, it is essential that the identity of the gas or gases inside such containers is evident to individuals handling and transporting the containers in order to prevent mix-ups. Many firms in the supply chain for medical gases, including those firms downstream from the manufacturers that initially produce the gas, receive and distribute gases for medical and non-medical use, and some non-medical gases may not meet compendial standards applicable to designated medical gases. Therefore, this proposal would require that a bulk or transport container bears the name of the designated medical gas or medically appropriate combination of designated medical gases contained therein, and that the accompanying documentation identifies that the product meets applicable compendial standards. These proposed requirements are expected to help prevent mix-ups and ensure that recipients of designated medical gases or medically appropriate combinations thereof in bulk or transport containers are provided information indicating that such gases meet applicable compendial standards.
In § 201.328(a)(1), FDA proposes technical changes to reflect that the requirements in § 211.94(e)(2) are proposed to be moved to § 213.94(e)(3). See section V.B.1 for more information on this proposed revision.
Proposed new § 201.328(d) would provide 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 and 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 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 allowing container owners to be clearly identified so that patients and healthcare professionals can contact the container owners if necessary. This provision is intended to help ensure that appropriate entities can be contacted regarding quality issues or adverse events. It is additionally intended to facilitate the return of cylinders to owners that may not also be medical gas manufacturers. The proposed inclusion of the container owner's information would not cause the container owner to be a “relabeler” for purposes of FDA's registration and listing requirements.
B. Proposed Current Good Manufacturing Practice Provisions
FDA proposes the establishment of part 213, which would contain the CGMP requirements for preparation of medical gases, including designated medical gases, for administration to humans or animals. If finalized as proposed, medical gases proposed to be subject to part 213 would no longer be subject to part 211. FDA also proposes conforming edits to part 210 so that applicable provisions would reflect the new CGMP regulations for medical gases in part 213. As proposed, part 213 would apply to the entity that initially produces a medical gas and also to any downstream firms that manufacture, process, pack, or hold medical gases, including firms that combine, commingle, refill, or distribute designated medical gases and medically appropriate combinations thereof. Part 213 is not intended to apply to entities further upstream in the supply chain from the entity that initially produces a medical gas. FDA seeks comment on the scope of these requirements, including the stage of product development at which they would apply and the entities that would be subject to the requirements. In this section, FDA will first describe proposed revisions to parts 210 and 211. Then FDA will describe the proposed requirements in part 213, including how they would differ from the requirements in part 211. Lastly, FDA will describe certain groups of CGMP requirements under part 211 that FDA is not proposing in part 213.
1. Proposed Revisions to Parts 210 and 211
FDA proposes conforming edits to parts 210 and 211 to account for the proposed new part 213. In part 210, FDA proposes to add references to part 213 in § 210.1(a) and (b) and in § 210.2(a) and (b) so that applicable provisions in part 210 would reflect the new CGMP regulations for medical gases in part 213.
In § 211.1(a), FDA proposes to add “medical gases as defined in § 213.3(b)(12)” to the parenthetical that currently excludes positron emission tomography drugs from part 211. Proposed part 213 would contain the CGMP requirements for medical gases.
FDA also proposes to delete § 211.94(e). Instead, proposed § 213.94 would contain updated requirements for medical gas containers and closures that are generally consistent with the current requirements in § 211.94(e), with some additional provisions. More information is in section V.B.6 of this document.
FDA proposes to delete the last sentence of § 211.125(c), which waives labeling reconciliation requirements for 360° wraparound labels on portable cryogenic medical gas containers because labeling reconciliation for medical gases would be addressed by proposed § 213.125(b).
FDA proposes to delete the reference to “containers of compressed medical oxygen” in § 211.132(c)(1), which is in a parenthetical that excludes certain products from the requirement for each retail package of an over-the-counter drug product covered by § 211.132 to bear a particular statement regarding its tamper-evident features. This reference would no longer be relevant if this proposed rule is finalized because medical gases (including compressed medical oxygen) would no longer be subject to part 211.
FDA proposes to delete the statement in § 211.170(b) that reserve samples of compressed medical gases need not be retained. Under the proposed rule, medical gases would be subject to proposed part 213, which would not include reserve sample requirements.
FDA proposes to delete the exception in § 211.196 that distribution records for compressed medical gas products are not required to contain lot or control numbers because distribution records requirements for medical gases would be addressed by proposed § 213.196.
2. General Provisions
Section 213.1 explains the scope of FDA's proposed CGMP requirements for medical gases. Proposed part 213 would contain the minimum CGMP requirements for preparation of all medical gases for administration to humans or animals, including designated medical gases, medically appropriate combinations of designated medical gases, medical gases that are approved under an application that was submitted to FDA under section 505 or 512 of the FD&C Act, and any marketed unapproved drugs that are medical gases. Because designated medical gases and other kinds of medical gases share many of the same physical characteristics and are manufactured, processed, packed, and held using similar operations and control strategies, FDA believes that continuing to have a single set of CGMP requirements for all medical gases is appropriate.
FDA does not consider the process of mixing or combining gases by a hospital or healthcare provider at the point of care and as part of the ordinary practice of treating individual patients to be activities subject to part 213.
Part 213 applies to all designated medical gases and medically appropriate combinations thereof, regardless of whether they are intended for use in humans, animals, or both.
Proposed § 213.3 includes several definitions that generally track those in part 210, some of which have been revised to tailor them more specifically to medical gases. Proposed § 213.3 also contains new definitions that are relevant to the manufacture, processing, packing, and holding of medical gases. Proposed paragraph (a) would generally apply the definitions and interpretations in section 201 of the FD&C Act to such terms when used in proposed part 213. Proposed paragraph (b) contains additional definitions as follows:
• The term “acceptance criteria” is proposed to be defined in § 213.3(b)(1) to mean 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). This is identical to the definition of the same term in part 210. The Agency believes that establishing clear product specifications and acceptance/rejection criteria for determining whether a lot or batch is acceptable will help ensure the identity, strength, quality, and purity of medical gases.
• Proposed § 213.3(b)(2) would define the term “batch” to mean “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.” This is generally consistent with the definition of the same term in part 210. The Agency believes this definition would allow for significant flexibility in defining a batch to address considerations raised by different types of firms and different manufacturing, processing, packing, and holding activities.
• The term “commingling or commingled” is proposed to be defined in § 213.3(b)(3) to refer to the act of combining one lot of designated medical gas or component with another lot or lots of the same designated medical gas or component. This is primarily intended to reflect the industry practice of combining designated medical gases of the same identity (
e.g.,
nitrogen and nitrogen) from multiple original manufacturers or lots, all of which meet compendial standards. This definition would be new in part 213.
• In proposed § 213.3(b)(4), the term “component” is revised. Compared to the definition in § 210.3(b)(2) it means any ingredient intended for use in the manufacture of a medical gas, including those that may not appear in such gas. The term does not include incoming designated medical gases. Different proposed requirements in part 213 would apply to components and incoming designated medical gases. These proposed requirements are described further in section V.B.6 of this proposed rule.
• Proposed § 213.3(b)(5) defines the term “designated medical gas.” This definition refers to the statutory definition found in section 575(1) of the FD&C Act and is intended to apply to the gases described in section 575(1) of the FD&C Act.
• FDA also proposes to add a definition of the term “FDA” in § 213.3(b)(6) to mean the Food and Drug Administration. This is consistent with other Agency regulations that contain a definition of FDA.
• Proposed § 213.3(b)(7) defines the term “in-process material” to mean “any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the medical gas.” This is generally consistent with the definition of the same term in part 210.
• FDA proposes in § 213.3(b)(8) to define “incoming designated medical gas” to mean a designated medical gas received from one source that 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. This definition is intended to cover designated medical gases that downstream entities receive from original manufacturers and other sources. However, incoming gases that are not designated medical gases but that are intended for use in the manufacture of a medical gas would be considered components. As described above, FDA proposes different requirements for components and incoming designated medical gases. This definition would be new in part 213.
• In proposed § 213.3(b)(9), the term “lot” is defined to mean a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits. In the case of a medical gas produced by continuous process, the term means a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits. This is generally consistent with the definition of the same term in part 210.
• FDA proposes to define “lot number, control number, or batch number” in § 213.3(b)(10) to mean “any distinctive combination of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of medical gas or other material can be determined” (§ 213.3(b)(11)). This is generally consistent with the definition of the same term in part 210.
• In proposed § 213.3(b)(11), the term “manufacture, processing, packing, or holding” is defined to include packaging and labeling operations, testing, and quality control of medical gases. This is generally consistent with the definition of the same term in part 210 because many provisions refer to these actions, and FDA intends that they have the same meaning as in part 210. FDA considers packaging in the context of these proposed requirements to include filling a container with a medical gas.
• FDA proposes in § 213.3(b)(12) that the term “medical gas” has the meaning given the term in section 575(2) of the FD&C Act. This would include designated medical gases, medically appropriate combinations of designated medical gases, medical gases that are approved under an application that was submitted to FDA under section 505 or 512 of the FD&C Act, and any marketed unapproved drugs that are medical gases. This term would not include gases that are used as excipients in drug products that are not medical gases (
e.g.,
propellants in inhalation drugs).
• FDA proposes to define “original manufacturer” in § 213.3(b)(13) to include persons or entities that initially produce a designated medical gas by chemical reaction, physical separation, compression of atmospheric air, purification of a gas, or other means. FDA's intent is to capture the various methods by which firms produce designated medical gases. A person who refills a designated medical gas into a new container, either for further distribution or at the delivery site, would not be considered an original manufacturer. Additionally, a person who creates a medically appropriate combination of designated medical gases would not be considered an original manufacturer. This proposed definition would be new in part 213.
• FDA's proposed definition of “quality unit” in § 213.3(b)(14) is any person or persons designated with the authority and responsibility for overall quality management and other responsibilities as defined in § 213.22. Under proposed part 213, the quality unit's responsibilities would include oversight of quality throughout the entire manufacturing process. We are proposing to use the term “quality unit” because the Agency believes this term more appropriately reflects current terminology. As FDA has previously noted, the Agency considers “quality control unit” (defined in § 210.3(b)(15)) and “quality unit” to be synonymous. FDA proposes an updated definition for part 213 that focuses on “overall quality management” rather than quality control. The Agency believes that this definition would better reflect industry practice and the Agency's understanding of the responsibilities of the quality unit.
• FDA's proposed definition of “strength” in § 213.3(b)(15) is generally consistent with the definition in part 210, and contains two parts: (1) The concentration of the medical gas (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or (2) the potency, that is, the therapeutic activity of the medical gas as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard).
FDA seeks comment on whether there are other terms, including those that are used in this proposed rule or in parts 210 and 211, that the Agency should define in part 213.
3. Organization and Personnel
Proposed § 213.22 describes the responsibilities of the quality unit and is similar in scope to § 211.22. Proposed paragraphs (a) through (d) are generally consistent with paragraphs (a) through (d) in § 211.22, with one notable change: FDA proposes to use the term “quality unit” instead of “quality control unit.” Paragraph (a) would require that there be a quality unit with the responsibility and authority to approve or reject all components, medical gas containers and closures, in-process materials, packaging material, labeling, and medical gases, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. Additionally, the quality unit would be responsible for approving or rejecting medical gases manufactured, processed, packed, or held under contract by another company. The Agency believes that assigning dedicated staff to these quality responsibilities is critical to ensuring the identity, strength, quality, and purity of the medical gas.
Paragraph (b) would require that there be made available to the quality unit adequate laboratory facilities for the testing and approval (or rejection) of components, medical gas containers and closures, packaging materials, in-process materials, and medical gases. The availability of such facilities would help the quality unit perform its functions.
Under paragraph (c), the quality unit would have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the medical gas. The Agency believes this provision would provide clarity regarding these responsibilities and that the quality unit is best positioned to determine whether these procedures and specifications are appropriate.
Paragraph (d) would state that the responsibilities and procedures applicable to the quality unit shall be in writing and shall be followed. The Agency believes this would help provide additional assurance for reliable continuation of established policies and procedures regarding product quality.
Paragraph (e) would clarify that quality unit personnel may perform other functions if there are appropriate written controls in place to ensure such other functions are performed separately from quality unit responsibilities and such other functions do not interfere with the quality unit's responsibilities or subordinate the quality unit's responsibilities to any other unit. Small
firms that manufacture, process, pack, or hold a drug, including medical gases, have limited personnel who may have multiple roles within the firm. So long as there are appropriate written controls in place to ensure that other functions do not interfere with the quality unit's responsibilities or subordinate the quality unit's responsibilities to any other unit, FDA considers it acceptable for quality unit personnel to perform these other functions.
Proposed § 213.25 addresses personnel qualifications and responsibilities. Paragraph (a) would contain requirements for personnel education, training, and experience that are generally consistent with those contained in § 211.25, except as described below. Under proposed § 213.25(a), persons engaged in the manufacture, processing, packing, or holding of a medical gas would be required to have the education, training, and experience (or any combination thereof) to enable them to perform assigned functions. Training would have to be in the employee's particular operations and in CGMP (including in the applicable CGMP regulations and written procedures required thereunder). Training in CGMP would have to be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them. FDA proposes to specify in § 213.25(a) that written documentation must be maintained demonstrating employees' completion of training, including the date, type of training, and results of any completion criteria, such as test results. The Agency believes that these requirements would be sufficient to allow firms to maintain properly trained staff capable of accomplishing all required tasks. This paragraph would apply to all personnel engaged in the manufacture, processing, packing, or holding of a medical gas, including supervisors and subordinates. Therefore, we are not proposing a separate requirement similar to § 211.25(b) regarding supervisor responsibilities in this proposed rule.
Paragraph (b) would require that there be an adequate number of qualified personnel to perform manufacturing, processing, packing, and holding activities for each medical gas. The scope of this proposed requirement is the same as in § 211.25(c). This proposed requirement is important to ensure that all steps related to manufacturing, processing, packing, and holding are performed or monitored appropriately. What would constitute “adequate” personnel would depend in part on the size and complexity of the operations being performed.
Paragraph (c) would restrict access to “limited-access areas” to authorized personnel only. This proposed requirement is the same as § 211.28(c) and is important for medical gases because of the danger associated with mishandling medical gases and the risks to patients if such gases are improperly manufactured.
In § 213.34, FDA proposes requirements regarding consultants that are generally consistent with requirements that currently apply to medical gases under § 211.34. FDA does not see a need for different training and experience requirements for consultants advising on medical gases compared to other drug products. Consultants would be required to have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Further, records would be required to be maintained that state the name, address, and qualifications of any consultants and the type of service they provide.
4. Buildings and Facilities
FDA proposes a more limited set of building and facilities requirements for the manufacture, processing, packing, or holding of medical gases compared to part 211. FDA's primary concern regarding buildings and facilities used for these products is the risk of mix-ups because multiple gases are often produced at these buildings and facilities, and a gas mix-up could lead to patient harm. Additionally, while the risk of contamination is diminished for medical gases because they are generally manufactured in a closed, sealed system, periodic cleaning and maintenance is necessary for all buildings and facilities, so buildings and facilities must be designed to facilitate such cleaning and maintenance. The proposed requirements in this subpart are intended to address these risks, taking into account the unique manufacturing processes for medical gases.
Proposed § 213.42(a) 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. Specifically, buildings and facilities would be required to be of adequate design to prevent mix-ups between components, incoming designated medical gases, medical gas containers and closures, labeling, in-process materials, or medical gases. FDA proposes to specify “buildings and facilities” in this section and elsewhere because some medical gas operations, including storage, can be performed outdoors without affecting the safety, identity, strength, quality, and purity of the product. FDA expects that there will be multiple ways of achieving adequate design and adequate space for all manufacturing operations that prevent mix-ups and allow for necessary cleaning and maintenance. Multiple gases are often manufactured at the same facility, and a mix-up could result in a patient receiving the wrong gas, which could be fatal. Therefore, it is essential that buildings and facilities be designed to enable personnel to clearly identify which equipment and materials are being used for which gas, to avoid such mix-ups. Moreover, while contaminants such as ordinary dust and dirt are unlikely to enter a closed system, such contamination can still occur, for example, at the point at which a gas is transferred from one container to another.
Proposed § 213.42(b) would require that operations be performed within specifically defined areas of adequate size, with separated or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mix-ups during the following procedures:
• Receipt, identification, storage, and withholding from use of components or incoming designated medical gases, medical gas containers and closures, and labeling, pending the appropriate sampling, testing, or examination by the quality unit before release for manufacturing or packaging;
• Holding rejected components, incoming designated medical gases, medical gas containers and closures, and labeling before disposition;
• Storage of released components, incoming designated medical gases, medical gas containers and closures, and labeling;
• Storage of in-process materials;
• Manufacturing and processing operations;
• Packaging and labeling operations;
• Quarantine storage before release of medical gases;
• Storage of medical gases after release; and
• Control and laboratory operations.
Where multiple gases are being produced at the same facility, it is important for staff to be able to easily determine which gas is being manufactured in each area of the facility. These requirements will also help personnel distinguish between received, in-process, and finished product. FDA anticipates that firms can
meet this requirement with physical barriers, signage, or both, though firms may use other appropriate means. Proposed § 213.42(b) would further require that the flow of components, incoming designated medical gases, containers, closures, labeling, in-process materials, and medical gases be designed to prevent contamination and mix-ups.
Under proposed § 213.42(c), any building or facility used in the manufacture, processing, packing or holding of a medical gas shall be maintained in a clean condition so as to assure the safety, identity, strength, quality, and purity of the gas. Additionally, § 213.42(c) would require that written procedures applicable to the maintenance and cleaning of buildings and facilities be established and followed. FDA believes this proposed requirement is more limited than the sanitation requirement in § 211.56(a), and that it is better tailored to medical gas production, which involves a generally lower risk of contamination than other drug products. The condition of buildings and facilities that would be considered clean for medical gas production is expected to be different from the condition of buildings and facilities that would be considered clean for production of other drug products, where greater risks of contamination generally exist.
5. Equipment
Subpart D contains proposed requirements for equipment. Proposed § 213.63 would require that equipment be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. FDA expects that the design of the facility and equipment will allow for appropriate cleaning and maintenance (for example, personnel can access all equipment that must be cleaned). FDA expects that firms will ensure that pigtails, valves, hoses, and similar connectors are kept clean and maintained.
Proposed § 213.65 addresses equipment construction and is similar to § 211.65. Paragraph (a) would require that equipment be constructed so that surfaces that contact components, in-process materials, or medical gases are not reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the medical gas beyond the official or other established requirements. Paragraph (b) would require that substances required for operations, such as lubricants or coolants, shall not come into contact with components, containers, closures, in-process materials, or medical gases so as to alter the safety, identity, strength, quality or purity of the medical gas beyond the official or other established requirements.
FDA proposes equipment maintenance and cleaning requirements under § 213.67. These proposed requirements differ from those that currently apply to medical gases under § 211.67 and reflect the differences in appropriate practices for routine cleaning of equipment associated with the manufacturing, processing, packing, and holding of medical gases. Paragraph (a) would require that written procedures be established, maintained, and followed for adequate cleaning and maintenance of equipment. Procedures would be required to include the following:
• Assignment of responsibility for cleaning and maintaining equipment;
• maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;
• a sufficiently detailed description of the methods, equipment, and materials used in cleaning and maintenance, as well as the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance;
• removal or obliteration of previous batch identification;
• protection of clean equipment from contamination prior to use; and
• inspection of equipment for cleanliness immediately before use.
FDA anticipates that these procedures would address, among other things: Cleaning, or verifying as clean, equipment and product contact surfaces prior to initial use, after potential exposure to a contaminant, or as part of maintenance if such maintenance may expose the product contact surfaces to potential contamination; maintaining equipment at appropriate intervals to prevent malfunctions or contamination; and inspecting or testing systems prior to returning to service, to assure that no residual cleaning agents are present.
Proposed paragraph (b) specifies that such procedures shall not alter the safety, identity, strength, quality, or purity of the medical gas beyond established requirements.
Paragraph (c) would require that records be kept of cleaning, maintenance, and inspection as specified in § 213.180.
Proposed § 213.68 addresses requirements for automatic, mechanical, and electronic equipment used in the manufacture of medical gases. Paragraph (a) would require that such automatic, mechanical, and electronic equipment 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 be maintained. Ensuring that automated, mechanical, and electronic equipment is properly functioning is critical to ensuring the safety, strength, identity, quality, and purity of a gas. Without such checks, firms could manufacture gases that fail to meet compendial standards, or that are not appropriate for the ultimate patients' needs.
Paragraph (b) would require validation of computerized systems that record, store, or use data. The validation necessary would depend on how the computerized system is used in the manufacturing process.
In paragraph (c), FDA would require the maintenance of backup files of data entered into computer systems, though such backups would not be required where certain data, such as calculations, are eliminated by computerization or other automated processes.
Paragraph (d) would require that appropriate change control be used whenever modifications are made to computerized systems to assure that any changes do not adversely affect data integrity or product quality. FDA expects that this will include that manufacturers evaluate proposed changes with affected departments, that the proposed changes are assessed for revalidation where appropriate, and that activities are documented. Records would also be required to be maintained of such modifications.
6. Control of Incoming Designated Medical Gas, Components, and Medical Gas Containers and Closures
Subpart E contains proposed requirements for control of incoming designated medical gases, components, and medical gas containers and closures. Proposed § 213.80(a) and (b) are similar to paragraphs (a) and (b) of § 211.80, though the proposed requirements would also apply expressly to incoming designated medical gases. Paragraph (a) would require sufficiently detailed written procedures to be developed and followed describing the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components, incoming designated medical gases, and medical gas containers and closures. Paragraph (b) would require that components, incoming designated medical gases, and medical gas containers and closures be handled and stored in a manner to prevent contamination and mix-ups. As previously mentioned, medical gases are
generally manufactured in a closed, pressurized system, and gas mix-ups generally pose a more significant risk than contamination, considering previous incidents in which patients were administered the wrong gas (Ref. 8). However, while contamination poses a lower risk, there still exists the possibility for contamination. FDA believes that different controls would likely be appropriate for medical gas manufacturers to prevent contamination than would be expected for producers of other drugs.
Proposed paragraph (c) would require that lots of incoming designated medical gases or components be assigned a unique identification number, regardless of whether the incoming lot is used directly as supply or commingled with an existing supply. This would help facilitate the tracing of product once it enters distribution.
FDA is not proposing that part 213 include the requirements described in paragraphs (c) and (d) in § 211.80. FDA believes it is unnecessary to include the requirement in § 211.80(c) that product be stored off the floor and suitably spaced to permit cleaning and inspection. Sealed medical gas containers are designed to protect gases from contamination and external conditions, and their size and weight make storage off the floor impracticable in many settings. FDA also is not proposing to include in part 213 the requirement in § 211.80(d) that each container or grouping of containers for components or drug product containers, or closures be identified with a distinctive code for each lot in each shipment received. Gas containers are reused, and inspection of containers prior to reuse would be required under proposed § 213.84(a). Thus, FDA believes that other lot identification requirements in proposed part 213 are sufficient to track product.
Proposed § 213.82 addresses the receipt and storage of incoming designated medical gases. The proposed requirements differ from currently applicable requirements in § 211.82 to better reflect the use of incoming designated medical gases in further manufacturing. Under proposed paragraph (a), a firm would have to verify and record upon receipt of a designated medical gas that the shipment contains a signed certificate of analysis (COA) from the supplier, and that the COA contains the following:
• The supplier's name;
• the name of the incoming designated medical gas;
• the lot number or another unique identification number;
• the actual analytical result obtained for strength, as well as the results of other tests performed (FDA expects these tests would include tests sufficient to demonstrate conformance with compendial standards);
• identification of the test method(s) used for analysis;
• the NDA and/or NADA number of the incoming designated medical gas; and
• the supplier representative's signature and the date of signature.
If the incoming designated medical gas is obtained from a supplier other than the original manufacturer, the shipment would also have to include complete information from the original manufacturer's COA. The firm would also be required to establish and maintain a program to ensure the reliability of the supplier's capabilities through appropriate assessment and testing procedures. This is essential to ensuring that the information in the COA is accurate, and thus that the incoming designated medical gas meets relevant standards.
Proposed paragraph (b) would require that an identity test be conducted on incoming designated medical gases upon receipt. FDA understands that this is consistent with current industry practice (Ref. 2), and because designated medical gas manufacturers supplying the gas will conduct full compendial testing, and the firm receiving the incoming designated medical gas would conduct full compendial testing prior to release (see proposed § 213.165), FDA believes this is an appropriate level of review.
FDA proposes § 213.84 regarding testing and approval or rejection of components, containers, and closures. Paragraph (a) would require that components, containers, and closures (including valves) be examined for conformance with appropriate written procedures and specifications, and approved or rejected, prior to the manufacturing or filling process. Firms can meet this proposed requirement by testing for conformance with written specifications. In lieu of such examination by the firm, a statement of verification that the component, container, or closure meets specifications may be accepted from the supplier, provided that the firm establishes and maintains a program to ensure the reliability of the supplier's capabilities through appropriate assessment and testing provisions. This requirement would be satisfied with an auditing system. This type of evaluation system is intended to ensure the integrity of components, containers, and closures for the entire period of use. Rejected items would need to be handled in accordance with § 213.89.
Under proposed paragraph (b), firms would be required to take appropriate actions to protect against container and closure leaks. This would include performing leak tests on containers and closures at the time of fill and after fill but prior to release. FDA has evaluated inspectional findings from 2003 to 2021 and identified numerous instances of leaking or empty containers reported by customers and patients, following release by the manufacturer (Ref. 9). Because of the location and delayed timing of these defects, it appears some are likely not detectable prior to release. Therefore, additional controls 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. For example, the inclusion of representative leak tests at additional intervals, such as upon pick-up or receipt of the container by the manufacturer, may be an additional adequate control. FDA seeks comment, with related data and explanation, from manufacturers, distributors, and end users of medical gases and other interested parties on whether leak testing at the time of fill and after fill but prior to release would sufficiently ensure the integrity of the container closure system for the period of use, and whether additional periodic leak tests would enhance the ability to correct and prevent container closure defects that are only detectable after they leave the manufacturer.
Proposed paragraph (c) would require that components be sampled, tested, and approved or rejected as appropriate prior to use. Firms would be able to meet this proposed requirement 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. Components are not always used in the manufacture of designated medical gases, but when they are used, FDA believes these proposed requirements are reasonable.
Proposed § 213.89 is similar to the requirements in § 211.89 in that rejected components, containers, and closures would need to be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable, but proposed § 213.89 would also apply to incoming designated medical gases.
Such a quarantine system need not include physical quarantining, as other methods can adequately ensure that unsuitable products are not used. FDA proposes to add a requirement that rejected components, incoming designated medical gases, and medical gas containers and closures be documented and assessed. This additional proposed requirement would help to ensure that any trends that warrant further investigation can be identified.
Proposed § 213.94 would contain additional requirements for medical gas containers and closures. Paragraph (a) is generally consistent with the requirements in § 211.94(a) and would require that containers and closures not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the medical gas beyond the official or established requirements.
Under paragraph (b), container closure systems would be required to provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the medical gas. This is generally consistent with the requirements in § 211.94(b).
Paragraph (c) would require that medical gas containers and closures be clean to assure that they are suitable for their intended use. This is generally consistent with § 211.94(c), but FDA does not propose to include the requirements related to sterilization or removal of pyrogenic properties, as those are not relevant to medical gases.
Under proposed paragraph (d), standards or specifications, methods of testing, and, where indicated, methods of cleaning shall be written and followed for medical gas containers and closures. This is generally consistent with § 211.94(d), but FDA does not propose to include the requirements related to sterilization or removal of pyrogenic properties, as those are not relevant to medical gases.
Proposed paragraph (e) is a revised version of § 211.94(e) and would contain requirements for medical gas containers and closures. In paragraph (e)(1), FDA proposes that 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. Proposed § 213.94(e)(1) is consistent with § 211.94(e)(1). Consistent with § 211.94(e)(1), FDA proposes 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. The Agency believes only such manufacturers should be able to remove or replace gas-specific use outlet connections that are attached to the valve body. Also, consistent with § 211.94(e)(1), FDA proposes 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 at § 868.5655). The Agency believes all portable cryogenic medical gas containers should have gas-specific use outlet connections that are attached to the valve body in order to prevent gas mix-ups. FDA seeks comment regarding whether the scope of the exception to the term “portable cryogenic medical gas container” is appropriate, especially as the exception would include small cryogenic containers for use by individual patients.
Under paragraph (e)(2), FDA proposes to add the requirement that 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) have a working gauge sufficient to indicate whether the container has an adequate supply of medical gas for continued use. This is intended to enable end users, such as healthcare practitioners, patients, and caretakers, to monitor the gas remaining in the container. Without such a gauge, end users may not be able to determine when the container needs to be refilled or replaced. Additionally, if a container is stored for a long period of time before use and, during that time, slowly vents or leaks, the end user will be able to determine with a working gauge whether there is still gas in the container. FDA believes that the term “working gauge” would allow for flexibility, so that firms may use the type of gauge appropriate to measure the remaining volume or weight of medical gas, in liquid or gaseous form, as appropriate. FDA believes that the proposed requirement to have a working gauge would help to assure the safety, identity, strength, quality, and purity of medical gases in portable cryogenic containers and small cryogenic containers for use by individual patients throughout their period of use.
Paragraph (e)(3) would contain the label and coloring requirements that currently apply to medical gases under § 211.94(e)(2), except that it would not include the requirement that the labeling not be susceptible to becoming worn or inadvertently detached during normal use. Because medical gas containers are reused and distributed among multiple entities, FDA believes that labeling inspection requirements proposed in this rulemaking would be sufficient to assure that labeling that enters into distribution is complete, accurate, durable, and readable, and that unsuitable labeling is replaced.
7. Production and Process Controls
Subpart F contains FDA's proposed requirements for production and process controls for medical gases. The proposed requirements in § 213.100(a) and (b) are generally consistent with the currently applicable requirements in § 211.100. Proposed paragraph (a) would require written procedures for production and process controls designed to assure that medical gases have the identity, strength, quality, and purity they purport or are represented to have. The procedures would need to include all requirements in subpart F. Further, the procedures, including any changes, would need to be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit. Paragraph (b) would require that written production and process control procedures be followed in the execution of the various production and process control functions and documented at the time of performance, and that deviations be recorded and justified. FDA believes that the existing requirements for developing and following written procedures for production and process controls are appropriate for medical gases because they would help ensure consistent compliance with a firm's established procedures for production of medical gases.
In § 213.101, FDA proposes different requirements for charge-in of components and incoming designated medical gases than those in § 211.101. Proposed paragraph (a) would require that, except when a monograph or
formulary specifies a range, the batch be formulated with the intent to provide 100 percent of the labeled or established amount of each medical gas. Where a monograph or formulary specifies a range for the contents of a medical gas, the medical gas would be required to be formulated with the intent to provide an amount within that specified range. Because medical gases are often manufactured continuously in a closed system, weighing, measuring, and subdividing components is generally not performed. Paragraph (b) would require that components and incoming designated medical gases added to in-process supply or final product containers be weighed or measured as appropriate. Final product and in-process supply containers would also be required to 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, as well as the unique lot number assigned.
Proposed § 213.110 would include a more limited set of sampling and testing requirements than the existing requirements in § 211.110, which contain several testing requirements that are inapplicable to medical gases (including tablet or capsule weight variation, disintegration time, and dissolution time and rate). Paragraph (a) would require that in-process materials be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality unit during the production process. Under paragraph (b), written procedures would be required to be established and followed describing the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures would need to be established to monitor the output and to validate the performance of those manufacturing processes. This is important for assuring batch uniformity and the integrity of drug products. Paragraph (c) would require that rejected in-process materials be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable. FDA believes that these proposed requirements would be sufficient to help ensure that medical gases are manufactured according to specifications and prevent mix-ups or the accidental use of rejected or quarantined product.
8. Packaging and Labeling Control
Proposed subpart G would contain packaging and labeling control requirements. FDA proposes packaging and labeling materials examination and usage criteria in § 213.122. The proposed requirements in paragraphs (a) through (e) are generally consistent with the current requirements in paragraphs (a) through (e) in § 211.122. Paragraph (a) would require that there be sufficiently detailed written procedures describing the receipt, identification, storage, handling, sampling, examination and/or testing of labeling and packaging materials and that such procedures be followed. Further, paragraph (a) would require that labeling and packaging materials be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a medical gas. Paragraph (b) would state that labeling or packaging materials may be approved and released for use if they meet appropriate written specifications, and that they must be rejected if they do not meet such specifications to prevent their use in operations for which they are unsuitable. Paragraph (c) would require that records be maintained for each shipment of each different labeling and packaging material indicating receipt, examination, and whether the materials were accepted or rejected. Paragraph (d) would require that labels and other labeling materials for each different medical gas, strength, or quantity of contents be stored with suitable identification to avoid mix-ups. Further, access to storage would need to be limited to authorized personnel. Paragraph (e) would require the destruction of obsolete and outdated materials, as well as materials that do not meet applicable requirements.
Under paragraph (f), FDA would require one of three special control procedures for packaging and labeling operations: Dedicated labeling and packaging lines for each strength of each medical gas; use of appropriate electronic or electromechanical equipment to conduct a 100 percent examination for correct labeling during or after completion of finishing operations; or use of visual inspection to conduct a 100 percent examination for correct labeling during or after completion of labeling operations for hand-applied labeling (which would need to be performed by one person and independently verified by a second person). The Agency believes that utilizing one of these procedures is critical to preventing mix-ups. Paragraph (g) would require monitoring of printing devices on, or associated with, manufacturing lines used to imprint labeling upon the unit label or case to assure that all imprinting conforms to the print specified in the batch production record. Finally, paragraph (h) would allow the reuse of labels if they are legible, properly affixed to the container, and otherwise meet all applicable requirements. Unlike most drug containers, medical gas containers are reused many times and made of extremely durable materials. FDA believes that the proposed requirements in this section would be sufficient to ensure the quality and legibility of medical gas labels.
In proposed § 213.125, FDA would establish requirements for issuing labeling. Paragraph (a) would require that labeling and packaging operations be controlled to prevent labeling and product mix-ups, and that procedures be written and followed describing in sufficient detail the control procedures employed for the issuance of labeling. Proposed paragraph (b) would require use of procedures to reconcile the quantities of labeling issued, used, and returned, and would require evaluation of discrepancies found between the quantity of medical gas and the quantity of labeling issued when such discrepancies are outside narrow preset limits based on historical operating data. Such discrepancies would need to be investigated in accordance with proposed § 213.192.
Labeling reconciliation is proposed to be waived for cut or roll labeling if a 100 percent examination for correct labeling is performed in accordance with proposed § 213.122(f)(2) (100 percent electronic or electromechanical examination of labeling). Labeling reconciliation would also be waived for 360° wraparound labels on portable cryogenic medical gas containers. FDA is proposing to retain the label reconciliation requirement for medical gases except in the circumstances in which it would be waived, consistent with § 211.125, because label reuse may introduce risk into the labeling process that would not be present with unlabeled containers. While reuse of cylinder labels and 100 percent verification of hand-applied labels on medical gas cylinders through visual inspection provides some assurance of correct labeling, such examination does not preclude the need for quality assurance steps, such as label reconciliation, to be built into the labeling process. The periodic replacement of cylinder labels that are worn, damaged or missing introduces variability and subjectivity into the determination of which and how many containers need new labels, potentially
increasing the risk of mislabeling. The Agency considers label reconciliation procedures, designed commensurate with the risk, to be essential to the overall control of labels to minimize the potential for mix-ups.
Paragraph (c) would require that excess lot number stickers or decals bearing lot or control numbers be discarded. FDA expects that this will help prevent product mix-ups or the inclusion of incorrect lot information on a gas container. Finally, paragraph (d) would exempt bulk or transport containers (as defined in proposed § 201.161(c)(3)) from § 213.125. FDA believes that it is not necessary for this provision to apply to bulk or transport containers because end users are generally not expected to handle or use these containers to directly administer the gas to patients.
Proposed § 213.130 would require that written procedures be developed and followed to assure that the correct labels, labeling, and packaging materials are used for medical gases, similar to the requirements in § 211.130. These procedures would be required to incorporate the following features. Paragraph (a) would require physical or spatial separation from operations on other products. FDA expects this proposed requirement would help to prevent mix-ups. Additionally, FDA proposes to use the term “other products” because some firms that manufacture medical gases may also manufacture gases for non-medical purposes, such as for industrial use. Paragraph (b) would require that filled, unlabeled containers of medical gases that are set aside be identified and handled for future labeling operations to preclude mislabeling of individual containers, lots, or portions of lots. It would not be necessary to apply identification directly to each individual container, but the firm would need to be able to identify the name, strength, quantity of contents, and lot or control number of such containers. For example, this could be done through signage in the area in which the containers are stored.
FDA proposes in paragraph (c) that the medical gas be identified with a lot or control number that permits determination of the history of the manufacture and control of the batch. The lot or control number of the medical gas could be identified by use of a separate identification sticker or decal and would not need to be contiguous with other labeling information. Paragraph (d) would require, like the existing requirement in § 211.130(d), that packaging and labeling materials be examined for suitability and correctness before packaging operations, and that such examination be documented in the batch production record. FDA proposes to add a provision allowing product labels, including 360° wraparound labels, to be reused if they meet all applicable labeling requirements, all information on the label is legible, and the label is in good condition.
Paragraph (e) proposes the same requirements as those that currently apply under existing § 211.130(e). Under this proposal, firms would be required to inspect packaging and labeling facilities immediately before use to assure that all medical gases have been removed from previous operations. Moreover, this proposal would require inspection to assure that packaging and labeling materials unsuitable for subsequent operations have been removed, and the results of such inspection have been documented in the batch production records.
FDA proposes paragraph (f), which would exempt bulk or transport containers (as defined in proposed § 201.161(c)(3)) from the requirements of § 213.130, provided they are identified with the name of the product contained therein and accompanied by documentation identifying the product as meeting applicable compendial standards. It is unnecessary for bulk and transport containers to bear the information required by this section because patients and healthcare providers are not expected to utilize them directly to administer a gas.
9. Holding and Distribution
Subpart H would establish holding and distribution requirements. Proposed § 213.150 would contain requirements for warehousing and distribution procedures. Paragraph (a) would require that written procedures be established and followed describing the distribution of medical gases. Such procedures would be required to include a system by which the distribution of each lot can be readily determined to facilitate any necessary recalls. FDA believes that the requirement in § 211.150(a) to distribute the oldest approved stock of a drug product first (often called the “first-in, first-out” requirement) is unnecessary to include in this proposed rule, as medical gases are generally not expected to expire or degrade under ordinary storage conditions. Paragraph (b) would require that written procedures be established and followed regarding warehousing of medical gases, similar to the requirements in § 211.142(a). These procedures would be required to include procedures for the quarantine of such gases before release by the quality unit. Unlike the current requirements in § 211.142(b), the proposed requirements would not include procedures regarding the conditions of drug storage because sealed, closed containers are generally expected to protect the gas inside from a wide range of environmental conditions. Moreover, the Agency believes the requirements in proposed §§ 213.42 and 213.80 would sufficiently address storage and handling.
10. Laboratory Controls
Subpart I proposes requirements for laboratory controls. In proposed § 213.160, FDA would incorporate the existing requirements in § 211.160, with one difference in § 213.160(b)(4). Proposed paragraph (a) would require that the establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by subpart I, including any changes, be drafted by the appropriate organizational unit and reviewed and approved by the quality unit. Such requirements would have to be followed and documented at the time of performance, and deviations recorded and justified.
Under proposed paragraph (b), laboratory controls would be required to include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, medical gas containers, closures, in-process materials, labeling, and medical gases conform to appropriate standards of identity, strength, quality, and purity, and include the following four elements:
• Determination of conformity to applicable written specifications for the acceptance of each lot within each shipment of components, medical gas containers and closures, and labeling used in the manufacture, processing, packing, or holding of a medical gas. The specifications would be required to include a description of the sampling and testing procedures used. Samples would need to be representative and adequately identified. Such procedures would also need to require appropriate retesting of any component, medical gas container, or closure that is subject to deterioration. See § 213.160(b)(1).
• Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples would need to be representative and properly identified. See § 213.160(b)(2).
• Determination of conformance to written descriptions of sampling procedures and appropriate
specifications for medical gases. Such samples would need to be representative and properly identified. See § 213.160(b)(3).
• The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met, or verification of such calibration. Instruments, apparatus, gauges, and recording devices not meeting established specifications would not be able to be used. See § 213.160(b)(4). This differs from § 211.160(b)(4) in that FDA proposes to require calibration or verification of calibration of instruments, apparatus, gauges, and recording devices. In the medical gas industry, some downstream entities may not conduct their own calibration. FDA believes that verification of calibration is necessary if the entity does not conduct its own calibration.
Proposed § 213.165 would contain requirements for testing and release of medical gases for distribution. Paragraph (a) would require that there be appropriate laboratory determination of satisfactory conformance to final specifications for each batch, including the identity and strength, prior to release. The Agency omitted the requirements in § 211.165(b) from its proposal because generally there is less risk of microbial contamination for medical gases.
Section 213.165(b) would require that any sampling and testing plans be described in written procedures, and that such written procedures be followed. Such plans would need to include the method of sampling, the number of units per batch, and acceptance criteria. FDA believes it is unnecessary to incorporate in proposed § 213.165(b) the more detailed requirements regarding acceptance criteria described in § 211.165(d).
Proposed § 213.165(c) would require that the accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm be validated and documented. This may be done in accordance with proposed § 213.194(a)(2). Further, the suitability of all testing methods would need to be verified under actual conditions of use.
FDA proposes § 213.165(d), which 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 is not proposing to include the provision stating that reprocessing may be performed or the requirements for using reprocessed material. The Agency is not aware of reprocessing that occurs for medical gases. However, we welcome comment on this issue, including any example scenarios in which such gases are reprocessed.
Finally, FDA would clarify in § 213.165(e) that the proposed requirements in § 213.165 would not apply to the filling of a designated medical gas or medically appropriate combination via liquid to liquid into a container at a delivery site, often referred to by industry as “curbside filling.” Because such filling operations are not expected to result in any material change in the gas being filled (for example, oxygen continues to be oxygen after filling), the gas is not expected to fall out of conformance with the requirements in § 213.165 if it is in conformance earlier in the distribution chain and stored under proper conditions.
FDA proposes in § 213.166 stability testing and expiration dating requirements for medical gases marketed under applications submitted under section 505 or 512 of the FD&C Act. Under proposed paragraph (a), any stability testing performed and any expiration date established for medical gases marketed under applications submitted under section 505 or 512 of the FD&C Act would need to be in accordance with the proposed requirements described in subsection (b), subject to the conditions established in their approved applications, if any. Under this proposed rule, stability testing and expiration dating would not be required for all medical gases. However, stability testing, expiration dating, or both would be required for some medical gases (for example, these would be necessary when required by an approved application for the safe and effective use of the drug, or stability testing would be necessary when an applicant chooses to label its product with an expiration date regardless of whether one is needed for safe and effective use under an approved application). FDA believes that this proposed requirement would allow for flexibility in determining whether stability testing, expiration dating, or both are necessary for a particular gas. Furthermore, specific stability testing requirements may vary depending on the particular gas.
Proposed paragraph (b) would contain requirements to assure that the medical gas meets applicable standards of identity, strength, quality, and purity at the time of use:
• The stability testing program would need to be designed to assess the stability characteristics of the medical gas and its container closure system. The results of stability testing would need to be used in determining appropriate storage conditions and any expiration dates included on the label. The stability program shall include the appropriate sample size, test intervals, container closure systems, and storage conditions for samples retained for testing.
• Any expiration dates included on the label would be required to appear in accordance with § 201.17.
• Stability would need to be evaluated periodically to ensure that the medical gas continues to meet the standards for identity, strength, quality, and purity stated on the labeling to support the expiration date.
FDA is not proposing stability testing or expiration dating requirements for designated medical gases, as they are not expected to expire or degrade. Additionally, the proposed leak testing and working gauge requirements in this proposed rule are expected to address concerns regarding the container closure system's ability to prevent leakage. If a designated medical gas manufacturer chooses to include an expiration date on its container, FDA expects that such a date would be determined by appropriate stability testing that reflects the stability of the gas and the integrity of the container closure system.
11. Records
Proposed subpart J would contain requirements for records. Because FDA is not proposing to require the labeling of medical gases to bear expiration dates, except as proposed in § 213.166, the proposed requirements in § 213.180 differ from the requirements in § 211.180. Paragraph (a) would provide that all records that would be required under part 213, or copies of such records, be readily available for authorized inspection during the retention period and are subject to copying as part of such an inspection. The records would be able to be kept at either the establishment where the activities described in such records occurred or at another location from which the records can be immediately retrieved. Retrieval via computer or other electronic means would meet this requirement. Per paragraph (b), all records would have to be legible, stored to prevent deterioration or loss, and either original or accurate reproductions of original records. Paragraph (c) would require that all records that would be required to be maintained in compliance with part 213 be maintained
for at least 3 years from the date the batch of medical gas is distributed, except where otherwise provided. This timeframe is the same as that used in § 211.180(a) for over-the-counter drugs lacking expiration dating.
Paragraph (d) would require that written records required under part 213 be maintained so that their data can be used for evaluating, at least annually, the quality standards of each medical gas to determine the need for changes in specifications or manufacturing or control procedures. Written procedures would also have to be established and followed for such evaluations. The procedures would also be required to include provisions for a review of a representative number of batches, whether approved or rejected, and, where applicable, records associated with the batch, and a review of complaints, recalls, returned or salvaged medical gases, and investigations conducted under § 213.192 for each gas. Under paragraph (e), firms would be required to develop written procedures for notifying responsible firm officials of any recalls, reports of inspectional observations by FDA, regulatory actions related to good manufacturing practice taken by FDA, or any investigations resulting from adverse event complaints.
Proposed § 213.182 would require that there be a written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use. These records would be required, as part of individual equipment logs, to show the date, time, product, and lot number of each batch processed. Individual equipment logs would not be required for equipment dedicated to one product, but lots or batches would have to follow in numerical order and be manufactured in numerical sequence in such a case. Also, where dedicated equipment is employed, the records of cleaning, maintenance, and use would be required to be part of the batch record. The individuals performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under § 213.68, just the person verifying such cleaning and maintenance) would have to date and sign or initial the log indicating the work was performed. Entries in the log would be required to be in chronological order. While FDA recognizes that cleaning of a closed, pressurized system is not always appropriate, when it is applicable, it is essential to maintain adequate records of such cleaning.
FDA proposes in § 213.184 a more limited set of recordkeeping requirements for components, medical gas containers and closures, and labeling than those described in § 211.184. The records would include the results of any test or examination performed (including those performed pursuant to §§ 213.84 and 213.122) and the conclusions derived from the test or examination; documentation of the examination and review of labels and labeling for conformity with established specifications in accordance with §§ 213.122 and 213.130; and the disposition of rejected components, containers, closures, and labeling. Medical gas containers are generally reused many times before they are taken out of service. FDA believes that the proposed requirements in §§ 213.84, 213.122, and 213.130 to evaluate containers and labeling are appropriate and sufficient to assure the quality of containers and the accuracy and legibility of their labels.
In § 213.186, FDA proposes master production and control recordkeeping requirements that are more tailored to medical gases than the current requirements in § 211.186. Paragraph (a) would require that master production and control records for each medical gas be prepared, dated, and signed to assure uniformity from batch to batch. Paragraph (a) would also require that the preparation of such records be described in a written procedure, and that such written procedure be followed. Paragraph (b) proposes to require certain information for each master production and control record. The records would be required to include: The product name and strength; a list of all components and any incoming designated medical gases used in manufacturing designated by names or codes sufficiently specific to indicate any special quality characteristics; a description of the containers, closures, and packaging materials and labels; and complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.
These proposed requirements differ from the requirements in § 211.186 because of the differences in manufacturing and distribution of medical gases. For example, because medical gas manufacturing generally includes some venting of gas, measuring calculated excess of component, theoretical weight, and theoretical yield is infeasible.
In lieu of the requirements found in § 211.188, FDA proposes § 213.189, which would impose batch production and control recordkeeping requirements for each batch of medical gas produced. Paragraph (a) would require batch production and control records to be prepared for each batch of medical gas produced. Paragraph (b) would require that batch production and control records include documentation that each significant step in the manufacturing, processing, packing, and holding process was accomplished, including:
• Dates and times of each significant step, including in-process and laboratory tests as applicable. This documentation would include any prefill, filling, or post-filling inspections, which are essential to assuring product meets applicable standards.
• A description of the container for the medical gas, including the number and size of the containers filled as applicable. The containers used in manufacturing and filling operations can vary significantly, so documenting the containers is important for tracking purposes.
• 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. 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.
• Any investigation made according to § 213.192.
Proposed § 213.192 would contain production record review requirements for medical gases. Under paragraph (a), manufacturing production and control records, including those for packaging and labeling, would need to be reviewed and approved by the quality unit to determine compliance with all established, approved written procedures before release or distribution of a batch. The quality unit would also be required to review production records to determine whether errors or unexplained discrepancies have occurred prior to batch release. If any
errors or unexplained discrepancies have occurred, or a batch or any component of the batch fails to meet specifications, the firm would be required to conduct thorough investigations and take appropriate corrective actions. FDA further proposes to require a written record of the investigation, including the conclusions and followup. However, for entities that fill at a delivery site, paragraph (b) would require that production and control records be reviewed and approved by the quality unit to determine compliance with all established, approved written procedures within 1 business day after fill. FDA believes this additional time is needed for reviewing such records associated with filling at a delivery site because delivery personnel typically conduct such filling at multiple locations. As such, it is impractical for the quality unit to be present at the time of filling, and the characteristics of the gas are not expected to change during the filling process. Therefore, the Agency believes it is appropriate for the quality unit to review production and control records shortly after delivery is completed.
FDA recognizes that, because containers and labels are reused many times for medical gases, firms are generally unable to trace the history of a cylinder's use or identify the root cause of a cylinder-related problem. Nevertheless, if an error or unexplained discrepancy associated with a cylinder is identified, or if a cylinder is found not to meet any of its specifications, FDA believes it is necessary for the firm to conduct a thorough investigation to identify the problem and take appropriate corrective action, such as taking a faulty cylinder out of circulation. FDA believes this proposal would establish production record review requirements that would assure that medical gases meet the requirements of the FD&C Act as to safety and have the identity, strength, quality, and purity they are purported or represented to possess.
FDA is also proposing § 213.194, which would impose laboratory recordkeeping requirements. Paragraph (a) would require that laboratory records related to the manufacture of a medical gas include complete data derived from all tests necessary to ensure compliance with established specifications and standards, including examinations and assays. Laboratories would have to keep a complete record of all data created in the course of each test, including the records described in paragraphs (a)(1) through (4), as follows:
• A description of the sample, the batch or lot number to be tested, the date the sample was taken, and the date the sample was tested.
• The test method used, the test result, how the results compare with established standards of identity, strength, quality, and purity for the component, container, in-process materials (as applicable), and medical gas tested, a record of any calculations performed and any calculated results, and the unit of measurement of the result. It would not be necessary to provide the actual calculation where the result is evident through use of simple addition and subtraction (for example 100 − 0.1 = 99.9).
• Where applicable, any graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific component, in-process material, or medical gas for each lot tested.
• The initials or signature of the person performing the test as well as a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.
Paragraph (b) would require that complete records be maintained of any modification of an established test method. These records would need to include the reason for the modification and data to verify that the modification produced results that are at least as accurate and reliable for the material being tested as the established method. Paragraph (c) would require that complete records be maintained of any testing and standardization of laboratory reference standards, reagents, and standard solutions. These requirements are the same as those that currently apply to medical gases under § 211.194(b) and (c).
Paragraph (d) would require that complete records be maintained of the periodic calibration or verification of calibration of laboratory instruments, apparatus, gauges, and recording devices that would be required by § 213.160(b)(4). This paragraph differs from § 211.194(d) in that it would allow for verification of calibration. It is FDA's understanding that it is common for some medical gas equipment to be calibrated by a supplier or other entity prior to arrival at the laboratory.
Paragraph (e) would require that complete records be maintained of all stability testing performed in accordance with proposed § 213.166. This requirement is consistent with the current requirement in § 211.194(e). As described above, only a subset of medical gases are expected to be subject to stability testing requirements, but for such gases, documentation of stability testing is essential to ensuring that the gas will maintain its stability for the expected timeframe.
Under proposed § 213.196, distribution records would be required to contain the name of the product, the lot or batch number, the consignee's contact information, and the date and quantity shipped. FDA believes that including the lot or batch number is essential to properly tracking and tracing product in the event a safety issue is discovered. Information about the dosage form, as required in § 211.196, is not necessary for medical gases because the dosage form is always “gas.” For medical air and medically appropriate combinations of designated medical gases, the distribution record would also need to include the percentage of each gas. FDA believes that this information is essential to prevent mix-ups because the concentration of each component would be clearly determined.
Proposed § 213.198 contains proposed requirements for complaint files that are similar to those requirements that currently apply to medical gases under § 211.198. Paragraph (a) would require that written procedures be established and followed for the receipt and handling of all written and oral complaints concerning a medical gas. These procedures would have to include a quality unit review of any complaint involving the possible failure of a medical gas to meet its specification as well as an investigation to determine the cause of the failure. An out-of-specification medical gas (for example, a combination containing higher quantities of oxygen than intended) could result in serious patient harm if administered. These procedures would also be required to include provisions for determining the need for an investigation under § 213.192 and determining whether the complaint represents an event that would need to be reported under proposed part 230.
Paragraph (b) would require that a written record of each complaint be maintained. This record would have to include the name of the medical gas, the lot or batch number, the name of the complainant, the date the complaint was received, the nature of the complaint, and the response to the complaint. It would also be required to include the findings of any investigation and followup. If an investigation is not conducted, the record would need to include the reason that an investigation was found not to be necessary and the name of the responsible person making such a determination.
Paragraph (c) would require the maintenance of complaint files in a manner such that they would be readily available for inspection by the firm or by FDA during an inspection. Complaint files would be required to be maintained for at least 1 year after the date that the complaint was received or for at least 3 years after distribution of the medical gas, whichever is longer. This proposed record retention period is the same as that used in § 211.180(a) for certain over-the-counter drugs lacking expiration dating and would facilitate review and evaluation by the firm of information that is received after the event, thus facilitating the firm's ability to observe trends over time.
12. Returned and Salvaged Medical Gases
Subpart K contains proposed requirements for returned and salvaged medical gases. FDA proposes in § 213.204 to require that returned medical gases be identified as such and held. Moreover, 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 would need to be destroyed unless examination, testing, or other investigations prove the gas meets appropriate standards of safety, identity, strength, quality, or purity. These requirements would apply to situations in which a distributed medical gas is sent back to a firm due to a quality issue. Firms would need to maintain certain records of returned medical gases. Further, if the reason for a medical gas being returned implicates associated batches, an appropriate investigation pursuant to proposed § 213.192 would need to be conducted. Procedures for holding, testing, and use of returned medical gases would need to be in writing and followed. Proposed § 213.204 would not apply to the routine refilling of a cryogenic medical gas containers in the normal course of business unless the container was returned for a quality issue.
Proposed section 213.204 is largely the same as current § 211.204, with an added provision regarding routine refilling. FDA believes that the current requirements for returned drug product are appropriate for medical gases. However, the proposed routine refilling provision would be essential to address the fact that small amounts of gas are expected to remain in a returned container that will be reused. This situation is uncommon for other types of drug products, but medical gas containers are generally reusable, and complete purging of a container is impracticable. Another notable difference compared to § 211.204 is the omission of reprocessing requirements, as it is FDA's understanding that reprocessing of returned medical gases does not occur. Generally, gases are reused if they meet specifications; otherwise, they are vented. FDA requests comment on this issue.
Section 213.208 would allow the salvaging of medical gases that have been subjected to improper storage conditions unless the gas's container has been subjected to adverse conditions that impact the identity, strength, quality, and purity of the medical gas, or the integrity of the container closure. These requirements would apply to situations in which a medical gas has been subject to improper storage conditions under the control of a firm responsible for the manufacture, processing, packing, or holding of the gas. Scenarios in which this may arise include natural disasters, facility structural damage (such as a building collapse), or exposure to smoke in the event of a fire. If there is a question whether the medical gas has been subjected to improper storage conditions, salvaging would only be permitted if there is evidence from laboratory tests that the gas meets all applicable standards of identity, strength, quality and purity, and the closure is not compromised. Section 213.208 also would require that firms maintain and follow written procedures for the holding, testing, and use of salvaged medical gases. While medical gases in sealed containers are generally considered unlikely to be affected by adverse conditions, such as natural disasters or significant changes in temperature, humidity, or pressure, a medical gas container could be damaged by such circumstances. Therefore, it is essential for firms to evaluate any containers potentially affected by adverse conditions.
13. Notable Part 211 Provisions FDA Does Not Propose To Include in Part 213
In this section, FDA discusses existing CGMP provisions of note that the Agency has not proposed for inclusion in part 213. In the proposed CGMP requirements described above in this section, FDA addressed some individual requirements in part 211 that the Agency has not proposed for inclusion in part 213, but this section addresses some other sets of requirements that are outside the scope of the above discussion. We specifically request public comment on these areas.
The requirements in § 211.28(a), (b), and (d) regarding personnel responsibilities are not included in this proposed rule. Medical gases are generally manufactured, stored, combined, and distributed under pressure in closed systems. Therefore, the risk of contamination is generally lower than for other drugs. FDA believes that the other requirements that would be established by this proposed rule would sufficiently address the risk of contamination in medical gases.
FDA is not proposing to include certain buildings and facilities requirements from part 211, subpart C, in proposed part 213, subpart C (specifically §§ 211.44 through 211.58) because they are not relevant to the manufacture, processing, packing, and holding of medical gases, or because the proposed requirements in § 213.42 sufficiently address these issues. For example, FDA believes that specific lighting requirements are not necessary because the risk of lightbulbs breaking and contaminating the gas inside a closed manufacturing system is remote. Moreover, FDA believes that the level of lighting at a facility would be sufficiently addressed by the requirements in § 213.42 to ensure that the design, space, and placement of equipment in a facility help protect against mix-ups (for example, we interpret this to mean that, among other things, employees have sufficient light to read labels). Similarly, specific ventilation requirements are not necessary because the closed manufacturing system for medical gases is generally unaffected by external factors such as air quality in the facility. Other specific requirements in part 211 regarding plumbing, sewage, and sanitation are also unnecessary because the risk of contamination is extremely low and because the proposed requirements in part 213 would adequately address these concerns.
The current requirements for filters in § 211.72 are also not included in this proposed rule. Because medical gases are not administered as injectable drugs, the requirements in § 211.72 are not relevant. FDA seeks comment on the need for filter requirements.
Because medical gases are generally not expected to expire or degrade under ordinary storage conditions, FDA does not believe it is necessary to include in this proposed rule the requirements in § 211.86 regarding using the oldest approved stock first or § 211.87 regarding retesting product that has been stored for long periods of time or whose containers have been exposed to air.
FDA is not proposing to include a calculation of yield requirement similar to § 211.103. Gas loss is expected during manufacturing and can be variable even under normal operating conditions. The requirements proposed in part 213 would be sufficient to determine that the medical gas in the container is the amount and type indicated by the label and required by the final product specifications. Therefore, such a requirement would not provide useful information to firms or FDA.
FDA is not proposing to include an equipment identification requirement similar to § 211.105. Because equipment used for medical gas manufacturing is expected to be specific to the gas being manufactured, there is typically no changeover of machinery for firms to track. Accordingly, FDA does not believe such a requirement is necessary to assure the safety, identity, strength, quality, and purity of medical gases.
FDA is not proposing to include time limitations on production similar to § 211.111 because medical gases are generally not expected to expire or degrade under ordinary storage conditions. FDA also is not proposing to include requirements regarding the control of microbiological contamination similar to § 211.113 because the risk of contamination is extremely low for these products.
FDA is not proposing to include a requirement similar to § 211.115, which establishes requirements for reprocessing. The Agency is not aware that reprocessing occurs for medical gases. Rather, it is FDA's understanding that gases not meeting specifications generally would be vented. However, as mentioned above, we welcome comment on this issue, including any example scenarios in which medical gases are reprocessed.
FDA is not proposing to include the drug product inspection requirements in § 211.134. Because cylinders are reused many times, FDA believes that the labeling inspection provisions in proposed § 213.122(f) would assure proper product labeling.
FDA is not proposing to include the reserve sampling requirements in § 211.170 because the requirements in § 211.170 are not appropriate for medical gases. The proposed sampling requirements elsewhere in part 213 would be sufficient to address sampling for in-process and finished medical gases.
14. Proposed Revisions to 21 CFR Part 4 CGMP Requirements
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). However, a gas cylinder with a simple on/off valve (
i.e.,
without a pressure regulator) would generally not be considered a device. Combination products are subject to part 4, subpart A (21 CFR part 4, subpart A), which clarifies the application of CGMP regulations to combination products and provides a streamlined approach to demonstrate CGMP compliance for facilities that manufacture co-packaged or single-entity combination products.
FDA intends to amend part 4, subpart A to reflect the new requirements for medical gases under part 213 and clarify how to comply with part 4, as amended. FDA proposes to include in 21 CFR 4.2 a definition of the term “medical gas” consistent with the definition in proposed part 213, as well as a definition of “medical gas CGMPs” that refers to part 213.
FDA also proposes to revise § 4.3(a) (21 CFR 4.3(a)) to account for combination products that contain a medical gas. For such products, part 213 would apply rather than parts 210 and 211, as described in proposed new § 4.3(e).
FDA proposes to include in § 4.4(b) (21 CFR 4.4(b)) specific provisions for combination products that include a medical gas as a drug constituent part to enable use of a streamlined approach for designing and implementing a CGMP operating system that complies with CGMP requirements for medical gas-device combination products akin to the streamlined approaches available for other drug-device combination products. FDA believes that when a manufacturer of a medical gas-device combination product demonstrates that its CGMP operating system complies with part 213 in full, the provisions from part 820 (21 CFR part 820), with which manufacturers must demonstrate compliance, should be the same as those currently listed in § 4.4(b)(1) because part 213 covers the same general areas as part 211, and FDA is not aware of device characteristics that would necessitate a different approach. If a medical gas-device combination product manufacturer demonstrates that its CGMP operating system complies with part 820 in full, FDA believes that the following proposed requirements from part 213 would be appropriate to ensure that critical aspects of medical gas production are addressed:
• Section 213.84. Testing and approval or rejection of components, containers, and closures.
• Section 213.94. Medical gas containers and closures.
• Section 213.122. Materials examination and usage criteria.
• Section 213.165. Testing and release for distribution.
• Section 213.166. Stability testing and expiration dating for medical gases marketed under applications submitted under section 505 or 512 of the FD&C Act.
• Section 213.204. Returned medical gases.
• Section 213.208. Salvaging of medical gases.
FDA proposes to make other conforming edits as needed, such as revising § 4.4(e) to include a reference to part 213, and to clarify (where appropriate) throughout part 4, subpart A the requirements for medical gases.
FDA specifically seeks comment on this proposal, including: (1) Which part 213 provisions should be included in the list of provisions for combination products containing a medical gas as a drug constituent part for which the CGMP operating system has been shown to comply with part 820; (2) whether the part 820 provisions listed in § 4.4(b)(1) should be revised for combination products containing a medical gas as a drug constituent part to include other 820 requirements or to remove certain existing references to part 820 call-outs; and (3) whether it is appropriate to permit manufacturers to have the option of choosing to demonstrate compliance with part 213 in full along with the part 820 call-out provisions or compliance with part 820 in full along with the part 213 call-out provisions.
The Agency believes that part 4, subpart A helps ensure appropriate implementation of CGMP requirements for combination products while avoiding unnecessary redundancy in CGMP operating systems for these products, and that, given the benefits of the approach in part 4, subpart A, it should include combination products that contain a medical gas. FDA expects that sponsors of medical gases submitted under section 505 of the FD&C Act with a delivery system are already aware that they are producing a combination product, and as such should already be familiar with the requirements in part 4, subpart A. For firms that combine a designated medical gas or medically appropriate combination of designated medical gases with a finished, off-the-shelf device, FDA expects that the burden for complying with the device CGMP requirements would be relatively low. In some cases, firms may be able to leverage information from their device supplier to demonstrate compliance
with device call-outs. Additionally, some device provisions are not expected to apply in all cases; some class I devices are exempt from the design control requirements in 21 CFR 820.30, and the installation and servicing requirements in 21 CFR 820.170 and 820.200, respectively, are not applicable to all devices.
C. Proposed Certification and Annual Reporting Provisions
The proposed rule would establish, within new part 230, regulations setting forth the requirements for obtaining certification of a designated medical gas pursuant to section 576 of the FD&C Act. Since the passage of FDASIA, many applicants have sought marketing authorization for a designated medical gas under section 576 of the FD&C Act, and this proposed rule would codify that process in FDA's regulations while also providing additional clarity where necessary. As proposed, part 230 would contain the requirements for filing a certification request for a designated medical gas for human use, animal use, or both. FDA is also proposing to make certain provisions in parts 314 and 514 inapplicable to designated medical gases, given that part 230 would apply instead.
Sections 575 and 576 of the FD&C Act also authorize FDA to deem certain medical gases not listed in section 575(1)(A) through (G) to be designated medical gases (FD&C Act section 575(1)(H)) and to certify designated medical gases or medically appropriate combinations of such gases for certain indications for use not listed in section 576(a)(3)(A)(i)(I) through (VII) (FD&C Act section 576(a)(3)(A)(i)(VIII)). The Agency is not proposing regulations implementing these provisions as part of this rulemaking because the Agency does not expect to deem additional medical gases to be designated medical gases at this time. In addition, the Agency does not expect to certify designated medical gases for indications beyond those currently described in section 576 of the FD&C Act at this time. If, in the future, FDA decides it would be appropriate to deem additional medical gases to be designated medical gases or to certify designated medical gases or medically appropriate combinations of such gases for additional indications for use, FDA expects to undertake such actions without the need for further rulemaking.
FDA also notes that section 575(1)(F) of the FD&C Act provides that carbon monoxide is a designated medical gas if it “meets the standards set forth in an official compendium.” Section 201(j) of the FD&C Act defines “official compendium” to include the U.S. Pharmacopeia (USP), the official Homeopathic Pharmacopeia of the United States (HPUS), the official National Formulary (NF), or any supplement to any of them. There is currently no monograph in the USP or NF for carbon monoxide. There is a HPUS monograph for carbon monoxide, though it is inapplicable to carbon monoxide as a designated medical gas for use in lung diffusion testing. FDA does not intend to object to the marketing of carbon monoxide for use in lung diffusion testing as long as the product conforms to one of the alternatives in the Center for Drug Evaluation and Research's Manual of Policies and Procedures 5310.7 Rev. 1,
Acceptability of Standards from Alternative Compendia (BP/EP/JP)
(Ref. 10). This proposed approach is consistent with the draft policy described in the draft guidance for industry entitled “Certification Process for Designated Medical Gases” (Ref. 1). If and when a monograph entitled “Carbon Monoxide” is added to the USP or NF, FDA expects original manufacturers that wish to continue marketing carbon monoxide to promptly submit a certification request.
1. Definitions
Proposed § 230.3(b)(2) defines the term “applicant.” An applicant is proposed to be defined as any person or entity who submits a certification request for a designated medical gas under part 230, including supplements. This is generally the original manufacturer. An applicant would also include any person or entity who owns a granted certification for a designated medical gas under part 230. This definition is generally consistent with FDA's use of the term “applicant” with regard to NDAs and ANDAs (see 21 CFR 314.3(b)), as well as NADAs and ANADAs (see 21 CFR 514.3).
FDA also proposes to define “certification request” as a submission under section 576 of the FD&C Act requesting certification of a medical gas as a designated medical gas. After a certification request is deemed to be granted, a designated medical gas 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 of the FD&C Act, subject to all applicable postapproval requirements, for the applicable indications for use described in section 576(a)(3)(A)(i)(I) through (VIII) of the FD&C Act.
FDA proposes to define “FDA or Agency” to mean the Food and Drug Administration, consistent with other Agency regulations.
2. General Requirements for All Certification Submission Types
Proposed § 230.50 would establish the general requirements related to designated medical gas certification requests. The requirements would apply to all submission types. Proposed § 230.50(a)(1) would provide that the certification process described in part 230, subpart B applies to designated medical gases for the indications described in section 576(a)(3)(A)(i) of the FD&C Act. Currently, manufacturers who intend to market medical gases that do not meet the definition of designated medical gas, or who intend to market designated medical gases for indications not described in section 576(a)(3)(A)(i) of the FD&C Act, must obtain approval of that medical gas under part 314 or part 514, or both, as applicable. For example, if an applicant intends to market nitrous oxide for a use other than analgesia (see section 576(a)(3)(A)(i)(III) of the FD&C Act), the certification process in proposed part 230 would not be available for that drug product at this time. If FDA deems additional indications for use appropriate under section 576(a)(3)(A)(i)(VIII) of the FD&C Act, the certification process could extend to designated medical gases for those uses. However, as of the date of this proposed rule, FDA has not deemed any additional indications for use to be appropriate for any designated medical gases.
Also in § 230.50(a)(1), FDA proposes to require any person who seeks to initially intr
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