Federal Register, Volume 87 Issue 99 (Monday, May 23, 2022)

[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

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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

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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

------------------------------------------------------------------------
Abbreviation/acronym What it means
------------------------------------------------------------------------
API.......................... Active Pharmaceutical Ingredient.
CDER......................... Center for Drug Evaluation and Research.
CFR.......................... Code of Federal Regulations.
CGMP......................... Current Good Manufacturing Practice.
COA.......................... Certificate of Analysis.
CVM.......................... Center for Veterinary Medicine.
FAR.......................... Field Alert Report.
FD&C Act..................... Federal Food, Drug, and Cosmetic Act.
FDA or Agency................ Food and Drug Administration.
FDASIA....................... Food and Drug Administration Safety and
Innovation Act.
FR........................... Federal Register.
ICSR......................... Individual Case Safety Report.
NDA.......................... New Drug Application.
NADA......................... New Animal Drug Application.
NF........................... National Formulary.
OMB.......................... Office of Management and Budget.
PRIA......................... Preliminary Regulatory Impact Analysis.
USP.......................... United States Pharmacopeia.
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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;

[[Page 31345]]

(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.

[[Page 31346]]

(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