Document ID: FDA-2021-N-1333-0019
Agency: fda
Document Type: Proposed Rule
Title: Current Good Manufacturing Practice, Certification, Postmarketing Safety Reporting, and Labeling Requirements for Certain Medical Gases
Posted Date: 2022-05-23T04:00Z

[Federal Register Volume 87, Number 99 (Monday, May 23, 2022)]
[Proposed Rules]
[Pages 31302-31356]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-10458]

[[Page 31301]]

Vol. 87

Monday,

No. 99

May 23, 2022

Part II

 Department of Health and Human Services

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Food and Drug Administration

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21 CFR Parts 4, 16, 201, et al.

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

  Federal Register / Vol. 87, No. 99 / Monday, May 23, 2022 / Proposed 
Rules  

[[Page 31302]]

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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.

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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

[[Page 31303]]

Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, 
301-796-8767, [email protected].
    With regard to the information collection: Domini Bean, Office of 
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-5733, 
[email protected].

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'').\1\ 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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    \1\ Section 576(a)(3)(A)(i) of the FD&C Act provides that ``[a] 
designated medical gas for which a certification is granted under 
paragraph (2) is deemed, alone or in combination, as medically 
appropriate, with another designated medical gas or gases for which 
a certification or certifications have been granted, to have in 
effect an approved application under section 505 or 512, subject to 
all applicable postapproval requirements,'' for certain indications 
for use. FDA interprets the term ``combination'' in this section to 
mean two or more distinct designated medical gases that are mixed 
together. For example, a mixture of oxygen and nitrous oxide that 
each meet the standards set forth in an official compendium could 
constitute a medically appropriate combination of designated medical 
gases. However, the addition of oxygen to a container that already 
contains oxygen would not result in a medically appropriate 
combination of designated medical gases because only one kind of 
designated medical gas would be present in the container.
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    We 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

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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

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     Abbreviation/acronym                    What it means
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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.
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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

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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),\2\ after taking into account any 
investigational new drug application or investigational new animal drug 
file \3\ 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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    \2\ The functions of the Secretary described herein have been 
delegated to FDA.
    \3\ 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.
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    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

[[Page 31306]]

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[deg] 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).\4\ 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).\5\ 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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    \4\ 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).
    \5\ These Executive Orders were revoked by Executive Order 
13992.
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    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

[[Page 31307]]

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 Sec.  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 Sec.  
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 Sec.  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 
Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  201.51(b)(4), labeling for net quantity 
of contents is not required for bulk or transport containers, as 
defined in Sec.  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 Sec.  
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 Sec.  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 Sec.  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)

[[Page 31308]]

(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 Sec.  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 Sec.  201.161(a) and 
instead refer to ``designated medical gas.'' FDA proposes these 
revisions to Sec.  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 Sec.  201.161; these 
gases are not included in the list of gases in Sec.  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 
Sec.  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 
Sec.  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 
Sec.  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 Sec.  201.161 referencing 
Sec. Sec.  201.328 and 211.94(e)(2). FDA believes it is unnecessary for 
Sec.  201.161 to reference compliance with Sec. Sec.  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 Sec.  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 (Sec.  
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 Sec.  
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 Sec.  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 (Sec.  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 Sec.  
201.161(a)(1)(ii) for the listed gases other than oxygen, as well

[[Page 31309]]

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 Sec.  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 Sec.  
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 Sec.  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 Sec.  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 Sec.  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 Sec.  201.328(a)(1), FDA proposes technical changes to reflect 
that the requirements in Sec.  211.94(e)(2) are proposed to be moved to 
Sec.  213.94(e)(3). See section V.B.1 for more information on this 
proposed revision.
    Proposed new Sec.  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.

[[Page 31310]]

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 Sec.  210.1(a) and (b) and in Sec.  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 Sec.  211.1(a), FDA proposes to add ``medical gases as defined 
in Sec.  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 Sec.  211.94(e). Instead, proposed 
Sec.  213.94 would contain updated requirements for medical gas 
containers and closures that are generally consistent with the current 
requirements in Sec.  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 Sec.  211.125(c), which 
waives labeling reconciliation requirements for 360[deg] wraparound 
labels on portable cryogenic medical gas containers because labeling 
reconciliation for medical gases would be addressed by proposed Sec.  
213.125(b).
    FDA proposes to delete the reference to ``containers of compressed 
medical oxygen'' in Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  
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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  213.3(b)(4), the term ``component'' is 
revised. Compared to the definition in Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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

[[Page 31311]]

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 Sec.  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 Sec.  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'' (Sec.  213.3(b)(11)). This is 
generally consistent with the definition of the same term in part 210.
     In proposed Sec.  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 Sec.  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 Sec.  
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 Sec.  
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 Sec.  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 Sec.  
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 Sec.  
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 Sec.  213.22 describes the responsibilities of the quality 
unit and is similar in scope to Sec.  211.22. Proposed paragraphs (a) 
through (d) are generally consistent with paragraphs (a) through (d) in 
Sec.  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

[[Page 31312]]

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 Sec.  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 Sec.  211.25, except as described 
below. Under proposed Sec.  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 Sec.  
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 Sec.  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 Sec.  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 
Sec.  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 Sec.  213.34, FDA proposes requirements regarding consultants 
that are generally consistent with requirements that currently apply to 
medical gases under Sec.  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 Sec.  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 Sec.  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

[[Page 31313]]

meet this requirement with physical barriers, signage, or both, though 
firms may use other appropriate means. Proposed Sec.  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 Sec.  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, Sec.  
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 Sec.  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 
Sec.  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 Sec.  213.65 addresses equipment construction and is 
similar to Sec.  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 
Sec.  213.67. These proposed requirements differ from those that 
currently apply to medical gases under Sec.  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 Sec.  213.180.
    Proposed Sec.  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 Sec.  213.80(a) and (b) are similar to paragraphs 
(a) and (b) of Sec.  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

[[Page 31314]]

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 Sec.  211.80. FDA believes it is 
unnecessary to include the requirement in Sec.  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 Sec.  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 Sec.  213.84(a). Thus, FDA believes that other lot 
identification requirements in proposed part 213 are sufficient to 
track product.
    Proposed Sec.  213.82 addresses the receipt and storage of incoming 
designated medical gases. The proposed requirements differ from 
currently applicable requirements in Sec.  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 Sec.  213.165), FDA believes 
this is an appropriate level of review.
    FDA proposes Sec.  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 Sec.  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 Sec.  213.89 is similar to the requirements in Sec.  
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 Sec.  213.89 would also apply to 
incoming designated medical gases.

[[Page 31315]]

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 Sec.  213.94 would contain additional requirements for 
medical gas containers and closures. Paragraph (a) is generally 
consistent with the requirements in Sec.  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 
Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  213.94(e)(1) is consistent with Sec.  
211.94(e)(1). Consistent with Sec.  211.94(e)(1), FDA proposes to 
define ``manufacturer'' for purposes of Sec.  213.94(e)(1) to include 
any individual or firm that fills high-pressure medical gas cylinders 
or cryogenic medical gas containers. 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 Sec.  211.94(e)(1), FDA proposes to define ``portable 
cryogenic medical gas container'' for purposes of Sec.  213.94(e)(1) as 
one that is capable of being transported and is intended to be attached 
to a medical gas supply system within a hospital, healthcare entity, 
nursing home, other facility, or home healthcare setting, or is a base 
unit used to fill small cryogenic gas containers for use by individual 
patients. The term would not include cryogenic containers that are not 
designed to be connected to a medical gas supply system, e.g., tank 
trucks, trailers, rail cars, or small cryogenic gas containers for use 
by individual patients (including portable liquid oxygen units as 
defined at Sec.  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 Sec.  
213.94(e)(1) as well as small cryogenic gas containers for use by 
individual patients (including portable liquid oxygen units as defined 
in Sec.  868.5655) 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 Sec.  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 Sec.  
213.100(a) and (b) are generally consistent with the currently 
applicable requirements in Sec.  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 Sec.  213.101, FDA proposes different requirements for charge-in 
of components and incoming designated medical gases than those in Sec.  
211.101. Proposed paragraph (a) would require that, except when a 
monograph or

[[Page 31316]]

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 Sec.  213.110 would include a more limited set of sampling 
and testing requirements than the existing requirements in Sec.  
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 Sec.  213.122. The proposed requirements in 
paragraphs (a) through (e) are generally consistent with the current 
requirements in paragraphs (a) through (e) in Sec.  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 Sec.  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 Sec.  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 Sec.  213.122(f)(2) (100 percent electronic 
or electromechanical examination of labeling). Labeling reconciliation 
would also be waived for 360[deg] 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 Sec.  
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

[[Page 31317]]

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 Sec.  
201.161(c)(3)) from Sec.  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 Sec.  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 Sec.  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 Sec.  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[deg] 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 Sec.  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 Sec.  201.161(c)(3)) from the 
requirements of Sec.  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 Sec.  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 
Sec.  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 Sec.  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 
Sec.  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 Sec. Sec.  213.42 and 213.80 would 
sufficiently address storage and handling.
10. Laboratory Controls
    Subpart I proposes requirements for laboratory controls. In 
proposed Sec.  213.160, FDA would incorporate the existing requirements 
in Sec.  211.160, with one difference in Sec.  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 Sec.  
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 Sec.  213.160(b)(2).
     Determination of conformance to written descriptions of 
sampling procedures and appropriate

[[Page 31318]]

specifications for medical gases. Such samples would need to be 
representative and properly identified. See Sec.  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 Sec.  213.160(b)(4). This differs from Sec.  
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 Sec.  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 Sec.  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 Sec.  213.165(b) 
the more detailed requirements regarding acceptance criteria described 
in Sec.  211.165(d).
    Proposed Sec.  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 Sec.  213.194(a)(2). Further, the suitability of all 
testing methods would need to be verified under actual conditions of 
use.
    FDA proposes Sec.  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 Sec.  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 Sec.  213.165(e) that the proposed 
requirements in Sec.  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 Sec.  
213.165 if it is in conformance earlier in the distribution chain and 
stored under proper conditions.
    FDA proposes in Sec.  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 Sec.  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 Sec.  213.166, the proposed 
requirements in Sec.  213.180 differ from the requirements in Sec.  
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

[[Page 31319]]

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 Sec.  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 
Sec.  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 Sec.  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 Sec.  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 Sec.  213.184 a more limited set of recordkeeping 
requirements for components, medical gas containers and closures, and 
labeling than those described in Sec.  211.184. The records would 
include the results of any test or examination performed (including 
those performed pursuant to Sec. Sec.  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 Sec. Sec.  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 Sec. Sec.  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 Sec.  213.186, FDA proposes master production and control 
recordkeeping requirements that are more tailored to medical gases than 
the current requirements in Sec.  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 Sec.  
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 Sec.  211.188, FDA proposes 
Sec.  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 Sec.  213.192.
    Proposed Sec.  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

[[Page 31320]]

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 Sec.  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 Sec.  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 Sec.  213.160(b)(4). This paragraph differs from Sec.  
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 Sec.  
213.166. This requirement is consistent with the current requirement in 
Sec.  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 Sec.  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 Sec.  
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 Sec.  213.198 contains proposed requirements for complaint 
files that are similar to those requirements that currently apply to 
medical gases under Sec.  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 Sec.  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.

[[Page 31321]]

    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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  
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 
Sec.  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 Sec.  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 Sec. Sec.  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 Sec.  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 Sec.  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 Sec.  211.72 are also not 
included in this proposed rule. Because medical gases are not 
administered as injectable drugs, the requirements in Sec.  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 Sec.  
211.86 regarding using the oldest approved stock first or Sec.  211.87 
regarding retesting product that has been stored for long periods of 
time or whose containers have been exposed to air.

[[Page 31322]]

    FDA is not proposing to include a calculation of yield requirement 
similar to Sec.  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 Sec.  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 Sec.  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 Sec.  211.113 because the risk 
of contamination is extremely low for these products.
    FDA is not proposing to include a requirement similar to Sec.  
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 Sec.  211.134. Because cylinders are reused many times, 
FDA believes that the labeling inspection provisions in proposed Sec.  
213.122(f) would assure proper product labeling.
    FDA is not proposing to include the reserve sampling requirements 
in Sec.  211.170 because the requirements in Sec.  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 Sec.  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 Sec.  4.3(e).
    FDA proposes to include in Sec.  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 Sec.  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 Sec.  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 Sec.  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

[[Page 31323]]

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 Sec.  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 Sec.  230.50 would establish the general requirements 
related to designated medical gas certification requests. The 
requirements would apply to all submission types. Proposed Sec.  
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 Sec.  230.50(a)(1), FDA proposes to require any person who 
seeks to initially introduce or deliver for introduction a designated 
medical gas into interstate commerce to file a request for 
certification. An applicant would be required to identify its intention 
to market their designated medical gas for human use, animal use, or 
both. If a certification is deemed to be granted, a designated medical 
gas, alone or in combination, as medically appropriate, with another 
designated medical gas or other designated medical gases for which a 
certification or certifications have been granted, would be deemed to 
have in effect, for the uses described in section 576(a)(3)(A)(i) of 
the FD&C Act:
     An approved application under section 505 of the FD&C Act, 
if the applicant requested certification solely for human use;
     an approved application under section 512 of the FD&C Act, 
if the

[[Page 31324]]

applicant requested certification solely for animal use; or
     approved applications under sections 505 and 512 of the 
FD&C Act, if the applicant requested certification for both human and 
animal use.
    (See section 576(a)(3)(A)(i); see also proposed Sec.  230.105.) 
Applicants should submit one request per designated medical gas, 
regardless of how many of their facilities manufacture or will 
manufacture that designated medical gas. Persons who receive a 
designated medical gas from an applicant or another person and fill the 
gas into containers, including via liquid to liquid at a delivery site, 
are not expected to submit certification requests under part 230 
because the gas they are handling should be the subject of a granted 
certification held by another entity. (See also proposed Sec.  213.82.)
    Proposed Sec.  230.50(a)(2) would describe the relationship between 
the proposed certification requirements in part 230 and parts 314 and 
514. Proposed Sec.  230.50(a)(2) would provide that any person that 
proposes to market a medical gas that is a new drug for human use must 
obtain approval under part 314, and any person that proposes to market 
a medical gas that is a new animal drug for animal use must obtain 
approval under part 514, unless the medical gas meets the definition of 
a designated medical gas, and the medical gas is proposed to be 
marketed, alone or in combination (as medically appropriate), with 
another designated medical gas or gases for which a certification or 
certifications have been granted, for a use described under section 
576(a)(3)(A)(i) of the FD&C Act. ``New drug'' and ``new animal drug'' 
are defined in section 201(p) and (v) of the FD&C Act.
    Proposed Sec.  230.50(b) would outline the information that must be 
submitted in a certification request. In addition, though not a 
proposed requirement in this proposed rule, FDA recommends that the 
applicant include a cover letter describing the purpose of the 
submission (e.g., original certification, amendment to supply 
additional information requested by FDA). Such cover letters often 
provide context and information that would be helpful to the Agency as 
it processes certification requests. Under Sec.  230.50(b)(1), the 
certification request would need to include the name, address, 
telephone number, and email address of the person or entity requesting 
certification. If the address of the entity requesting certification is 
not in the United States, the certification request would need to 
contain the name and address of, and be countersigned by, an attorney, 
agent, or other authorized official who resides or maintains a place of 
business within the United States. Under Sec.  230.50(b)(2), the 
certification request would also need to identify the type of 
submission as one of the following:
     Original certification request: An initial request for 
certification by an applicant for certification of a medical gas as a 
designated medical gas.
     Amendment to a pending submission: A submission related to 
a pending submission that revises existing information or provides 
additional information, including responses to Information Request 
Letters.
     Resubmission: A complete submission that has been revised 
and submitted again following a previous denial (if the applicant 
chooses to resubmit its submission, it would need to provide a written 
response to all deficiencies identified in FDA's denial letter, along 
with other information required for certification requests; this would 
help assure that past deficiencies are addressed before applicants 
resubmit, thus promoting the efficient use of Agency resources)
     Supplement to a granted certification: Any submission that 
contains a change to a certification that was previously granted.
     Other: Any submission that does not fit into one of the 
other categories described in this list.
    Under Sec.  230.50(b)(3), the applicant would also need to include 
a description of the designated medical gas. Each designated medical 
gas certification request would need to include the name of the gas, as 
well as a certification statement that the designated medical gas meets 
the appropriate compendial standard. FDA intends to develop a 
designated medical gas certification form which would include a 
certification statement. The Agency anticipates the form would have OMB 
approval prior to the finalization of any proposed rule.
    Under Sec.  230.50(b)(4), applicants would also be required to 
include certain facility information in the certification request, 
including the name and address of the facility or facilities where the 
designated medical gas will be initially produced. FDA uses the term 
``facility'' in this proposed provision to be consistent with the 
terminology in section 576(a)(1)(C) of the FD&C Act, which requires 
that a certification request include ``[t]he name and address of the 
facility or facilities where the medical gas is or will be 
manufactured.'' For purposes of this proposed regulation, the term 
``facility'' would be synonymous with the term ``establishment'' as it 
is used in part 207 (21 CFR part 207). Other facilities that only 
perform subsequent activities such as transfilling, mixing, or filling 
at a delivery site would not be considered ``facilities'' for purposes 
of this proposed regulation. Applicants would also need to include a 
brief description of the manufacturing or processing activities 
performed at each facility listed in the certification, which would 
include chemical reaction, physical separation, compression of 
atmospheric air, purification of a gas, or other activities to produce 
a designated medical gas. Applicants would also need to include an FDA 
Establishment Identifier (FEI), if one exists, and a Unique Facility 
Identifier (UFI) in accordance with the requirements of part 207 and 
section 510 of the FD&C Act (21 U.S.C. 360). If an applicant intends to 
open a new facility to manufacture the designated medical gas, FDA 
recognizes that the applicant may not have an FEI at the time of the 
certification request, as FEIs are generally assigned upon registration 
of a new establishment. However, for existing facilities, including the 
FEI in the certification request will assist FDA in monitoring its 
establishment inventory. Regarding the UFI, inclusion of this 
information will assist the Agency in linking certification requests to 
registration information required by section 510(b)(1) of the FD&C Act 
and 21 CFR 207.25(e). FDA's preferred UFI is the Data Universal 
Numbering System (DUNS) number (Ref. 11). Firms can acquire a DUNS 
number at no cost. For amendments and supplements, only changes to the 
list of facilities would need to be submitted.
    Under proposed Sec.  230.50(b)(5), the applicant would be required 
to certify in its certification request that its methods, facilities, 
and controls used in manufacturing, processing, packing, and holding of 
the designated medical gas, as applicable, are adequate to ensure the 
gas's safety, identity, strength, quality, and purity. This 
certification would be met by completing a field on the certification 
form referenced above. This information is critical to determining 
whether the medical gas manufactured at the facility is a designated 
medical gas because it meets applicable compendial standards (FD&C Act 
section 576(a)(1)(D)). Designated medical gases generally have narrow 
compendial standards, and requiring an applicant to certify that it 
employs appropriate methods, facilities, and controls would help ensure 
consistent, quality manufacture of a gas that meets such standards.
    Lastly, under Sec.  230.50(b)(6), if the Agency deems any other 
information

[[Page 31325]]

appropriate to determine whether the gas meets the definition of a 
designated medical gas, the applicant would be required to provide that 
additional information as well. This would generally be in the form of 
a written request by FDA for the additional information. The applicant 
may also provide other information that the applicant believes will 
assist the Secretary in evaluating the request.
    Though FDA is not proposing changes to its registration and listing 
regulations as they apply to designated medical gases, FDA notes that 
firms must also comply with applicable registration and listing 
requirements in section 510 of the FD&C Act and part 207. For example, 
firms must register establishments and list designated medical gases, 
or update existing registration and listing information, pursuant to 
part 207, subparts B and D.
    Proposed Sec.  230.50(c) would describe the requirements for 
submitting a certification request. Applicants would be required to 
submit a signed, completed request for certification either in an 
electronic format that FDA can process, review, and archive, or in hard 
copy by submitting two paper copies to the Center for Drug Evaluation 
and Research (CDER) Central Document Room. FDA encourages submission of 
certification requests through the NextGen Portal at https://edm.fda.gov. FDA intends to assign an NDA or NADA number (or both, if 
the applicant has expressed its intent to market the medical gas for 
human and animal use) for reference purposes when an original 
certification request is filed. If certification is granted, the 
applicant should use these application numbers in all further 
submissions to the Agency. If certification is not granted, and the 
applicant resubmits their certification request in the future, the 
previously assigned NDA and/or NADA number would continue to be the 
relevant application number(s).
    Section 230.65 would allow applicants to withdraw a certification 
request that has not been deemed granted. An applicant could notify FDA 
that it withdraws its certification request at any time prior to the 
certification being deemed granted. Withdrawal of a certification 
request would not preclude refiling. If a certification request is 
withdrawn, FDA would retain the certification request, and if the 
applicant requests a copy via Freedom of Information Act (FOIA) 
request, FDA would provide it pursuant to the fee schedule in FDA's 
public information regulations.
3. Supplements and Other Changes to a Granted Certification
    Section 230.70(a) of the proposed rule would require an applicant 
to submit a supplement if any information in the certification request 
has changed after the request has been deemed granted, including, but 
not limited to, the addition of a new facility manufacturing the 
designated medical gas, a change in contact information, or a change in 
the corporate name. FDA anticipates these are the most common types of 
information in the request that might change after certification has 
been deemed granted.
    Under proposed Sec.  230.70(b), the supplement would need to 
include a signed, completed request for certification form with the 
updated information in compliance with the requirements of Sec.  
230.50, and would need to be submitted no later than 30 calendar days 
after the date the change occurred. FDA proposes that supplements may 
be submitted after the fact because the Agency does not anticipate that 
the types of changes submitted in a supplement would need to be 
approved before the change occurs.
4. Change in Ownership of a Certification That Has Been Granted
    Proposed Sec.  230.72 would address situations in which a 
designated medical gas certification that has been granted undergoes a 
change in ownership, for example, due to a merger or acquisition. 
Proposed Sec.  230.72 would expressly allow for the transfer of 
ownership of such a certification. When a transfer occurs, both the new 
and former owners would be required to submit certain information to 
FDA. Under proposed paragraph (a), the former owner would be required 
to submit a letter or other document explaining that all rights to the 
certification have been transferred to the new owner. Under proposed 
paragraph (b), the new owner would be required to submit a supplement 
under Sec.  230.70 signed by the new owner describing any changes in 
the conditions in the granted certification, and a letter or other 
document identifying the date the transfer of ownership is effective.
5. Annual Report
    Proposed Sec.  230.80(a) would require applicants to submit an 
annual report each year within 60 calendar days of the anniversary of 
the date the certification was deemed granted. Section 576(a)(2) of the 
FD&C Act provides that a certification request is deemed to be granted 
unless, within 60 days of its filing, FDA denies the request based on 
certain findings; FDA interprets the period of 60 days in this 
provision to mean a period of 60 calendar days. The applicant would be 
required to submit a signed, completed annual report form either in an 
electronic format that FDA can process, review, and archive, or in hard 
copy by submitting two paper copies to CDER's Central Document Room. 
The annual report would be required to contain the following 
information from the prior 12 months, pursuant to proposed Sec.  
230.80(b):
     A summary of any significant new information that might 
affect the safety, effectiveness, or labeling of the designated medical 
gas. The applicant would also be required to include any actions it has 
taken or intends to take as a result of this information.
     The applicant would need to include the National Drug Code 
(NDC) numbers, the quantities distributed for domestic use, and the 
quantities distributed for foreign use. The disclosure of financial or 
pricing data would not be required.
     Any changes to the applicant's name or contact 
information. This information would need to be submitted in a 
supplement no later than 30 calendar days after the change occurred 
pursuant to proposed Sec.  230.70, but the Agency believes that 
receiving all current information consolidated in an annual report will 
help FDA keep track of applicants and ensure that the Agency has 
current information.
     The applicant would need to include a list of current 
facilities, and a list of facilities that were used since the previous 
annual report (or since the certification was deemed granted) but are 
no longer in use.
    This information would be critical to allow FDA to evaluate all 
changes to the product and its manufacturing since the most recent 
report and determine whether any changes have the potential to alter 
the identity of the gas such that it no longer meets the applicable 
compendial standard or the definition of a designated medical gas.
6. FDA Review of Certification Submissions
    Under proposed Sec.  230.100(a), as part of its review, FDA would 
consider information submitted with the certification submission along 
with any other available, relevant information of which FDA becomes 
aware. Such information could include information obtained from State 
or Federal officials, FDA inspection reports, or any other source. Per 
Sec.  230.100(b), FDA proposes the following grounds for denying a 
submission:

[[Page 31326]]

     The medical gas that is the subject of the submission is 
not a designated medical gas. For example, FDA currently would deny a 
certification request for oxygen that fails to meet the standards for 
Oxygen, USP.
     The submission does not contain the required information 
or otherwise appears to lack sufficient information to determine that 
the medical gas is a designated medical gas. This may occur if the 
applicant fails to certify that the medical gas meets the applicable 
compendial standards, or if FDA obtains evidence that the medical gas 
fails to meet applicable compendial standards.
     The applicant's methods, facilities, and controls used for 
the manufacture, processing, and handling of the designated medical 
gas, as applicable, are not adequate to ensure its safety, identity, 
strength, quality, and purity, or
     Denying the request is otherwise necessary to protect the 
public health.
    Under proposed Sec.  230.100(c), within 60 calendar days of filing 
of a certification submission, FDA could contact the applicant to 
request additional information regarding the submission if it 
determines that the submission is missing required information, that 
FDA needs such information to determine whether the medical gas is a 
designated medical gas, or that FDA determines such information is 
necessary to protect the public health. This proposed provision would 
help applicants correct or complete their submission, or decide to 
withdraw, in a timely and efficient manner. Section 576(a)(2) of the 
FD&C Act provides that a certification request is deemed to be granted 
unless, within 60 days of its filing, FDA denies the request based on 
certain findings; FDA interprets the date of filing under this 
provision to mean the date that the certification request is received 
by the Agency. Upon receipt of an amendment to a pending certification 
request, this 60-day period would restart to allow FDA sufficient time 
to review new information received. FDA may find that the submission 
lacks sufficient information if, within the 60-day review period, FDA 
is unable to contact the applicant to obtain and evaluate the missing 
information or if FDA is able to contact the applicant but is not 
provided with the additional information within the 60-day review 
period.
    Proposed Sec.  230.100(d) would provide that, within 60 calendar 
days of filing of a submission, if FDA makes one of the findings 
described in proposed Sec.  230.100(b), FDA will notify the applicant 
in writing that the submission is denied and provide the basis for 
FDA's determination.
7. When a Certification Submission Is Deemed Granted
    Proposed Sec.  230.105 would provide that, unless FDA makes one of 
the findings described in Sec.  230.100(b) and notifies the applicant 
within 60 calendar days of filing that the submission is denied, 
certification is deemed to be granted and the designated medical gas 
will be deemed to have in effect an approved application under section 
505 or 512 of the FD&C Act, or both, for the indications specified in 
section 576(a)(3)(A)(i) of the FD&C Act. FDA would notify the applicant 
in writing and intends to post the letter on the Agency's website. The 
designated medical gas for which a certification is deemed granted 
would be subject to all applicable postapproval requirements. If, 
however, FDA has not responded during the 60-day review time period, 
the applicant may begin marketing their designated medical gas unless 
and until FDA withdraws or revokes approval.
8. Withdrawal or Revocation of Approval of an Application for a 
Designated Medical Gas
    Proposed Sec.  230.150 describes requirements concerning withdrawal 
or revocation of approval of an application for a designated medical 
gas. Proposed paragraph (a) addresses withdrawal of approval. FDA 
proposes that it will notify the applicant and afford an opportunity 
for a hearing on a proposal to withdraw approval of the application 
under the procedure in Sec.  314.200 (21 CFR 314.200), Sec.  514.200 
(21 CFR 514.200), or both, as applicable, for any of the grounds listed 
in proposed paragraph (a)(1). FDA proposes that if the Secretary of the 
Department of Health and Human Services has suspended approval on a 
finding that there is an imminent hazard to public health, FDA will 
initiate the withdrawal process. Additionally, FDA proposes that it 
will initiate the withdrawal process if it makes any of the following 
findings:
     Clinical or other experience, tests, or other scientific 
data show that the designated medical gas is unsafe for use under the 
conditions of use upon the basis of which the application was approved;
     New evidence of clinical experience not available to FDA 
until after the application was approved, or tests by new methods, or 
tests by methods not deemed reasonably applicable when the application 
was approved, evaluated together with the evidence available when the 
application was approved, reveal that the designated medical gas is not 
shown to be safe for use under the conditions of use upon the basis of 
which the application was approved;
     Upon the basis of new information before FDA with respect 
to the designated medical gas, evaluated together with the evidence 
available when the application was approved, that there is a lack of 
substantial evidence from adequate and well-controlled investigations 
as defined in 21 CFR 314.126, that the designated medical gas will have 
the effect it is purported or represented to have under the conditions 
of use prescribed, recommended, or suggested in its labeling; or
     The application contains any untrue statement of a 
material fact.
    In Sec.  230.150(a)(2), FDA proposes that it may notify the 
applicant and afford an opportunity for a hearing on a proposal to 
withdraw approval of the application under the procedure in Sec.  
314.200, Sec.  514.200, or both, as applicable, if FDA makes any of the 
following findings:
     The applicant has failed to establish a system for 
maintaining required records, or has repeatedly or deliberately failed 
to maintain required records or to make required reports applicable to 
designated medical gases, including under sections 505(k) and 512(l) of 
the FD&C Act, part 230, and part 213, or that the applicant has refused 
to permit access to, or copying or verification of, its records;
     On the basis of new information before FDA, evaluated 
together with the evidence available when the application was approved, 
the methods used in, or the facilities and controls used for, the 
manufacture, processing, and packing of the designated medical gas are 
inadequate to ensure and preserve its identity, strength, quality, and 
purity and were not made adequate within a reasonable time after 
receipt of written notice from the Agency;
     On the basis of new information before FDA, evaluated 
together with the evidence available when the application was approved, 
the labeling of the designated medical gas, based on a fair evaluation 
of all material facts, is false or misleading in any particular, and 
the labeling was not corrected by the applicant within a reasonable 
time after receipt of written notice from the Agency; or
     The applicant has failed to comply with the notice 
requirements of section 510(j)(2) of the FD&C Act (pertaining to the 
requirements regarding product listing updates).
    Section 576(a)(4)(A) of the FD&C Act makes clear that the authority 
to

[[Page 31327]]

withdraw or suspend approval under section 505(e) applies to designated 
medical gases that are deemed to have in effect approved applications 
under section 505 or 512. FDA believes the grounds proposed in Sec.  
230.150(a)(1) and (2) are consistent with the bases for withdrawing an 
application under section 505(e) of the FD&C Act.
    Under proposed Sec.  230.150(a)(3), FDA would also withdraw 
approval if the applicant requests its withdrawal because the 
designated medical gas subject to the application is no longer being 
marketed, provided none of the conditions listed in proposed paragraphs 
(a)(1) or (a)(2) applies. FDA proposes to consider such a written 
request for withdrawal to be a waiver of an opportunity for hearing 
otherwise provided for in this section. Such withdrawal, when requested 
by the applicant, would be without prejudice to refiling.
    Under proposed paragraph (a)(4), FDA could notify an applicant that 
it believes a potential problem associated with a designated medical 
gas is sufficiently serious that the designated medical gas should be 
removed from the market and may ask the applicant to waive the 
opportunity for hearing otherwise provided under this section, to 
permit FDA to withdraw approval, and to remove voluntarily the product 
from the market. If the applicant agrees, FDA would not make a finding 
under paragraph (a), but would withdraw approval in a notice published 
in the Federal Register that contains a brief summary of FDA's and the 
applicant's views of the reasons for withdrawal.
    Proposed paragraph (a)(5) provides that, if FDA withdraws an 
approval, the Agency will publish a notice in the Federal Register 
announcing the withdrawal of approval. This is consistent with the 
Agency's current practice to announce withdrawn approvals.
    Under proposed paragraph (b), FDA could revoke the grant of a 
certification if FDA determines, after providing the applicant with 
notice and opportunity for an informal hearing in accordance with 21 
CFR part 16, that the request for certification contains any material 
omission or falsification. This is intended to implement section 
576(a)(4)(B) of the FD&C Act. FDA proposes corresponding edits to 21 
CFR 16.1(b)(2) to include reference to this provision.
9. Proposed Changes to Part 314
    FDA proposes carving out designated medical gases from certain 
provisions in part 314 for which a corresponding provision specific to 
designated medical gases is proposed to be added to part 230. FDA also 
proposes carving out designated medical gases from certain provisions 
of part 314 that are not relevant to designated medical gases. Proposed 
new Sec.  314.1(c) (21 CFR 314.1(c)) would list the provisions that FDA 
proposes no longer apply to designated medical gases.
    A number of provisions in part 314 would continue to apply to 
designated medical gases.\7\ Section 314.80(g) (21 CFR 314.80(g)), 
regarding the electronic submission of safety reports, would continue 
to apply. FDA anticipates that the electronic format for submission of 
human drug individual case safety reports (ICSRs) will be the same as 
for other human drugs, and that existing guidance will be appropriate 
for human designated medical gas ICSRs.
---------------------------------------------------------------------------

    \7\ FDA has described its intention to issue a proposed rule 
that, among other things, would amend part 314 to modernize 
postmarketing safety reporting requirements for drugs (see RIN 0910-
AI61 on Fall 2021 Unified Agenda of Regulatory and Deregulatory 
Actions), and FDA intends to update proposed Sec.  314.1(c) to 
address any new or modified provisions added by that rulemaking that 
would not apply to designated medical gases.
---------------------------------------------------------------------------

    The following provisions in Sec.  314.81 (21 CFR 314.81) also would 
continue to apply:
     Sec.  314.81(b)(3), which addresses submission of 
advertisements and promotional labeling, special reports upon written 
request from the Agency, notification of permanent discontinuance or an 
interruption in manufacturing, and the requirements for withdrawing an 
approved drug product from sale;
     Sec.  314.81(c), which addresses submitting information 
related to multiple applications and patient identification 
requirements; and
     Sec.  314.81(d), which authorizes FDA to withdraw approval 
of an application for failure to make reports required under Sec.  
314.81.
    FDA is not aware of any reason to exempt applicants from these 
requirements, though the Agency requests comment on the burden 
associated with complying with these provisions.
    Subparts E and G of part 314 would also continue to apply. FDA has 
not identified any reason to establish different requirements and 
procedures for hearings, imports and exports, drug master files, or 
public disclosure of Agency records related to designated medical 
gases.
10. Proposed Changes to Part 514
    Similarly, FDA proposes carving out designated medical gases from 
provisions in part 514 for which a provision specific to designated 
medical gases is proposed to be added to part 230. FDA also proposes 
carving out provisions that do not apply to certification requests for 
designated medical gases. Proposed revisions to Sec.  514.1(a) list the 
provisions that FDA proposes no longer apply to designated medical 
gases. FDA proposes that the data confidentiality requirements, hearing 
procedures, and judicial review process would continue to apply because 
FDA has not identified any reason to establish different procedures for 
designated medical gases. Within Sec.  514.80, FDA proposes revisions 
to the table and to paragraph (a) to further explain that NADAs for 
designated medical gases are not subject to the reporting requirements 
in Sec.  514.80 and are instead subject to part 230.

D. Proposed Postmarketing Quality and Safety Reporting Provisions

    Also within part 230, FDA proposes new postmarketing safety 
reporting requirements for designated medical gases.
1. Definitions
    Proposed Sec.  230.3(a) would incorporate relevant definitions from 
sections 201 and 575 of the FD&C Act. Additionally, FDA proposes 
several additional definitions in Sec.  230.3(b) related to 
postmarketing safety reports along with the definitions described in 
section V.C. above. FDA proposes to define ``adverse event'' to mean 
any untoward medical occurrence associated with the use of a designated 
medical gas in humans or animals, whether or not it is considered 
related to the designated medical gas. This would include adverse 
events occurring in the course of the use of a designated medical gas, 
adverse events occurring from overdose (whether accidental or 
intentional), adverse events occurring from abuse, adverse events 
occurring from discontinuation (such as physiological withdrawal), and 
any failure of expected pharmacological action.
    The proposed definitions of ``ICSR'' and ``ICSR attachments'' would 
be generally consistent with the definitions of those terms in Sec.  
314.80(a). FDA proposes to define ``ICSR'' to mean a description of an 
adverse event related to an individual patient or subject. The Agency 
proposes to define ``ICSR attachment'' to mean documents related to the 
adverse event described in an ICSR, such as medical records, hospital 
discharge summaries, or other documentation.
    FDA proposes to define ``life-threatening adverse event'' to mean 
any

[[Page 31328]]

adverse event that places the patient, in the view of the initial 
reporter, at immediate risk of death from the adverse event as it 
occurred. This term would not include an adverse event that, had it 
occurred in a more severe form, might have caused death.
    The proposed definition of ``minimum data set for an ICSR for an 
adverse event'' is generally consistent with the list of minimum data 
elements for a postmarketing ICSR described in the 2001 draft guidance 
for industry ``Postmarketing Safety Reporting for Human Drug and 
Biological Products Including Vaccines'' (Postmarketing Safety 
Reporting Draft Guidance) (Ref. 12). FDA proposes that a minimum data 
set for an ICSR for an adverse event include the following four 
elements: (1) An identifiable patient, (2) an identifiable reporter, 
(3) a suspect designated medical gas, and (4) an adverse event.
    FDA proposes to define ``nonapplicant'' in a manner that is 
generally consistent with how the term is described in Sec.  
314.80(c)(1)(iii). A nonapplicant would be defined as anyone other than 
the applicant whose name appears on the label of a designated medical 
gas container as a manufacturer, packer, or distributor.
    FDA proposes to include a definition of ``serious adverse event.'' 
Under this proposed definition, an adverse event would be considered 
serious if it results in: Death; a life-threatening adverse event; 
inpatient hospitalization or prolongation of existing hospitalization; 
a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; or a congenital anomaly/birth 
defect. Important medical events that may not result in one of the 
above outcomes may be considered serious adverse events when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
study subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of product 
dependency or product abuse. Additional examples in animals include 
severe hypersensitivity reactions or respiratory distress.
2. Field Alert Reports
    Section 230.205 contains the proposed requirements for field alert 
reporting for distributed designated medical gases and articles. 
Applicants would be required to submit a field alert report (FAR) to 
the FDA district office that is responsible for their facility 
concerning (a) information concerning any incident that causes the 
designated medical gas or its labeling to be mistaken for, or applied 
to, another article; and (b) information concerning any bacteriological 
contamination, or significant chemical, physical, or other change or 
deterioration in the designated medical gas, or failure of one or more 
distributed batches to meet established specifications. FARs would be 
required to be submitted within 3 working days of receipt by the 
applicant. FDA considers working days to be any day from Monday through 
Friday, excluding U.S. Federal holidays (Ref. 13). The Agency seeks 
comment on the appropriateness of the 3-day reporting period. FDA would 
accept receipt of a FAR by telephone or other rapid communication if 
the applicant promptly follows up in writing. Email is an appropriate 
method for rapid communication as well as followup. Proposed Sec.  
230.205 would also contain requirements for identifying a FAR 
submission.
    Proposed Sec.  230.205 is generally consistent with the FAR 
requirements in Sec.  314.81(b)(1). FDA proposes to establish Sec.  
230.205 to clarify that designated medical gases for both human and 
animal use would need to follow the same FAR requirements. FDA is not 
aware of any reason to establish different requirements for designated 
medical gases for animal use.
3. General Reporting Requirements for Designated Medical Gas Adverse 
Events
    Proposed Sec.  230.210 would contain general requirements for 
reporting adverse events related to designated medical gases.
    Proposed Sec.  230.210(a) would require applicants and 
nonapplicants to promptly review all safety information that the 
applicant or nonapplicant receives or otherwise obtains from any source 
(including both foreign and domestic sources). Examples of such sources 
would include safety information from commercial marketing experience, 
reports in the published scientific and medical literature, unpublished 
scientific papers, and reports from regulatory authorities (this would 
include domestic and foreign authorities).
    As described below in sections V.D.4 and V.D.5, applicants and 
nonapplicants would be required to submit safety reports for designated 
medical gases pursuant to Sec. Sec.  230.220 (for human use) and 
230.230 (for animal use). Applicants and nonapplicants for a designated 
medical gas with both an approved NDA and an approved NADA would be 
subject to both the human reporting requirements in Sec.  230.220 and 
the animal reporting requirements in Sec.  230.230. However, both sets 
of reporting requirements would not apply at the same time for a given 
event. For example, if an adverse event associated with the use of a 
designated medical gas in a human patient occurs, the proposed 
requirements in Sec.  230.220 would apply, but the proposed 
requirements in Sec.  230.230 would not. Conversely, if an adverse 
event associated with the use of a designated medical gas in an animal 
patient occurs, the proposed requirements in Sec.  230.230 would apply, 
but the proposed requirements in Sec.  230.220 would not. In addition, 
if an adverse event occurs in a human from exposure during use of the 
gas in an animal patient, the proposed requirements in Sec.  230.230 
would apply, but those in Sec.  230.220 would not. FDA considers an 
applicant responsible for information known to its employees, 
affiliates, and contractors. FDA would similarly consider a 
nonapplicant responsible for information known to its employees, 
affiliates, and contractors.
    Under proposed Sec.  230.210(b)(1), reports or information 
submitted by applicants or nonapplicants (and any release by FDA of 
such reports or information) under Sec.  230.220 or 230.230 would not 
necessarily reflect a conclusion that the report or information 
constitutes an admission that the designated medical gas caused or 
contributed to an adverse effect. Additionally, under proposed Sec.  
230.210(b)(2), applicants and nonapplicants would not need to admit, 
and they could deny, that the report or information submitted under 
Sec.  230.220 or Sec.  230.230 constitutes an admission that the 
designated medical gas caused or contributed to an adverse effect.
4. Human Designated Medical Gas ICSR Requirements
    Proposed Sec.  230.220 would contain requirements for submission of 
ICSRs associated with the use of a designated medical gas in humans. 
Under proposed Sec.  230.220(a)(1), both applicants and nonapplicants 
would be required to submit each ICSR associated with the use of a 
designated medical gas in humans described in Sec.  230.220(b) to FDA 
as soon as possible, but no later than 15 calendar days from the date 
when the applicant or nonapplicant has both met the reporting criteria 
in paragraph (b) and acquired a minimum data set for an ICSR for that 
adverse event.
    The proposed timeframe for reporting adverse events under Sec.  
230.220(a)(1) is

[[Page 31329]]

15 calendar days. In contrast to Sec.  314.80(c)(1)(iii), which 
describes circumstances under which a nonapplicant can elect to submit 
adverse drug experience reports to the applicant instead of FDA, FDA 
proposes in Sec.  230.220 to require both applicants and nonapplicants 
to report adverse events involving designated medical gases directly to 
FDA. There are a large number of downstream entities that would meet 
the definition of ``nonapplicant'' and that combine, distribute, and 
fill designated medical gases, compared to a small number of upstream 
entities that would meet the definition of ``applicant.'' These 
downstream nonapplicants may receive designated medical gases from 
multiple sources, including multiple applicants, and the gases may be 
commingled within a single tank. Therefore, FDA anticipates that it 
would be challenging for a downstream nonapplicant to trace the suspect 
gas to a specific upstream applicant if the nonapplicant becomes aware 
of a safety issue.
    FDA also proposes that the 15-day period would be triggered upon 
the applicant both meeting the reporting criteria described in proposed 
Sec.  230.220(b) and acquiring a minimum data set for an ICSR for an 
adverse event. This proposed requirement would help ensure that a 
minimum level of information is obtained prior to submission of the 
report so that the Agency has a more complete picture of the incident. 
Lastly, FDA is not proposing to include a requirement that an adverse 
event be unexpected to be subject to the proposed reporting 
requirement. Because designated medical gases are not required to be 
studied in clinical trials, which are commonly conducted for other 
drugs, to be certified under section 576 of the FD&C Act, designated 
medical gas applicants are not expected to generate the type of 
labeling information about expected adverse events that sponsors of 
other types of drugs typically generate during product development. 
Thus, we expect that the applicants and nonapplicants for designated 
medical gases that would have reporting obligations under this proposed 
rule would not be able to determine whether an adverse event was 
unexpected.
    FDA is not proposing a requirement for periodic safety reporting 
for designated medical gases of the type required under Sec.  
314.80(c)(2). This would codify FDA's current approach with regard to 
the submission of periodic adverse drug experience reports as described 
in the March 2015 Compliance Program Guidance Manual 7356.002E, (Ref. 
14). We do not believe it is necessary to incorporate such a 
requirement in the proposed postmarket safety reporting regulations 
that would apply to designated medical gases, but we welcome comment on 
this issue.
    Proposed Sec.  230.220(a)(2) would provide that applicants and 
nonapplicants should not resubmit ICSRs that they obtained from the FDA 
Adverse Event Reporting System database or that FDA forwarded to them. 
This is generally consistent with Sec.  314.80(b). FDA encourages 
applicants and nonapplicants not to resubmit such ICSRs. Duplicative 
reports can divert Agency resources away from other safety priorities 
and, if not identified as duplicates, may obscure signal 
identification.
    Under proposed Sec.  230.220(a)(3), applicants and nonapplicants 
would be required to submit to FDA new information they receive or 
otherwise obtain that is related to a previously-submitted ICSR or an 
ICSR that was sent to the applicant by FDA. Such information would need 
to be submitted within 15 calendar days after the applicant or 
nonapplicant receives or otherwise obtains the new information. If an 
applicant or nonapplicant receives or otherwise obtains new information 
related to a previously submitted ICSR, they would have to submit the 
information to FDA under this proposed rule. For example, if a 
physician submits information to an applicant about an adverse event 
related to the applicant's designated medical gas, the applicant 
submits an ICSR based on that information, and the physician updates 
the applicant in the future, any new information would need to be 
submitted to FDA as new information within 15 calendar days. This 
proposed requirement is important to ensure that FDA becomes aware of 
any new information that arises about the adverse event.
    Proposed paragraph (b) would describe two types of ICSRs that must 
be submitted to FDA. First, applicants and nonapplicants would be 
required to report serious adverse events received. This would include 
ICSRs for serious adverse events reported to the applicant or 
nonapplicant spontaneously (such as reports initiated by patients, 
consumers, and healthcare professionals) as well as ICSRs for serious 
adverse events obtained from published scientific and medical journals 
either as case reports or as the result of a formal clinical trial. 
Unlike the safety reporting requirements in part 314, FDA is not 
proposing to include a requirement that the event be unexpected. 
Designated medical gases do not have traditional product labels that 
most human drugs and animal drugs bear, and their applicants generally 
have not conducted traditional clinical trials that would typically 
generate robust adverse reaction information. Therefore, required 
serious adverse events must be submitted regardless of expectedness.
    In proposed Sec.  230.220(b)(1)(iii), FDA proposes to include one 
exception to the requirement that serious adverse events be reported 
within 15 calendar days. ICSRs would not be required for reports of a 
patient death in cases where the patient was administered oxygen, 
unless the applicant or nonapplicant is aware of evidence to suggest 
that the death was caused by the administration of oxygen. FDA 
recognizes that oxygen is commonly administered during end-of-life care 
or to patients with a life-threatening disease or who are otherwise in 
critical condition. Accordingly, FDA believes that unless there is 
evidence to suggest that the administration of oxygen caused a 
patient's death, such reports are unlikely to reflect an underlying 
safety signal.
    Second, FDA proposes that, upon notification by FDA, an applicant 
would be required to submit, in a timeframe established by FDA, ICSRs 
for any adverse events that would not be required under proposed Sec.  
230.220(b)(1). FDA would specify the adverse events to be reported as 
well as the reason for requiring its reporting to the Agency. For 
example, FDA might take such action if it identifies a potential safety 
signal that would not otherwise be reported under Sec.  230.220(b)(1), 
but the Agency needs additional information to fully evaluate the 
safety signal, including its seriousness and scope.
    Under the proposed requirements in Sec.  230.220, ICSRs would not 
need to be submitted for fires associated with oxygen use if the 
patient did not also experience a reportable adverse event. Applicants 
and nonapplicants who become aware of patients who experience a 
reportable adverse event associated with a fire related to oxygen use 
(such as burns or smoke inhalation) would be required to submit an 
ICSR. Because it is well-known that oxygen accelerates combustion and 
that smoking near an oxygen source can cause a fire, FDA believes it is 
unnecessary to receive reports in which the patient does not experience 
an adverse event.
    Proposed paragraph (c) would describe the process for completing 
and submitting an ICSR. Under paragraph (c)(1), FDA proposes to require 
submission of ICSRs and ICSR attachments in electronic format that

[[Page 31330]]

FDA can process, review, and archive, as described in Sec.  
314.80(g)(1). Should this proposed rule be finalized, FDA would 
incorporate designated medical gases into existing guidances on 
electronic submission of postmarketing safety reports under Sec.  
314.80(g)(1), as designated medical gases would be expected to use the 
same electronic reporting mechanism. Under Sec.  230.220(c)(1)(ii), 
applicants and nonapplicants would be able to request in writing a 
temporary waiver of the requirements in Sec.  230.220(c)(1)(i), as 
described in Sec.  314.80(g)(2) (see also Ref. 15). Further, FDA would 
grant such waivers on a limited basis and for good cause shown.
    Under proposed paragraph (c)(2), FDA proposes additional reporting 
requirements. Proposed paragraph (c)(2) would direct applicant and 
nonapplicants to submit each ICSR only once and would require 
applicants and nonapplicants to submit a separate ICSR for each patient 
who experiences an adverse event reportable under paragraph (b). FDA 
also proposes to require that adverse event terms described in an ICSR 
be coded using standardized medical terminology (e.g., the Medical 
Dictionary for Regulatory Activities). The use of standardized medical 
terminology facilitates sharing of regulatory information 
internationally for human medical products (Ref. 16). Additionally, the 
use of standardized medical terminology will facilitate electronic 
transmission of safety information in a format that FDA can process, 
review, and archive, as required under Sec.  314.80(g)(1). ICSRs 
submitted under Sec.  230.220 would be required to contain at least the 
minimum data set for an ICSR for an adverse event. The applicant or 
nonapplicant would need to actively seek the minimum data set in a 
manner consistent with proposed paragraph (f) and document and maintain 
records of their efforts. Inclusion of the minimum data set would 
similarly facilitate electronic transmission of safety information in 
the necessary format for FDA to process, review, and archive. Proposed 
paragraph (c)(2) would also require that the applicant or nonapplicant 
complete all known, available elements of an ICSR described in proposed 
paragraph (d). For adverse events, applicants and nonapplicants would 
be required to actively seek any information needed to complete all 
applicable elements, consistent with the written procedures that would 
be required under proposed paragraph (f), and to document and maintain 
records of their efforts to obtain the missing information. However, if 
an adverse event is reportable under proposed Sec.  230.220(b) but the 
ICSR is missing certain elements listed in paragraph (d) (i.e., 
elements other than the required minimum data set), FDA would still 
receive and review the ICSR. Lastly, proposed paragraph (c)(2) would 
require an applicant or nonapplicant to submit the following types of 
supporting documentation in an ICSR, if available:
     A copy of the autopsy report if the patient died, or a 
hospital discharge summary if the patient was hospitalized (to be 
submitted as an ICSR attachment in the manner specified); and
     A copy of the published article for each ICSR of an 
adverse event obtained from published scientific and medical literature 
(to be submitted as an ICSR attachment in the manner specified).
    FDA seeks comment on the burden associated with complying with 
these proposed requirements. These proposed requirements also include 
required timeframes, translation of foreign language documents, and 
cross-referencing in the case of multiple ICSRs related to the same 
article.
    Proposed paragraph (d) would describe the information to be 
included in an ICSR. This is generally the same list as in Sec.  
314.80(f), with a few exceptions. First, FDA is not proposing to 
require that the applicant or nonapplicant state whether the product is 
a combination product. Second, FDA does not propose to require the 
submission to include an expiration date because designated medical 
gases are not generally expected to have an expiration date under 
proposed part 213. Third, FDA does not propose to require the applicant 
or nonapplicant to state whether the product is a prescription or 
nonprescription product. With the exception of oxygen for limited uses 
identified in section 576(b)(2)(A) of the FD&C Act, all designated 
medical gases are for prescription use, and the Agency expects that to 
continue to be the case. Fourth, FDA has proposed to combine the 
contact information in Sec.  314.80(f)(5)(i) and (ii) into one bullet. 
Fifth, we propose to clarify in Sec.  230.220(d)(5)(iv) that the 
applicant or nonapplicant would be required to submit the NDA and/or 
NADA number for their certification. Lastly, FDA proposes to require 
that the applicant or nonapplicant state whether the ICSR is an 
expedited report, rather than stating whether the ICSR is a 15-day 
alert report.
    Proposed paragraph (e) would contain recordkeeping requirements. 
Applicants and nonapplicants would be required to maintain records of 
information related to adverse events under proposed Sec.  230.220 for 
up to 10 years from the initial receipt of information. These records 
would need to be maintained regardless of whether the information was 
submitted to FDA. The records would also need to include raw data, 
correspondence, and any other information relating to the evaluation 
and reporting of adverse event information that is received or 
otherwise obtained by the applicant or nonapplicant. These proposed 
requirements are generally consistent with the requirements in Sec.  
314.80(j). FDA also proposes that, upon written notice, the applicant 
or nonapplicant would need to submit any or all of these records to FDA 
within 5 calendar days after receipt of the notice. Applicants and 
nonapplicants would also need to permit authorized FDA employees to 
access, copy, and verify these established and maintained records, at 
reasonable times. These proposed requirements will help facilitate the 
review of new and emergent safety issues, including of potential safety 
signals that may be associated with nonserious adverse events, which 
would not be required to be reported to FDA under proposed paragraph 
(b)(1).
    Proposed paragraph (f) would require that applicants and 
nonapplicants develop written procedures to fulfill their obligations 
under proposed Sec.  230.220 for the surveillance, receipt, evaluation, 
and reporting of adverse event information. This proposed requirement 
is generally consistent with existing requirements in Sec.  314.80(b) 
and is appropriate for designated medical gases. Additionally, we 
propose to specify that these procedures would need to address employee 
training and the obtaining and processing of adverse event information 
from other applicants and nonapplicants. Employee training is important 
to ensure that all personnel who may receive or handle adverse event 
information on the company's behalf fully understand their 
responsibilities. Processing adverse event information from other 
parties is also critical because of the many layers of distribution 
typical for designated medical gases.
    Proposed paragraph (g) would contain proposed patient privacy 
provisions. Rather than including patient names and addresses in 
reports under proposed Sec.  230.220, proposed paragraph (g) would 
recommend that applicants and nonapplicants assign a unique code to 
identify patients. Proposed paragraph (g) would recommend that 
applicants and nonapplicants include the name of the reporter from whom 
the information was received as part of the initial reporter 
information, even if the patient

[[Page 31331]]

is the reporter. As set forth in FDA's public information regulations 
in part 20, FDA generally may not disclose the names of patients, 
individual reporters, healthcare professionals, hospitals, and 
geographical identifiers submitted to FDA in adverse event reports. 
This is similar to the patient privacy provisions for other drugs in 
Sec.  314.80(i), though FDA proposes to expand these requirements to 
nonapplicants.
5. Animal Designated Medical Gas Adverse Event Reporting Requirements
    Proposed Sec.  230.230 would contain requirements for submission of 
adverse event reports related to the use of a designated medical gas in 
animals. Proposed Sec.  230.230(a) would govern the types of reports 
that would be required to be submitted to FDA.
    Under proposed Sec.  230.230(a)(1), applicants and nonapplicants 
must submit adverse event reports to FDA as soon as possible but no 
later than within 15 calendar days of first receiving the information. 
Reports are required for serious adverse events the applicant or 
nonapplicant receives from others as well as reports from published 
literature, regardless of whether the applicant or nonapplicant 
believes the event is related to the designated medical gas. FDA 
proposes an exception to the reporting requirements for the death of an 
animal that was administered oxygen, unless the applicant or 
nonapplicant becomes aware of evidence to suggest that the 
administration of oxygen caused the death. As is the case with human 
use of oxygen, FDA expects that oxygen will be administered to animals 
that are in critical condition. For such animals, death is expected to 
be a common outcome, so unless evidence suggests a causal relationship 
between oxygen and the death, FDA does not believe that adverse event 
reporting in that instance will shed new light on the safety of oxygen.
    Proposed Sec.  230.230(a)(2) would require that applicants and 
nonapplicants report adverse events that do not qualify for serious 
adverse event reporting under paragraph (a)(1) if notified by FDA to do 
so. This proposed requirement would allow FDA to obtain information 
regarding other safety signals if the Agency determines additional 
information is necessary to help protect animal or public health.
    As is the case for designated medical gases for human use, FDA 
would like to clarify that the proposed rule would not require 
submission of reports for fires associated with oxygen use if the 
animal patient did not experience an adverse event. Fires associated 
with oxygen use would be required to be reported if the animal patient 
experiences an adverse event. Because it is known that oxygen 
accelerates combustion and that smoking or open flames near an oxygen 
source can cause a fire, FDA believes it is not necessary to receive 
reports in which the animal patient did not experience a serious 
adverse event.
    Proposed Sec.  230.230(a)(3) would state that applicants and 
nonapplicants should not resubmit any adverse event reports obtained 
from FDA's adverse event reporting database or that FDA forwards to the 
applicant or nonapplicant, in order to minimize duplication.
    The format of adverse event reporting for animal use is addressed 
in proposed Sec.  230.230(b). FDA proposes to require submission in an 
electronic format, and that data in electronic submissions conform to 
the data elements in Form FDA 1932 and the Agency's technical documents 
on how to provide electronic submissions (e.g., method of transmission 
and processing, media, file formats, preparation and organization of 
files). The proposed rule would allow FDA to issue updated technical 
documents, as necessary. The most current information on submitting 
postmarketing safety reports to the Center for Veterinary Medicine 
(CVM) in electronic format can be found on CVM's web page at https://www.fda.gov/IndustryReportAnimalAE (see, e.g., ``Instructions for 
Electronic Submission of Mandatory Adverse Event Reports to FDA CVM'') 
(Ref. 17). As in the corresponding provision for designated medical 
gases for human use, under proposed 230.230(b)(2), applicants and 
nonapplicants would be able to request in writing a temporary waiver of 
the electronic reporting requirements.
    Proposed paragraph (c) contains recordkeeping requirements. 
Applicants and nonapplicants must maintain records of information 
related to adverse event reports for up to 5 years from the initial 
receipt of information. These records must be maintained regardless of 
whether the information was submitted to FDA. The records must also 
include raw data, correspondence, and any other information relating to 
the evaluation and reporting of such information that is received or 
otherwise obtained by the applicant or nonapplicant. These proposed 
requirements are generally consistent with the requirements in proposed 
230.220(e), though FDA proposes a retention period of 5 years, 
consistent with other animal safety reporting requirements. FDA also 
proposes to require that, upon written notice, the applicant or 
nonapplicant must submit these records to FDA within 5 calendar days 
after receipt of the notice. Because applicants and nonapplicants would 
not be required to submit nonserious adverse event reports, retaining 
the ability to collect records not submitted to the Agency would help 
FDA address questions that arise as FDA evaluates safety signals. 
Applicants and nonapplicants must also permit authorized FDA employees 
to access, copy, and verify these established and maintained records, 
at reasonable times. These proposed requirements will help facilitate 
the review of new and emergent safety issues.
6. Part 4 Postmarketing Safety Reporting Requirements
    As mentioned above, some medical gases are marketed as part of a 
combination product. The Agency believes some clarification is needed 
regarding the applicability of the postmarketing safety reporting 
requirements in part 4, subpart B to such medical gases.
    Because proposed part 230 would only apply to designated medical 
gases, medical gases under applications submitted under section 505 of 
the FD&C Act would continue to be subject to the postmarketing safety 
reporting requirements in part 314. Additionally, if the medical gas is 
part of a combination product that received marketing authorization 
(e.g., under an application submitted under section 505 of the FD&C 
Act), the requirements in part 4, subpart B currently apply. FDA 
proposes no changes for such products with regard to safety reporting 
requirements.
    As proposed in this section, new part 230 would apply to applicants 
and nonapplicants of designated medical gases subject to the 
certification requirements in section 576 of the FD&C Act. As explained 
in 21 CFR 4.100, part 4, subpart B does not apply to combination 
products that have not received marketing authorization. Therefore, 
part 4, subpart B would not apply to designated medical gases that are 
part of a combination product that did not receive marketing 
authorization. However, other reporting requirements may apply, e.g., 
the medical device reporting requirements in 21 CFR part 803 if such 
combination product includes a device constituent part. Further, if 
proposed part 230 is finalized, the safety reporting requirements 
therein would apply to such combination product that includes a 
designated medical gas.

[[Page 31332]]

VI. Proposed Effective Date

    FDA proposes that any final rule based on this proposal become 
effective 18 months after publication in the Federal Register. The 
Agency anticipates that some proposed requirements will result in 
changes to cylinders as they are returned from service, and that it may 
take some time for firms to make required changes to all cylinders. We 
believe that 18 months is an appropriate amount of time to enable firms 
to make such changes. FDA solicits comment on this proposed compliance 
date.

VII. Preliminary Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). We 
believe that this proposed rule is not a significant regulatory action 
as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because this proposed rule would more specifically tailor the 
current good manufacturing practice requirements for medical gases, add 
new oxygen labeling requirements, clarify the medical gas certification 
process, and clarify adverse event reporting requirements, this rule 
would create small net cost savings for small entities, and we propose 
to certify that the proposed rule will not have a significant economic 
impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $165 million, using the most current (2021) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.
    This proposed rule, if finalized, would establish, within part 213, 
CGMP regulations specific to medical gases. These proposed regulations 
include many of the same categories of requirements as the general drug 
CGMP regulations but are tailored to reflect differences in how medical 
gases are manufactured, packaged, labeled, stored, and distributed. 
This proposed rule, if finalized, would make limited changes to the 
labeling requirements of part 201 including requiring that a ``no 
smoking'' statement, a ``no vaping'' statement, and graphic warning 
symbol be added to oxygen designated medical gas containers to reduce 
the risk of fire. This proposed rule, if finalized, would codify and 
clarify the process for obtaining a certification to market designated 
medical gases. Recommendations for how to request a certification for 
designated medical gases are currently included in a draft guidance. 
This proposed rule, if finalized, would establish new postmarketing 
safety reporting regulations for designated medical gases that would 
address human and animal use and more specifically reflect the 
development, manufacturing, and distribution of designated medical 
gases.
    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.
    Table 1 summarizes the estimated benefits and costs of the proposed 
rule, if finalized. The annualized benefits would range from $0.00 
million to $6.48 million with a primary estimate of $3.24 million over 
a 10-year span at a 7 percent discount rate. Annualized at a 3 percent 
discount rate these benefits would range from $0.00 million to $6.86 
million with a primary estimate of $3.43 million. The annualized costs 
would range from $1.38 million to $4.95 million with a primary estimate 
of $3.03 million at a 7 percent discount rate. Annualized at a 3 
percent discount rate these costs would range from $1.23 million to 
$4.77 million with a primary estimate of $2.88 million.
    The present value of the estimated benefits would range from $0.00 
million to $51.98 million with a primary estimate of $26.02 million at 
a 7 percent discount rate and from $0.00 million to $65.37 million with 
a primary estimate of $32.73 million at a 3 percent discount rate. The 
present value of the estimated costs would range from $11.06 million to 
$39.71 million with a primary estimate of $24.33 million at a 7 percent 
discount rate and from $11.74 million to $45.49 million with a primary 
estimate of $27.49 million at a 3 percent discount rate.

                                  Table 1--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                           Units
                                          Primary       Low        High    ------------------------------------
               Category                  estimate    estimate    estimate      Year      Discount     Period                      Notes
                                                                              dollars    rate (%)     covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $millions/          $3.24       $0.00       $6.43        2020           7          10  Most benefits are cost savings to
     year.                                    3.43        0.00        6.86        2020           3          10   industry while the remaining are cost
                                                                                                                 savings for FDA due to a more
                                                                                                                 streamlined inspection process.
    Annualized Quantified.............  ..........  ..........  ..........  ..........           7  ..........
                                        ..........  ..........  ..........  ..........           3  ..........
                                       -----------------------------------------------------------------------------------------------------------------
    Qualitative.......................  ..........  ..........  ..........  ..........  ..........  ..........
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 31333]]

 
Costs:
    Annualized Monetized $millions/           3.03        1.38        4.95        2020           7          10
     year.                                    2.88        1.23        4.77        2020           3          10
    Annualized Quantified.............  ..........  ..........  ..........  ..........           7  ..........
                                        ..........  ..........  ..........  ..........           3  ..........
                                       -----------------------------------------------------------------------------------------------------------------
    Qualitative.......................  ..........  ..........  ..........  ..........  ..........  ..........
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized Monetized        ..........  ..........  ..........  ..........           7  ..........
     $millions/year.                    ..........  ..........  ..........  ..........           3  ..........
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
                                       -----------------------------------------------------------------------------------------------------------------
    Other Annualized Monetized          ..........  ..........  ..........  ..........           7  ..........
     $millions/year.                    ..........  ..........  ..........  ..........           3  ..........
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: None.............................................................................................................
    Small Business: Not significant.....................................................................................................................
    Wages: None.........................................................................................................................................
    Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    FDA conducted a regulatory flexibility analysis of the impact of 
the proposed rule on small entities. Approximately 41 percent of 
domestic entities that would be affected by the proposed rule are small 
according to Small Business Administration (SBA) size standards. We 
estimate that the highest single year cost for a firm could be as high 
as 0.788 percent while the average costs to receipts ratio is 0.007 
percent. Therefore, our analysis of the impact of the proposed rule on 
small entities suggests that small firms will not be significantly 
affected by the proposed regulation, if finalized.
    We have developed a comprehensive Preliminary Economic Analysis of 
Impacts that assesses the impacts of the proposed rule. The full 
preliminary analysis of economic impacts is available in the docket for 
this proposed rule (Ref. 18) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h), (j), and (k) that this 
action is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

IX. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3521). A description of these provisions is given in 
the Description section of this document with an estimate of the annual 
reporting, recordkeeping, and third-party disclosure burden. Included 
in the burden estimate is the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.
    FDA invites comments on these topics: (1) Whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Current Good Manufacturing Practice, Certification, 
Postmarketing Safety Reporting, and Labeling Requirements for Certain 
Medical Gases.
    Description: This rulemaking is amending existing regulations and 
establishing new regulatory requirements pertaining to medical gases.
    Description of Respondents: Respondents to this information 
collection are entities who manufacture, process, pack, label, or 
distribute certain medical gases.

1. Product Jurisdiction and Combination Products; OMB Control No. 0910-
0523--Revision

    FDA recognizes that some medical gases are marketed as part of a 
combination product. For example, a medical gas may be marketed with a 
device constituent part (for example, a portable liquid oxygen unit or 
a pressure regulator). Combination products are subject to information 
collection provisions found in 21 CFR parts 3 and 4, which prescribe 
content and format requirements associated with marketing applications, 
together with applicable recordkeeping and reporting requirements.
    FDA proposes to revise provisions in part 4 to account for 
combination products that contain a medical gas, as FDA proposes 
medical gases to be subject to proposed part 213, and to clarify (where 
appropriate) applicable medical gases requirements throughout part 4. 
We believe that the revisions impose no new burden associated with 
information collection currently approved under OMB control number 
0910-0523 and invite comment on our assumptions.

[[Page 31334]]

2. Labeling Requirements for Prescription Drugs; OMB Control No. 0910-
0572--Revision

    We estimate the burden of the information collection as follows:

                                               Table 2--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                   Number of
        Activity; proposed CFR section            Number of     disclosures per     Total annual        Average burden  per disclosure       Total hours
                                                 respondents     respondent \2\   disclosures \2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Labeling of bulk or transport containers used           1,696               2.36            4,000  0.1 (6 minutes)........................           400
 to hold designated medical gases; Sec.
 201.161(b).
On the container label, identify the owner of           1,696               2.36            4,000  0.1 (6 minutes)........................           400
 a designated medical gas container or a
 container of a medically appropriate
 combination of designated medical gases. If
 the container owner is not the manufacturer,
 packer, or distributor of the gas, identify
 that information on the label; Sec.
 201.328(d).
                                              ----------------------------------------------------------------------------------------------------------
    Total....................................  ..............  .................            8,000  .......................................           800
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with the information collection.
\2\ Totals have been rounded to the nearest whole number.

    Regulations in part 201 govern the statement of ingredients and 
declaration of net quantity of contents with regard to prescription 
drug product labeling.
    The proposed revisions to the regulations would require that firms 
identify bulk or transport containers with the name of the product 
contained therein and that containers be accompanied by documentation 
that identifies the product as meeting applicable compendial standards. 
Bulk or transport containers are excluded from the proposed definition 
of final use containers. Because these large containers are removed 
from the point of care and we do not expect that patients and 
healthcare practitioners will use them directly to administer 
designated medical gas, FDA does not believe that firms' bulk or 
transport containers need to bear the information that we would require 
under proposed Sec.  201.161(a). However, to prevent mix-ups, it is 
essential that the identity of the gas inside such containers is 
evident to individuals who handle and transport the containers. FDA 
expects that these proposed requirements will help prevent mix-ups and 
ensure that recipients of medical gases in bulk or transport containers 
are provided information indicating that such gases meet applicable 
compendial standards.
    Based on our experience with similar information collection, we 
estimate that 1,696 firms will label 4,000 containers and assume firms 
will expend 6 minutes (0.1 hours) to identify the containers with the 
name of the product and place documentation that identifies the product 
as meeting applicable compendial standards, totaling 400 hours 
annually.
    Proposed Sec.  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 (that is, it need not be contiguous with other 
labeling on the container), but if the container owner is not the 
manufacturer, packer, or distributor of the gas, that information shall 
be clearly stated. FDA recognizes the complex distribution system for 
designated medical gases and medically appropriate combinations of 
designated medical gases and the importance of each entity in the 
distribution chain being clearly identified so that patients and 
healthcare professionals can contact the appropriate entity if 
necessary. We intend for this provision to help ensure that appropriate 
entities can be contacted about quality issues or adverse events. In 
addition, the proposed labeling requirement would facilitate the return 
of cylinders to owners who may not also be medical gas manufacturers. 
FDA proposes that including the container owner's information will not 
cause the container owner to be a ``relabeler'' for purposes of FDA's 
registration and listing requirements.
    Based on our experience with similar information collection, we 
estimate that 1,696 firms will identify on a designated medical gas 
container or a container of a medically appropriate combination of 
designated medical gases the name of the container owner who may not 
also be the manufacturer, packer, or distributor of the gas. We assume 
firms would include this label on 4,000 containers and will expend 6 
minutes (0.1 hours) to perform this activity, totaling 400 hours 
annually.

3. Current Good Manufacturing Practice for Medical Gases; OMB Control 
No. 0910-NEW

    We estimate the burden of the information collection as follows:

                                                   Table 3--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                   Number of
                                                  Number of       records per     Total annual
        Activity; proposed CFR section          recordkeepers     recordkeeper     records \2\       Average burden  per recordkeeping       Total hours
                                                                      \2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
New Start Up SOP; Sec.   213.42..............            1,696                1           1,696  13.......................................        22,048
SOP Maintenance; Sec.   213.42...............            1,696                1           1,696  0.65 (39 minutes)........................         1,102
New Start Up SOP; Sec.   213.208.............            1,696                1           1,696  13.......................................        22,048
SOP Maintenance Sec.   213.208...............            1,696                1           1,696  0.65 (39 minutes)........................         1,102
Documentation of completion of training; Sec.            1,696               10          16,960  0.083 (5 minutes)........................         1,408
   213.25(a).
Consultants' records of sufficient education,            1,696            0.336             571  0.5 (30 minutes).........................           286
 training, and experience, or any combination
 thereof; Sec.   213.34.
Firms' records of equipment maintenance and              1,696          43.7676          74,230  0.25 (15 minutes)........................        18,557
 cleaning; Sec.   213.67(c).
Maintain records for modifications to                    1,696            6.734          11,420  0.25 (15 minutes)........................         2,855
 automatic, mechanical, and electronic
 equipment; Sec.   213.68(d).

[[Page 31335]]

 
Receipt and storage of incoming designated               1,380              417         575,460  0.25 (15 minutes)........................       143,865
 medical gases; Sec.   213.82(a).
Records of rejected components; Sec.   213.89            1,380             24.2          33,400  0.083 (5 minutes)........................         2,772
Maintain records for each shipment received              1,696          43.7676          74,230  0.25 (15 minutes)........................        18,558
 of each different labeling and packaging
 material indicating receipt, examination,
 and whether accepted or rejected; Sec.
 213.122(c).
Document results of inspections in the batch             1,696           67.334         114,200  0.25 (15 minutes)........................        28,550
 production records; Sec.   213.130(e).
Maintain written records so that data therein            1,696             0.27             457  0.25 (15 minutes)........................           114
 can be used for evaluating, at least
 annually, the quality standards of each
 medical gas to determine the need for
 changes in specifications or manufacturing
 or control procedures; Sec.   213.180(d).
Maintain record of equipment cleaning and use            1,696             1.76           2,969  0.16 (10 minutes)........................           475
 log maintenance; Sec.   213.182.
Maintain records for components, medical gas             1,696            2.626           4,454  0.33 (19.8 minutes)......................         1,470
 containers and closures, and labeling; Sec.
  213.184.
Maintain master production and control                   1,696           13.467          22,840  2........................................        45,680
 records; Sec.   213.186.
Maintain batch production and control                    1,696           21.883          37,115  1.3 (78 minutes).........................        48,250
 records; Sec.   213.189.
Maintain record of the investigation; Sec.               1,696             2.69           4,568  1........................................         4,568
 213.192(a).
Maintain laboratory records; Sec.                        1,696           33.667          57,100  0.5 (30 minutes).........................        28,550
 213.194(b) through (e).
Maintain distribution records; Sec.   213.196            1,696           33.667          57,100  0.25 (15 minutes)........................        14,275
Maintain written records of each complaint;              1,696            6.733          11,420  1........................................        11,420
 Sec.   213.198(b).
                                              ----------------------------------------------------------------------------------------------------------
    Total....................................  ...............  ...............       1,105,278  .........................................       417,953
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with the information collection.
\2\ Totals have been rounded to the nearest whole number.

    FDA proposes to establish part 213 setting forth CGMP requirements 
applicable to medical gases. If finalized, part 213 would apply to 
firms that manufacture a medical gas and would also establish 
requirements applicable to firms that subsequently combine, commingle, 
refill, or distribute medical gases.
    The proposed regulations include recordkeeping requirements 
pertaining to personnel qualifications and responsibilities of persons 
who are engaged in the manufacturing, processing, packing, or holding 
of a medical gas.
    Provisions under proposed Sec.  213.42(c) include recordkeeping to 
document the development and implementation of written procedures to 
ensure that firms maintain a clean condition for any building used to 
manufacture, process, pack, or hold a medical gas so as to ensure the 
safety, identity, strength, quality, and purity of the gas. Firms would 
need to develop written procedures that apply to maintaining and 
cleaning buildings. Based on available data, we estimate 1,696 firms 
will each develop and implement written procedures to maintain and 
clean buildings. We assume it will take 13 hours to perform this 
activity, totaling 22,048 hours annually. Firms would also maintain 
these procedures. Based on available data, we estimate 1,696 firms 
would each maintain written procedures to maintain and clean buildings. 
We assume it will take 39 minutes (0.65 hours) to perform this 
activity, totaling 1,102 hours annually.
    Similarly, under proposed Sec.  213.208, firms would be required to 
develop and implement written procedures for the holding, testing, and 
use of salvaged medical gases. Based on available data, we estimate 
1,696 firms will develop and implement written procedures for the 
holding, testing, and use of salvaged medical gases. We assume it will 
take 13 hours for firms to perform this activity, totaling 22,048 hours 
annually. Based on available data, 1,696 firms will prepare written 
procedures (1 procedure each) for the holding, testing, and use of 
salvaged medical gases. We assume it takes 0.65 hours to perform this 
activity, totaling 1,102 hours annually.
    The proposed regulations would provide that employee training be 
included in the firm operations. Recordkeeping would be established to 
demonstrate that qualified individuals conduct training on a continuing 
basis and with sufficient frequency to allow employees to remain 
familiar with applicable requirements. Based on available data, we 
estimate that 1,696 firms will prepare written documentation pertaining 
to employee training. We assume 10 employees per firm will create 
16,960 records (10 records per firm) and that it will take 5 minutes 
(0.083 hours) to prepare the records, for a total of 1,408 hours 
annually.
    Under proposed Sec.  213.34, records demonstrating that consultants 
have sufficient education, training, and experience, or any combination 
thereof, to advise on the subject for which they are retained will be 
required. Based on available data, we estimate that 1,696 firms will 
maintain 571 records of consultants' education, training, and 
experience, or any combination thereof and assume it will take 30 
minutes (0.5 hours) to perform this activity, totaling 286 hours 
annually.
    Based on available data, we estimate that 1,696 firms will maintain 
74,230 records of equipment maintenance and cleaning and assume it will 
take 15 minutes (0.25 hours) to perform this activity, totaling 18,557 
hours annually.
    Based on available data, we estimate 1,696 firms will develop and 
implement 11,420 written procedures for automatic, mechanical, and 
electronic equipment and assume firms will expend 15 minutes (0.25 
hours) to perform this activity, totaling 2,855 hours annually.
    As provided for in the proposed regulations, if an incoming 
designated medical gas is obtained from a supplier other than the 
original manufacturer, the shipment would also need to include specific 
information. To ensure the reliability of appropriate assessment and 
testing, firms will be required to establish and maintain a program to 
ensure the reliability of the supplier's capabilities through 
appropriate assessment and testing procedures. Based on assumptions 
found in our Preliminary Regulatory Impact Analysis (PRIA), we estimate 
that 1,380 firms would verify and document records upon receipt of a 
designated medical gas. We assume firms will maintain

[[Page 31336]]

575,460 records (417 records each (1 delivery per week of oxygen for 1 
year (52 deliveries) plus 1 delivery per night of nitrogen for 1 year 
(365 deliveries)). We further assume firms will expend 15 minutes (0.25 
hours) each (104 hours in total for each firm) to perform this 
activity, totaling approximately 143,865 hours annually.
    Proposed Sec.  213.89 would require that firms identify and control 
rejected components, containers, and closures under a quarantine system 
designed to prevent their use in operations for which they are 
unsuitable. Proposed Sec.  213.89 also applies to incoming designated 
medical gases. Quarantine systems would not need to include physical 
quarantining because other methods can adequately ensure that 
unsuitable products are not used. Based on assumptions found in section 
II.F.4.b of the PRIA, we estimate that 1,380 downstream firms would 
need to assess and document 33.4 million medical gas components, 
containers, and closures annually. We assume that firms would reject 0 
to 0.1 percent of all containers. These firms will maintain a total of 
33,400 records of rejected components and we assume will expend 5 
minutes (0.083 hours) to perform this activity, totaling 2,772 hours 
annually.
    Under proposed Sec.  213.122(c), firms would need to maintain 
records for each shipment received of each different labeling and 
packaging material indicating receipt, examination, and whether 
accepted or rejected. Based on available data, we estimate 1,696 firms 
will prepare 74,230 records to document each shipment received of each 
different labeling and packaging material indicating receipt, 
examination, and whether accepted or rejected. We assume it will take 
15 minutes (0.25 hours) to perform this activity, totaling 18,558 hours 
annually.
    Under proposed 213.130(e), firms would need to document results of 
inspections concerning packaging and labeling in the batch production 
records. Based on available data, we estimate 1,696 firms will document 
results of inspections in the batch production records in approximately 
114,200 records. We assume it will take 15 minutes (0.25 hours) per 
record to perform this activity, totaling 28,550 hours annually.
    As described in section V.B.11 of this document and proposed Sec.  
213.180(d), firms would need to maintain written records so that data 
therein can be used for evaluating, at least annually, the quality 
standards of each medical gas to determine the need for changes in 
specifications or manufacturing or control procedures. Based on 
available data, we estimate 1,696 firms will prepare 457 records. We 
assume it will take 15 minutes (0.25 hours) to perform this activity, 
totaling 114 hours annually.
    Under proposed Sec.  213.182 and as described in section V.B.11 of 
this document, firms would need to maintain a written record of major 
equipment cleaning, maintenance (except routine maintenance such as 
lubrication and adjustments), and use. Based on available data, we 
estimate 1,696 firms will prepare 2,969 records documenting major 
equipment cleaning, maintenance (except routine maintenance such as 
lubrication and adjustments), and use. We assume it will take 10 
minutes (0.16 hours) to perform this activity, totaling 475 hours 
annually.
    As described in section V.B.11 of this document and under proposed 
Sec.  213.184, firms would need to maintain certain records concerning 
components, medical gas containers and closures, and labeling. Based on 
assumptions found in our PRIA, we estimate 1,696 firms will prepare 
4,454 records for components, medical gas containers and closures, and 
labeling. We assume firms will expend 19.8 minutes (0.33 hours) to 
perform this activity, totaling 1,470 hours annually.
    As discussed in section V.B.11 of this document and estimates for 
the number of firms calculated throughout the PRIA, under proposed 
Sec.  213.186, to ensure uniformity from batch to batch, firms would 
need to prepare, date, and sign master production and control records 
for each medical gas. Based on data from existing information 
collection requests and estimates for the number of firms calculated 
throughout the PRIA, we estimate 1,696 firms will prepare and maintain 
approximately 22,840 master production and control records and assume 
it will require 2 hours for firms to perform this activity, totaling 
45,680 hours annually.
    Under proposed Sec.  213.189 and as described in section V.B.11 of 
this document, firms would need to maintain batch production and 
control records. These records would need to include documentation that 
the firm has accomplished each significant step in the manufacturing, 
processing, packing, or holding of the medical gas produced. Based on 
data from existing information collection requests and estimates for 
the number of firms calculated throughout the PRIA, we estimate 1,696 
firms will prepare and maintain 37,115 batch production and control 
records. We assume it will require 78 minutes (1.3 hours) for firms to 
perform this activity, totaling 48,250 hours annually.
    Section V.B.11 of this document and proposed Sec.  213.192(a) 
describe production record review. Per paragraph (a), firms would need 
to maintain a written record of the investigation and include the 
conclusions and followup. Based on data from existing information 
collection requests and estimates for the number of firms calculated 
throughout the PRIA, we estimate 1,696 firms will prepare and maintain 
4,568 laboratory records and that it will require 1 hour for firms to 
perform this activity, totaling 4,568 hours annually.
    Under proposed Sec.  213.194(b) through (e) and as described in 
section V.B.11 of this document, firms would need to maintain certain 
laboratory records. Based on available data, we estimate 1,696 firms 
will prepare and maintain 57,100 laboratory records and assume it will 
require 30 minutes (0.5 hours) for firms to perform this activity, 
totaling 28,550 hours annually.
    As described in section V.B.11 of this document, proposed Sec.  
213.196 describes certain proposed requirements for distribution 
records. Based on available data, we estimate 1,696 firms will prepare 
and maintain 57,100 distribution records and assume it will require 15 
minutes (0.25 hours) for firms to perform this activity, totaling 
14,275 hours annually.
    As discussed under proposed Sec.  213.198(b), firms would be 
required to maintain written records of each complaint regarding 
medical gases. Our full discussion is shown in section V.B.11 of this 
document. Based on assumptions found in our PRIA, we estimate 1,696 
firms will maintain 11,420 records of complaints. We assume it will 
require approximately 1 hour for firms to perform this activity, 
totaling 11,420 hours annually.

4. Certification Process and Postmarketing Quality and Safety 
Reporting; OMB Control No. 0910-NEW

[[Page 31337]]

                                  Table 4--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
 Activity; proposed CFR section      Number of     responses per   Total annual   Average burden    Total hours
                                    respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
Submission of certification                    5               1               5               3              15
 requests and certification form
 that includes any resubmissions
 and amendments to pending
 requests; Sec.   230.50........
Submission of supplements to                   4               1               4               3              12
 certification requests and
 other changes; Sec.   230.70...
Submission of requests to                      2               2               4               2               8
 transfer ownership of
 certification, including new
 address and the owner's
 submission of any change in the
 conditions in the granted
 certification; Sec.   230.72...
Annual reports; Sec.   230.80...              50            2.16             108               2             216
Field alert reports; Sec.                  1,380           0.002               3               8              24
 230.205........................
CDER: Submission of ICSRs (Sec.            1,430            0.12             172               6           1,032
  230.220(a) through (d)).......
CDER's maintenance of records              1,430            0.48             686              16          10,976
 for human designated medical
 gas ICSR requirements (Sec.
 230.220(e))....................
CVM's recordkeeping requirements           1,696          0.0044             7.5               5            37.5
 related to adverse event
 reports (Sec.   230.230(c))....
CVM: Submission of adverse event           1,696          0.0044             7.5               5            37.5
 reports; Sec.   230.230........
CVM: Waiver request from                   1,696          0.0044             7.5               5            37.5
 electronic submission
 requirement; Sec.   230.230....
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............         1,004.5  ..............        12,395.5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Totals have been rounded to the nearest whole number.

    Proposed Sec.  230.50 (see section V.C.2 of this document) would 
establish the general requirements for requesting a designated medical 
gas certification for all submission types and would outline the 
information that must be included in certification request submissions.
    The proposed regulations would require applicants to include 
facility information in certification requests. Such information would 
include, among others, name and address of the original manufacturing 
facility or facilities where the gas is or will be manufactured.
    Proposed section 230.50 would also provide for the submission of 
additional information if FDA deems it appropriate to determine whether 
a medical gas meets the definition of a designated medical gas. This 
information would generally be in the form of a written request by FDA 
for the additional information.
    Based on assumptions found in our PRIA, we estimate that five 
respondents will submit a total of five certification requests 
annually, including certification forms for original and resubmissions. 
We assume each certification request will require 3 hours to prepare 
and submit, totaling 15 hours annually.
    Under proposed Sec.  230.65, applicants would be allowed to 
withdraw a certification request that has not been deemed granted. An 
applicant could notify FDA that it withdraws its certification request 
at any time before the certification is deemed granted. Upon an 
applicant's withdrawal of a certification request, FDA would retain the 
certification request, and if the applicant requests a copy via FOIA 
request, FDA would provide it pursuant to the fee schedule in FDA's 
public information regulations. Since the passage of FDASIA, FDA has 
received several certification requests but has not received any 
withdrawal requests. FDA has no other data on which to provide a burden 
estimate. Therefore, the Agency does not expect to receive withdrawal 
requests except in exceedingly rare situations.
    Proposed Sec.  230.70, as discussed in section V.C.3 of the 
proposed rule would require applicants to submit a supplement if any 
information in the granted certification has changed. The proposed 
regulation would prescribe information to be included in a supplement 
submission.
    Based on our experience with similar information collection, we 
estimate four applicants will submit supplements and assume, each 
submission will require 3 hours to prepare, totaling 12 hours annually.
    Proposed Sec.  230.72 would govern changes in ownership of a 
granted certification. An example of when a change in ownership could 
occur is during a merger or acquisition. Upon a change in ownership, 
the regulations would require that both the new and previous owner 
notify FDA.
    Based on related submissions received by FDA over the last few 
years and averaged accordingly, we estimate two respondents will submit 
four letters or other supporting documents, and assume it will take 2 
hours to complete this task, totaling 8 hours annually.
    To assist respondents with the proposed submission requirements 
associated with proposed Sec.  230.80 (annual reports), we are 
developing an annual report form.
    Based on our records and informal requests received upon announcing 
this rulemaking, we estimate that 50 applicants will submit to FDA 108 
annual reports (a total of 108 reports). We assume firms will expend 2 
hours to perform this activity, totaling 216 hours annually.
    Our estimate associated with proposed requirements in Sec.  230.205 
for field alert reporting for designated medical gases is based on our 
experience with similar reports that FDA received in 2019 and 2020.
    We estimate that 1,380 applicants and nonapplicants will submit to 
FDA three FARs. We assume respondents will expend approximately 8 hours 
to perform this activity, totaling 24 hours annually.
    Proposed Sec.  230.210 would require that applicants and 
nonapplicants promptly review all safety information that the applicant 
or nonapplicant receives or otherwise obtains from any source 
(including both foreign and domestic sources). Applicants and 
nonapplicants would generate reports from their review and submit them 
under proposed Sec. Sec.  230.220 and 230.230.
    As described under proposed Sec.  230.220(a) through (d) (see 
section V.D.4 of this document), firms would be required to submit 
ICSRs associated with the use of a designated medical gas in humans.
    Proposed Sec.  230.220 (see section V.D.4 of this document) would 
contain requirements for submission of ICSRs associated with the use of 
a designated medical gas in humans. Under proposed Sec.  230.220(a)(1), 
applicants and nonapplicants would be required to submit each ICSR as 
soon as possible, but no later than 15 calendar days from the date the 
applicant or nonapplicant has met the reporting criteria under proposed 
Sec.  230.220(b) and acquired a

[[Page 31338]]

minimum data set for an ICSR for that adverse event.
    Under proposed Sec.  230.220(a)(3), applicants and nonapplicants 
would submit new information they receive or otherwise obtain about a 
previously submitted ICSR to FDA. The proposed regulation would 
prescribe reporting schedules to ensure FDA becomes aware of any new 
information that arises about the adverse event.
    Based on assumptions found in our PRIA and a review of safety 
report data, we estimate that 1,430 applicants and nonapplicants will 
submit to FDA 172 ICSRs annually. We assume it will take 6 hours for 
respondents to perform this activity, totaling 1,032 hours annually.
    Proposed Sec.  230.220(b) would describe the types of ICSRs that 
applicants and nonapplicants would need to report for human use. Under 
proposed Sec.  230.220(b)(1), applicants and nonapplicants would be 
required to submit ICSRs for serious adverse events. Under proposed 
Sec.  230.220(b)(2), FDA proposes to require an applicant to report to 
FDA, in a timeframe established by FDA, ICSRs for any adverse events 
that would not be required under proposed Sec.  230.220(b)(1) upon 
notification by FDA.
    Proposed Sec.  230.220(e) would prescribe content and format 
requirements for records pertaining to human designated medical gas 
adverse events. For a period of 10 years from the initial receipt of 
information, each applicant or nonapplicant would be required to 
maintain records of information relating to adverse events, whether or 
not submitted to FDA. These records would need to include raw data, 
correspondence, and any other information relating to evaluating and 
reporting adverse event information that is received or otherwise 
obtained by the applicant or nonapplicant. Upon written notice by FDA, 
the applicant or nonapplicant would need to submit any and all of these 
records to FDA within 5 calendar days after receipt of the notice. The 
applicant or nonapplicant would need to permit any authorized FDA 
employee, at reasonable times, to access, copy, and verify the 
established and maintained records described in this section.
    Based on available data, we estimate that 1,430 manufacturers will 
create 686 records pertaining to human designated medical gas 
requirements and that it would take approximately 16 hours to perform 
this activity, totaling 10,976 hours.
    Proposed Sec.  230.220(c) and (d) would include additional 
requirements for the content and format of ICSRs.
    Based on available data, we assume all firms (1,696) will 
distribute designated medical gases for human and animal use and invite 
comment on our assumption.
    Under proposed Sec.  230.230(a)(1), an applicant or nonapplicant 
would need to submit serious adverse events related to the use of a 
designated medical gas in animals to FDA as soon as possible but no 
later than 15 calendar days from first receiving the information. The 
applicant or nonapplicant would need to submit the report to FDA in 
electronic format as described under proposed Sec.  230.230(b)(1) of 
this section, unless the applicant or nonapplicant obtains a waiver 
under proposed Sec.  230.230(b)(2) of this section or FDA requests the 
report in an alternate format.
    Under proposed Sec.  230.230(a)(2), upon notification by FDA, 
applicants and nonapplicants would need to submit reports of adverse 
events associated with the use of a designated medical gas in animals 
that do not qualify for reporting under proposed Sec.  230.230(a)(1) of 
this section. The notice would specify the adverse events to be 
reported and the reason for requiring the reports.
    We estimate approximately 7.5 records will be submitted per year 
and estimate that it will take approximately 5 hours to perform this 
activity, totaling 37.5 hours. We also estimate that approximately 7.5 
reports will be maintained yearly and estimate it will take 5 hours to 
perform this activity, totaling 37.5 hours.
    Under proposed Sec.  230.230(b)(2), an applicant or nonapplicant 
could request, in writing, a temporary waiver of the electronic 
submission requirements under proposed Sec.  230.230(b)(1). An 
applicant or nonapplicant would need to provide the initial request by 
telephone or email to CVM's Division of Veterinary Product Safety, with 
prompt written followup submitted as a letter to the granted 
certification or certifications. FDA would grant waivers on a limited 
basis for good cause shown. If FDA grants a waiver, the applicant or 
nonapplicant would need to comply with the conditions for reporting 
specified by FDA upon granting the waiver.
    We estimate approximately 7.5 waiver requests will be submitted 
annually and estimate it will take 5 hours to perform this activity, 
totaling 37.5 hours annually.
    To ensure that comments on information collection are received, OMB 
recommends that written comments be through reginfo.gov (see 
ADDRESSES). All comments should be identified with the title of the 
information collection.
    In compliance with the PRA (44 U.S.C. 3407(d)), we have submitted 
the information collection provisions of this proposed rule to OMB for 
review. These information collection requirements will not be effective 
until FDA publishes a final rule, OMB approves the information 
collection requirements, and the rule goes into effect. FDA will 
announce OMB approval of these requirements in the Federal Register.

X. Federalism

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

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13175. We have tentatively 
determined that the proposed rule does not contain policies that would 
have a substantial direct effect on one or more Indian Tribes, on the 
relationship between the Federal Government and Indian Tribes, or on 
the distribution of power and responsibilities between the Federal 
Government and Indian Tribes. The Agency solicits comments from tribal 
officials on any potential impact on Indian Tribes from this proposed 
action.

XII. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. FDA has verified the website addresses, as of

[[Page 31339]]

the date this document publishes in the Federal Register, but websites 
are subject to change over time.

*1. Food and Drug Administration (FDA) draft guidance for industry 
``Certification Process for Designated Medical Gases,'' November 
2015, available at https://www.fda.gov/media/85013/download.
*2. FDA, Medical Gas Regulation Public Workshops, available at 
https://www.fda.gov/drugs/news-events-human-drugs/medical-gas-regulation-public-workshops.
3. Lacasse, Y., M. L[eacute]gar[eacute], and F. Maltais, ``E-
cigarette Use in Patients Receiving Home Oxygen Therapy,'' Canadian 
Respiratory Journal, vol. 22, no. 2, 83-85, March/April 2015. 
https://downloads.hindawi.com/journals/crj/2015/215932.pdf.
*4. Benowitz, N.M., ``E-cigarette Explosion in a Patient Room,'' 
PSNet, April 2019. https://psnet.ahrq.gov/web-mm/e-cigarette-explosion-patient-room.
5. Fire & Rescue NSW, ``Fire Research Report--E-Cigarette Fire Risks 
and Reported Incidents,'' January 30, 2015. https://www.icao.int/safety/dangerousgoods/dgpwg15/dgpwg.15.ip.004.2.en.app.pdf.
6. Rudy, S.F. and E.L. Durmowicz, ``Electronic Nicotine Delivery 
Systems: Overheating, Fires and Explosions,'' Tobacco Control, 
26:10-18, 2017. https://tobaccocontrol.bmj.com/content/tobaccocontrol/26/1/10.full.pdf.
*7. FDA, Response to petition submitted by Compressed Gas 
Association, Docket No. 87P-0167/CP1, September 19, 1996.
*8. FDA, Public Health Advisory, ``Guidance for Hospitals, Nursing 
Homes, and Other Health Care Facilities,'' March 2001, available at 
https://www.fda.gov/media/70999/download.
*9. Kreiter, P., T.G. Bizjak, and R.L. Friedman, ``Preventing 
Patients From Receiving Leaking or Empty Containers of Medical Gas: 
A Review of Inspectional Findings From 2003 to 2021,'' CDER Office 
of Manufacturing Quality, December 2021, U.S. Food and Drug 
Administration.
*10. CDER, Manual of Policies and Procedures 5310.7 Rev. 1, 
``Acceptability of Standards from Alternative Compendia (BP/EP/
JP),'' available at https://www.fda.gov/media/72412/download.
*11. FDA guidance for industry ``Specification of the Unique 
Facility Identifier (UFI) System for Drug Establishment 
Registration,'' November 2014, available at https://www.fda.gov/media/89926/download.
*12. FDA draft guidance for industry ``Postmarketing Safety 
Reporting for Human Drug and Biological Products Including 
Vaccines,'' March 2001, available at https://www.fda.gov/media/73593/download.
*13. FDA guidance for industry ``Field Alert Report Submission--
Questions and Answers,'' July 2021, available at https://www.fda.gov/media/114549/download.
*14. FDA, Compliance Program Guidance Manual 7356.002E, ``Compressed 
Medical Gases,'' March 15, 2015, available at https://www.fda.gov/media/75194/download.
*15. FDA draft guidance for industry ``Providing Submissions in 
Electronic Format--Postmarketing Safety Reports,'' June 2014, 
available at https://www.fda.gov/media/71176/download.
16. International Council on Harmonization, MedDRA, available at 
https://www.ich.org/page/meddra.
*17. FDA, Veterinary Adverse Event Reporting for Manufacturers, 
available at https://www.fda.gov/IndustryReportAnimalAE.
*18. FDA, Preliminary Regulatory Impact Analysis: Current Good 
Manufacturing Practice, Certification, Postmarketing Safety 
Reporting, and Labeling Requirements for Certain Medical Gases, 
available at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

List of Subjects

21 CFR Part 4

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

21 CFR Part 16

    Administrative practice and procedure.

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 210

    Drugs, Packaging and containers.

21 CFR Part 211

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

21 CFR Part 213

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

21 CFR Part 230

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

21 CFR Part 314

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

21 CFR Part 514

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

    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, the 
Food and Drug Administration proposes to amend chapter I of title 21 of 
the Code of Federal Regulations as follows:

PART 4--REGULATION OF COMBINATION PRODUCTS

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

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

0
2. Revise Sec.  4.2 to read as follows:

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

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

[[Page 31340]]

that is a constituent part of a combination product is considered a 
medical gas within the meaning of the medical gas CGMPs.
    Drug CGMPs refers to the current good manufacturing practice 
regulations set forth in parts 210 and 211 of this chapter.
    HCT/Ps refers to human cell, tissue, and cellular and tissue-based 
products, as defined in Sec.  1271.3(d) of this chapter. An HCT/P that 
is not solely regulated under section 361 of the Public Health Service 
Act may be a constituent part of a combination product. Such an HCT/P 
is subject to part 1271 of this chapter and is also regulated as a 
drug, device, and/or biological product.
    Manufacture includes, but is not limited to, designing, 
fabricating, assembling, filling, processing, testing, labeling, 
packaging, repackaging, holding, and storage.
    Medical gas CGMPs refers to the current good manufacturing practice 
regulations set forth in part 213 of this chapter.
    QS regulation refers to the quality system regulation in part 820 
of this chapter.
    Single-entity combination product has the meaning set forth in 
Sec.  3.2(e)(1) of this chapter.
    Type of constituent part refers to the category of the constituent 
part, which can be either a biological product, a device, or a drug, as 
these terms are defined under this section.
0
3. Amend Sec.  4.3 by revising paragraphs (a), (c), and (d), and adding 
paragraph (e) as follows:

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

* * * * *
    (a) The current good manufacturing practice requirements in parts 
210 and 211 of this chapter apply to a combination product that 
includes a drug constituent part other than a medical gas;
* * * * *
    (c) The current good manufacturing practice requirements among the 
requirements (including standards) for biological products in parts 600 
through 680 of this chapter apply to a combination product that 
includes a biological product constituent part to which those 
requirements would apply if that constituent part were not part of a 
combination product;
    (d) The current good tissue practice requirements including donor 
eligibility requirements for HCT/Ps in part 1271 of this chapter apply 
to a combination product that includes an HCT/P; and
    (e) The current good manufacturing practice requirements in part 
213 of this chapter apply to a combination product that includes a drug 
that is a medical gas.
0
4. Amend Sec.  4.4 by:
0
a. Revising paragraphs (b)(1) introductory text, (b)(2) introductory 
text, and (e);
0
b. Redesignating paragraphs (b)(3) and (b)(4) as (b)(4) and (b)(5), 
respectively; and
0
c. Adding new paragraph (b)(3).
    The revisions and addition read as follows:

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

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

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

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

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

0
6. In Sec.  16.1, revise paragraph (b)(2) by numerically adding an 
entry for ``Sec.  230.150(b)'' to read as follows:

Sec.  16.1  Scope.

* * * * *
    (b) * * *
    (2) * * *
    Sec.  230.150(b), relating to revocation of the grant of a 
certification for a designated medical gas.
* * * * *

PART 201--LABELING

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

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

0
8. In Sec.  201.1, revise paragraph (b) to read as follows:

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

* * * * *
    (b) As used in this section, and for purposes of section 502(a) and 
(b)(1) of

[[Page 31341]]

the Federal Food, Drug, and Cosmetic Act, the manufacturer of a drug 
product is the person who performs all of the following operations that 
are required to produce the product:
    (1) Mixing,
    (2) Granulating,
    (3) Milling,
    (4) Molding,
    (5) Lyophilizing,
    (6) Tableting,
    (7) Encapsulating,
    (8) Coating,
    (9) Sterilizing,
    (10) Filling sterile or aerosol drugs into dispensing containers, 
and
    (11) With respect to a medical gas, fabricating the gas by chemical 
reaction, physical separation, compression of atmospheric air, 
purification (e.g., re-processing an industrial gas into a medical 
gas), by combining two or more distinct medical gases, or by other 
process.
* * * * *
0
9. In Sec.  201.10, revise paragraph (d)(2) to read as follows:

Sec.  201.10  Drugs; statement of ingredients.

* * * * *
    (d) * * *
    (2) A statement of the percentage of an ingredient in a drug shall, 
if the term percent is used without qualification, mean percent weight-
in-weight, if the ingredient and the drug are both solids, or if the 
ingredient is a liquid and the drug is a solid; percent weight in 
volume at 68 [deg]F. (20 [deg]C.), if the ingredient is a solid and the 
drug is a liquid; percent volume in volume at 68 [deg]F. (20 [deg]C.), 
if both the ingredient and the drug are liquids, except that alcohol 
shall be stated in terms of percent volume of absolute alcohol at 60 
[deg]F. (15.56 [deg]C.); and percent volume in volume if the ingredient 
is a designated medical gas (as defined in Sec.  201.161(c)(1)).
* * * * *
0
10. In Sec.  201.51, revise paragraphs (a) and (b) to read as follows:

Sec.  201.51  Declaration of net quantity of contents.

    (a) The label of a prescription or insulin-containing drug in 
package form shall bear a declaration of the net quantity of contents. 
This shall be expressed in the terms of weight, measure, numerical 
count, or a combination of numerical count and weight or measure. The 
statement of quantity of drugs in tablet, capsule, ampule, or other 
unit dosage form shall be expressed in terms of numerical count; the 
statement of quantity for drugs in other dosage forms shall be in terms 
of weight if the drug is solid, semi-solid, or viscous, in terms of 
fluid measure if the drug is liquid, or in terms of volume measure if 
the drug is a designated medical gas (as defined in Sec.  
201.161(c)(1)) or a medically appropriate combination of designated 
medical gases in a gaseous state. When the drug quantity statement is 
in terms of the numerical count of the drug units, it shall be 
augmented to give the weight or measure of the drug units or the 
quantity of each active ingredient in each drug unit or, when quantity 
does not accurately reflect drug potency, a statement of the drug 
potency.
    (b) Statements of weight of the contents shall in the case of 
prescription drugs be expressed in terms of avoirdupois pound, ounce, 
and grain or of kilogram, gram, and subdivisions thereof. A statement 
of liquid measure of the contents shall in the case of prescription 
drugs other than designated medical gases and medically appropriate 
combinations thereof be expressed in terms of the U.S. gallon of 231 
cubic inches and quart, pint, fluid-ounce, and fluid-dram subdivisions 
thereof, or of the liter and milliliter, or cubic centimeter, and shall 
express the volume at 68 [deg]F. (20 [deg]C.). A statement of the 
liquid measure of the contents in the case of insulin-containing drugs 
shall be expressed in terms of the liter and milliliter, or cubic 
centimeter, and shall express the volume at 68 [deg]F. (20 [deg]C.). A 
statement of the measure of the contents shall in the case of 
designated medical gases (as defined in Sec.  201.161(c)(1)) and 
medically appropriate combinations thereof be expressed as follows:
    (1) If in a gaseous state in a high pressure container, it shall be 
expressed in liters or cubic feet based on the filled pressure at 70 
[deg]F.;
    (2) If in a liquefied compressed gas state in a high pressure 
container, it shall be expressed in gaseous liters or by an appropriate 
net weight statement;
    (3) If in a liquefied state in a portable cryogenic container, it 
shall be expressed in gaseous liters, liquid liters (if identified as a 
liquid measure), gallons, or by an appropriate net weight statement at 
the time of fill;
    (4) If in a bulk or transport container (as defined in Sec.  
201.161(c)(3)), labeling for net quantity of contents is not required;
* * * * *
0
11. In Sec.  201.105 revise the introductory text paragraph to read as 
follows:

Sec.  201.105   Veterinary drugs.

    A drug subject to the requirements of section 503(f)(1) of the act 
shall be exempt from section 502(f)(1) of the act if it is a designated 
medical gas (as defined in Sec.  201.161(c)(1)) or a medically 
appropriate combination of designated medical gases and is in 
compliance with Sec.  201.161, or if all the following conditions are 
met:
* * * * *
0
12. Revise Sec.  201.161 to read as follows:

Sec.  201.161   Medical gases.

    (a) The requirements of sections 503(b)(4) and 502(f) of the 
Federal Food, Drug, and Cosmetic Act are deemed to have been met for a 
designated medical gas or a medically appropriate combination of 
designated medical gases if the labeling on its final use container 
bears the following:
    (1) In the case of oxygen:
    (i) A warning statement providing that uninterrupted use of high 
concentrations of oxygen over a long duration, without monitoring its 
effect on oxygen content of arterial blood, may be harmful; that oxygen 
should not be used on patients who have stopped breathing unless used 
in conjunction with resuscitative equipment; and, in the case of oxygen 
that may be provided without a prescription for use in the event of 
depressurization or other environmental oxygen deficiency, or for 
oxygen deficiency or for use in emergency resuscitation when 
administered by properly trained personnel, a warning statement 
providing that oxygen may be used for emergency use only when 
administered by properly trained personnel for oxygen deficiency and 
resuscitation, and that for all other medical applications a 
prescription is required.
    (ii) A clear and prominent warning containing the statements ``No 
Smoking'' and ``No Vaping'' and a graphic symbol conveying that 
smoking, vaping, and open flames near oxygen are dangerous.
    (2) In the case of a designated medical gas other than oxygen, and 
in the case of medically appropriate combinations of any designated 
medical gases:
    (i) A warning statement providing that the administration of the 
gas or gas combination (as applicable) may be hazardous or 
contraindicated; and that the gas or gas combination (as applicable) 
should be used only by or under the supervision of a licensed 
practitioner who is experienced in the use and administration of the 
gas or gas combination (as applicable) and is familiar with the 
indications, effects, dosages, methods, and frequency and duration of 
administration, and with the hazards, contraindications, and side 
effects and the precautions to be taken.
    (ii) The symbol ``Rx only.''

[[Page 31342]]

    (3) Appropriate directions and warnings concerning storage and 
handling.
    (b) A designated medical gas or medically appropriate combination 
of designated medical gases in a bulk or transport container must be 
identified with the name of the product contained therein and 
accompanied by documentation identifying the product as meeting 
applicable compendial standards.
    (c) For purposes of this section:
    (1) A ``designated medical gas'' means a drug that:
    (i) Is manufactured or stored in a liquefied, nonliquefied, or 
cryogenic state;
    (ii) Is administered as a gas; and
    (iii) Meets the definition in section 575(1) of the Federal Food, 
Drug, and Cosmetic Act.
    (2) A ``final use container'' means a container that is for direct 
use or access by a patient or healthcare provider to administer a 
designated medical gas or medically appropriate combination of 
designated medical gases. The term ``final use container'' does not 
include bulk or transport containers and does not include containers 
that are described in Sec.  868.5655 of this chapter.
    (3) A ``bulk or transport container'' means a container used to 
transport or store designated medical gases or medically appropriate 
combinations of designated medical gases and that is not used directly 
to administer such gases to a patient.
0
13. In Sec.  201.328, revise paragraph (a)(1) introductory text and add 
paragraph (d) to read as follows.

Sec.  201.328   Labeling of medical gas containers.

    (a) * * *
    (1) Each portable cryogenic medical gas container must be 
conspicuously marked with a 360[deg] wraparound label identifying its 
contents. Such label must meet the requirements of Sec.  213.94(e)(3) 
of this chapter and the following additional requirements.
* * * * *
    (d) Notwithstanding Sec.  201.1, a container filled with a 
designated medical gas (as defined in Sec.  201.161(c)(1)) or medically 
appropriate combination of designated medical gases may bear a 
statement identifying the name of the owner of the container or the 
address to which the container should be returned after use. Such 
statement may appear on a separate sticker or decal. If the owner of 
the medical gas container is not the manufacturer, packer, or 
distributor of the designated medical gas or medically appropriate 
combination of designated medical gases, that shall be clearly stated 
on the container. The addition of such statement shall not cause the 
owner of the cylinder to be a ``relabeler'' for purposes of 
registration and listing under part 207 of this chapter.

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

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

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

0
15. In Sec.  210.1, revise paragraphs (a) and (b) to read as follows:

Sec.  210.1   Status of current good manufacturing practice 
regulations.

    (a) The regulations set forth in this part and in parts 211, 213, 
225, and 226 of this chapter contain the minimum current good 
manufacturing practice for methods to be used in, and the facilities or 
controls to be used for, the manufacture, processing, packing, or 
holding of a drug to assure that such drug meets the requirements of 
the act as to safety, and has the identity and strength and meets the 
quality and purity characteristics that it purports or is represented 
to possess.
    (b) The failure to comply with any regulation set forth in this 
part and in parts 211, 213, 225, and 226 of this chapter in the 
manufacture, processing, packing, or holding of a drug shall render 
such drug to be adulterated under section 501(a)(2)(B) of the act and 
such drug, as well as the person who is responsible for the failure to 
comply, shall be subject to regulatory action.
* * * * *
0
16. In Sec.  210.2, revise paragraphs (a) and (b) to read as follows:

Sec.  210.2   Applicability of current good manufacturing practice 
regulations.

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

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED 
PHARMACEUTICALS

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

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

0
18. In Sec.  211.1, revise paragraph (a) to read as follows:

Sec.  211.1   Scope.

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

Sec.  211.94   [Amended]

0
19. In Sec.  211.94, remove paragraph (e).
0
20. In Sec.  211.125 revise paragraph (c) to read as follows:

Sec.  211.125   Labeling issuance.

* * * * *
    (c) Procedures shall be used to reconcile the quantities of 
labeling issued, used, and returned, and shall require evaluation of 
discrepancies found between the quantity of drug product finished and 
the quantity of labeling issued when such discrepancies are outside 
narrow preset limits based on historical operating data. Such 
discrepancies shall be investigated in accordance with Sec.  211.192. 
Labeling reconciliation is waived for cut or roll labeling if a 100-
percent examination for correct labeling is performed in accordance 
with Sec.  211.122(g)(2).
* * * * *
0
21. In Sec.  211.132, revise paragraph (c)(1) introductory text to read 
as follows:

[[Page 31343]]

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

* * * * *
    (c) * * *
    (1) In order to alert consumers to the specific tamper-evident 
feature(s) used, each retail package of an OTC drug product covered by 
this section (except ammonia inhalant in crushable glass ampules or 
aerosol products that depend upon the power of a liquefied or 
compressed gas to expel the contents from the container) is required to 
bear a statement that:
* * * * *
0
22. In Sec.  211.170, revise paragraph (b) introductory text to read as 
follows:

Sec.  211.170   Reserve samples.

* * * * *
    (b) An appropriately identified reserve sample that is 
representative of each lot or batch of drug product shall be retained 
and stored under conditions consistent with product labeling. The 
reserve sample shall be stored in the same immediate container-closure 
system in which the drug product is marketed or in one that has 
essentially the same characteristics. The reserve sample consists of at 
least twice the quantity necessary to perform all the required tests, 
except those for sterility and pyrogens. Except for those for drug 
products described in paragraph (b)(2) of this section, reserve samples 
from representative sample lots or batches selected by acceptable 
statistical procedures shall be examined visually at least once a year 
for evidence of deterioration unless visual examination would affect 
the integrity of the reserve sample. Any evidence of reserve sample 
deterioration shall be investigated in accordance with Sec.  211.192. 
The results of the examination shall be recorded and maintained with 
other stability data on the drug product. The retention time is as 
follows:
* * * * *
0
23. Revise Sec.  211.196 to read as follows:

Sec.  211.196   Distribution records.

    Distribution records shall contain the name and strength of the 
product and description of the dosage form, name and address of the 
consignee, date and quantity shipped, and lot or control number of the 
drug product.
0
24. Add part 213 to subchapter C to read as follows:

PART 213--CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICAL GASES

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

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

Subpart A--General Provisions

Sec.  213.1  Scope.

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

Sec.  213.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of 
the Federal Food, Drug, and Cosmetic Act shall be applicable to such 
terms when used in this part.
    (b) The following definitions of terms apply to this part:
    (1) Acceptance criteria means the product specifications and 
acceptance/rejection criteria, such as acceptable quality level and 
unacceptable quality level, with an associated sampling plan, that are 
necessary for making a decision to accept or reject a lot or batch (or 
any other convenient subgroups of manufactured units).
    (2) Batch means a specific quantity of a medical gas or other 
material that is intended to have uniform character and quality, within 
specified limits, and is produced according to a single manufacturing 
order during the same cycle of manufacture.
    (3) Commingling or commingled refers to the act of combining one 
lot of designated medical gas or component with another lot or lots of 
the same designated medical gas or component.
    (4) Component means any ingredient intended for use in the 
manufacture of a medical gas, including those that may not appear in 
such gas. It does not include an incoming designated medical gas.
    (5) Designated medical gas means a drug that is manufactured or 
stored in a liquefied, nonliquefied, or cryogenic state; is 
administered as a gas; and is defined in section 575(1) of the Federal 
Food, Drug, and Cosmetic Act.
    (6) FDA means the Food and Drug Administration.
    (7) In-process material means any material fabricated, compounded, 
blended, or derived by chemical reaction that is produced for, and used 
in, the preparation of the medical gas.

[[Page 31344]]

    (8) Incoming designated medical gas means 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.
    (9) Lot means a batch, or a specific identified portion of a batch, 
having uniform character and quality within specified limits; or, in 
the case of a medical gas produced by continuous process, it is a 
specific identified amount produced in a unit of time or quantity in a 
manner that assures its having uniform character and quality within 
specified limits.
    (10) Lot number, control number, or batch number means any 
distinctive combination of letters, numbers, or symbols, or any 
combination of them, from which the complete history of the 
manufacture, processing, packing, holding, and distribution of a batch 
or lot of medical gas, or other material can be determined.
    (11) Manufacture, processing, packing, or holding of medical gases 
includes packaging and labeling operations, testing, and quality 
control.
    (12) Medical gas has the meaning given the term in section 575(2) 
of the Federal Food, Drug, and Cosmetic Act.
    (13) Original manufacturer means the person or entity that 
initially produces a designated medical gas by chemical reaction, 
physical separation, compression of atmospheric air, purification 
(e.g., re-processing an industrial gas into a medical gas), or other 
means.
    (14) Quality unit means any person or persons designated with the 
authority and responsibility for overall quality management and other 
responsibilities as defined in Sec.  213.22.
    (15) Strength means:
    (i) The concentration of the medical gas (for example, weight/
weight, weight/volume, or unit dose/volume basis), and/or
    (ii) The potency, that is, the therapeutic activity of the medical 
gas as indicated by appropriate laboratory tests or by adequately 
developed and controlled clinical data (expressed, for example, in 
terms of units by reference to a standard).

Subpart B--Organization and Personnel

Sec.  213.22   Responsibilities of quality unit.

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

Sec.  213.25   Personnel qualifications and responsibilities.

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

Sec.  213.34   Consultants.

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

Subpart C--Buildings and Facilities

Sec.  213.42   Design and construction features.

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

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    (vi) Packaging and labeling operations;
    (vii) Quarantine storage before release of medical gases;
    (viii) Storage of medical gases after release; and
    (ix) Control and laboratory operations.
    (2) The flow of components, incoming designated medical gases, 
medical gas containers and closures, labeling, in-process materials, 
and medical gases through the buildings and facilities shall be 
designed to prevent contamination and mix-ups.
    (c) Any building or facility used in the manufacture, processing, 
packing, or holding of a medical gas shall be maintained in a clean 
condition so as to assure the safety, identity, strength, quality, and 
purity of the medical gas. Written procedures applicable to the 
maintenance and cleaning of buildings and facilities shall be 
established and followed.

Subpart D--Equipment

Sec.  213.63   Equipment design, size, and location.

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

Sec.  213.65   Equipment construction.

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

Sec.  213.67   Equipment maintenance and cleaning.

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

Sec.  213.68   Automatic, mechanical, and electronic equipment.

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

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

Sec.  213.80   General requirements.

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

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

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

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

    (a) Components, containers, and closures (including valves) shall 
be examined for conformance with appropriate written procedures and 
specifications, and approved or rejected, prior to the manufacturing or 
filling process. In lieu of such examination by the firm, a statement 
of verification that the component, container, or closure meets 
specifications may be accepted from the supplier, provided that the 
firm establishes and maintains a program to ensure the reliability of 
the supplier's capabilities through appropriate assessment and testing 
provisions. Any rejected items shall be handled in accordance with 
Sec.  213.89.

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    (b) Firms shall take appropriate actions to protect against 
container and closure leaks, which shall include performing leak tests 
on containers and closures at the time of fill and after fill but prior 
to release.
    (c) Each component shall be sampled, tested, and approved or 
rejected as appropriate prior to use. This requirement can be met by 
performing testing for conformance with written specifications or by an 
identity test on the component accompanied by an acceptable certificate 
of analysis from the supplier, provided that the firm establishes and 
maintains a program to ensure the reliability of the supplier's 
capabilities through appropriate assessment and testing procedures.

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

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

Sec.  213.94   Medical gas containers and closures.

    (a) Medical gas containers and closures shall not be reactive, 
additive, or absorptive so as to alter the safety, identity, strength, 
quality, or purity of the gas beyond the official or established 
requirements.
    (b) Container closure systems shall provide adequate protection 
against foreseeable external factors in storage and use that can cause 
deterioration or contamination of the medical gas.
    (c) Medical gas containers and closures shall be clean to assure 
that they are suitable for their intended use.
    (d) Standards or specifications, methods of testing, and, where 
indicated, methods of cleaning shall be written and followed for 
medical gas containers and closures.
    (e) Medical gas containers and closures must meet the following 
requirements--
    (1) Gas-specific use outlet connections. Portable cryogenic medical 
gas containers that are not manufactured with permanent gas use outlet 
connections (e.g., those that have been silver-brazed) must have gas-
specific use outlet connections that are attached to the valve body so 
that they cannot be readily removed or replaced (without making the 
valve inoperable and preventing the containers' use) except by the 
manufacturer. For the purposes of this paragraph, the term 
``manufacturer'' includes any individual or firm that fills high-
pressure medical gas cylinders or cryogenic medical gas containers. For 
the purposes of this section, a ``portable cryogenic medical gas 
container'' is one that is capable of being transported and is intended 
to be attached to a medical gas supply system within a hospital, 
healthcare entity, nursing home, other facility, or home healthcare 
setting, or is a base unit used to fill small cryogenic gas containers 
for use by individual patients. The term does not include cryogenic 
containers that are not designed to be connected to a medical gas 
supply system, e.g., tank trucks, trailers, rail cars, or small 
cryogenic gas containers for use by individual patients (including 
portable liquid oxygen units as defined at Sec.  868.5655 of this 
chapter).
    (2) Gauges for certain medical gas containers. Portable cryogenic 
medical gas containers as described in paragraph (e)(1) of this section 
and small cryogenic gas containers for use by individual patients 
(including portable liquid oxygen units as defined at Sec.  868.5655 of 
this chapter) must have a working gauge sufficient to indicate whether 
the container contains an adequate supply of medical gas for continued 
use.
    (3) Label and coloring requirements. The labeling specified at 
Sec.  201.328(a) of this chapter must be affixed to the container in a 
manner that does not interfere with other labeling. Each such label as 
well as materials used for coloring medical gas containers must be 
reasonably resistant to fading, durable when exposed to atmospheric 
conditions, and not readily soluble in water.

Subpart F--Production and Process Controls

Sec.  213.100   Written procedures; deviations.

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

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

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

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

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

Subpart G--Packaging and Labeling Control

Sec.  213.122   Materials examination and usage criteria.

    (a) There shall be written procedures describing in sufficient 
detail the receipt, identification, storage, handling, sampling, 
examination, and/or testing of labeling and packaging materials; such

[[Page 31347]]

written procedures shall be followed. Labeling and packaging materials 
shall be representatively sampled, and examined or tested upon receipt 
and before use in packaging or labeling of a medical gas.
    (b) Any labeling or packaging materials meeting appropriate written 
specifications may be approved and released for use. Any labeling or 
packaging materials that do not meet such specifications shall be 
rejected to prevent their use in operations for which they are 
unsuitable.
    (c) Records shall be maintained for each shipment received of each 
different labeling and packaging material indicating receipt, 
examination, and whether accepted or rejected.
    (d) Labels and other labeling materials for each different medical 
gas, strength, or quantity of contents, shall be stored with suitable 
identification to avoid mix-ups. Access to the label storage area shall 
be limited to authorized personnel.
    (e) Labels, labeling, and other packaging materials that are 
obsolete, outdated, or that do not meet applicable requirements shall 
be destroyed.
    (f) Packaging and labeling operations shall include one of the 
following special control procedures:
    (1) Dedication of labeling and packaging lines to each different 
strength of each different medical gas;
    (2) Use of appropriate electronic or electromechanical equipment to 
conduct a 100-percent examination for correct labeling during or after 
completion of finishing operations; or
    (3) Use of visual inspection to conduct a 100-percent examination 
for correct labeling during or after completion of labeling operations 
for hand-applied labeling. Such examination shall be performed by one 
person and independently verified by a second person.
    (g) Printing devices on, or associated with, manufacturing lines 
used to imprint labeling upon the unit label or case shall be monitored 
to assure that all imprinting conforms to the print specified in the 
batch production record.
    (h) Labels may be reused if they are legible, properly affixed to 
the container, and otherwise meet all applicable requirements.

Sec.  213.125   Labeling issuance.

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

Sec.  213.130   Packaging and labeling operations.

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

Subpart H--Holding and Distribution

Sec.  213.150   Warehousing and distribution procedures.

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

Subpart I--Laboratory Controls

Sec.  213.160   General requirements.

    (a) The establishment of any specifications, standards, sampling 
plans, test procedures, or other laboratory control mechanisms required 
by this subpart, including any change in such specifications, 
standards, sampling plans, test procedures, or other laboratory control 
mechanisms, shall be drafted by the appropriate organizational unit and 
reviewed and approved by the quality unit. The requirements in this 
subpart shall be followed and shall be documented at the time of 
performance. Any deviation from the written specifications, standards, 
sampling plans, test procedures, or other laboratory control mechanisms 
shall be recorded and justified.
    (b) Laboratory controls shall include the establishment of 
scientifically sound and appropriate specifications, standards, 
sampling plans, and test procedures designed to assure that components, 
medical gas containers and closures, in-process materials, labeling, 
and medical gases conform to appropriate standards of identity, 
strength, quality, and purity. Laboratory controls shall include:
    (1) Determination of conformity to applicable written 
specifications for the acceptance of each lot within each shipment of 
components, medical gas containers and closures, and labeling used in 
the manufacture, processing,

[[Page 31348]]

packing, or holding of a medical gas. The specifications shall include 
a description of the sampling and testing procedures used. Samples 
shall be representative and adequately identified. Such procedures 
shall also require appropriate retesting of any component, container, 
or closure that is subject to deterioration.
    (2) Determination of conformance to written specifications and a 
description of sampling and testing procedures for in-process 
materials. Such samples shall be representative and properly 
identified.
    (3) Determination of conformance to written descriptions of 
sampling procedures and appropriate specifications for medical gases. 
Such samples shall be representative and properly identified.
    (4) The calibration or verification of calibration for instruments, 
apparatus, gauges, and recording devices at suitable intervals in 
accordance with an established written program containing specific 
directions, schedules, limits for accuracy and precision, and 
provisions for remedial action in the event accuracy and/or precision 
limits are not met. Instruments, apparatus, gauges, and recording 
devices not meeting established specifications shall not be used.

Sec.  213.165   Testing and release for distribution.

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

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

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

Subpart J--Records

Sec.  213.180   General requirements.

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

Sec.  213.182   Equipment cleaning and use log.

    A written record of major equipment cleaning, maintenance (except 
routine maintenance such as lubrication and adjustments), and use shall 
be included in individual equipment logs that show the date, time, 
product, and lot number of each batch processed. If equipment is 
dedicated to manufacture of one product, then individual equipment logs 
are not required, provided that lots or batches of such product follow 
in numerical order and are manufactured in numerical sequence. In cases 
where dedicated equipment is employed, the records of cleaning, 
maintenance, and use shall be part of the batch record. The persons 
performing and double-checking the cleaning and maintenance (or, if the 
cleaning and maintenance is performed using automated equipment under 
Sec.  213.68, just the person verifying the cleaning and maintenance 
done by the automated equipment) shall date and sign or initial the log 
indicating that the work was performed. Entries in the log shall be in 
chronological order.

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

    These records shall include the following:
    (a) The results of any test or examination performed (including 
those performed as required by Sec.  213.84 or Sec.  213.122) and the 
conclusions derived therefrom.

[[Page 31349]]

    (b) Documentation of the examination and review of labels and 
labeling for conformity with established specifications in accordance 
with Sec. Sec.  213.122 and 213.130.
    (c) The disposition of rejected components, medical gas containers 
and closures, and labeling.

Sec.  213.186   Master production and control records.

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

Sec.  213.189   Batch production and control records.

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

Sec.  213.192   Production record review.

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

Sec.  213.194   Laboratory records.

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

Sec.  213.196   Distribution records.

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

Sec.  213.198   Complaint files.

    (a) Written procedures shall be established and followed for the 
receipt and handling of all written or oral complaints concerning a 
medical gas. These procedures must include quality unit review of any 
complaint involving the possible failure of a medical gas to meet any 
of its specifications and an investigation to determine the cause of 
the failure. Such procedures shall include provisions for determining 
the need for an investigation in accordance with Sec.  213.192 as well 
as determining whether the complaint represents an event that is 
required to be reported to FDA under part 230 of this chapter.
    (b) A written record of each complaint regarding a medical gas must 
be maintained. The record must include the name of the gas, the lot or 
batch number, the name of the complainant, the date the complaint was 
received, the nature of the complaint, and the response to the 
complaint. It must also include the findings of any investigation and 
followup. Where an investigation is not conducted, the written record 
shall include the reason that an investigation

[[Page 31350]]

was found not to be necessary and the name of the responsible person 
making such a determination.
    (c) Complaint files shall be maintained in a manner such that they 
are readily available for inspection by the firm or by FDA during an 
inspection. Complaint files shall be maintained for at least 1 year 
after the date the complaint was received or for at least 3 years after 
distribution of the medical gas, whichever is longer.

Subpart K--Returned and Salvaged Medical Gases

Sec.  213.204   Returned medical gases.

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

Sec.  213.208   Salvaging of medical gases.

    Medical gases in containers that have been subjected to improper 
storage conditions may be salvaged unless their containers have been 
subjected to adverse conditions that impact the identity, strength, 
quality, and purity of the product or integrity of the container 
closure. Whenever there is a question whether medical gases have been 
subjected to such conditions, salvaging operations may be conducted 
only if there is evidence from laboratory tests that such gases meet 
all applicable standards of identity, strength, quality, and purity, 
and the integrity of the container closure system is not compromised. 
Procedures for the holding, testing, and use of salvaged medical gases 
shall be in writing and shall be followed.
0
25. Add part 230 to subchapter C to read as follows:

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

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

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

Subpart A--General Provisions

Sec.  230.1   Scope of this part.

    (a) This part sets forth procedures and requirements for the 
submission to, and the review by, the Food and Drug Administration of 
certifications to market designated medical gases under sections 575 
and 576 of the Federal Food, Drug, and Cosmetic Act, as well as 
amendments and supplements to those certifications. This part also sets 
forth the postmarketing safety reporting requirements for designated 
medical gases.
    (b) References in this part to regulations in the Code of Federal 
Regulations are to chapter I of title 21, unless otherwise noted.

Sec.  230.2   Purpose.

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

Sec.  230.3   Definitions.

    (a) The definitions and interpretations contained in sections 201 
and 575 of the Federal Food, Drug, and Cosmetic Act apply to those 
terms when used in this part of this chapter.
    (b) The following definitions of terms apply to this part:
    (1) Adverse event means any untoward medical occurrence associated 
with the use of a designated medical gas in humans or animals, whether 
or not it is considered related to the designated medical gas. An 
adverse event can occur in the course of the use of a designated 
medical gas; from overdose of a designated medical gas, whether 
accidental or intentional; from abuse of a designated medical gas; from 
discontinuation of the designated medical gas (e.g., physiological 
withdrawal); and it includes any failure of expected pharmacological 
action.
    (2) Applicant means any person or entity who submits a 
certification request for a designated medical gas under this part, 
including a supplement, and any person or entity who owns a granted 
certification for a designated medical gas under this part.
    (3) Certification request means a submission under section 576 of 
the Federal Food, Drug, and Cosmetic Act requesting certification of a 
medical gas as a designated medical gas.
    (4) FDA or Agency means the Food and Drug Administration.
    (5) Individual case safety report (ICSR) means a description of an 
adverse event related to an individual patient or subject.
    (6) ICSR attachments means documents related to the adverse event 
described in an ICSR, such as medical records, hospital discharge 
summaries, or other documentation.
    (7) Life-threatening adverse event means any adverse event that 
places the patient, in the view of the initial reporter, at immediate 
risk of death from the adverse event as it occurred, i.e., it does not 
include an adverse event that, had it occurred in a more severe form, 
might have caused death.
    (8) Minimum data set for an ICSR for an adverse event means the 
minimum four elements required for reporting an ICSR of an adverse 
event: An identifiable patient, an identifiable reporter, a suspect 
designated medical gas, and an adverse event.
    (9) Nonapplicant means any person other than the applicant whose 
name appears on the label of a designated

[[Page 31351]]

medical gas container as a manufacturer, packer, or distributor.
    (10) Serious adverse event means:
    (i) An adverse event is considered ``serious'' if it results in any 
of the following outcomes:
    (A) Death;
    (B) A life-threatening adverse event;
    (C) Inpatient hospitalization or prolongation of existing 
hospitalization;
    (D) A persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; and/or
    (E) A congenital anomaly/birth defect.
    (ii) Other events that may be considered serious adverse events: 
Important medical events that may not result in one of the listed 
outcomes in this definition may be considered serious adverse events 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or study subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Examples include: Allergic bronchospasm requiring intensive treatment 
in an emergency department or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of 
product dependency or product abuse. Additional examples in animals 
include: Severe hypersensitivity reactions or respiratory distress.

Subpart B--Certification of Designated Medical Gases

Sec.  230.50   General requirements for all submission types.

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

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

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

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

    (a) The applicant must submit a supplement if any information in 
the certification request changes after the

[[Page 31352]]

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

Sec.  230.72   Change in ownership of a granted certification.

    An applicant may transfer ownership of its certification. At the 
time of transfer the new and former owners are required to submit 
information to FDA as follows:
    (a) The former owner must submit a letter or other document that 
states that all rights to the certification have been transferred to 
the new owner.
    (b) The new owner must submit a supplement under Sec.  230.70 
signed by the new owner describing any changes in the conditions in the 
granted certification and a letter or other document containing the 
date that the change in ownership is effective.

Sec.  230.80   Annual report.

    (a) The applicant must submit each year within 60 calendar days of 
the anniversary of the date the certification was deemed granted, an 
annual report containing the information described in paragraph (b) of 
this section. The applicant must submit a signed, completed annual 
report form either in an electronic format that FDA can process, 
review, and archive, or in hard copy by submitting two paper copies to 
the Central Document Room, Center for Drug Evaluation and Research, 
Food and Drug Administration, 5901-B Ammendale Road, Beltsville, MD 
20705.
    (b) The report must contain, for the prior 12 months, the following 
information in the order listed:
    (1) Summary. A brief summary of significant new information that 
might affect the safety, effectiveness, or labeling of the designated 
medical gas, including any actions the applicant has taken or intends 
to take as a result of this new information.
    (2) Distribution data. Information about the quantity of the 
designated medical gas distributed by the applicant. The information 
must include the National Drug Code (NDC) numbers and the quantities 
distributed for domestic use and the quantities distributed for foreign 
use. Disclosure of financial or pricing data is not required.
    (3) Administrative changes. Any changes to the applicant's name or 
contact information.
    (4) Current facilities. A list of current facilities, and a list of 
facilities that are no longer in use.

Sec.  230.100   FDA review of submissions.

    (a) In reviewing a submission pursuant to Sec.  230.50, FDA will 
consider information provided with the submission along with any other 
available, relevant information of which FDA becomes aware, including 
information obtained from State or Federal officials, FDA inspection 
reports, or any other source.
    (b) FDA will deny a submission if FDA finds that:
    (1) The medical gas that is the subject of the submission is not a 
designated medical gas;
    (2) The submission does not contain the required information or 
otherwise appears to lack sufficient information to determine that the 
medical gas is a designated medical gas;
    (3) The applicant's methods, facilities, and controls used for the 
manufacture, processing, and handling of the designated medical gas, as 
applicable, are not adequate to ensure its safety, identity, strength, 
quality, and purity; or
    (4) Denying the request is otherwise necessary to protect the 
public health.
    (c) Within 60 calendar days of filing of a submission, FDA may 
contact the applicant to request additional information regarding the 
submission if it determines that required information is not included 
in the submission, that FDA needs such information to determine whether 
the medical gas is a designated medical gas, or that FDA determines 
such information is necessary to protect the public health. Upon 
receipt of an amendment to a pending certification request, this 60-day 
review period will restart. If FDA is not able to contact the applicant 
to obtain and evaluate the information within the 60-day review period, 
FDA may find that the submission lacks sufficient information to permit 
a determination that the medical gas is a designated medical gas and 
deny the submission. If FDA is able to contact the applicant but is not 
provided with the additional information requested within the 60-day 
review period, FDA may find that the request lacks sufficient 
information to permit a determination that the medical gas is a 
designated medical gas and deny the submission.
    (d) Within 60 calendar days of filing of a submission, if FDA makes 
one of the findings described in Sec.  230.100(b), FDA will notify the 
applicant in writing that the submission is denied and provide the 
basis for FDA's determination.

Sec.  230.105   When a submission is deemed granted.

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

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

    (a) Withdrawal.
    (1) FDA will notify the applicant, and afford an opportunity for a 
hearing on a proposal to withdraw approval of the application under the 
procedure in Sec. Sec.  314.200, 514.200, or both, as applicable, if 
any of the following apply:
    (i) The Secretary of Health and Human Services has suspended the 
approval of the application for a designated medical gas on a finding 
that there is an imminent hazard to the public health. FDA will 
promptly afford the applicant an expedited hearing following summary 
suspension on a finding of imminent hazard to health.
    (ii) FDA finds:
    (A) That clinical or other experience, tests, or other scientific 
data show that the designated medical gas is unsafe for use under the 
conditions of use upon the basis of which the application was approved; 
or
    (B) That new evidence of clinical experience not available to FDA 
until after the application was approved, or tests by new methods, or 
tests by methods not deemed reasonably applicable when the application 
was approved, evaluated together with the evidence available when the 
application was approved, reveal that the designated medical gas is not 
shown to be safe for use under the conditions of use upon the basis of 
which the application was approved; or
    (C) Upon the basis of new information before FDA with respect to 
the designated medical gas, evaluated together with the evidence 
available when the application was approved, that there is a lack of 
substantial evidence from adequate and well-controlled investigations 
as defined in Sec.  314.126 of this chapter, that the designated 
medical gas will have the effect it is purported or represented to

[[Page 31353]]

have under the conditions of use prescribed, recommended, or suggested 
in its labeling; or
    (D) That the application contains any untrue statement of a 
material fact.
    (2) FDA may notify the applicant, and afford an opportunity for a 
hearing on a proposal to withdraw approval of the application under the 
procedure in Sec. Sec.  314.200, 514.200, or both, as applicable, if 
the Agency finds:
    (i) That the applicant has failed to establish a system for 
maintaining required records, or has repeatedly or deliberately failed 
to maintain required records or to make required reports applicable to 
designated medical gases, including under sections 505(k) and 512(l) of 
the Federal Food, Drug, and Cosmetic Act and this part and part 213 of 
this chapter, or that the applicant has refused to permit access to, or 
copying or verification of, its records.
    (ii) That on the basis of new information before FDA, evaluated 
together with the evidence available when the application was approved, 
the methods used in, or the facilities and controls used for, the 
manufacture, processing, and packing of the designated medical gas are 
inadequate to ensure and preserve its identity, strength, quality, and 
purity and were not made adequate within a reasonable time after 
receipt of written notice from the Agency.
    (iii) That on the basis of new information before FDA, evaluated 
together with the evidence available when the application was approved, 
the labeling of the designated medical gas, based on a fair evaluation 
of all material facts, is false or misleading in any particular, and 
the labeling was not corrected by the applicant within a reasonable 
time after receipt of written notice from the Agency.
    (iv) That the applicant has failed to comply with the notice 
requirements of section 510(j)(2) of the Federal Food, Drug, and 
Cosmetic Act.
    (3) FDA will withdraw approval of an application if the applicant 
requests its withdrawal because the designated medical gas subject to 
the application is no longer being marketed, provided none of the 
conditions listed in paragraphs (a)(1) and (2) of this section applies 
to the designated medical gas. FDA will consider a written request for 
a withdrawal under this clause to be a waiver of an opportunity for 
hearing otherwise provided for in this section. Withdrawal of approval 
of an application under this clause is without prejudice to refiling.
    (4) FDA may notify an applicant that it believes a potential 
problem associated with a designated medical gas is sufficiently 
serious that the designated medical gas should be removed from the 
market and may ask the applicant to waive the opportunity for hearing 
otherwise provided for under this section, to permit FDA to withdraw 
approval of the application for the product, and to remove voluntarily 
the product from the market. If the applicant agrees, the Agency will 
not make a finding under paragraph (a) of this section, but will 
withdraw approval of the application in a notice published in the 
Federal Register that contains a brief summary of the Agency's and the 
applicant's views of the reasons for withdrawal.
    (5) If FDA withdraws an approval, FDA will publish a notice in the 
Federal Register announcing the withdrawal of approval.
    (b) Revocation. FDA may revoke the grant of a certification if FDA 
determines, after providing the applicant with notice and opportunity 
for an informal hearing in accordance with part 16 of this chapter, 
that the request for certification contains any material omission or 
falsification.

Subpart C--Postmarketing Quality and Safety Reporting

Sec.  230.205   Field alert reports.

    The applicant shall submit all information described in paragraphs 
(a) and (b) of this section about distributed designated medical gases 
and articles to the FDA district office that is responsible for the 
facility involved within 3 working days of receipt by the applicant. 
The information may be provided by telephone or other rapid 
communication means, with prompt written followup. The report and its 
mailing cover should be plainly marked: ``Designated Medical Gas--Field 
Alert Report.''
    (a) Information concerning any incident that causes the designated 
medical gas or its labeling to be mistaken for, or applied to, another 
article.
    (b) Information concerning any bacteriological contamination, or 
any significant chemical, physical, or other change or deterioration in 
the distributed designated medical gas, or any failure of one or more 
distributed batches of the designated medical gas to meet established 
specifications.

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

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

Sec.  230.220   Human designated medical gas ICSR requirements.

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

[[Page 31354]]

scientific and medical journals either as case reports or as the result 
of a formal clinical trial.
    (iii) Exception to reporting requirements for serious adverse 
events. Notwithstanding paragraph (b)(1)(i) and (ii) of this section, 
ICSRs are not required for reports of the death of a patient who was 
administered oxygen, unless the applicant or nonapplicant is aware of 
evidence to suggest that the death was caused by the administration of 
oxygen.
    (2) Other adverse event reports to be submitted upon notification 
by FDA. Upon notification by FDA, applicants and nonapplicants must 
submit, in a timeframe established by FDA, ICSRs for any adverse event 
that are not required under paragraph (b)(1) of this section. The 
notification will specify the adverse events to be reported and the 
reason for requiring the reports.
    (c) Completing and submitting ICSRs. This paragraph describes how 
to complete and submit ICSRs required under this section.
    (1) Electronic format for submissions.
    (i) ICSRs and ICSR attachments must be in an electronic format that 
FDA can process, review, and archive, as described in Sec.  
314.80(g)(1) of this chapter.
    (ii) An applicant or nonapplicant may request, in writing, a 
temporary waiver of the requirements in paragraph (c)(1)(i) of this 
section, as described in Sec.  314.80(g)(2). These waivers will be 
granted on a limited basis for good cause shown.
    (2) Submitting ICSRs.
    (i) Single submission of each ICSR. Submit each ICSR only once.
    (ii) Separate ICSR for each patient. The applicant or nonapplicant 
must submit a separate ICSR for each patient who experiences an adverse 
event reportable under paragraph (b) of this section.
    (iii) Coding terms. The adverse event terms described in the ICSR 
must be coded using standardized medical terminology.
    (iv) Minimum data set. All ICSRs submitted under this section must 
contain at least the minimum data set for an ICSR for an adverse event. 
The applicant or nonapplicant must actively seek the minimum data set 
in a manner consistent with the written procedures under paragraph (f) 
of this section. Applicants and nonapplicants must document and 
maintain records of their efforts to obtain the minimum data set.
    (v) ICSR elements. The applicant or nonapplicant must complete all 
known, available elements of an ICSR as specified in paragraph (d) of 
this section.
    (A) For adverse events, applicants and nonapplicants must actively 
seek any information needed to complete all applicable elements, 
consistent with their written procedures under paragraph (f) of this 
section.
    (B) Applicants and nonapplicants must document and maintain records 
of their efforts to obtain the missing information.
    (vi) Supporting documentation. An applicant or nonapplicant must 
submit the following types of supporting documentation in an ICSR, if 
available:
    (A) A copy of the autopsy report if the patient died, or a copy of 
the hospital discharge summary if the patient was hospitalized. The 
applicant or nonapplicant must submit each document as an ICSR 
attachment. The ICSR attachment must be submitted either with the 
initial ICSR or no later than 15 calendar days after obtaining the 
document. English translations of foreign language documents must be 
provided.
    (B) A copy of the published article as an ICSR attachment for each 
ICSR of an adverse event obtained from the published scientific and 
medical literature. Foreign language articles must be accompanied by an 
English translation of the abstract. When submitting more than one ICSR 
from the same published article, the applicant or nonapplicant must 
submit only one copy of the article with one of the ICSRs. For the 
remaining ICSRs not accompanied by a copy of the published article, the 
applicant or nonapplicant must include the cross-reference to the 
specific ICSR to which the article is attached.
    (d) Information reported on ICSRs. ICSRs must include the following 
information, subject to paragraph (c)(2)(v) of this section:
    (1) Patient information, which includes:
    (i) Patient identification code;
    (ii) Patient age at the time of adverse event, or date of birth;
    (iii) Patient gender; and
    (iv) Patient weight.
    (2) Adverse event, which includes:
    (i) Outcome attributed to adverse event;
    (ii) Date of adverse event;
    (iii) Date of ICSR submission;
    (iv) Description of adverse event;
    (v) Adverse event term(s);
    (vi) Description of relevant tests conducted, including dates and 
laboratory data; and
    (vii) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect designated medical gas(es), which includes:
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the adverse event abated after the use of the 
designated medical gas(es) stopped or the dose was reduced;
    (vi) Whether the adverse event reappeared after reintroduction of 
the designated medical gas(es);
    (vii) Lot number;
    (viii) National Drug Code (NDC) number; and
    (ix) Concomitant medical products and therapy dates.
    (4) Initial reporter information, which includes:
    (i) Name, address, email address, and telephone number;
    (ii) Whether the initial reporter is a healthcare professional; and
    (iii) Occupation, if a healthcare professional.
    (5) Applicant or nonapplicant information, which includes:
    (i) Applicant or nonapplicant name, address, email address, and 
telephone number;
    (ii) Report source, such as spontaneous, literature, or study;
    (iii) Date the report was received by applicant or nonapplicant;
    (iv) New drug application and/or new animal drug application 
number;
    (v) Whether the ICSR is an expedited report;
    (vi) Whether the ICSR is an initial report or followup report; and
    (vii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (e) Recordkeeping.
    (1) For a period of 10 years from the initial receipt of 
information, each applicant or nonapplicant must maintain records of 
information relating to adverse events under this section, whether or 
not submitted to FDA.
    (2) These records must include raw data, correspondence, and any 
other information relating to the evaluation and reporting of adverse 
event information that is received or otherwise obtained by the 
applicant or nonapplicant.
    (3) Upon written notice by FDA, the applicant or nonapplicant must 
submit any or all of these records to FDA within 5 calendar days after 
receipt of the notice. The applicant or nonapplicant must permit any 
authorized FDA employee, at reasonable times, to access, copy, and 
verify these established and maintained records described in this 
section.
    (f) Written procedures. The applicant or nonapplicant must develop 
written

[[Page 31355]]

procedures needed to fulfill the requirements in this section for the 
surveillance, receipt, evaluation, and reporting to FDA of adverse 
event information, including procedures for employee training and for 
obtaining and processing adverse event information from other 
applicants and nonapplicants.
    (g) Patient privacy. An applicant or nonapplicant should not 
include in reports under this section the names and addresses of 
individual patients; instead, the applicant or nonapplicant should 
assign a unique code for identification of the patient. The applicant 
or nonapplicant should include the name of the reporter from whom the 
information was received as part of the initial reporter information, 
even when the reporter is the patient. As set forth in FDA's public 
information regulations in part 20 of this chapter, FDA generally may 
not disclose the names of patients, individual reporters, healthcare 
professionals, hospitals, and geographical identifiers submitted to FDA 
in adverse event reports.

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

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

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

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

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

0
27. In Sec.  314.1, redesignate paragraph (c) as paragraph (d) and add 
new paragraph (c) to read as follows:

Sec.  314.1  Scope of this part.

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

PART 514--NEW ANIMAL DRUG APPLICATIONS

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

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

0
29. In Sec.  514.1, add an eighth sentence to the end of paragraph (a) 
to read as follows:

Sec.  514.1  Applications.

    (a) * * * The following provisions do not apply to designated 
medical gases, which are subject to the certification requirements 
under part 230 of this

[[Page 31356]]

chapter: Sec. Sec.  514.1(b) through 514.8, 514.12, and 514.15; and 
Subpart B.
* * * * *
0
30. Amend Sec.  514.80 by:
0
a. In the intro text table adding a new entry after the sixth row.
0
b. Adding a new paragraph (a)(6).
    The additions read as follows.

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

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

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

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

    Dated: May 9, 2022.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2022-10458 Filed 5-20-22; 8:45 am]
BILLING CODE 4164-01-P