31302 Federal Register / Vol. 87, No. 99 / Monday, May 23, 2022 / Proposed Rules 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 4, 16, 201, 210, 211, 213, 

230, 314, and 514 

[Docket No. FDA–2021–N–1333] 

RIN 0910–AH96 

Current Good Manufacturing Practice, 

Certification, Postmarketing Safety 

Reporting, and Labeling Requirements 

for Certain Medical Gases 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is proposing new regulations that 

would amend the requirements 

concerning current good manufacturing 

practice (CGMP) and postmarketing 

safety reporting that apply to certain 

medical gases. FDA further proposes to 

establish regulations regarding 

certification of designated medical gases 

and amend the labeling regulations that 

apply to certain medical gases. This 

action, if finalized, will clarify the 

regulatory obligations of entities that 

manufacture, process, pack, label, or 

distribute certain medical gases, as well 

as reduce regulatory burden in this area. 

This proposed rule is intended to 

establish requirements that are more 

specifically tailored to the medical gas 

industry. 

DATES: Submit either electronic or 

written comments on the proposed rule 

by August 22, 2022. Submit written 

comments (including recommendations) 

on the collection of information under 

the Paperwork Reduction Act of 1995 by 

July 22, 2022. 

ADDRESSES: You may submit comments 

as follows. Please note that late, 

untimely filed comments will not be 

considered. Electronic comments must 

be submitted on or before August 22, 

2022. The https://www.regulations.gov 

electronic filing system will accept 

comments until 11:59 p.m. Eastern Time 

at the end of August 22, 2022. 

Comments received by mail/hand 

delivery/courier (for written/paper 

submissions) will be considered timely 

if they are postmarked or the delivery 

service acceptance receipt is on or 

before that date. 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Comments submitted electronically, 

including attachments, to https://

www.regulations.gov will be posted to 

the docket unchanged. Because your 

comment will be made public, you are 

solely responsible for ensuring that your 

comment does not include any 

confidential information that you or a 

third party may not wish to be posted, 

such as medical information, your or 

anyone else’s Social Security number, or 

confidential business information, such 

as a manufacturing process. Please note 

that if you include your name, contact 

information, or other information that 

identifies you in the body of your 

comments, that information will be 

posted on https://www.regulations.gov. 

• If you want to submit a comment 

with confidential information that you 

do not wish to be made available to the 

public, submit the comment as a 

written/paper submission and in the 

manner detailed (see ‘‘Written/Paper 

Submissions’’ and ‘‘Instructions’’). 

Written/Paper Submissions 

Submit written/paper submissions as 

follows: 

• Mail/Hand delivery/Courier (for 

written/paper submissions): Dockets 

Management Staff (HFA–305), Food and 

Drug Administration, 5630 Fishers 

Lane, Rm. 1061, Rockville, MD 20852. 

• For written/paper comments 

submitted to the Dockets Management 

Staff, FDA will post your comment, as 

well as any attachments, except for 

information submitted, marked and 

identified, as confidential, if submitted 

as detailed in ‘‘Instructions.’’ 

Instructions: All submissions received 

must include the Docket No. FDA– 

2021–N–1333 for ‘‘Current Good 

Manufacturing Practice, Certification, 

Postmarketing Safety Reporting, and 

Labeling Requirements for Certain 

Medical Gases.’’ Received comments, 

those filed in a timely manner (see 

ADDRESSES), will be placed in the docket 

and, except for those submitted as 

‘‘Confidential Submissions,’’ publicly 

viewable at https://www.regulations.gov 

or at the Dockets Management Staff 

between 9 a.m. and 4 p.m., Monday 

through Friday, 240–402–7500. 

• Confidential Submissions—To 

submit a comment with confidential 

information that you do not wish to be 

made publicly available, submit your 

comments only as a written/paper 

submission. You should submit two 

copies total. One copy will include the 

information you claim to be confidential 

with a heading or cover note that states 

‘‘THIS DOCUMENT CONTAINS 

CONFIDENTIAL INFORMATION.’’ The 

Agency will review this copy, including 

the claimed confidential information, in 

its consideration of comments. The 

second copy, which will have the 

claimed confidential information 

redacted/blacked out, will be available 

for public viewing and posted on 

https://www.regulations.gov. Submit 

both copies to the Dockets Management 

Staff. If you do not wish your name and 

contact information to be made publicly 

available, you can provide this 

information on the cover sheet and not 

in the body of your comments and you 

must identify this information as 

‘‘confidential.’’ Any information marked 

as ‘‘confidential’’ will not be disclosed 

except in accordance with 21 CFR 10.20 

and other applicable disclosure law. For 

more information about FDA’s posting 

of comments to public dockets, see 80 

FR 56469, September 18, 2015, or access 

the information at: https://

www.govinfo.gov/content/pkg/FR-2015- 

09-18/pdf/2015-23389.pdf. 

Docket: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852, 240–402–7500. 

Submit comments on information 

collection issues under the Paperwork 

Reduction Act of 1995 to the Office of 

Management and Budget (OMB) at 

https://www.reginfo.gov/public/do/ 

PRAMain. Find these particular 

information collections by selecting 

‘‘Currently under Review—Open for 

Public Comments’’ or by using the 

search function. The titles of the 

proposed collections are: 

• Current Good Manufacturing Practice 

(CGMP): Manufacturing, Processing, 

Packing, and Holding of Drugs; GMP 

for Finished Pharmaceuticals 

(Including Medical Gases and Active 

Pharmaceutical Ingredients); OMB 

control number 0910–0139—Revision 

• Requirements on Content and Format 

of Labeling for Human Prescription 

Drug and Biological Products; OMB 

control number 0910–0572—Revision 

• Current Good Manufacturing Practice 

for Medical Gases; OMB control 

number for 21 CFR part 213—New 

• Certification and Postmarketing 

Reporting for Designated Medical 

Gases; OMB control number for 21 

CFR part 230—New 

FOR FURTHER INFORMATION CONTACT:

With regard to the proposed rule: 

David Faranda, Center for Drug 

Evaluation and Research, Food and 


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Federal Register / Vol. 87, No. 99 / Monday, May 23, 2022 / Proposed Rules 31303 

1Section 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. 

Drug Administration, 10903 New 

Hampshire Ave., Silver Spring, MD 

20993, 301–796–8767, David.Faranda@

fda.hhs.gov. 

With regard to the information 

collection: Domini Bean, Office of 

Operations, Food and Drug 

Administration, Three White Flint 

North, 10A–12M, 11601 Landsdown St., 

North Bethesda, MD 20852, 301–796– 

5733, PRAStaff@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Executive Summary 

A. Purpose of the Proposed Rule 

B. Summary of the Major Provisions of the 

Proposed Rule 

C. Legal Authority 

D. Costs and Benefits 

II. Table of Abbreviations/Commonly Used 

Acronyms in This Document 

III. Background 

A. Introduction 

B. Need for the Regulation 

C. FDA’s Current Regulatory Framework 

D. History of the Rulemaking 

IV. Legal Authority 

V. Description of the Proposed Rule 

A. Proposed Labeling Provisions 

B. Proposed Current Good Manufacturing 

Practice Provisions 

C. Proposed Certification and Annual 

Reporting Provisions 

D. Proposed Postmarketing Quality and 

Safety Reporting Provisions 

VI. Proposed Effective Date 

VII. Preliminary Economic Analysis of 

Impacts 

VIII. Analysis of Environmental Impact 

IX. Paperwork Reduction Act of 1995 

X. Federalism 

XI. Consultation and Coordination With 

Indian Tribal Governments 

XII. References 

I. Executive Summary 

A. Purpose of the Proposed Rule 

Section 756 of the Consolidated 

Appropriations Act, 2017 (Pub. L. 115– 

31) required FDA to issue final 

regulations revising the Federal drug 

regulations with respect to medical 

gases by July 15, 2017. These proposed 

regulations, if finalized, would satisfy 

that requirement and are intended to be 

more specifically tailored to the medical 

gas industry and decrease regulatory 

burden where appropriate. 

FDA proposes revisions to its labeling 

regulations to provide clarity and 

consistency regarding how information 

is presented in the labeling of certain 

medical gases, as well as to ensure 

important safety information is 

included. FDA also proposes new 

CGMP regulations for medical gases to 

reflect appropriate requirements for the 

manufacturing, processing, packing, and 

holding of such products. These 

proposed regulations generally cover the 

same categories of provisions as the 

CGMP regulations in parts 210 and 211 

(21 CFR parts 210 and 211) (hereafter 

the ‘‘general drug CGMP regulations’’), 

revised as appropriate for medical gases. 

FDA also proposes regulations that 

would implement and clarify the 

certification process for designated 

medical gases described in section 576 

of the Federal Food, Drug, and Cosmetic 

Act (FD&C Act) (21 U.S.C. 360ddd–1). 

Lastly, FDA proposes new 

postmarketing safety reporting 

regulations for designated medical gases 

that would address human and animal 

use and would better reflect the 

development, manufacturing, and 

distribution of designated medical 

gases. 

B. Summary of the Major Provisions of 

the Proposed Rule 

1. Labeling Provisions 

This proposed rule includes several 

proposed changes to FDA’s drug 

labeling regulations including adding 

certain operations required to produce a 

medical gas to the list of operations that 

are performed by its manufacturer. We 

propose to revise the requirements for 

stating the ingredients in the labeling of 

a designated medical gas or medically 

appropriate combination of designated 

medical gases (referred to hereafter in 

this preamble as ‘‘medically appropriate 

combination’’).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. 

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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31304 Federal Register / Vol. 87, No. 99 / Monday, May 23, 2022 / Proposed Rules 

provide additional clarity where 

necessary. These proposed requirements 

would govern the process for applicants 

to file a certification request and 

supplements as well as the contents of 

such a request. The regulations would 

set forth requirements concerning the 

transfer of ownership of a certification 

from one entity to another. 

We are proposing to require the 

submission of a streamlined annual 

report, including the required contents 

and timing for submission. 

These proposed regulations would set 

forth requirements that are similar to the 

recommendations described in the 

November 2015 draft guidance for 

industry ‘‘Certification Process for 

Designated Medical Gases’’ (November 

25, 2015, 80 FR 73771) (Ref. 1). 

4. Postmarketing Safety Reporting 

Provisions 

FDA is proposing new postmarketing 

safety reporting regulations for 

designated medical gases and general 

safety reporting requirements for all 

certified designated medical gases. 

We also propose adverse event 

reporting requirements related to the 

use of designated medical gases in 

humans and animals. For designated 

medical gases that are certified for 

human use and deemed to have in effect 

an approved application under section 

505 of the FD&C Act (21 U.S.C. 355), we 

are proposing that applicants and 

nonapplicants be required to report 

serious adverse events within 15 

calendar days from when the applicant 

or nonapplicant has both met certain 

reporting criteria and acquired certain 

minimum data. 

We are also proposing requirements 

for the contents and format of 

submissions, including an electronic 

submission requirement, the process for 

requesting a waiver of the electronic 

submission requirement, recordkeeping 

requirements, written procedures 

requirements, and patient privacy 

provisions. 

For designated medical gases that are 

certified for animal use and deemed to 

have in effect an approved application 

under section 512 of the FD&C Act (21 

U.S.C. 360b), we are proposing that 

applicants and nonapplicants be 

required to submit serious adverse event 

reports to FDA within 15 calendar days 

from when the applicant or 

nonapplicant has met certain reporting 

criteria and that recordkeeping 

requirements related to adverse events 

are maintained. 

C. Legal Authority 

Sections 501, 502, 505, 512, 575, 576, 

and 704 of the FD&C Act (21 U.S.C. 351, 

352, 355, 360b, 360ddd, 360ddd–1, and 

374), in conjunction with our general 

rulemaking authority in section 701(a) 

of the FD&C Act (21 U.S.C. 371(a)) serve 

as our principal legal authority for this 

proposed rule. 

D. Costs and Benefits 

The costs of this proposed rule, if 

finalized, would be primarily driven by 

new labeling requirements, regulatory 

clarification leading to firms becoming 

compliant with existing requirements, 

and added CGMP requirements 

including a requirement for portable 

cryogenic containers to have a working 

gauge. The cost savings of this proposed 

rule, if finalized, would be primarily 

driven by removing CGMP requirements 

that would not apply to medical gases, 

such as removing certain building and 

facility requirements, or modifying 

CGMP requirements so that they would 

be more well-tailored to medical gases, 

which may streamline inspections. The 

annualized benefits are estimated to be 

$3.24 million at a 7 percent discount 

rate over 10 years. The annualized costs 

are estimated to be $3.03 million at a 7 

percent discount rate over 10 years. 

II. Table of Abbreviations/Commonly 

Used Acronyms in This Document 

Abbreviation/acronym What it means 

API ...................................................................... Active Pharmaceutical Ingredient. 

CDER .................................................................. Center for Drug Evaluation and Research. 

CFR ..................................................................... Code of Federal Regulations. 

CGMP ................................................................. Current Good Manufacturing Practice. 

COA .................................................................... Certificate of Analysis. 

CVM .................................................................... Center for Veterinary Medicine. 

FAR ..................................................................... Field Alert Report. 

FD&C Act ............................................................ Federal Food, Drug, and Cosmetic Act. 

FDA or Agency ................................................... Food and Drug Administration. 

FDASIA ............................................................... Food and Drug Administration Safety and Innovation Act. 

FR ....................................................................... Federal Register. 

ICSR ................................................................... Individual Case Safety Report. 

NDA .................................................................... New Drug Application. 

NADA .................................................................. New Animal Drug Application. 

NF ....................................................................... National Formulary. 

OMB .................................................................... Office of Management and Budget. 

PRIA .................................................................... Preliminary Regulatory Impact Analysis. 

USP ..................................................................... United States Pharmacopeia. 

III. Background 

A. Introduction 

On July 9, 2012, the Food and Drug 

Administration Safety and Innovation 

Act (FDASIA, Pub. L. 112–144) was 

signed into law, establishing a new 

marketing pathway and specific 

requirements for the regulation of 

designated medical gases. Section 756 of 

the Consolidated Appropriations Act, 

2017, required FDA to issue final 

regulations revising the Federal drug 

regulations with respect to medical 

gases by July 15, 2017. 

The Agency has engaged with 

stakeholders and Congress to evaluate 

the need for changes to regulatory 

requirements for medical gases. This 

proposed rule is being published to 

address the areas for which FDA has 

determined regulatory changes are 

needed. 

B. Need for the Regulation 

Medical gases have historically been 

manufactured, labeled, and distributed 

in a manner different than most other 

drugs. Under section 576 of the FD&C 

Act, the process for obtaining marketing 

authorization for a designated medical 

gas also differs from the process for 

obtaining marketing authorization for 

other human and animal drugs. 

Moreover, because of these differences, 

sponsors of designated medical gases do 


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Federal Register / Vol. 87, No. 99 / Monday, May 23, 2022 / Proposed Rules 31305 

2The functions of the Secretary described herein 

have been delegated to FDA. 

3We 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. 

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 welltailored 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). 

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 


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31306 Federal Register / Vol. 87, No. 99 / Monday, May 23, 2022 / Proposed Rules 

4The 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). 

5These Executive Orders were revoked by 

Executive Order 13992. 

deemed to have been met if its labeling 

bears a warning that it can only be used 

for emergency use, and that for all other 

medical applications a prescription is 

required. 

Pursuant to section 577 of the FD&C 

Act, a designated medical gas, alone or 

in a medically appropriate combination 

with another designated medical gas or 

gases deemed under section 576 to have 

in effect an approved application, shall 

not be assessed prescription drug user 

fees under section 736(a) of the FD&C 

Act (21 U.S.C. 379h(a)) or animal drug 

user fees under section 740(a) of the 

FD&C Act (21 U.S.C. 379j–12(a)) on the 

basis of such deemed approval. 

FDA’s drug regulations also include 

several requirements specific to medical 

gases. FDA labeling regulations under 

part 201 (21 CFR part 201) that currently 

address the labeling of medical gases 

include the following: 

• Section 201.25(b)(1)(i)(D), which 

exempts medical gases from bar code 

label requirements that otherwise apply 

to human prescription drug products; 

• Section 201.161, which exempts 

certain medical gases from specified 

requirements if, among other things, 

applicable warning statements and 

information concerning storage and 

handling are included in the labeling; 

and 

• Section 201.328, which describes 

certain labeling requirements for 

portable cryogenic medical gas 

containers and high-pressure medical 

gas cylinders, including a color coding 

system. 

FDA’s CGMP regulations under parts 

210 and 211 that currently specifically 

address the manufacturing, labeling, 

and containers and closures for medical 

gases include the following: 

• Section 211.94(e), which provides 

container and closure requirements for 

medical gases, including gas-specific 

outlet connections and label and 

coloring requirements; 

• Section 211.125(c), which waives 

labeling reconciliation requirements for 

360° wraparound labels on portable 

cryogenic medical gas containers; 

• Section 211.170(b), which exempts 

compressed medical gases from the 

requirement to retain reserve samples; 

and 

• Section 211.196, which exempts 

compressed medical gas products from 

the requirement that distribution 

records contain lot or control numbers. 

D. History of the Rulemaking 

In developing this proposed rule, FDA 

held three public workshops (Ref. 2), on 

December 15, 2017, February 9, 2018, 

and May 11, 2018, and opened a docket 

for public comment (FDA–2018–N– 

1214).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. 

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 


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process under section 576 of the FD&C 

Act, including certain postapproval 

requirements; and 

• Establish postmarketing safety 

reporting requirements specific to 

designated medical gases. 

A. Proposed Labeling Provisions 

FDA proposes revisions to the 

labeling regulations in part 201 related 

to medical gases. 

1. Definitions 

Proposed § 201.161(c)(1) defines the 

term ‘‘designated medical gas.’’ This 

definition refers to the statutory 

definition found in section 575(1) of the 

FD&C Act and is intended to apply to 

the same gases described in section 

575(1) of the FD&C Act. 

The term ‘‘final use container’’ is 

defined in proposed § 201.161(c)(2) to 

mean a container that is for direct use 

or access by a patient or healthcare 

provider to administer a designated 

medical gas or medically appropriate 

combination of designated medical 

gases. The following would not be 

included in the proposed definition of 

‘‘final use container’’: 

• Bulk or transport containers, or 

• containers described in § 868.5655 

(21 CFR 868.5655). 

The Agency specifically requests 

comment on the scope of the proposed 

definition of ‘‘final use container’’ and 

how it relates to current labeling 

practice. 

The term ‘‘bulk or transport 

container’’ is defined in proposed 

§ 201.161(c)(3) to mean a container used 

to transport or store designated medical 

gases or medically appropriate 

combinations of designated medical 

gases and that is not used directly to 

administer such gases to a patient. This 

definition would cover storage tanks, 

storage banks, railcars, and tanker 

trucks. It would also include containers 

that are connected to medical gas 

supply systems (for example, cylinders 

connected to a hospital’s oxygen 

system). 

2. Description of Proposed Provisions 

In § 201.1(b), FDA proposes to add 

certain operations that are required to 

produce a medical gas to the list of 

operations that are performed by its 

manufacturer for purposes of section 

502(a) and (b)(1) of the FD&C Act and 

as used in the Agency’s labeling 

regulations in part 201. FDA proposes 

that fabricating a medical gas by 

chemical reaction, physical separation, 

compression of atmospheric air, 

purification (e.g., reprocessing an 

industrial gas into a medical gas), by 

combining two or more distinct medical 

gases, or by other process, would 

constitute an operation performed by a 

manufacturer. Medical gases are 

produced via several different 

processes, including air separation, 

chemical synthesis, and compression, 

and FDA believes the proposed 

language would address all such 

processes. However, under the proposed 

language, repacking or filling operations 

in which a finished medical gas is 

transferred from one container to 

another, including a container that 

contains the same medical gas 

(sometimes referred to as transfilling or 

‘‘curbside filling’’ activities at the point 

of use), would not be considered an 

operation performed by a manufacturer 

for purposes of the labeling regulations 

in part 201 (note that transfilling would 

be considered a manufacturing activity 

for purposes of the proposed CGMP 

regulations under part 213), so long as 

those operations are limited to 

transferring finished gas from one 

container to another without any change 

or transformation of the gas. FDA also 

notes that this provision refers to 

‘‘medical gas’’ instead of ‘‘designated 

medical gas’’ because the processes used 

to produce designated medical gases 

and other types of medical gases 

generally fit within the broad categories 

of processes described in the proposed 

language. The Agency believes that 

clarification is needed for all medical 

gases, and as such, FDA proposes to list 

operations that are required to produce 

a medical gas as operations that are 

performed by its manufacturer, 

regardless of whether the medical gas is 

a designated medical gas. 

FDA proposes to revise § 201.10(d)(2) 

to specify the format for a statement of 

ingredients for designated medical 

gases. FDA proposes that the statement 

of the percentage of a designated 

medical gas in a drug product be 

expressed in percent volume/volume. 

The intent of this provision is to better 

clarify and consistently display the 

amount of each designated medical gas 

present in a container. 

FDA proposes to revise § 201.51, 

which requires the label of a 

prescription drug in package form to 

bear a declaration of net quantity of 

contents. In paragraph (a), FDA 

proposes to clarify that the statement of 

quantity of designated medical gases 

and medically appropriate combinations 

thereof in a gaseous state shall be in 

terms of volume measure. In paragraph 

(b), FDA proposes to clarify that the 

statement of liquid measure currently 

described in the regulation would not 

apply to designated medical gases or 

medically appropriate combinations 

thereof. Rather, FDA proposes separate 

requirements for the declaration of net 

quantity in the labels of designated 

medical gases or medically appropriate 

combinations thereof in a: 

• Gaseous state in a high-pressure 

container; 

• Liquefied compressed gas state in a 

high-pressure container; or 

• Liquefied state in a portable 

cryogenic container. 

FDA recognizes that some reasonable 

level of product loss due to venting or 

evaporation is expected during 

manufacture; thus, minor deviations 

between the stated net quantity and the 

actual net quantity that result from 

normal venting over time would not 

cause the product to be misbranded. 

FDA believes that the information in 

201.51(b)(1) through (3) can be included 

on a separate sticker or decal on the 

container, and need not be contiguous 

with other portions of required labeling. 

Under proposed § 201.51(b)(4), labeling 

for net quantity of contents is not 

required for bulk or transport 

containers, as defined in § 201.161(c)(3). 

Examples of such containers include 

storage tanks, storage banks, railcars, 

and tanker trucks. 

FDA proposes that designated 

medical gases and medically 

appropriate combinations for animal use 

utilize the same labeling information as 

designated medical gases and medically 

appropriate combinations for human 

use. Accordingly, FDA proposes to 

amend § 201.105 to exempt designated 

medical gases and medically 

appropriate combinations from the 

misbranding requirements of section 

502(f)(1) of the FD&C Act if they are in 

compliance with the labeling 

requirements of § 201.161. This 

proposal is intended to allow 

manufacturers to have one set of 

labeling that can be utilized for both 

human and animal use of their 

designated medical gases. 

Manufacturers will not necessarily 

know at the time of manufacture, filling, 

or distribution how their gas will be 

used. Additionally, FDA expects that 

requiring two separate sets of labeling 

would create a significant burden on 

industry with little or no benefit to 

product safety or patient outcomes. 

Because FDA is not aware of any reason 

to require different information for 

animal use, the Agency believes 

utilization of the same labeling for both 

human and animal use is appropriate. 

FDA proposes several revisions to 

§ 201.161 in addition to the proposed 

definitions described above. Under 

proposed paragraph (a), the 

requirements of section 503(b)(4) 

(concerning when a drug’s label must 

bear the symbol ‘‘Rx only’’) and 502(f) 


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6The 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. 

(requiring a drug’s labeling to bear 

adequate directions for use and certain 

adequate warnings) of the FD&C Act are 

deemed to have been met for a 

designated medical gas or a medically 

appropriate combination of designated 

medical gases if the labeling on its final 

use container bears certain information 

depending on the specific gas or gases 

it contains. Each of the proposed 

revisions is described in turn below. 

FDA proposes revisions to the 

statement describing the effect of 

compliance with this section. FDA 

proposes this revision to more closely 

align with section 576(a)(3)(A)(ii) of the 

FD&C Act. FDA does not believe it is 

necessary for § 201.161(a) to include 

exemptions from 21 CFR 201.100(b)(2), 

(3), and (c)(1), given that section 

576(a)(3)(A)(ii) of the FD&C Act 

provides a separate way of satisfying the 

requirements of section 502(f) for 

designated medical gases. 

FDA proposes to remove the list of 

gases in § 201.161(a) and instead refer to 

‘‘designated medical gas.’’ FDA 

proposes these revisions to § 201.161 for 

consistency with section 576(a)(3)(A)(ii) 

of the FD&C Act. The proposed 

revisions would bring medical air and 

carbon monoxide that meet the 

definition of ‘‘designated medical gas’’ 

within the scope of § 201.161; these 

gases are not included in the list of 

gases in § 201.161 currently but are 

designated medical gases for which a 

certification can be granted under 

section 576 of the FD&C Act. Instead of 

adding medical air and carbon 

monoxide to the list of gases, FDA 

proposes to revise the first sentence to 

clarify that all designated medical gases 

and medically appropriate combinations 

thereof are within the scope of 

§ 201.161(a). Should other medical gases 

be added to the definition of 

‘‘designated medical gas’’ pursuant to 

section 575(1)(H) of the FD&C Act in the 

future, this proposed revision would 

make the provisions of § 201.161 

applicable to such gases without the 

need to amend this regulation further. 

This proposed revision would also 

ensure that all designated medical gases 

other than oxygen, including medical 

air and carbon monoxide, and medically 

appropriate combinations of designated 

medical gases are required to bear the 

label statements in proposed 

§ 201.161(a)(2) in order for sections 

503(b)(4) and 502(f) to be deemed to be 

met for such gas or gases. 

FDA proposes to remove the language 

in § 201.161 referencing §§ 201.328 and 

211.94(e)(2). FDA believes it is 

unnecessary for § 201.161 to reference 

compliance with §§ 201.328 and 

211.94(e)(2) as a condition for sections 

503(b)(4) and 502(f) to be deemed to be 

met. 

Additionally, FDA proposes to revise 

paragraph (a) to require that the final 

use container of a designated medical 

gas or medically appropriate 

combination of gases must bear the 

required information in order for 

sections 503(b)(4) and 502(f) to be 

deemed to be met for such gas or gases. 

This proposed revision is intended to 

clarify that the warnings, directions, and 

other information in § 201.161(a) must 

appear in the labeling of the final use 

container of a designated medical gas or 

medically appropriate combination of 

designated medical gases in order for 

the requirements of sections 503(b)(4) 

and 502(f) of the FD&C Act to be 

deemed to be met for such gas or gases, 

consistent with the requirements in 

section 576(a)(3)(A)(ii) of the FD&C Act. 

In the case of oxygen, FDA proposes 

to require the final use container to bear 

a warning statement providing the 

following (§ 201.161(a)(1)(i)): 

• Uninterrupted use of high 

concentrations of oxygen over a long 

duration, without monitoring its effect 

on oxygen content of arterial blood, may 

be harmful; 

• oxygen should not be used on 

patients who have stopped breathing 

unless used in conjunction with 

resuscitative equipment; and 

• in the case of oxygen that may be 

provided without a prescription for use 

in the event of depressurization or other 

environmental oxygen deficiency, or for 

oxygen deficiency or for use in 

emergency resuscitation when 

administered by properly trained 

personnel, a warning that the oxygen 

can be used for emergency use only 

when administered by properly trained 

personnel for oxygen deficiency and 

resuscitation, and that for all other 

medical applications a prescription is 

required. 

This is the same information currently 

required in § 201.161(a)(1)(i) for oxygen. 

FDA believes this information is 

important to convey the risks of using 

oxygen and is consistent with the 

requirements in section 576(a)(3)(A)(ii) 

and (b)(2) of the FD&C Act. 

FDA proposes § 201.161(a)(1)(ii), 

which would require clear and 

prominent ‘‘no smoking’’ and ‘‘no 

vaping’’ warning statements and a 

graphic warning symbol on the label of 

oxygen final use containers indicating 

that smoking, vaping, and open flames 

near oxygen are dangerous. Such a 

graphic symbol may be based on those 

created by standards development 

organizations. FDA is aware of 

numerous instances of fires related to 

the medical use of oxygen, most often 

related to individuals smoking in the 

vicinity of an oxygen tank in operation. 

Additionally, FDA has become aware of 

some reports that vaping products 6

have been linked to medical oxygen 

fires and explosions (Refs. 3 to 6). These 

events can cause death and serious 

injury to the patient, as well as 

cohabitants, neighbors, and first 

responders. Oxygen cylinders generally 

contain warnings regarding keeping oil, 

grease, combustibles, heat, sparks, and 

flame away from the product (though 

language varies from cylinder to 

cylinder). However, this language is 

generally in very fine print, is not 

expressed in a manner that is clear to 

lay users, and does not mention 

smoking or vaping directly. The purpose 

of this proposed provision is to include 

in product labeling a plain-language 

warning against smoking, vaping, or 

using open flames near an operating 

oxygen tank. Because many patients on 

oxygen therapy have smoking-related 

illnesses, and because some patients 

may continue to smoke or vape during 

treatment, FDA believes that the 

proposed warning will help mitigate the 

risk of fires during the administration of 

oxygen. The proposed ‘‘no smoking’’ 

and ‘‘no vaping’’ warning statements 

and graphic symbol may appear on a 

separate sticker or decal displaying the 

information on the container or be 

painted directly on the container. The 

Agency will continue to consider other 

risks of combustion as well. 

In the case of all designated medical 

gases other than oxygen, and in the case 

of medically appropriate combinations 

of designated medical gases, FDA 

proposes to require the final use 

container to bear the following 

information (§ 201.161(a)(2)(i) and (ii)): 

• A warning statement providing that 

the administration of the gas or gas 

combination (as applicable) may be 

hazardous or contraindicated; and 

• a warning statement providing that 

the gas or gas combination (as 

applicable) should be used only by or 

under the supervision of a licensed 

practitioner who is experienced in the 

use and administration of the gas or gas 

combination (as applicable) and is 

familiar with the indications, effects, 

dosages, methods, and frequency and 

duration of administration, and with the 

hazards, contraindications, and side 

effects and the precautions to be taken. 

This is the same information currently 

required in § 201.161(a)(1)(ii) for the 

listed gases other than oxygen, as well 


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as for medically appropriate 

combinations of the listed gases. In 

addition, FDA proposes to require that 

the labeling on the final use container 

of designated medical gases other than 

oxygen and medically appropriate 

combinations of designated medical 

gases bear the symbol ‘‘Rx only.’’ FDA 

believes this information is important to 

convey the risks of using these gases 

and is consistent with the requirements 

in section 576(a)(3)(A)(ii) and (b)(1) of 

the FD&C Act. 

Under proposed § 201.161(a)(3), the 

labeling on the final use container for all 

designated medical gases and medically 

appropriate combinations thereof would 

be required to bear appropriate 

directions and warnings concerning 

storage and handling. FDA believes this 

proposed revision is consistent with the 

current requirement in § 201.161(a)(2). 

The Agency proposes this revision to 

reflect the language in section 

576(a)(3)(A)(ii)(III) of the FD&C Act on 

this issue. 

The Agency has received comments 

recommending that it issue a separate 

warning statement requirement for 

medical air that states that medical air 

may be used without a prescription for 

breathing support when administered 

by properly trained personnel. FDA has 

decided not to propose a warning 

statement for medical air that is 

different from the warning statement 

proposed for designated medical gases 

other than oxygen, nor does FDA 

otherwise propose to exercise its 

authority under section 503(b)(3) of the 

FD&C Act to remove medical air from 

the requirements of section 503(b)(1). In 

the 2016 final rule entitled ‘‘Medical 

Gas Containers and Closures; Current 

Good Manufacturing Practice 

Requirements,’’ FDA responded to 

comments asserting that certain nonprescription uses of medical air are 

medically appropriate by deciding not 

to finalize its proposal to add medical 

air to the list of gases at § 201.161(a) and 

stating that it would continue to 

consider what would constitute an 

appropriate warning statement for 

medical air (81 FR 81685 at 81689; 

November 18, 2016). Since the 

publication of the 2016 final rule, FDA 

has continued to consider this issue, 

and the Agency remains unaware of any 

uses for medical air that would be 

appropriate for nonprescription use, and 

no new information supporting such 

uses has been provided since the 

Agency last addressed this issue in a 

citizen petition response to the 

Compressed Gas Association (Ref. 7). 

FDA believes that medical air intended 

for use by properly trained personnel in 

a healthcare setting should remain a 

prescription use subject to the 

requirements of section 503(b)(1) of the 

FD&C Act. The Agency specifically 

requests comment on this issue. 

Proposed new § 201.161(b) would 

create separate labeling requirements for 

bulk or transport containers used for 

designated medical gases or medically 

appropriate combinations of designated 

medical gases. FDA proposes to require 

that such containers be identified with 

the name of the product contained 

therein and be accompanied by 

documentation identifying the product 

as meeting applicable compendial 

standards. As discussed in this section, 

bulk or transport containers are 

excluded from the proposed definition 

of final use containers. Because these 

large containers are generally removed 

from the point of care and are not 

expected to be used directly to 

administer a designated medical gas or 

medically appropriate combination of 

designated medical gases to a patient, 

FDA does not believe that such 

containers need to bear the information 

that would be required under proposed 

§ 201.161(a). However, it is essential 

that the identity of the gas or gases 

inside such containers is evident to 

individuals handling and transporting 

the containers in order to prevent mixups. Many firms in the supply chain for 

medical gases, including those firms 

downstream from the manufacturers 

that initially produce the gas, receive 

and distribute gases for medical and 

non-medical use, and some non-medical 

gases may not meet compendial 

standards applicable to designated 

medical gases. Therefore, this proposal 

would require that a bulk or transport 

container bears the name of the 

designated medical gas or medically 

appropriate combination of designated 

medical gases contained therein, and 

that the accompanying documentation 

identifies that the product meets 

applicable compendial standards. These 

proposed requirements are expected to 

help prevent mix-ups and ensure that 

recipients of designated medical gases 

or medically appropriate combinations 

thereof in bulk or transport containers 

are provided information indicating that 

such gases meet applicable compendial 

standards. 

In § 201.328(a)(1), FDA proposes 

technical changes to reflect that the 

requirements in § 211.94(e)(2) are 

proposed to be moved to § 213.94(e)(3). 

See section V.B.1 for more information 

on this proposed revision. 

Proposed new § 201.328(d) would 

provide that the owner of a designated 

medical gas container or a container of 

a medically appropriate combination of 

designated medical gases may be 

identified on the container. This 

statement may appear on a separate 

sticker or decal on the container and 

need not be contiguous with other 

labeling on the container, but if the 

container owner is not the 

manufacturer, packer, or distributor of 

the gas, that shall be clearly stated. FDA 

recognizes the complex distribution 

system for designated medical gases and 

medically appropriate combinations of 

designated medical gases and the 

importance of allowing container 

owners to be clearly identified so that 

patients and healthcare professionals 

can contact the container owners if 

necessary. This provision is intended to 

help ensure that appropriate entities can 

be contacted regarding quality issues or 

adverse events. It is additionally 

intended to facilitate the return of 

cylinders to owners that may not also be 

medical gas manufacturers. The 

proposed inclusion of the container 

owner’s information would not cause 

the container owner to be a ‘‘relabeler’’ 

for purposes of FDA’s registration and 

listing requirements. 

B. Proposed Current Good 

Manufacturing Practice Provisions 

FDA proposes the establishment of 

part 213, which would contain the 

CGMP requirements for preparation of 

medical gases, including designated 

medical gases, for administration to 

humans or animals. If finalized as 

proposed, medical gases proposed to be 

subject to part 213 would no longer be 

subject to part 211. FDA also proposes 

conforming edits to part 210 so that 

applicable provisions would reflect the 

new CGMP regulations for medical 

gases in part 213. As proposed, part 213 

would apply to the entity that initially 

produces a medical gas and also to any 

downstream firms that manufacture, 

process, pack, or hold medical gases, 

including firms that combine, 

commingle, refill, or distribute 

designated medical gases and medically 

appropriate combinations thereof. Part 

213 is not intended to apply to entities 

further upstream in the supply chain 

from the entity that initially produces a 

medical gas. FDA seeks comment on the 

scope of these requirements, including 

the stage of product development at 

which they would apply and the entities 

that would be subject to the 

requirements. In this section, FDA will 

first describe proposed revisions to parts 

210 and 211. Then FDA will describe 

the proposed requirements in part 213, 

including how they would differ from 

the requirements in part 211. Lastly, 

FDA will describe certain groups of 

CGMP requirements under part 211 that 

FDA is not proposing in part 213. 


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1. Proposed Revisions to Parts 210 and 

211 

FDA proposes conforming edits to 

parts 210 and 211 to account for the 

proposed new part 213. In part 210, 

FDA proposes to add references to part 

213 in § 210.1(a) and (b) and in 

§ 210.2(a) and (b) so that applicable 

provisions in part 210 would reflect the 

new CGMP regulations for medical 

gases in part 213. 

In § 211.1(a), FDA proposes to add 

‘‘medical gases as defined in 

§ 213.3(b)(12)’’ to the parenthetical that 

currently excludes positron emission 

tomography drugs from part 211. 

Proposed part 213 would contain the 

CGMP requirements for medical gases. 

FDA also proposes to delete 

§ 211.94(e). Instead, proposed § 213.94 

would contain updated requirements for 

medical gas containers and closures that 

are generally consistent with the current 

requirements in § 211.94(e), with some 

additional provisions. More information 

is in section V.B.6 of this document. 

FDA proposes to delete the last 

sentence of § 211.125(c), which waives 

labeling reconciliation requirements for 

360° wraparound labels on portable 

cryogenic medical gas containers 

because labeling reconciliation for 

medical gases would be addressed by 

proposed § 213.125(b). 

FDA proposes to delete the reference 

to ‘‘containers of compressed medical 

oxygen’’ in § 211.132(c)(1), which is in 

a parenthetical that excludes certain 

products from the requirement for each 

retail package of an over-the-counter 

drug product covered by § 211.132 to 

bear a particular statement regarding its 

tamper-evident features. This reference 

would no longer be relevant if this 

proposed rule is finalized because 

medical gases (including compressed 

medical oxygen) would no longer be 

subject to part 211. 

FDA proposes to delete the statement 

in § 211.170(b) that reserve samples of 

compressed medical gases need not be 

retained. Under the proposed rule, 

medical gases would be subject to 

proposed part 213, which would not 

include reserve sample requirements. 

FDA proposes to delete the exception 

in § 211.196 that distribution records for 

compressed medical gas products are 

not required to contain lot or control 

numbers because distribution records 

requirements for medical gases would 

be addressed by proposed § 213.196. 

2. General Provisions 

Section 213.1 explains the scope of 

FDA’s proposed CGMP requirements for 

medical gases. Proposed part 213 would 

contain the minimum CGMP 

requirements for preparation of all 

medical gases for administration to 

humans or animals, including 

designated medical gases, medically 

appropriate combinations of designated 

medical gases, medical gases that are 

approved under an application that was 

submitted to FDA under section 505 or 

512 of the FD&C Act, and any marketed 

unapproved drugs that are medical 

gases. Because designated medical gases 

and other kinds of medical gases share 

many of the same physical 

characteristics and are manufactured, 

processed, packed, and held using 

similar operations and control 

strategies, FDA believes that continuing 

to have a single set of CGMP 

requirements for all medical gases is 

appropriate. 

FDA does not consider the process of 

mixing or combining gases by a hospital 

or healthcare provider at the point of 

care and as part of the ordinary practice 

of treating individual patients to be 

activities subject to part 213. 

Part 213 applies to all designated 

medical gases and medically 

appropriate combinations thereof, 

regardless of whether they are intended 

for use in humans, animals, or both. 

Proposed § 213.3 includes several 

definitions that generally track those in 

part 210, some of which have been 

revised to tailor them more specifically 

to medical gases. Proposed § 213.3 also 

contains new definitions that are 

relevant to the manufacture, processing, 

packing, and holding of medical gases. 

Proposed paragraph (a) would generally 

apply the definitions and interpretations 

in section 201 of the FD&C Act to such 

terms when used in proposed part 213. 

Proposed paragraph (b) contains 

additional definitions as follows: 

• The term ‘‘acceptance criteria’’ is 

proposed to be defined in § 213.3(b)(1) 

to mean the product specifications and 

acceptance/rejection criteria, such as 

acceptable quality level and 

unacceptable quality level, with an 

associated sampling plan, that are 

necessary for making a decision to 

accept or reject a lot or batch (or any 

other convenient subgroups of 

manufactured units). This is identical to 

the definition of the same term in part 

210. The Agency believes that 

establishing clear product specifications 

and acceptance/rejection criteria for 

determining whether a lot or batch is 

acceptable will help ensure the identity, 

strength, quality, and purity of medical 

gases. 

• Proposed § 213.3(b)(2) would define 

the term ‘‘batch’’ to mean ‘‘a specific 

quantity of a medical gas or other 

material that is intended to have 

uniform character and quality, within 

specified limits, and is produced 

according to a single manufacturing 

order during the same cycle of 

manufacture.’’ This is generally 

consistent with the definition of the 

same term in part 210. The Agency 

believes this definition would allow for 

significant flexibility in defining a batch 

to address considerations raised by 

different types of firms and different 

manufacturing, processing, packing, and 

holding activities. 

• The term ‘‘commingling or 

commingled’’ is proposed to be defined 

in § 213.3(b)(3) to refer to the act of 

combining one lot of designated medical 

gas or component with another lot or 

lots of the same designated medical gas 

or component. This is primarily 

intended to reflect the industry practice 

of combining designated medical gases 

of the same identity (e.g., nitrogen and 

nitrogen) from multiple original 

manufacturers or lots, all of which meet 

compendial standards. This definition 

would be new in part 213. 

• In proposed § 213.3(b)(4), the term 

‘‘component’’ is revised. Compared to 

the definition in § 210.3(b)(2) it means 

any ingredient intended for use in the 

manufacture of a medical gas, including 

those that may not appear in such gas. 

The term does not include incoming 

designated medical gases. Different 

proposed requirements in part 213 

would apply to components and 

incoming designated medical gases. 

These proposed requirements are 

described further in section V.B.6 of this 

proposed rule. 

• Proposed § 213.3(b)(5) defines the 

term ‘‘designated medical gas.’’ This 

definition refers to the statutory 

definition found in section 575(1) of the 

FD&C Act and is intended to apply to 

the gases described in section 575(1) of 

the FD&C Act. 

• FDA also proposes to add a 

definition of the term ‘‘FDA’’ in 

§ 213.3(b)(6) to mean the Food and Drug 

Administration. This is consistent with 

other Agency regulations that contain a 

definition of FDA. 

• Proposed § 213.3(b)(7) defines the 

term ‘‘in-process material’’ to mean 

‘‘any material fabricated, compounded, 

blended, or derived by chemical 

reaction that is produced for, and used 

in, the preparation of the medical gas.’’ 

This is generally consistent with the 

definition of the same term in part 210. 

• FDA proposes in § 213.3(b)(8) to 

define ‘‘incoming designated medical 

gas’’ to mean a designated medical gas 

received from one source that is 

commingled with the same gas from 

another source, used in a medically 

appropriate combination of designated 

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another medical gas, or further 

distributed. This definition is intended 

to cover designated medical gases that 

downstream entities receive from 

original manufacturers and other 

sources. However, incoming gases that 

are not designated medical gases but 

that are intended for use in the 

manufacture of a medical gas would be 

considered components. As described 

above, FDA proposes different 

requirements for components and 

incoming designated medical gases. 

This definition would be new in part 

213. 

• In proposed § 213.3(b)(9), the term 

‘‘lot’’ is defined to mean a batch, or a 

specific identified portion of a batch, 

having uniform character and quality 

within specified limits. In the case of a 

medical gas produced by continuous 

process, the term means a specific 

identified amount produced in a unit of 

time or quantity in a manner that 

assures its having uniform character and 

quality within specified limits. This is 

generally consistent with the definition 

of the same term in part 210. 

• FDA proposes to define ‘‘lot 

number, control number, or batch 

number’’ in § 213.3(b)(10) to mean ‘‘any 

distinctive combination of letters, 

numbers, or symbols, or any 

combination of them, from which the 

complete history of the manufacture, 

processing, packing, holding, and 

distribution of a batch or lot of medical 

gas or other material can be 

determined’’ (§ 213.3(b)(11)). This is 

generally consistent with the definition 

of the same term in part 210. 

• In proposed § 213.3(b)(11), the term 

‘‘manufacture, processing, packing, or 

holding’’ is defined to include 

packaging and labeling operations, 

testing, and quality control of medical 

gases. This is generally consistent with 

the definition of the same term in part 

210 because many provisions refer to 

these actions, and FDA intends that they 

have the same meaning as in part 210. 

FDA considers packaging in the context 

of these proposed requirements to 

include filling a container with a 

medical gas. 

• FDA proposes in § 213.3(b)(12) that 

the term ‘‘medical gas’’ has the meaning 

given the term in section 575(2) of the 

FD&C Act. This would include 

designated medical gases, medically 

appropriate combinations of designated 

medical gases, medical gases that are 

approved under an application that was 

submitted to FDA under section 505 or 

512 of the FD&C Act, and any marketed 

unapproved drugs that are medical 

gases. This term would not include 

gases that are used as excipients in drug 

products that are not medical gases (e.g., 

propellants in inhalation drugs). 

• FDA proposes to define ‘‘original 

manufacturer’’ in § 213.3(b)(13) to 

include persons or entities that initially 

produce a designated medical gas by 

chemical reaction, physical separation, 

compression of atmospheric air, 

purification of a gas, or other means. 

FDA’s intent is to capture the various 

methods by which firms produce 

designated medical gases. A person who 

refills a designated medical gas into a 

new container, either for further 

distribution or at the delivery site, 

would not be considered an original 

manufacturer. Additionally, a person 

who creates a medically appropriate 

combination of designated medical 

gases would not be considered an 

original manufacturer. This proposed 

definition would be new in part 213. 

• FDA’s proposed definition of 

‘‘quality unit’’ in § 213.3(b)(14) is any 

person or persons designated with the 

authority and responsibility for overall 

quality management and other 

responsibilities as defined in § 213.22. 

Under proposed part 213, the quality 

unit’s responsibilities would include 

oversight of quality throughout the 

entire manufacturing process. We are 

proposing to use the term ‘‘quality unit’’ 

because the Agency believes this term 

more appropriately reflects current 

terminology. As FDA has previously 

noted, the Agency considers ‘‘quality 

control unit’’ (defined in § 210.3(b)(15)) 

and ‘‘quality unit’’ to be synonymous. 

FDA proposes an updated definition for 

part 213 that focuses on ‘‘overall quality 

management’’ rather than quality 

control. The Agency believes that this 

definition would better reflect industry 

practice and the Agency’s 

understanding of the responsibilities of 

the quality unit. 

• FDA’s proposed definition of 

‘‘strength’’ in § 213.3(b)(15) is generally 

consistent with the definition in part 

210, and contains two parts: (1) The 

concentration of the medical gas (for 

example, weight/weight, weight/ 

volume, or unit dose/volume basis), 

and/or (2) the potency, that is, the 

therapeutic activity of the medical gas 

as indicated by appropriate laboratory 

tests or by adequately developed and 

controlled clinical data (expressed, for 

example, in terms of units by reference 

to a standard). 

FDA seeks comment on whether there 

are other terms, including those that are 

used in this proposed rule or in parts 

210 and 211, that the Agency should 

define in part 213. 

3. Organization and Personnel 

Proposed § 213.22 describes the 

responsibilities of the quality unit and 

is similar in scope to § 211.22. Proposed 

paragraphs (a) through (d) are generally 

consistent with paragraphs (a) through 

(d) in § 211.22, with one notable change: 

FDA proposes to use the term ‘‘quality 

unit’’ instead of ‘‘quality control unit.’’ 

Paragraph (a) would require that there 

be a quality unit with the responsibility 

and authority to approve or reject all 

components, medical gas containers and 

closures, in-process materials, 

packaging material, labeling, and 

medical gases, and the authority to 

review production records to assure that 

no errors have occurred or, if errors 

have occurred, that they have been fully 

investigated. Additionally, the quality 

unit would be responsible for approving 

or rejecting medical gases 

manufactured, processed, packed, or 

held under contract by another 

company. The Agency believes that 

assigning dedicated staff to these quality 

responsibilities is critical to ensuring 

the identity, strength, quality, and 

purity of the medical gas. 

Paragraph (b) would require that there 

be made available to the quality unit 

adequate laboratory facilities for the 

testing and approval (or rejection) of 

components, medical gas containers and 

closures, packaging materials, inprocess 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 


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firms that manufacture, process, pack, 

or hold a drug, including medical gases, 

have limited personnel who may have 

multiple roles within the firm. So long 

as there are appropriate written controls 

in place to ensure that other functions 

do not interfere with the quality unit’s 

responsibilities or subordinate the 

quality unit’s responsibilities to any 

other unit, FDA considers it acceptable 

for quality unit personnel to perform 

these other functions. 

Proposed § 213.25 addresses 

personnel qualifications and 

responsibilities. Paragraph (a) would 

contain requirements for personnel 

education, training, and experience that 

are generally consistent with those 

contained in § 211.25, except as 

described below. Under proposed 

§ 213.25(a), persons engaged in the 

manufacture, processing, packing, or 

holding of a medical gas would be 

required to have the education, training, 

and experience (or any combination 

thereof) to enable them to perform 

assigned functions. Training would 

have to be in the employee’s particular 

operations and in CGMP (including in 

the applicable CGMP regulations and 

written procedures required 

thereunder). Training in CGMP would 

have to be conducted by qualified 

individuals on a continuing basis and 

with sufficient frequency to assure that 

employees remain familiar with CGMP 

requirements applicable to them. FDA 

proposes to specify in § 213.25(a) that 

written documentation must be 

maintained demonstrating employees’ 

completion of training, including the 

date, type of training, and results of any 

completion criteria, such as test results. 

The Agency believes that these 

requirements would be sufficient to 

allow firms to maintain properly trained 

staff capable of accomplishing all 

required tasks. This paragraph would 

apply to all personnel engaged in the 

manufacture, processing, packing, or 

holding of a medical gas, including 

supervisors and subordinates. 

Therefore, we are not proposing a 

separate requirement similar to 

§ 211.25(b) regarding supervisor 

responsibilities in this proposed rule. 

Paragraph (b) would require that there 

be an adequate number of qualified 

personnel to perform manufacturing, 

processing, packing, and holding 

activities for each medical gas. The 

scope of this proposed requirement is 

the same as in § 211.25(c). This 

proposed requirement is important to 

ensure that all steps related to 

manufacturing, processing, packing, and 

holding are performed or monitored 

appropriately. What would constitute 

‘‘adequate’’ personnel would depend in 

part on the size and complexity of the 

operations being performed. 

Paragraph (c) would restrict access to 

‘‘limited-access areas’’ to authorized 

personnel only. This proposed 

requirement is the same as § 211.28(c) 

and is important for medical gases 

because of the danger associated with 

mishandling medical gases and the risks 

to patients if such gases are improperly 

manufactured. 

In § 213.34, FDA proposes 

requirements regarding consultants that 

are generally consistent with 

requirements that currently apply to 

medical gases under § 211.34. FDA does 

not see a need for different training and 

experience requirements for consultants 

advising on medical gases compared to 

other drug products. Consultants would 

be required to have sufficient education, 

training, and experience, or any 

combination thereof, to advise on the 

subject for which they are retained. 

Further, records would be required to be 

maintained that state the name, address, 

and qualifications of any consultants 

and the type of service they provide. 

4. Buildings and Facilities 

FDA proposes a more limited set of 

building and facilities requirements for 

the manufacture, processing, packing, or 

holding of medical gases compared to 

part 211. FDA’s primary concern 

regarding buildings and facilities used 

for these products is the risk of mix-ups 

because multiple gases are often 

produced at these buildings and 

facilities, and a gas mix-up could lead 

to patient harm. Additionally, while the 

risk of contamination is diminished for 

medical gases because they are generally 

manufactured in a closed, sealed 

system, periodic cleaning and 

maintenance is necessary for all 

buildings and facilities, so buildings 

and facilities must be designed to 

facilitate such cleaning and 

maintenance. The proposed 

requirements in this subpart are 

intended to address these risks, taking 

into account the unique manufacturing 

processes for medical gases. 

Proposed § 213.42(a) would require 

that buildings and facilities used in the 

manufacture, processing, packing, or 

holding of a medical gas be of adequate 

design, including adequate space, for 

the orderly placement of equipment and 

materials to prevent mix-ups and allow 

for adequate cleaning, maintenance, and 

proper operations. Specifically, 

buildings and facilities would be 

required to be of adequate design to 

prevent mix-ups between components, 

incoming designated medical gases, 

medical gas containers and closures, 

labeling, in-process materials, or 

medical gases. FDA proposes to specify 

‘‘buildings and facilities’’ in this section 

and elsewhere because some medical 

gas operations, including storage, can be 

performed outdoors without affecting 

the safety, identity, strength, quality, 

and purity of the product. FDA expects 

that there will be multiple ways of 

achieving adequate design and adequate 

space for all manufacturing operations 

that prevent mix-ups and allow for 

necessary cleaning and maintenance. 

Multiple gases are often manufactured 

at the same facility, and a mix-up could 

result in a patient receiving the wrong 

gas, which could be fatal. Therefore, it 

is essential that buildings and facilities 

be designed to enable personnel to 

clearly identify which equipment and 

materials are being used for which gas, 

to avoid such mix-ups. Moreover, while 

contaminants such as ordinary dust and 

dirt are unlikely to enter a closed 

system, such contamination can still 

occur, for example, at the point at which 

a gas is transferred from one container 

to another. 

Proposed § 213.42(b) would require 

that operations be performed within 

specifically defined areas of adequate 

size, with separated or defined areas or 

such other control systems for the firm’s 

operations as are necessary to prevent 

contamination or mix-ups during the 

following procedures: 

• Receipt, identification, storage, and 

withholding from use of components or 

incoming designated medical gases, 

medical gas containers and closures, 

and labeling, pending the appropriate 

sampling, testing, or examination by the 

quality unit before release for 

manufacturing or packaging; 

• Holding rejected components, 

incoming designated medical gases, 

medical gas containers and closures, 

and labeling before disposition; 

• Storage of released components, 

incoming designated medical gases, 

medical gas containers and closures, 

and labeling; 

• Storage of in-process materials; 

• Manufacturing and processing 

operations; 

• Packaging and labeling operations; 

• Quarantine storage before release of 

medical gases; 

• Storage of medical gases after 

release; and 

• Control and laboratory operations. 

Where multiple gases are being 

produced at the same facility, it is 

important for staff to be able to easily 

determine which gas is being 

manufactured in each area of the 

facility. These requirements will also 

help personnel distinguish between 

received, in-process, and finished 

product. FDA anticipates that firms can 


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meet this requirement with physical 

barriers, signage, or both, though firms 

may use other appropriate means. 

Proposed § 213.42(b) would further 

require that the flow of components, 

incoming designated medical gases, 

containers, closures, labeling, in-process 

materials, and medical gases be 

designed to prevent contamination and 

mix-ups. 

Under proposed § 213.42(c), any 

building or facility used in the 

manufacture, processing, packing or 

holding of a medical gas shall be 

maintained in a clean condition so as to 

assure the safety, identity, strength, 

quality, and purity of the gas. 

Additionally, § 213.42(c) would require 

that written procedures applicable to 

the maintenance and cleaning of 

buildings and facilities be established 

and followed. FDA believes this 

proposed requirement is more limited 

than the sanitation requirement in 

§ 211.56(a), and that it is better tailored 

to medical gas production, which 

involves a generally lower risk of 

contamination than other drug products. 

The condition of buildings and facilities 

that would be considered clean for 

medical gas production is expected to 

be different from the condition of 

buildings and facilities that would be 

considered clean for production of other 

drug products, where greater risks of 

contamination generally exist. 

5. Equipment 

Subpart D contains proposed 

requirements for equipment. Proposed 

§ 213.63 would require that equipment 

be of appropriate design, adequate size, 

and suitably located to facilitate 

operations for its intended use and for 

its cleaning and maintenance. FDA 

expects that the design of the facility 

and equipment will allow for 

appropriate cleaning and maintenance 

(for example, personnel can access all 

equipment that must be cleaned). FDA 

expects that firms will ensure that 

pigtails, valves, hoses, and similar 

connectors are kept clean and 

maintained. 

Proposed § 213.65 addresses 

equipment construction and is similar 

to § 211.65. Paragraph (a) would require 

that equipment be constructed so that 

surfaces that contact components, inprocess materials, or medical gases are 

not reactive, additive, or absorptive so 

as to alter the safety, identity, strength, 

quality, or purity of the medical gas 

beyond the official or other established 

requirements. Paragraph (b) would 

require that substances required for 

operations, such as lubricants or 

coolants, shall not come into contact 

with components, containers, closures, 

in-process materials, or medical gases so 

as to alter the safety, identity, strength, 

quality or purity of the medical gas 

beyond the official or other established 

requirements. 

FDA proposes equipment 

maintenance and cleaning requirements 

under § 213.67. These proposed 

requirements differ from those that 

currently apply to medical gases under 

§ 211.67 and reflect the differences in 

appropriate practices for routine 

cleaning of equipment associated with 

the manufacturing, processing, packing, 

and holding of medical gases. Paragraph 

(a) would require that written 

procedures be established, maintained, 

and followed for adequate cleaning and 

maintenance of equipment. Procedures 

would be required to include the 

following: 

• Assignment of responsibility for 

cleaning and maintaining equipment; 

• maintenance and cleaning 

schedules, including, where 

appropriate, sanitizing schedules; 

• a sufficiently detailed description of 

the methods, equipment, and materials 

used in cleaning and maintenance, as 

well as the methods of disassembling 

and reassembling equipment as 

necessary to assure proper cleaning and 

maintenance; 

• removal or obliteration of previous 

batch identification; 

• protection of clean equipment from 

contamination prior to use; and 

• inspection of equipment for 

cleanliness immediately before use. 

FDA anticipates that these procedures 

would address, among other things: 

Cleaning, or verifying as clean, 

equipment and product contact surfaces 

prior to initial use, after potential 

exposure to a contaminant, or as part of 

maintenance if such maintenance may 

expose the product contact surfaces to 

potential contamination; maintaining 

equipment at appropriate intervals to 

prevent malfunctions or contamination; 

and inspecting or testing systems prior 

to returning to service, to assure that no 

residual cleaning agents are present. 

Proposed paragraph (b) specifies that 

such procedures shall not alter the 

safety, identity, strength, quality, or 

purity of the medical gas beyond 

established requirements. 

Paragraph (c) would require that 

records be kept of cleaning, 

maintenance, and inspection as 

specified in § 213.180. 

Proposed § 213.68 addresses 

requirements for automatic, mechanical, 

and electronic equipment used in the 

manufacture of medical gases. 

Paragraph (a) would require that such 

automatic, mechanical, and electronic 

equipment be routinely calibrated, 

inspected, and checked, according to a 

written program designed to ensure 

proper performance, and that written 

procedures and records of calibration, 

inspections, and checks be maintained. 

Ensuring that automated, mechanical, 

and electronic equipment is properly 

functioning is critical to ensuring the 

safety, strength, identity, quality, and 

purity of a gas. Without such checks, 

firms could manufacture gases that fail 

to meet compendial standards, or that 

are not appropriate for the ultimate 

patients’ needs. 

Paragraph (b) would require 

validation of computerized systems that 

record, store, or use data. The validation 

necessary would depend on how the 

computerized system is used in the 

manufacturing process. 

In paragraph (c), FDA would require 

the maintenance of backup files of data 

entered into computer systems, though 

such backups would not be required 

where certain data, such as calculations, 

are eliminated by computerization or 

other automated processes. 

Paragraph (d) would require that 

appropriate change control be used 

whenever modifications are made to 

computerized systems to assure that any 

changes do not adversely affect data 

integrity or product quality. FDA 

expects that this will include that 

manufacturers evaluate proposed 

changes with affected departments, that 

the proposed changes are assessed for 

revalidation where appropriate, and that 

activities are documented. Records 

would also be required to be maintained 

of such modifications. 

6. Control of Incoming Designated 

Medical Gas, Components, and Medical 

Gas Containers and Closures 

Subpart E contains proposed 

requirements for control of incoming 

designated medical gases, components, 

and medical gas containers and 

closures. Proposed § 213.80(a) and (b) 

are similar to paragraphs (a) and (b) of 

§ 211.80, though the proposed 

requirements would also apply 

expressly to incoming designated 

medical gases. Paragraph (a) would 

require sufficiently detailed written 

procedures to be developed and 

followed describing the receipt, 

identification, storage, handling, 

sampling, testing, and approval or 

rejection of components, incoming 

designated medical gases, and medical 

gas containers and closures. Paragraph 

(b) would require that components, 

incoming designated medical gases, and 

medical gas containers and closures be 

handled and stored in a manner to 

prevent contamination and mix-ups. As 

previously mentioned, medical gases are 


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generally manufactured in a closed, 

pressurized system, and gas mix-ups 

generally pose a more significant risk 

than contamination, considering 

previous incidents in which patients 

were administered the wrong gas (Ref. 

8). However, while contamination poses 

a lower risk, there still exists the 

possibility for contamination. FDA 

believes that different controls would 

likely be appropriate for medical gas 

manufacturers to prevent contamination 

than would be expected for producers of 

other drugs. 

Proposed paragraph (c) would require 

that lots of incoming designated medical 

gases or components be assigned a 

unique identification number, 

regardless of whether the incoming lot 

is used directly as supply or 

commingled with an existing supply. 

This would help facilitate the tracing of 

product once it enters distribution. 

FDA is not proposing that part 213 

include the requirements described in 

paragraphs (c) and (d) in § 211.80. FDA 

believes it is unnecessary to include the 

requirement in § 211.80(c) that product 

be stored off the floor and suitably 

spaced to permit cleaning and 

inspection. Sealed medical gas 

containers are designed to protect gases 

from contamination and external 

conditions, and their size and weight 

make storage off the floor impracticable 

in many settings. FDA also is not 

proposing to include in part 213 the 

requirement in § 211.80(d) that each 

container or grouping of containers for 

components or drug product containers, 

or closures be identified with a 

distinctive code for each lot in each 

shipment received. Gas containers are 

reused, and inspection of containers 

prior to reuse would be required under 

proposed § 213.84(a). Thus, FDA 

believes that other lot identification 

requirements in proposed part 213 are 

sufficient to track product. 

Proposed § 213.82 addresses the 

receipt and storage of incoming 

designated medical gases. The proposed 

requirements differ from currently 

applicable requirements in § 211.82 to 

better reflect the use of incoming 

designated medical gases in further 

manufacturing. Under proposed 

paragraph (a), a firm would have to 

verify and record upon receipt of a 

designated medical gas that the 

shipment contains a signed certificate of 

analysis (COA) from the supplier, and 

that the COA contains the following: 

• The supplier’s name; 

• the name of the incoming 

designated medical gas; 

• the lot number or another unique 

identification number; 

• the actual analytical result obtained 

for strength, as well as the results of 

other tests performed (FDA expects 

these tests would include tests sufficient 

to demonstrate conformance with 

compendial standards); 

• identification of the test method(s) 

used for analysis; 

• the NDA and/or NADA number of 

the incoming designated medical gas; 

and 

• the supplier representative’s 

signature and the date of signature. 

If the incoming designated medical 

gas is obtained from a supplier other 

than the original manufacturer, the 

shipment would also have to include 

complete information from the original 

manufacturer’s COA. The firm would 

also be required to establish and 

maintain a program to ensure the 

reliability of the supplier’s capabilities 

through appropriate assessment and 

testing procedures. This is essential to 

ensuring that the information in the 

COA is accurate, and thus that the 

incoming designated medical gas meets 

relevant standards. 

Proposed paragraph (b) would require 

that an identity test be conducted on 

incoming designated medical gases 

upon receipt. FDA understands that this 

is consistent with current industry 

practice (Ref. 2), and because designated 

medical gas manufacturers supplying 

the gas will conduct full compendial 

testing, and the firm receiving the 

incoming designated medical gas would 

conduct full compendial testing prior to 

release (see proposed § 213.165), FDA 

believes this is an appropriate level of 

review. 

FDA proposes § 213.84 regarding 

testing and approval or rejection of 

components, containers, and closures. 

Paragraph (a) would require that 

components, containers, and closures 

(including valves) be examined for 

conformance with appropriate written 

procedures and specifications, and 

approved or rejected, prior to the 

manufacturing or filling process. Firms 

can meet this proposed requirement by 

testing for conformance with written 

specifications. In lieu of such 

examination by the firm, a statement of 

verification that the component, 

container, or closure meets 

specifications may be accepted from the 

supplier, provided that the firm 

establishes and maintains a program to 

ensure the reliability of the supplier’s 

capabilities through appropriate 

assessment and testing provisions. This 

requirement would be satisfied with an 

auditing system. This type of evaluation 

system is intended to ensure the 

integrity of components, containers, and 

closures for the entire period of use. 

Rejected items would need to be 

handled in accordance with § 213.89. 

Under proposed paragraph (b), firms 

would be required to take appropriate 

actions to protect against container and 

closure leaks. This would include 

performing leak tests on containers and 

closures at the time of fill and after fill 

but prior to release. FDA has evaluated 

inspectional findings from 2003 to 2021 

and identified numerous instances of 

leaking or empty containers reported by 

customers and patients, following 

release by the manufacturer (Ref. 9). 

Because of the location and delayed 

timing of these defects, it appears some 

are likely not detectable prior to release. 

Therefore, additional controls may be 

needed to further protect against 

container and closure leaks to provide 

sufficient assurance of the durability of 

the container closure system throughout 

its period of use. For example, the 

inclusion of representative leak tests at 

additional intervals, such as upon pickup or receipt of the container by the 

manufacturer, may be an additional 

adequate control. FDA seeks comment, 

with related data and explanation, from 

manufacturers, distributors, and end 

users of medical gases and other 

interested parties on whether leak 

testing at the time of fill and after fill but 

prior to release would sufficiently 

ensure the integrity of the container 

closure system for the period of use, and 

whether additional periodic leak tests 

would enhance the ability to correct and 

prevent container closure defects that 

are only detectable after they leave the 

manufacturer. 

Proposed paragraph (c) would require 

that components be sampled, tested, 

and approved or rejected as appropriate 

prior to use. Firms would be able to 

meet this proposed requirement by 

performing testing for conformance with 

written specifications or by an identity 

test on the component accompanied by 

an acceptable COA from the supplier, 

provided that the firm establishes and 

maintains a program to ensure the 

reliability of the supplier’s capabilities 

through appropriate assessment and 

testing procedures. Components are not 

always used in the manufacture of 

designated medical gases, but when 

they are used, FDA believes these 

proposed requirements are reasonable. 

Proposed § 213.89 is similar to the 

requirements in § 211.89 in that rejected 

components, containers, and closures 

would need to be identified and 

controlled under a quarantine system 

designed to prevent their use in 

manufacturing or processing operations 

for which they are unsuitable, but 

proposed § 213.89 would also apply to 

incoming designated medical gases. 


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Such a quarantine system need not 

include physical quarantining, as other 

methods can adequately ensure that 

unsuitable products are not used. FDA 

proposes to add a requirement that 

rejected components, incoming 

designated medical gases, and medical 

gas containers and closures be 

documented and assessed. This 

additional proposed requirement would 

help to ensure that any trends that 

warrant further investigation can be 

identified. 

Proposed § 213.94 would contain 

additional requirements for medical gas 

containers and closures. Paragraph (a) is 

generally consistent with the 

requirements in § 211.94(a) and would 

require that containers and closures not 

be reactive, additive, or absorptive so as 

to alter the safety, identity, strength, 

quality, or purity of the medical gas 

beyond the official or established 

requirements. 

Under paragraph (b), container 

closure systems would be required to 

provide adequate protection against 

foreseeable external factors in storage 

and use that can cause deterioration or 

contamination of the medical gas. This 

is generally consistent with the 

requirements in § 211.94(b). 

Paragraph (c) would require that 

medical gas containers and closures be 

clean to assure that they are suitable for 

their intended use. This is generally 

consistent with § 211.94(c), but FDA 

does not propose to include the 

requirements related to sterilization or 

removal of pyrogenic properties, as 

those are not relevant to medical gases. 

Under proposed paragraph (d), 

standards or specifications, methods of 

testing, and, where indicated, methods 

of cleaning shall be written and 

followed for medical gas containers and 

closures. This is generally consistent 

with § 211.94(d), but FDA does not 

propose to include the requirements 

related to sterilization or removal of 

pyrogenic properties, as those are not 

relevant to medical gases. 

Proposed paragraph (e) is a revised 

version of § 211.94(e) and would 

contain requirements for medical gas 

containers and closures. In paragraph 

(e)(1), FDA proposes that portable 

cryogenic medical gas containers that 

are not manufactured with permanent 

gas use outlet connections (e.g., those 

that have been silver-brazed) must have 

gas-specific use outlet connections that 

are attached to the valve body so that 

they cannot be readily removed or 

replaced (without making the valve 

inoperable and preventing the 

container’s use) except by the 

manufacturer. Proposed § 213.94(e)(1) is 

consistent with § 211.94(e)(1). 

Consistent with § 211.94(e)(1), FDA 

proposes to define ‘‘manufacturer’’ for 

purposes of § 213.94(e)(1) to include any 

individual or firm that fills highpressure medical gas cylinders or 

cryogenic medical gas containers. The 

Agency believes only such 

manufacturers should be able to remove 

or replace gas-specific use outlet 

connections that are attached to the 

valve body. Also, consistent with 

§ 211.94(e)(1), FDA proposes to define 

‘‘portable cryogenic medical gas 

container’’ for purposes of § 213.94(e)(1) 

as one that is capable of being 

transported and is intended to be 

attached to a medical gas supply system 

within a hospital, healthcare entity, 

nursing home, other facility, or home 

healthcare setting, or is a base unit used 

to fill small cryogenic gas containers for 

use by individual patients. The term 

would not include cryogenic containers 

that are not designed to be connected to 

a medical gas supply system, e.g., tank 

trucks, trailers, rail cars, or small 

cryogenic gas containers for use by 

individual patients (including portable 

liquid oxygen units as defined at 

§ 868.5655). The Agency believes all 

portable cryogenic medical gas 

containers should have gas-specific use 

outlet connections that are attached to 

the valve body in order to prevent gas 

mix-ups. FDA seeks comment regarding 

whether the scope of the exception to 

the term ‘‘portable cryogenic medical 

gas container’’ is appropriate, especially 

as the exception would include small 

cryogenic containers for use by 

individual patients. 

Under paragraph (e)(2), FDA proposes 

to add the requirement that portable 

cryogenic medical gas containers as 

defined in proposed § 213.94(e)(1) as 

well as small cryogenic gas containers 

for use by individual patients (including 

portable liquid oxygen units as defined 

in § 868.5655) have a working gauge 

sufficient to indicate whether the 

container has an adequate supply of 

medical gas for continued use. This is 

intended to enable end users, such as 

healthcare practitioners, patients, and 

caretakers, to monitor the gas remaining 

in the container. Without such a gauge, 

end users may not be able to determine 

when the container needs to be refilled 

or replaced. Additionally, if a container 

is stored for a long period of time before 

use and, during that time, slowly vents 

or leaks, the end user will be able to 

determine with a working gauge 

whether there is still gas in the 

container. FDA believes that the term 

‘‘working gauge’’ would allow for 

flexibility, so that firms may use the 

type of gauge appropriate to measure the 

remaining volume or weight of medical 

gas, in liquid or gaseous form, as 

appropriate. FDA believes that the 

proposed requirement to have a working 

gauge would help to assure the safety, 

identity, strength, quality, and purity of 

medical gases in portable cryogenic 

containers and small cryogenic 

containers for use by individual patients 

throughout their period of use. 

Paragraph (e)(3) would contain the 

label and coloring requirements that 

currently apply to medical gases under 

§ 211.94(e)(2), except that it would not 

include the requirement that the 

labeling not be susceptible to becoming 

worn or inadvertently detached during 

normal use. Because medical gas 

containers are reused and distributed 

among multiple entities, FDA believes 

that labeling inspection requirements 

proposed in this rulemaking would be 

sufficient to assure that labeling that 

enters into distribution is complete, 

accurate, durable, and readable, and that 

unsuitable labeling is replaced. 

7. Production and Process Controls 

Subpart F contains FDA’s proposed 

requirements for production and 

process controls for medical gases. The 

proposed requirements in § 213.100(a) 

and (b) are generally consistent with the 

currently applicable requirements in 

§ 211.100. Proposed paragraph (a) 

would require written procedures for 

production and process controls 

designed to assure that medical gases 

have the identity, strength, quality, and 

purity they purport or are represented to 

have. The procedures would need to 

include all requirements in subpart F. 

Further, the procedures, including any 

changes, would need to be drafted, 

reviewed, and approved by the 

appropriate organizational units and 

reviewed and approved by the quality 

unit. Paragraph (b) would require that 

written production and process control 

procedures be followed in the execution 

of the various production and process 

control functions and documented at 

the time of performance, and that 

deviations be recorded and justified. 

FDA believes that the existing 

requirements for developing and 

following written procedures for 

production and process controls are 

appropriate for medical gases because 

they would help ensure consistent 

compliance with a firm’s established 

procedures for production of medical 

gases. 

In § 213.101, FDA proposes different 

requirements for charge-in of 

components and incoming designated 

medical gases than those in § 211.101. 

Proposed paragraph (a) would require 

that, except when a monograph or 


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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 inprocess supply or final product 

containers be weighed or measured as 

appropriate. Final product and inprocess supply containers would also be 

required to identify the name of the 

component or designated medical gas or 

the name and percentage of each 

component or designated medical gas if 

they contain multiple components or 

designated medical gases, as well as the 

unique lot number assigned. 

Proposed § 213.110 would include a 

more limited set of sampling and testing 

requirements than the existing 

requirements in § 211.110, which 

contain several testing requirements that 

are inapplicable to medical gases 

(including tablet or capsule weight 

variation, disintegration time, and 

dissolution time and rate). Paragraph (a) 

would require that in-process materials 

be tested for identity, strength, quality, 

and purity as appropriate, and approved 

or rejected by the quality unit during the 

production process. Under paragraph 

(b), written procedures would be 

required to be established and followed 

describing the in-process controls, and 

tests, or examinations to be conducted 

on appropriate samples of in-process 

materials of each batch. Such control 

procedures would need to be 

established to monitor the output and to 

validate the performance of those 

manufacturing processes. This is 

important for assuring batch uniformity 

and the integrity of drug products. 

Paragraph (c) would require that 

rejected in-process materials be 

identified and controlled under a 

quarantine system designed to prevent 

their use in manufacturing or processing 

operations for which they are 

unsuitable. FDA believes that these 

proposed requirements would be 

sufficient to help ensure that medical 

gases are manufactured according to 

specifications and prevent mix-ups or 

the accidental use of rejected or 

quarantined product. 

8. Packaging and Labeling Control 

Proposed subpart G would contain 

packaging and labeling control 

requirements. FDA proposes packaging 

and labeling materials examination and 

usage criteria in § 213.122. The 

proposed requirements in paragraphs (a) 

through (e) are generally consistent with 

the current requirements in paragraphs 

(a) through (e) in § 211.122. Paragraph 

(a) would require that there be 

sufficiently detailed written procedures 

describing the receipt, identification, 

storage, handling, sampling, 

examination and/or testing of labeling 

and packaging materials and that such 

procedures be followed. Further, 

paragraph (a) would require that 

labeling and packaging materials be 

representatively sampled, and examined 

or tested upon receipt and before use in 

packaging or labeling of a medical gas. 

Paragraph (b) would state that labeling 

or packaging materials may be approved 

and released for use if they meet 

appropriate written specifications, and 

that they must be rejected if they do not 

meet such specifications to prevent their 

use in operations for which they are 

unsuitable. Paragraph (c) would require 

that records be maintained for each 

shipment of each different labeling and 

packaging material indicating receipt, 

examination, and whether the materials 

were accepted or rejected. Paragraph (d) 

would require that labels and other 

labeling materials for each different 

medical gas, strength, or quantity of 

contents be stored with suitable 

identification to avoid mix-ups. Further, 

access to storage would need to be 

limited to authorized personnel. 

Paragraph (e) would require the 

destruction of obsolete and outdated 

materials, as well as materials that do 

not meet applicable requirements. 

Under paragraph (f), FDA would 

require one of three special control 

procedures for packaging and labeling 

operations: Dedicated labeling and 

packaging lines for each strength of each 

medical gas; use of appropriate 

electronic or electromechanical 

equipment to conduct a 100 percent 

examination for correct labeling during 

or after completion of finishing 

operations; or use of visual inspection to 

conduct a 100 percent examination for 

correct labeling during or after 

completion of labeling operations for 

hand-applied labeling (which would 

need to be performed by one person and 

independently verified by a second 

person). The Agency believes that 

utilizing one of these procedures is 

critical to preventing mix-ups. 

Paragraph (g) would require monitoring 

of printing devices on, or associated 

with, manufacturing lines used to 

imprint labeling upon the unit label or 

case to assure that all imprinting 

conforms to the print specified in the 

batch production record. Finally, 

paragraph (h) would allow the reuse of 

labels if they are legible, properly 

affixed to the container, and otherwise 

meet all applicable requirements. 

Unlike most drug containers, medical 

gas containers are reused many times 

and made of extremely durable 

materials. FDA believes that the 

proposed requirements in this section 

would be sufficient to ensure the quality 

and legibility of medical gas labels. 

In proposed § 213.125, FDA would 

establish requirements for issuing 

labeling. Paragraph (a) would require 

that labeling and packaging operations 

be controlled to prevent labeling and 

product mix-ups, and that procedures 

be written and followed describing in 

sufficient detail the control procedures 

employed for the issuance of labeling. 

Proposed paragraph (b) would require 

use of procedures to reconcile the 

quantities of labeling issued, used, and 

returned, and would require evaluation 

of discrepancies found between the 

quantity of medical gas and the quantity 

of labeling issued when such 

discrepancies are outside narrow preset 

limits based on historical operating 

data. Such discrepancies would need to 

be investigated in accordance with 

proposed § 213.192. 

Labeling reconciliation is proposed to 

be waived for cut or roll labeling if a 100 

percent examination for correct labeling 

is performed in accordance with 

proposed § 213.122(f)(2) (100 percent 

electronic or electromechanical 

examination of labeling). Labeling 

reconciliation would also be waived for 

360° wraparound labels on portable 

cryogenic medical gas containers. FDA 

is proposing to retain the label 

reconciliation requirement for medical 

gases except in the circumstances in 

which it would be waived, consistent 

with § 211.125, because label reuse may 

introduce risk into the labeling process 

that would not be present with 

unlabeled containers. While reuse of 

cylinder labels and 100 percent 

verification of hand-applied labels on 

medical gas cylinders through visual 

inspection provides some assurance of 

correct labeling, such examination does 

not preclude the need for quality 

assurance steps, such as label 

reconciliation, to be built into the 

labeling process. The periodic 

replacement of cylinder labels that are 

worn, damaged or missing introduces 

variability and subjectivity into the 

determination of which and how many 

containers need new labels, potentially 


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increasing the risk of mislabeling. The 

Agency considers label reconciliation 

procedures, designed commensurate 

with the risk, to be essential to the 

overall control of labels to minimize the 

potential for mix-ups. 

Paragraph (c) would require that 

excess lot number stickers or decals 

bearing lot or control numbers be 

discarded. FDA expects that this will 

help prevent product mix-ups or the 

inclusion of incorrect lot information on 

a gas container. Finally, paragraph (d) 

would exempt bulk or transport 

containers (as defined in proposed 

§ 201.161(c)(3)) from § 213.125. FDA 

believes that it is not necessary for this 

provision to apply to bulk or transport 

containers because end users are 

generally not expected to handle or use 

these containers to directly administer 

the gas to patients. 

Proposed § 213.130 would require 

that written procedures be developed 

and followed to assure that the correct 

labels, labeling, and packaging materials 

are used for medical gases, similar to the 

requirements in § 211.130. These 

procedures would be required to 

incorporate the following features. 

Paragraph (a) would require physical or 

spatial separation from operations on 

other products. FDA expects this 

proposed requirement would help to 

prevent mix-ups. Additionally, FDA 

proposes to use the term ‘‘other 

products’’ because some firms that 

manufacture medical gases may also 

manufacture gases for non-medical 

purposes, such as for industrial use. 

Paragraph (b) would require that filled, 

unlabeled containers of medical gases 

that are set aside be identified and 

handled for future labeling operations to 

preclude mislabeling of individual 

containers, lots, or portions of lots. It 

would not be necessary to apply 

identification directly to each 

individual container, but the firm would 

need to be able to identify the name, 

strength, quantity of contents, and lot or 

control number of such containers. For 

example, this could be done through 

signage in the area in which the 

containers are stored. 

FDA proposes in paragraph (c) that 

the medical gas be identified with a lot 

or control number that permits 

determination of the history of the 

manufacture and control of the batch. 

The lot or control number of the 

medical gas could be identified by use 

of a separate identification sticker or 

decal and would not need to be 

contiguous with other labeling 

information. Paragraph (d) would 

require, like the existing requirement in 

§ 211.130(d), that packaging and 

labeling materials be examined for 

suitability and correctness before 

packaging operations, and that such 

examination be documented in the 

batch production record. FDA proposes 

to add a provision allowing product 

labels, including 360° wraparound 

labels, to be reused if they meet all 

applicable labeling requirements, all 

information on the label is legible, and 

the label is in good condition. 

Paragraph (e) proposes the same 

requirements as those that currently 

apply under existing § 211.130(e). 

Under this proposal, firms would be 

required to inspect packaging and 

labeling facilities immediately before 

use to assure that all medical gases have 

been removed from previous operations. 

Moreover, this proposal would require 

inspection to assure that packaging and 

labeling materials unsuitable for 

subsequent operations have been 

removed, and the results of such 

inspection have been documented in the 

batch production records. 

FDA proposes paragraph (f), which 

would exempt bulk or transport 

containers (as defined in proposed 

§ 201.161(c)(3)) from the requirements 

of § 213.130, provided they are 

identified with the name of the product 

contained therein and accompanied by 

documentation identifying the product 

as meeting applicable compendial 

standards. It is unnecessary for bulk and 

transport containers to bear the 

information required by this section 

because patients and healthcare 

providers are not expected to utilize 

them directly to administer a gas. 

9. Holding and Distribution 

Subpart H would establish holding 

and distribution requirements. Proposed 

§ 213.150 would contain requirements 

for warehousing and distribution 

procedures. Paragraph (a) would require 

that written procedures be established 

and followed describing the distribution 

of medical gases. Such procedures 

would be required to include a system 

by which the distribution of each lot can 

be readily determined to facilitate any 

necessary recalls. FDA believes that the 

requirement in § 211.150(a) to distribute 

the oldest approved stock of a drug 

product first (often called the ‘‘first-in, 

first-out’’ requirement) is unnecessary to 

include in this proposed rule, as 

medical gases are generally not expected 

to expire or degrade under ordinary 

storage conditions. Paragraph (b) would 

require that written procedures be 

established and followed regarding 

warehousing of medical gases, similar to 

the requirements in § 211.142(a). These 

procedures would be required to 

include procedures for the quarantine of 

such gases before release by the quality 

unit. Unlike the current requirements in 

§ 211.142(b), the proposed requirements 

would not include procedures regarding 

the conditions of drug storage because 

sealed, closed containers are generally 

expected to protect the gas inside from 

a wide range of environmental 

conditions. Moreover, the Agency 

believes the requirements in proposed 

§§ 213.42 and 213.80 would sufficiently 

address storage and handling. 

10. Laboratory Controls 

Subpart I proposes requirements for 

laboratory controls. In proposed 

§ 213.160, FDA would incorporate the 

existing requirements in § 211.160, with 

one difference in § 213.160(b)(4). 

Proposed paragraph (a) would require 

that the establishment of any 

specifications, standards, sampling 

plans, test procedures, or other 

laboratory control mechanisms required 

by subpart I, including any changes, be 

drafted by the appropriate 

organizational unit and reviewed and 

approved by the quality unit. Such 

requirements would have to be followed 

and documented at the time of 

performance, and deviations recorded 

and justified. 

Under proposed paragraph (b), 

laboratory controls would be required to 

include the establishment of 

scientifically sound and appropriate 

specifications, standards, sampling 

plans, and test procedures designed to 

assure that components, medical gas 

containers, closures, in-process 

materials, labeling, and medical gases 

conform to appropriate standards of 

identity, strength, quality, and purity, 

and include the following four 

elements: 

• Determination of conformity to 

applicable written specifications for the 

acceptance of each lot within each 

shipment of components, medical gas 

containers and closures, and labeling 

used in the manufacture, processing, 

packing, or holding of a medical gas. 

The specifications would be required to 

include a description of the sampling 

and testing procedures used. Samples 

would need to be representative and 

adequately identified. Such procedures 

would also need to require appropriate 

retesting of any component, medical gas 

container, or closure that is subject to 

deterioration. See § 213.160(b)(1). 

• Determination of conformance to 

written specifications and a description 

of sampling and testing procedures for 

in-process materials. Such samples 

would need to be representative and 

properly identified. See § 213.160(b)(2). 

• Determination of conformance to 

written descriptions of sampling 

procedures and appropriate 


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specifications for medical gases. Such 

samples would need to be 

representative and properly identified. 

See § 213.160(b)(3). 

• The calibration of instruments, 

apparatus, gauges, and recording 

devices at suitable intervals in 

accordance with an established written 

program containing specific directions, 

schedules, limits for accuracy and 

precision, and provisions for remedial 

action in the event accuracy and/or 

precision limits are not met, or 

verification of such calibration. 

Instruments, apparatus, gauges, and 

recording devices not meeting 

established specifications would not be 

able to be used. See § 213.160(b)(4). This 

differs from § 211.160(b)(4) in that FDA 

proposes to require calibration or 

verification of calibration of 

instruments, apparatus, gauges, and 

recording devices. In the medical gas 

industry, some downstream entities may 

not conduct their own calibration. FDA 

believes that verification of calibration 

is necessary if the entity does not 

conduct its own calibration. 

Proposed § 213.165 would contain 

requirements for testing and release of 

medical gases for distribution. 

Paragraph (a) would require that there 

be appropriate laboratory determination 

of satisfactory conformance to final 

specifications for each batch, including 

the identity and strength, prior to 

release. The Agency omitted the 

requirements in § 211.165(b) from its 

proposal because generally there is less 

risk of microbial contamination for 

medical gases. 

Section 213.165(b) would require that 

any sampling and testing plans be 

described in written procedures, and 

that such written procedures be 

followed. Such plans would need to 

include the method of sampling, the 

number of units per batch, and 

acceptance criteria. FDA believes it is 

unnecessary to incorporate in proposed 

§ 213.165(b) the more detailed 

requirements regarding acceptance 

criteria described in § 211.165(d). 

Proposed § 213.165(c) would require 

that the accuracy, sensitivity, 

specificity, and reproducibility of test 

methods employed by the firm be 

validated and documented. This may be 

done in accordance with proposed 

§ 213.194(a)(2). Further, the suitability 

of all testing methods would need to be 

verified under actual conditions of use. 

FDA proposes § 213.165(d), which 

would require rejection of medical gases 

that fail to meet established standards or 

specifications and any other relevant 

quality criteria. This proposal is 

generally consistent with the 

requirements described in § 211.165(f), 

but FDA is not proposing to include the 

provision stating that reprocessing may 

be performed or the requirements for 

using reprocessed material. The Agency 

is not aware of reprocessing that occurs 

for medical gases. However, we 

welcome comment on this issue, 

including any example scenarios in 

which such gases are reprocessed. 

Finally, FDA would clarify in 

§ 213.165(e) that the proposed 

requirements in § 213.165 would not 

apply to the filling of a designated 

medical gas or medically appropriate 

combination via liquid to liquid into a 

container at a delivery site, often 

referred to by industry as ‘‘curbside 

filling.’’ Because such filling operations 

are not expected to result in any 

material change in the gas being filled 

(for example, oxygen continues to be 

oxygen after filling), the gas is not 

expected to fall out of conformance with 

the requirements in § 213.165 if it is in 

conformance earlier in the distribution 

chain and stored under proper 

conditions. 

FDA proposes in § 213.166 stability 

testing and expiration dating 

requirements for medical gases 

marketed under applications submitted 

under section 505 or 512 of the FD&C 

Act. Under proposed paragraph (a), any 

stability testing performed and any 

expiration date established for medical 

gases marketed under applications 

submitted under section 505 or 512 of 

the FD&C Act would need to be in 

accordance with the proposed 

requirements described in subsection 

(b), subject to the conditions established 

in their approved applications, if any. 

Under this proposed rule, stability 

testing and expiration dating would not 

be required for all medical gases. 

However, stability testing, expiration 

dating, or both would be required for 

some medical gases (for example, these 

would be necessary when required by 

an approved application for the safe and 

effective use of the drug, or stability 

testing would be necessary when an 

applicant chooses to label its product 

with an expiration date regardless of 

whether one is needed for safe and 

effective use under an approved 

application). FDA believes that this 

proposed requirement would allow for 

flexibility in determining whether 

stability testing, expiration dating, or 

both are necessary for a particular gas. 

Furthermore, specific stability testing 

requirements may vary depending on 

the particular gas. 

Proposed paragraph (b) would contain 

requirements to assure that the medical 

gas meets applicable standards of 

identity, strength, quality, and purity at 

the time of use: 

• The stability testing program would 

need to be designed to assess the 

stability characteristics of the medical 

gas and its container closure system. 

The results of stability testing would 

need to be used in determining 

appropriate storage conditions and any 

expiration dates included on the label. 

The stability program shall include the 

appropriate sample size, test intervals, 

container closure systems, and storage 

conditions for samples retained for 

testing. 

• Any expiration dates included on 

the label would be required to appear in 

accordance with § 201.17. 

• Stability would need to be 

evaluated periodically to ensure that the 

medical gas continues to meet the 

standards for identity, strength, quality, 

and purity stated on the labeling to 

support the expiration date. 

FDA is not proposing stability testing 

or expiration dating requirements for 

designated medical gases, as they are 

not expected to expire or degrade. 

Additionally, the proposed leak testing 

and working gauge requirements in this 

proposed rule are expected to address 

concerns regarding the container closure 

system’s ability to prevent leakage. If a 

designated medical gas manufacturer 

chooses to include an expiration date on 

its container, FDA expects that such a 

date would be determined by 

appropriate stability testing that reflects 

the stability of the gas and the integrity 

of the container closure system. 

11. Records 

Proposed subpart J would contain 

requirements for records. Because FDA 

is not proposing to require the labeling 

of medical gases to bear expiration 

dates, except as proposed in § 213.166, 

the proposed requirements in § 213.180 

differ from the requirements in 

§ 211.180. Paragraph (a) would provide 

that all records that would be required 

under part 213, or copies of such 

records, be readily available for 

authorized inspection during the 

retention period and are subject to 

copying as part of such an inspection. 

The records would be able to be kept at 

either the establishment where the 

activities described in such records 

occurred or at another location from 

which the records can be immediately 

retrieved. Retrieval via computer or 

other electronic means would meet this 

requirement. Per paragraph (b), all 

records would have to be legible, stored 

to prevent deterioration or loss, and 

either original or accurate reproductions 

of original records. Paragraph (c) would 

require that all records that would be 

required to be maintained in 

compliance with part 213 be maintained 


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for at least 3 years from the date the 

batch of medical gas is distributed, 

except where otherwise provided. This 

timeframe is the same as that used in 

§ 211.180(a) for over-the-counter drugs 

lacking expiration dating. 

Paragraph (d) would require that 

written records required under part 213 

be maintained so that their data can be 

used for evaluating, at least annually, 

the quality standards of each medical 

gas to determine the need for changes in 

specifications or manufacturing or 

control procedures. Written procedures 

would also have to be established and 

followed for such evaluations. The 

procedures would also be required to 

include provisions for a review of a 

representative number of batches, 

whether approved or rejected, and, 

where applicable, records associated 

with the batch, and a review of 

complaints, recalls, returned or salvaged 

medical gases, and investigations 

conducted under § 213.192 for each gas. 

Under paragraph (e), firms would be 

required to develop written procedures 

for notifying responsible firm officials of 

any recalls, reports of inspectional 

observations by FDA, regulatory actions 

related to good manufacturing practice 

taken by FDA, or any investigations 

resulting from adverse event 

complaints. 

Proposed § 213.182 would require 

that there be a written record of major 

equipment cleaning, maintenance 

(except routine maintenance such as 

lubrication and adjustments), and use. 

These records would be required, as 

part of individual equipment logs, to 

show the date, time, product, and lot 

number of each batch processed. 

Individual equipment logs would not be 

required for equipment dedicated to one 

product, but lots or batches would have 

to follow in numerical order and be 

manufactured in numerical sequence in 

such a case. Also, where dedicated 

equipment is employed, the records of 

cleaning, maintenance, and use would 

be required to be part of the batch 

record. The individuals performing and 

double-checking the cleaning and 

maintenance (or, if the cleaning and 

maintenance is performed using 

automated equipment under § 213.68, 

just the person verifying such cleaning 

and maintenance) would have to date 

and sign or initial the log indicating the 

work was performed. Entries in the log 

would be required to be in 

chronological order. While FDA 

recognizes that cleaning of a closed, 

pressurized system is not always 

appropriate, when it is applicable, it is 

essential to maintain adequate records 

of such cleaning. 

FDA proposes in § 213.184 a more 

limited set of recordkeeping 

requirements for components, medical 

gas containers and closures, and 

labeling than those described in 

§ 211.184. The records would include 

the results of any test or examination 

performed (including those performed 

pursuant to §§ 213.84 and 213.122) and 

the conclusions derived from the test or 

examination; documentation of the 

examination and review of labels and 

labeling for conformity with established 

specifications in accordance with 

§§ 213.122 and 213.130; and the 

disposition of rejected components, 

containers, closures, and labeling. 

Medical gas containers are generally 

reused many times before they are taken 

out of service. FDA believes that the 

proposed requirements in §§ 213.84, 

213.122, and 213.130 to evaluate 

containers and labeling are appropriate 

and sufficient to assure the quality of 

containers and the accuracy and 

legibility of their labels. 

In § 213.186, FDA proposes master 

production and control recordkeeping 

requirements that are more tailored to 

medical gases than the current 

requirements in § 211.186. Paragraph (a) 

would require that master production 

and control records for each medical gas 

be prepared, dated, and signed to assure 

uniformity from batch to batch. 

Paragraph (a) would also require that 

the preparation of such records be 

described in a written procedure, and 

that such written procedure be 

followed. Paragraph (b) proposes to 

require certain information for each 

master production and control record. 

The records would be required to 

include: The product name and 

strength; a list of all components and 

any incoming designated medical gases 

used in manufacturing designated by 

names or codes sufficiently specific to 

indicate any special quality 

characteristics; a description of the 

containers, closures, and packaging 

materials and labels; and complete 

manufacturing and control instructions, 

sampling and testing procedures, 

specifications, special notations, and 

precautions to be followed. 

These proposed requirements differ 

from the requirements in § 211.186 

because of the differences in 

manufacturing and distribution of 

medical gases. For example, because 

medical gas manufacturing generally 

includes some venting of gas, measuring 

calculated excess of component, 

theoretical weight, and theoretical yield 

is infeasible. 

In lieu of the requirements found in 

§ 211.188, FDA proposes § 213.189, 

which would impose batch production 

and control recordkeeping requirements 

for each batch of medical gas produced. 

Paragraph (a) would require batch 

production and control records to be 

prepared for each batch of medical gas 

produced. Paragraph (b) would require 

that batch production and control 

records include documentation that 

each significant step in the 

manufacturing, processing, packing, and 

holding process was accomplished, 

including: 

• Dates and times of each significant 

step, including in-process and 

laboratory tests as applicable. This 

documentation would include any 

prefill, filling, or post-filling 

inspections, which are essential to 

assuring product meets applicable 

standards. 

• A description of the container for 

the medical gas, including the number 

and size of the containers filled as 

applicable. The containers used in 

manufacturing and filling operations 

can vary significantly, so documenting 

the containers is important for tracking 

purposes. 

• Specific identification of each 

component and its source or in-process 

material used as applicable. 

• Measures of components used in 

the course of processing as applicable. 

• Testing results, including any inprocess test results and finished product 

test results. 

• Dated signature or initials of the 

persons performing and directly 

supervising or checking each significant 

event in the operation. 

• Inspection of the packaging and 

labeling area before and after use. 

• Complete labeling control records, 

including specimens or copies of all 

labeling used and label application and 

reconciliation records as appropriate. 

Because labeling does not always need 

to be applied due to the reuse of labels, 

documentation of these labeling control 

activities is important to help prevent 

mix-ups and the incorrect application of 

labeling. 

• Any investigation made according 

to § 213.192. 

Proposed § 213.192 would contain 

production record review requirements 

for medical gases. Under paragraph (a), 

manufacturing production and control 

records, including those for packaging 

and labeling, would need to be reviewed 

and approved by the quality unit to 

determine compliance with all 

established, approved written 

procedures before release or distribution 

of a batch. The quality unit would also 

be required to review production 

records to determine whether errors or 

unexplained discrepancies have 

occurred prior to batch release. If any 


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errors or unexplained discrepancies 

have occurred, or a batch or any 

component of the batch fails to meet 

specifications, the firm would be 

required to conduct thorough 

investigations and take appropriate 

corrective actions. FDA further proposes 

to require a written record of the 

investigation, including the conclusions 

and followup. However, for entities that 

fill at a delivery site, paragraph (b) 

would require that production and 

control records be reviewed and 

approved by the quality unit to 

determine compliance with all 

established, approved written 

procedures within 1 business day after 

fill. FDA believes this additional time is 

needed for reviewing such records 

associated with filling at a delivery site 

because delivery personnel typically 

conduct such filling at multiple 

locations. As such, it is impractical for 

the quality unit to be present at the time 

of filling, and the characteristics of the 

gas are not expected to change during 

the filling process. Therefore, the 

Agency believes it is appropriate for the 

quality unit to review production and 

control records shortly after delivery is 

completed. 

FDA recognizes that, because 

containers and labels are reused many 

times for medical gases, firms are 

generally unable to trace the history of 

a cylinder’s use or identify the root 

cause of a cylinder-related problem. 

Nevertheless, if an error or unexplained 

discrepancy associated with a cylinder 

is identified, or if a cylinder is found 

not to meet any of its specifications, 

FDA believes it is necessary for the firm 

to conduct a thorough investigation to 

identify the problem and take 

appropriate corrective action, such as 

taking a faulty cylinder out of 

circulation. FDA believes this proposal 

would establish production record 

review requirements that would assure 

that medical gases meet the 

requirements of the FD&C Act as to 

safety and have the identity, strength, 

quality, and purity they are purported or 

represented to possess. 

FDA is also proposing § 213.194, 

which would impose laboratory 

recordkeeping requirements. Paragraph 

(a) would require that laboratory records 

related to the manufacture of a medical 

gas include complete data derived from 

all tests necessary to ensure compliance 

with established specifications and 

standards, including examinations and 

assays. Laboratories would have to keep 

a complete record of all data created in 

the course of each test, including the 

records described in paragraphs (a)(1) 

through (4), as follows: 

• A description of the sample, the 

batch or lot number to be tested, the 

date the sample was taken, and the date 

the sample was tested. 

• The test method used, the test 

result, how the results compare with 

established standards of identity, 

strength, quality, and purity for the 

component, container, in-process 

materials (as applicable), and medical 

gas tested, a record of any calculations 

performed and any calculated results, 

and the unit of measurement of the 

result. It would not be necessary to 

provide the actual calculation where the 

result is evident through use of simple 

addition and subtraction (for example 

100 ¥ 0.1 = 99.9). 

• Where applicable, any graphs, 

charts, and spectra from laboratory 

instrumentation, properly identified to 

show the specific component, inprocess material, or medical gas for each 

lot tested. 

• The initials or signature of the 

person performing the test as well as a 

second person showing that the original 

records have been reviewed for 

accuracy, completeness, and 

compliance with established standards. 

Paragraph (b) would require that 

complete records be maintained of any 

modification of an established test 

method. These records would need to 

include the reason for the modification 

and data to verify that the modification 

produced results that are at least as 

accurate and reliable for the material 

being tested as the established method. 

Paragraph (c) would require that 

complete records be maintained of any 

testing and standardization of laboratory 

reference standards, reagents, and 

standard solutions. These requirements 

are the same as those that currently 

apply to medical gases under 

§ 211.194(b) and (c). 

Paragraph (d) would require that 

complete records be maintained of the 

periodic calibration or verification of 

calibration of laboratory instruments, 

apparatus, gauges, and recording 

devices that would be required by 

§ 213.160(b)(4). This paragraph differs 

from § 211.194(d) in that it would allow 

for verification of calibration. It is FDA’s 

understanding that it is common for 

some medical gas equipment to be 

calibrated by a supplier or other entity 

prior to arrival at the laboratory. 

Paragraph (e) would require that 

complete records be maintained of all 

stability testing performed in 

accordance with proposed § 213.166. 

This requirement is consistent with the 

current requirement in § 211.194(e). As 

described above, only a subset of 

medical gases are expected to be subject 

to stability testing requirements, but for 

such gases, documentation of stability 

testing is essential to ensuring that the 

gas will maintain its stability for the 

expected timeframe. 

Under proposed § 213.196, 

distribution records would be required 

to contain the name of the product, the 

lot or batch number, the consignee’s 

contact information, and the date and 

quantity shipped. FDA believes that 

including the lot or batch number is 

essential to properly tracking and 

tracing product in the event a safety 

issue is discovered. Information about 

the dosage form, as required in 

§ 211.196, is not necessary for medical 

gases because the dosage form is always 

‘‘gas.’’ For medical air and medically 

appropriate combinations of designated 

medical gases, the distribution record 

would also need to include the 

percentage of each gas. FDA believes 

that this information is essential to 

prevent mix-ups because the 

concentration of each component would 

be clearly determined. 

Proposed § 213.198 contains proposed 

requirements for complaint files that are 

similar to those requirements that 

currently apply to medical gases under 

§ 211.198. Paragraph (a) would require 

that written procedures be established 

and followed for the receipt and 

handling of all written and oral 

complaints concerning a medical gas. 

These procedures would have to 

include a quality unit review of any 

complaint involving the possible failure 

of a medical gas to meet its specification 

as well as an investigation to determine 

the cause of the failure. An out-ofspecification medical gas (for example, 

a combination containing higher 

quantities of oxygen than intended) 

could result in serious patient harm if 

administered. These procedures would 

also be required to include provisions 

for determining the need for an 

investigation under § 213.192 and 

determining whether the complaint 

represents an event that would need to 

be reported under proposed part 230. 

Paragraph (b) would require that a 

written record of each complaint be 

maintained. This record would have to 

include the name of the medical gas, the 

lot or batch number, the name of the 

complainant, the date the complaint 

was received, the nature of the 

complaint, and the response to the 

complaint. It would also be required to 

include the findings of any investigation 

and followup. If an investigation is not 

conducted, the record would need to 

include the reason that an investigation 

was found not to be necessary and the 

name of the responsible person making 

such a determination. 


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Paragraph (c) would require the 

maintenance of complaint files in a 

manner such that they would be readily 

available for inspection by the firm or 

by FDA during an inspection. 

Complaint files would be required to be 

maintained for at least 1 year after the 

date that the complaint was received or 

for at least 3 years after distribution of 

the medical gas, whichever is longer. 

This proposed record retention period is 

the same as that used in § 211.180(a) for 

certain over-the-counter drugs lacking 

expiration dating and would facilitate 

review and evaluation by the firm of 

information that is received after the 

event, thus facilitating the firm’s ability 

to observe trends over time. 

12. Returned and Salvaged Medical 

Gases 

Subpart K contains proposed 

requirements for returned and salvaged 

medical gases. FDA proposes in 

§ 213.204 to require that returned 

medical gases be identified as such and 

held. Moreover, if the conditions under 

which the returned gases have been 

held, stored, or shipped before or during 

their return, or if the condition of the 

gas, its container, carton, or labeling, as 

a result of storage or shipping, cast 

doubt on its safety, identity, strength, 

quality, or purity, the returned medical 

gas would need to be destroyed unless 

examination, testing, or other 

investigations prove the gas meets 

appropriate standards of safety, identity, 

strength, quality, or purity. These 

requirements would apply to situations 

in which a distributed medical gas is 

sent back to a firm due to a quality 

issue. Firms would need to maintain 

certain records of returned medical 

gases. Further, if the reason for a 

medical gas being returned implicates 

associated batches, an appropriate 

investigation pursuant to proposed 

§ 213.192 would need to be conducted. 

Procedures for holding, testing, and use 

of returned medical gases would need to 

be in writing and followed. Proposed 

§ 213.204 would not apply to the 

routine refilling of a cryogenic medical 

gas containers in the normal course of 

business unless the container was 

returned for a quality issue. 

Proposed section 213.204 is largely 

the same as current § 211.204, with an 

added provision regarding routine 

refilling. FDA believes that the current 

requirements for returned drug product 

are appropriate for medical gases. 

However, the proposed routine refilling 

provision would be essential to address 

the fact that small amounts of gas are 

expected to remain in a returned 

container that will be reused. This 

situation is uncommon for other types 

of drug products, but medical gas 

containers are generally reusable, and 

complete purging of a container is 

impracticable. Another notable 

difference compared to § 211.204 is the 

omission of reprocessing requirements, 

as it is FDA’s understanding that 

reprocessing of returned medical gases 

does not occur. Generally, gases are 

reused if they meet specifications; 

otherwise, they are vented. FDA 

requests comment on this issue. 

Section 213.208 would allow the 

salvaging of medical gases that have 

been subjected to improper storage 

conditions unless the gas’s container 

has been subjected to adverse 

conditions that impact the identity, 

strength, quality, and purity of the 

medical gas, or the integrity of the 

container closure. These requirements 

would apply to situations in which a 

medical gas has been subject to 

improper storage conditions under the 

control of a firm responsible for the 

manufacture, processing, packing, or 

holding of the gas. Scenarios in which 

this may arise include natural disasters, 

facility structural damage (such as a 

building collapse), or exposure to smoke 

in the event of a fire. If there is a 

question whether the medical gas has 

been subjected to improper storage 

conditions, salvaging would only be 

permitted if there is evidence from 

laboratory tests that the gas meets all 

applicable standards of identity, 

strength, quality and purity, and the 

closure is not compromised. Section 

213.208 also would require that firms 

maintain and follow written procedures 

for the holding, testing, and use of 

salvaged medical gases. While medical 

gases in sealed containers are generally 

considered unlikely to be affected by 

adverse conditions, such as natural 

disasters or significant changes in 

temperature, humidity, or pressure, a 

medical gas container could be damaged 

by such circumstances. Therefore, it is 

essential for firms to evaluate any 

containers potentially affected by 

adverse conditions. 

13. Notable Part 211 Provisions FDA 

Does Not Propose To Include in Part 213 

In this section, FDA discusses existing 

CGMP provisions of note that the 

Agency has not proposed for inclusion 

in part 213. In the proposed CGMP 

requirements described above in this 

section, FDA addressed some individual 

requirements in part 211 that the 

Agency has not proposed for inclusion 

in part 213, but this section addresses 

some other sets of requirements that are 

outside the scope of the above 

discussion. We specifically request 

public comment on these areas. 

The requirements in § 211.28(a), (b), 

and (d) regarding personnel 

responsibilities are not included in this 

proposed rule. Medical gases are 

generally manufactured, stored, 

combined, and distributed under 

pressure in closed systems. Therefore, 

the risk of contamination is generally 

lower than for other drugs. FDA believes 

that the other requirements that would 

be established by this proposed rule 

would sufficiently address the risk of 

contamination in medical gases. 

FDA is not proposing to include 

certain buildings and facilities 

requirements from part 211, subpart C, 

in proposed part 213, subpart C 

(specifically §§ 211.44 through 211.58) 

because they are not relevant to the 

manufacture, processing, packing, and 

holding of medical gases, or because the 

proposed requirements in § 213.42 

sufficiently address these issues. For 

example, FDA believes that specific 

lighting requirements are not necessary 

because the risk of lightbulbs breaking 

and contaminating the gas inside a 

closed manufacturing system is remote. 

Moreover, FDA believes that the level of 

lighting at a facility would be 

sufficiently addressed by the 

requirements in § 213.42 to ensure that 

the design, space, and placement of 

equipment in a facility help protect 

against mix-ups (for example, we 

interpret this to mean that, among other 

things, employees have sufficient light 

to read labels). Similarly, specific 

ventilation requirements are not 

necessary because the closed 

manufacturing system for medical gases 

is generally unaffected by external 

factors such as air quality in the facility. 

Other specific requirements in part 211 

regarding plumbing, sewage, and 

sanitation are also unnecessary because 

the risk of contamination is extremely 

low and because the proposed 

requirements in part 213 would 

adequately address these concerns. 

The current requirements for filters in 

§ 211.72 are also not included in this 

proposed rule. Because medical gases 

are not administered as injectable drugs, 

the requirements in § 211.72 are not 

relevant. FDA seeks comment on the 

need for filter requirements. 

Because medical gases are generally 

not expected to expire or degrade under 

ordinary storage conditions, FDA does 

not believe it is necessary to include in 

this proposed rule the requirements in 

§ 211.86 regarding using the oldest 

approved stock first or § 211.87 

regarding retesting product that has 

been stored for long periods of time or 

whose containers have been exposed to 

air. 


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FDA is not proposing to include a 

calculation of yield requirement similar 

to § 211.103. Gas loss is expected during 

manufacturing and can be variable even 

under normal operating conditions. The 

requirements proposed in part 213 

would be sufficient to determine that 

the medical gas in the container is the 

amount and type indicated by the label 

and required by the final product 

specifications. Therefore, such a 

requirement would not provide useful 

information to firms or FDA. 

FDA is not proposing to include an 

equipment identification requirement 

similar to § 211.105. Because equipment 

used for medical gas manufacturing is 

expected to be specific to the gas being 

manufactured, there is typically no 

changeover of machinery for firms to 

track. Accordingly, FDA does not 

believe such a requirement is necessary 

to assure the safety, identity, strength, 

quality, and purity of medical gases. 

FDA is not proposing to include time 

limitations on production similar to 

§ 211.111 because medical gases are 

generally not expected to expire or 

degrade under ordinary storage 

conditions. FDA also is not proposing to 

include requirements regarding the 

control of microbiological 

contamination similar to § 211.113 

because the risk of contamination is 

extremely low for these products. 

FDA is not proposing to include a 

requirement similar to § 211.115, which 

establishes requirements for 

reprocessing. The Agency is not aware 

that reprocessing occurs for medical 

gases. Rather, it is FDA’s understanding 

that gases not meeting specifications 

generally would be vented. However, as 

mentioned above, we welcome 

comment on this issue, including any 

example scenarios in which medical 

gases are reprocessed. 

FDA is not proposing to include the 

drug product inspection requirements in 

§ 211.134. Because cylinders are reused 

many times, FDA believes that the 

labeling inspection provisions in 

proposed § 213.122(f) would assure 

proper product labeling. 

FDA is not proposing to include the 

reserve sampling requirements in 

§ 211.170 because the requirements in 

§ 211.170 are not appropriate for 

medical gases. The proposed sampling 

requirements elsewhere in part 213 

would be sufficient to address sampling 

for in-process and finished medical 

gases. 

14. Proposed Revisions to 21 CFR Part 

4 CGMP Requirements 

FDA recognizes that some medical 

gases are marketed as part of a 

combination product. For example, a 

medical gas may be marketed with a 

device constituent part (for example, a 

portable liquid oxygen unit or a 

pressure regulator). However, a gas 

cylinder with a simple on/off valve (i.e., 

without a pressure regulator) would 

generally not be considered a device. 

Combination products are subject to 

part 4, subpart A (21 CFR part 4, subpart 

A), which clarifies the application of 

CGMP regulations to combination 

products and provides a streamlined 

approach to demonstrate CGMP 

compliance for facilities that 

manufacture co-packaged or singleentity combination products. 

FDA intends to amend part 4, subpart 

A to reflect the new requirements for 

medical gases under part 213 and clarify 

how to comply with part 4, as amended. 

FDA proposes to include in 21 CFR 4.2 

a definition of the term ‘‘medical gas’’ 

consistent with the definition in 

proposed part 213, as well as a 

definition of ‘‘medical gas CGMPs’’ that 

refers to part 213. 

FDA also proposes to revise § 4.3(a) 

(21 CFR 4.3(a)) to account for 

combination products that contain a 

medical gas. For such products, part 213 

would apply rather than parts 210 and 

211, as described in proposed new 

§ 4.3(e). 

FDA proposes to include in § 4.4(b) 

(21 CFR 4.4(b)) specific provisions for 

combination products that include a 

medical gas as a drug constituent part to 

enable use of a streamlined approach for 

designing and implementing a CGMP 

operating system that complies with 

CGMP requirements for medical gasdevice combination products akin to the 

streamlined approaches available for 

other drug-device combination 

products. FDA believes that when a 

manufacturer of a medical gas-device 

combination product demonstrates that 

its CGMP operating system complies 

with part 213 in full, the provisions 

from part 820 (21 CFR part 820), with 

which manufacturers must demonstrate 

compliance, should be the same as those 

currently listed in § 4.4(b)(1) because 

part 213 covers the same general areas 

as part 211, and FDA is not aware of 

device characteristics that would 

necessitate a different approach. If a 

medical gas-device combination product 

manufacturer demonstrates that its 

CGMP operating system complies with 

part 820 in full, FDA believes that the 

following proposed requirements from 

part 213 would be appropriate to ensure 

that critical aspects of medical gas 

production are addressed: 

• Section 213.84. Testing and 

approval or rejection of components, 

containers, and closures. 

• Section 213.94. Medical gas 

containers and closures. 

• Section 213.122. Materials 

examination and usage criteria. 

• Section 213.165. Testing and 

release for distribution. 

• Section 213.166. Stability testing 

and expiration dating for medical gases 

marketed under applications submitted 

under section 505 or 512 of the FD&C 

Act. 

• Section 213.204. Returned medical 

gases. 

• Section 213.208. Salvaging of 

medical gases. 

FDA proposes to make other 

conforming edits as needed, such as 

revising § 4.4(e) to include a reference to 

part 213, and to clarify (where 

appropriate) throughout part 4, subpart 

A the requirements for medical gases. 

FDA specifically seeks comment on 

this proposal, including: (1) Which part 

213 provisions should be included in 

the list of provisions for combination 

products containing a medical gas as a 

drug constituent part for which the 

CGMP operating system has been shown 

to comply with part 820; (2) whether the 

part 820 provisions listed in § 4.4(b)(1) 

should be revised for combination 

products containing a medical gas as a 

drug constituent part to include other 

820 requirements or to remove certain 

existing references to part 820 call-outs; 

and (3) whether it is appropriate to 

permit manufacturers to have the option 

of choosing to demonstrate compliance 

with part 213 in full along with the part 

820 call-out provisions or compliance 

with part 820 in full along with the part 

213 call-out provisions. 

The Agency believes that part 4, 

subpart A helps ensure appropriate 

implementation of CGMP requirements 

for combination products while 

avoiding unnecessary redundancy in 

CGMP operating systems for these 

products, and that, given the benefits of 

the approach in part 4, subpart A, it 

should include combination products 

that contain a medical gas. FDA expects 

that sponsors of medical gases 

submitted under section 505 of the 

FD&C Act with a delivery system are 

already aware that they are producing a 

combination product, and as such 

should already be familiar with the 

requirements in part 4, subpart A. For 

firms that combine a designated medical 

gas or medically appropriate 

combination of designated medical 

gases with a finished, off-the-shelf 

device, FDA expects that the burden for 

complying with the device CGMP 

requirements would be relatively low. 

In some cases, firms may be able to 

leverage information from their device 

supplier to demonstrate compliance 


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with device call-outs. Additionally, 

some device provisions are not expected 

to apply in all cases; some class I 

devices are exempt from the design 

control requirements in 21 CFR 820.30, 

and the installation and servicing 

requirements in 21 CFR 820.170 and 

820.200, respectively, are not applicable 

to all devices. 

C. Proposed Certification and Annual 

Reporting Provisions 

The proposed rule would establish, 

within new part 230, regulations setting 

forth the requirements for obtaining 

certification of a designated medical gas 

pursuant to section 576 of the FD&C 

Act. Since the passage of FDASIA, many 

applicants have sought marketing 

authorization for a designated medical 

gas under section 576 of the FD&C Act, 

and this proposed rule would codify 

that process in FDA’s regulations while 

also providing additional clarity where 

necessary. As proposed, part 230 would 

contain the requirements for filing a 

certification request for a designated 

medical gas for human use, animal use, 

or both. FDA is also proposing to make 

certain provisions in parts 314 and 514 

inapplicable to designated medical 

gases, given that part 230 would apply 

instead. 

Sections 575 and 576 of the FD&C Act 

also authorize FDA to deem certain 

medical gases not listed in section 

575(1)(A) through (G) to be designated 

medical gases (FD&C Act section 

575(1)(H)) and to certify designated 

medical gases or medically appropriate 

combinations of such gases for certain 

indications for use not listed in section 

576(a)(3)(A)(i)(I) through (VII) (FD&C 

Act section 576(a)(3)(A)(i)(VIII)). The 

Agency is not proposing regulations 

implementing these provisions as part 

of this rulemaking because the Agency 

does not expect to deem additional 

medical gases to be designated medical 

gases at this time. In addition, the 

Agency does not expect to certify 

designated medical gases for indications 

beyond those currently described in 

section 576 of the FD&C Act at this time. 

If, in the future, FDA decides it would 

be appropriate to deem additional 

medical gases to be designated medical 

gases or to certify designated medical 

gases or medically appropriate 

combinations of such gases for 

additional indications for use, FDA 

expects to undertake such actions 

without the need for further rulemaking. 

FDA also notes that section 575(1)(F) 

of the FD&C Act provides that carbon 

monoxide is a designated medical gas if 

it ‘‘meets the standards set forth in an 

official compendium.’’ Section 201(j) of 

the FD&C Act defines ‘‘official 

compendium’’ to include the U.S. 

Pharmacopeia (USP), the official 

Homeopathic Pharmacopeia of the 

United States (HPUS), the official 

National Formulary (NF), or any 

supplement to any of them. There is 

currently no monograph in the USP or 

NF for carbon monoxide. There is a 

HPUS monograph for carbon monoxide, 

though it is inapplicable to carbon 

monoxide as a designated medical gas 

for use in lung diffusion testing. FDA 

does not intend to object to the 

marketing of carbon monoxide for use in 

lung diffusion testing as long as the 

product conforms to one of the 

alternatives in the Center for Drug 

Evaluation and Research’s Manual of 

Policies and Procedures 5310.7 Rev. 1, 

Acceptability of Standards from 

Alternative Compendia (BP/EP/JP) (Ref. 

10). This proposed approach is 

consistent with the draft policy 

described in the draft guidance for 

industry entitled ‘‘Certification Process 

for Designated Medical Gases’’ (Ref. 1). 

If and when a monograph entitled 

‘‘Carbon Monoxide’’ is added to the USP 

or NF, FDA expects original 

manufacturers that wish to continue 

marketing carbon monoxide to promptly 

submit a certification request. 

1. Definitions 

Proposed § 230.3(b)(2) defines the 

term ‘‘applicant.’’ An applicant is 

proposed to be defined as any person or 

entity who submits a certification 

request for a designated medical gas 

under part 230, including supplements. 

This is generally the original 

manufacturer. An applicant would also 

include any person or entity who owns 

a granted certification for a designated 

medical gas under part 230. This 

definition is generally consistent with 

FDA’s use of the term ‘‘applicant’’ with 

regard to NDAs and ANDAs (see 21 CFR 

314.3(b)), as well as NADAs and 

ANADAs (see 21 CFR 514.3). 

FDA also proposes to define 

‘‘certification request’’ as a submission 

under section 576 of the FD&C Act 

requesting certification of a medical gas 

as a designated medical gas. After a 

certification request is deemed to be 

granted, a designated medical gas is 

deemed, alone or in combination, as 

medically appropriate, with another 

designated medical gas or gases for 

which a certification or certifications 

have been granted, to have in effect an 

approved application under section 505 

or 512 of the FD&C Act, subject to all 

applicable postapproval requirements, 

for the applicable indications for use 

described in section 576(a)(3)(A)(i)(I) 

through (VIII) of the FD&C Act. 

FDA proposes to define ‘‘FDA or 

Agency’’ to mean the Food and Drug 

Administration, consistent with other 

Agency regulations. 

2. General Requirements for All 

Certification Submission Types 

Proposed § 230.50 would establish the 

general requirements related to 

designated medical gas certification 

requests. The requirements would apply 

to all submission types. Proposed 

§ 230.50(a)(1) would provide that the 

certification process described in part 

230, subpart B applies to designated 

medical gases for the indications 

described in section 576(a)(3)(A)(i) of 

the FD&C Act. Currently, manufacturers 

who intend to market medical gases that 

do not meet the definition of designated 

medical gas, or who intend to market 

designated medical gases for indications 

not described in section 576(a)(3)(A)(i) 

of the FD&C Act, must obtain approval 

of that medical gas under part 314 or 

part 514, or both, as applicable. For 

example, if an applicant intends to 

market nitrous oxide for a use other 

than analgesia (see section 

576(a)(3)(A)(i)(III) of the FD&C Act), the 

certification process in proposed part 

230 would not be available for that drug 

product at this time. If FDA deems 

additional indications for use 

appropriate under section 

576(a)(3)(A)(i)(VIII) of the FD&C Act, the 

certification process could extend to 

designated medical gases for those uses. 

However, as of the date of this proposed 

rule, FDA has not deemed any 

additional indications for use to be 

appropriate for any designated medical 

gases. 

Also in § 230.50(a)(1), FDA proposes 

to require any person who seeks to 

initially 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 


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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 § 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 § 213.82.) 

Proposed § 230.50(a)(2) would 

describe the relationship between the 

proposed certification requirements in 

part 230 and parts 314 and 514. 

Proposed § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 230.50(b)(6), if the 

Agency deems any other information 


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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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 230.100(b), FDA proposes 

the following grounds for denying a 

submission: 


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• 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 § 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 § 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 

§ 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 § 230.105 would provide 

that, unless FDA makes one of the 

findings described in § 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 § 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 § 314.200 (21 

CFR 314.200), § 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 wellcontrolled 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 § 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 § 314.200, 

§ 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 


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7FDA 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 § 314.1(c) to address any new or 

modified provisions added by that rulemaking that 

would not apply to designated medical gases. 

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 § 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 § 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 § 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. 

The following provisions in § 314.81 

(21 CFR 314.81) also would continue to 

apply: 

• § 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; 

• § 314.81(c), which addresses 

submitting information related to 

multiple applications and patient 

identification requirements; and 

• § 314.81(d), which authorizes FDA 

to withdraw approval of an application 

for failure to make reports required 

under § 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 

§ 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 

§ 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 § 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 § 230.3(a) would 

incorporate relevant definitions from 

sections 201 and 575 of the FD&C Act. 

Additionally, FDA proposes several 

additional definitions in § 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 § 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 ‘‘lifethreatening adverse event’’ to mean any 


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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 § 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 § 230.205 would also contain 

requirements for identifying a FAR 

submission. 

Proposed § 230.205 is generally 

consistent with the FAR requirements in 

§ 314.81(b)(1). FDA proposes to 

establish § 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 § 230.210 would contain 

general requirements for reporting 

adverse events related to designated 

medical gases. 

Proposed § 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 §§ 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 § 230.220 and 

the animal reporting requirements in 

§ 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 § 230.220 would apply, 

but the proposed requirements in 

§ 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 § 230.230 would apply, 

but the proposed requirements in 

§ 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 § 230.230 would apply, 

but those in § 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 § 230.210(b)(1), 

reports or information submitted by 

applicants or nonapplicants (and any 

release by FDA of such reports or 

information) under § 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 

§ 230.210(b)(2), applicants and 

nonapplicants would not need to admit, 

and they could deny, that the report or 

information submitted under § 230.220 

or § 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 § 230.220 would contain 

requirements for submission of ICSRs 

associated with the use of a designated 

medical gas in humans. Under proposed 

§ 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 § 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 § 230.220(a)(1) is 


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15 calendar days. In contrast to 

§ 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 § 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 

§ 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 § 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 § 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 

§ 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 § 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 previouslysubmitted 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 § 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-oflife care or to patients with a lifethreatening 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 

§ 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 

§ 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 

§ 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 


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FDA can process, review, and archive, 

as described in § 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 § 314.80(g)(1), as 

designated medical gases would be 

expected to use the same electronic 

reporting mechanism. Under 

§ 230.220(c)(1)(ii), applicants and 

nonapplicants would be able to request 

in writing a temporary waiver of the 

requirements in § 230.220(c)(1)(i), as 

described in § 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 § 314.80(g)(1). ICSRs 

submitted under § 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 

§ 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 crossreferencing 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 § 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 

§ 314.80(f)(5)(i) and (ii) into one bullet. 

Fifth, we propose to clarify in 

§ 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 

§ 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 § 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 

§ 230.220 for the surveillance, receipt, 

evaluation, and reporting of adverse 

event information. This proposed 

requirement is generally consistent with 

existing requirements in § 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 § 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 


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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 § 314.80(i), though 

FDA proposes to expand these 

requirements to nonapplicants. 

5. Animal Designated Medical Gas 

Adverse Event Reporting Requirements 

Proposed § 230.230 would contain 

requirements for submission of adverse 

event reports related to the use of a 

designated medical gas in animals. 

Proposed § 230.230(a) would govern the 

types of reports that would be required 

to be submitted to FDA. 

Under proposed § 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 § 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 § 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 

§ 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. 


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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

Category Primary 

estimate 

Low 

estimate 

High 

estimate 

Units 

Notes Year 

dollars 

Discount 

rate 

(%) 

Period 

covered 

Benefits: 

Annualized Monetized $millions/year .................. $3.24 

3.43 

$0.00 

0.00 

$6.43 

6.86 

2020 

2020 

7 

3 

10 

10 

Most benefits are cost savings to industry while the 

remaining are cost savings for FDA due to a 

more streamlined inspection process. 

Annualized Quantified .......................................... ..................

..................

..................

..................

..................

..................

..................

..................

7 

3 

..................

..................

Qualitative ............................................................ .................. .................. .................. .................. .................. ..................


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TABLE 1—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF THE PROPOSED RULE—Continued 

Category Primary 

estimate 

Low 

estimate 

High 

estimate 

Units 

Notes Year 

dollars 

Discount 

rate 

(%) 

Period 

covered 

Costs: 

Annualized Monetized $millions/year .................. 3.03 

2.88 

1.38 

1.23 

4.95 

4.77 

2020 

2020 

7 

3 

10 

10 

Annualized Quantified .......................................... ..................

..................

..................

..................

..................

..................

..................

..................

7 

3 

..................

..................

Qualitative ............................................................ .................. .................. .................. .................. .................. ..................

Transfers: 

Federal Annualized Monetized $millions/year ..... ..................

..................

..................

..................

..................

..................

..................

..................

7 

3 

..................

..................

From/To ............................................................... From: To: 

Other Annualized Monetized $millions/year ........ ..................

..................

..................

..................

..................

..................

..................

..................

7 

3 

..................

..................

From/To ............................................................... From: To: 

Effects: 

State, Local or Tribal Government: None. 

Small Business: Not significant. 

Wages: None. 

Growth: None. 

FDA conducted a regulatory 

flexibility analysis of the impact of the 

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-fdaregulations. 

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 thirdparty 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. 


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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

Activity; proposed CFR section Number of 

respondents 

Number of 

disclosures per 

respondent 2

Total annual 

disclosures 2

Average burden 

per disclosure Total hours 

Labeling of bulk or transport containers used to hold designated 

medical gases; § 201.161(b).

1,696 2.36 4,000 0.1 (6 minutes) ......... 400 

On the container label, identify the owner of 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; § 201.328(d).

1,696 2.36 4,000 0.1 (6 minutes) ......... 400 

Total .............................................................................................. ........................ .............................. 8,000 ................................... 800 

1There are no capital costs or operating and maintenance costs associated with the information collection. 

2Totals 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 

§ 201.161(a). However, to prevent mixups, 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 § 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

Activity; proposed CFR section Number of 

recordkeepers 

Number of 

records per 

recordkeeper 2

Total annual 

records 2

Average burden 

per recordkeeping Total hours 

New Start Up SOP; § 213.42 ................................................................. 1,696 1 1,696 13 ................................ 22,048 

SOP Maintenance; § 213.42 .................................................................. 1,696 1 1,696 0.65 (39 minutes) ....... 1,102 

New Start Up SOP; § 213.208 ............................................................... 1,696 1 1,696 13 ................................ 22,048 

SOP Maintenance § 213.208 ................................................................. 1,696 1 1,696 0.65 (39 minutes) ....... 1,102 

Documentation of completion of training; § 213.25(a) ........................... 1,696 10 16,960 0.083 (5 minutes) ....... 1,408 

Consultants’ records of sufficient education, training, and experience, 

or any combination thereof; § 213.34.

1,696 0.336 571 0.5 (30 minutes) ......... 286 

Firms’ records of equipment maintenance and cleaning; § 213.67(c) ... 1,696 43.7676 74,230 0.25 (15 minutes) ....... 18,557 

Maintain records for modifications to automatic, mechanical, and electronic equipment; § 213.68(d).1,696 6.734 11,420 0.25 (15 minutes) ....... 2,855 


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TABLE 3—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1—Continued 

Activity; proposed CFR section Number of 

recordkeepers 

Number of 

records per 

recordkeeper 2

Total annual 

records 2

Average burden 

per recordkeeping Total hours 

Receipt and storage of incoming designated medical gases; 

§ 213.82(a).

1,380 417 575,460 0.25 (15 minutes) ....... 143,865 

Records of rejected components; § 213.89 ........................................... 1,380 24.2 33,400 0.083 (5 minutes) ....... 2,772 

Maintain records for each shipment received of each different labeling 

and packaging material indicating receipt, examination, and whether accepted or rejected; § 213.122(c).

1,696 43.7676 74,230 0.25 (15 minutes) ....... 18,558 

Document results of inspections in the batch production records; 

§ 213.130(e).

1,696 67.334 114,200 0.25 (15 minutes) ....... 28,550 

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; § 213.180(d).

1,696 0.27 457 0.25 (15 minutes) ....... 114 

Maintain record of equipment cleaning and use log maintenance; 

§ 213.182.

1,696 1.76 2,969 0.16 (10 minutes) ....... 475 

Maintain records for components, medical gas containers and closures, and labeling; § 213.184.1,696 2.626 4,454 0.33 (19.8 minutes) .... 1,470 

Maintain master production and control records; § 213.186 ................. 1,696 13.467 22,840 2 .................................. 45,680 

Maintain batch production and control records; § 213.189 .................... 1,696 21.883 37,115 1.3 (78 minutes) ......... 48,250 

Maintain record of the investigation; § 213.192(a) ................................. 1,696 2.69 4,568 1 .................................. 4,568 

Maintain laboratory records; § 213.194(b) through (e) .......................... 1,696 33.667 57,100 0.5 (30 minutes) ......... 28,550 

Maintain distribution records; § 213.196 ................................................ 1,696 33.667 57,100 0.25 (15 minutes) ....... 14,275 

Maintain written records of each complaint; § 213.198(b) ..................... 1,696 6.733 11,420 1 .................................. 11,420 

Total ................................................................................................ .......................... .......................... 1,105,278 ..................................... 417,953 

1There are no capital costs or operating and maintenance costs associated with the information collection. 

2Totals 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 § 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 § 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 § 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 


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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 § 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 

§ 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 § 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 § 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 § 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 

§ 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 § 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 § 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 § 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 § 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 § 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 

§ 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 


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TABLE 4—ESTIMATED ANNUAL REPORTING BURDEN 1

Activity; proposed CFR section Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

Total hours 

Submission of certification requests and certification form that includes any resubmissions and amendments to pending requests; § 230.50 ......................... 5 1 5 3 15 

Submission of supplements to certification requests and other changes; 

§ 230.70 ............................................................................................................. 4 1 4 3 12 

Submission of requests to transfer ownership of certification, including new address and the owner’s submission of any change in the conditions in the 

granted certification; § 230.72 ........................................................................... 2 2 4 2 8 

Annual reports; § 230.80 ....................................................................................... 50 2.16 108 2 216

Field alert reports; § 230.205 ................................................................................ 1,380 0.002 3 8 24

CDER: Submission of ICSRs (§ 230.220(a) through (d)) ..................................... 1,430 0.12 172 6 1,032 

CDER’s maintenance of records for human designated medical gas ICSR requirements (§ 230.220(e)) ................................................................................. 1,430 0.48 686 16 10,976 

CVM’s recordkeeping requirements related to adverse event reports 

(§ 230.230(c)) ..................................................................................................... 1,696 0.0044 7.5 5 37.5 

CVM: Submission of adverse event reports; § 230.230 ....................................... 1,696 0.0044 7.5 5 37.5 

CVM: Waiver request from electronic submission requirement; § 230.230 ......... 1,696 0.0044 7.5 5 37.5 

Total ............................................................................................................... ........................ ........................ 1,004.5 ........................ 12,395.5 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

2Totals have been rounded to the nearest whole number. 

Proposed § 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 § 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 § 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 § 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 § 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 § 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 § 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 §§ 230.220 and 230.230. 

As described under proposed 

§ 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 § 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 

§ 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 § 230.220(b) and acquired a 


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minimum data set for an ICSR for that 

adverse event. 

Under proposed § 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 § 230.220(b) would describe 

the types of ICSRs that applicants and 

nonapplicants would need to report for 

human use. Under proposed 

§ 230.220(b)(1), applicants and 

nonapplicants would be required to 

submit ICSRs for serious adverse events. 

Under proposed § 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 § 230.220(b)(1) 

upon notification by FDA. 

Proposed § 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 § 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 § 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 § 230.230(b)(1) of this section, 

unless the applicant or nonapplicant 

obtains a waiver under proposed 

§ 230.230(b)(2) of this section or FDA 

requests the report in an alternate 

format. 

Under proposed § 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 

§ 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 § 230.230(b)(2), an 

applicant or nonapplicant could 

request, in writing, a temporary waiver 

of the electronic submission 

requirements under proposed 

§ 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 


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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-humandrugs/medical-gas-regulation-publicworkshops. 

3. Lacasse, Y., M. Le ́gare ́, and F. Maltais, ‘‘Ecigarette 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/ecigarette-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/IndustryReport

AnimalAE. 

*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/aboutfda/reports/economic-impact-analysesfda-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 

■ 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. 

■ 2. Revise § 4.2 to read as follows: 

§ 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 § 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 § 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 § 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 § 4.3(a) through (e). 

Device has the meaning set forth in 

§ 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 

§ 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 


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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 § 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 § 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. 

■ 3. Amend § 4.3 by revising paragraphs 

(a), (c), and (d), and adding paragraph 

(e) as follows: 

§ 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. 

■ 4. Amend § 4.4 by: 

■ a. Revising paragraphs (b)(1) 

introductory text, (b)(2) introductory 

text, and (e); 

■ b. Redesignating paragraphs (b)(3) and 

(b)(4) as (b)(4) and (b)(5), respectively; 

and 

■ c. Adding new paragraph (b)(3). 

The revisions and addition read as 

follows: 

§ 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 § 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 

■ 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. 

■ 6. In § 16.1, revise paragraph (b)(2) by 

numerically adding an entry for 

‘‘§ 230.150(b)’’ to read as follows: 

§ 16.1 Scope. 

* * * * * 

(b) * * * 

(2) * * * 

§ 230.150(b), relating to revocation of 

the grant of a certification for a 

designated medical gas. 

* * * * * 

PART 201—LABELING 

■ 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. 

■ 8. In § 201.1, revise paragraph (b) to 

read as follows: 

§ 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 


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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., reprocessing an industrial gas into a 

medical gas), by combining two or more 

distinct medical gases, or by other 

process. 

* * * * * 

■ 9. In § 201.10, revise paragraph (d)(2) 

to read as follows: 

§ 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 °F. (20 °C.), if the 

ingredient is a solid and the drug is a 

liquid; percent volume in volume at 

68 °F. (20 °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 °F. 

(15.56 °C.); and percent volume in 

volume if the ingredient is a designated 

medical gas (as defined in 

§ 201.161(c)(1)). 

* * * * * 

■ 10. In § 201.51, revise paragraphs (a) 

and (b) to read as follows: 

§ 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 

§ 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, fluidounce, and fluid-dram subdivisions 

thereof, or of the liter and milliliter, or 

cubic centimeter, and shall express the 

volume at 68 °F. (20 °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 °F. (20 

°C.). A statement of the measure of the 

contents shall in the case of designated 

medical gases (as defined in 

§ 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 °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 § 201.161(c)(3)), labeling 

for net quantity of contents is not 

required; 

* * * * * 

■ 11. In § 201.105 revise the 

introductory text paragraph to read as 

follows: 

§ 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 § 201.161(c)(1)) or a 

medically appropriate combination of 

designated medical gases and is in 

compliance with § 201.161, or if all the 

following conditions are met: 

* * * * * 

■ 12. Revise § 201.161 to read as 

follows: 

§ 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.’’ 


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(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 § 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. 

■ 13. In § 201.328, revise paragraph 

(a)(1) introductory text and add 

paragraph (d) to read as follows. 

§ 201.328 Labeling of medical gas 

containers. 

(a) * * * 

(1) Each portable cryogenic medical 

gas container must be conspicuously 

marked with a 360° wraparound label 

identifying its contents. Such label must 

meet the requirements of § 213.94(e)(3) 

of this chapter and the following 

additional requirements. 

* * * * * 

(d) Notwithstanding § 201.1, a 

container filled with a designated 

medical gas (as defined in 

§ 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 

■ 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. 

■ 15. In § 210.1, revise paragraphs (a) 

and (b) to read as follows: 

§ 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. 

* * * * * 

■ 16. In § 210.2, revise paragraphs (a) 

and (b) to read as follows: 

§ 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 

■ 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. 

■ 18. In § 211.1, revise paragraph (a) to 

read as follows: 

§ 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 § 213.3(b)(12) of this 

chapter) for administration to humans 

or animals. 

* * * * * 

§ 211.94 [Amended] 

■ 19. In § 211.94, remove paragraph (e). 

■ 20. In § 211.125 revise paragraph (c) to 

read as follows: 

§ 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 

§ 211.192. Labeling reconciliation is 

waived for cut or roll labeling if a 100- 

percent examination for correct labeling 

is performed in accordance with 

§ 211.122(g)(2). 

* * * * * 

■ 21. In § 211.132, revise paragraph 

(c)(1) introductory text to read as 

follows: 


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§ 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: 

* * * * * 

■ 22. In § 211.170, revise paragraph (b) 

introductory text to read as follows: 

§ 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 § 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: 

* * * * * 

■ 23. Revise § 211.196 to read as 

follows: 

§ 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. 

■ 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 

§ 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. 

§ 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. 


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(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 § 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 

§ 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, inprocess 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. 

§ 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. 

§ 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 

§ 213.42 Design and construction features. 

(a)(1) Any buildings and facilities 

used in the manufacture, processing, 

packing, or holding of a medical gas 

shall be of adequate design, including 

having adequate space, for the orderly 

placement of equipment and materials 

to prevent mix-ups between: 

(i) Components; 

(ii) Incoming designated medical 

gases; 

(iii) Medical gas containers and 

closures; 

(iv) Labeling; 

(v) In-process materials; or 

(vi) Medical gases. 

(2) Such buildings and facilities shall 

also allow for adequate cleaning, 

maintenance, and proper operations. 

(b)(1) Operations shall be performed 

within specifically defined areas of 

adequate size. There shall be separate or 

defined areas or such other control 

systems for the firm’s operations as are 

necessary to prevent contamination or 

mix-ups during the course of the 

following procedures: 

(i) Receipt, identification, storage, and 

withholding from use of components, 

incoming designated medical gases, 

medical gas containers and closures, 

and labeling, pending the appropriate 

sampling, testing, or examination by the 

quality unit before release for 

manufacturing or packaging; 

(ii) Holding rejected components, 

incoming designated medical gases, 

medical gas containers and closures, 

and labeling before disposition; 

(iii) Storage of released components, 

incoming designated medical gases, 

medical gas containers and closures, 

and labeling; 

(iv) Storage of in-process materials; 

(v) Manufacturing and processing 

operations; 


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(vi) Packaging and labeling 

operations; 

(vii) Quarantine storage before release 

of medical gases; 

(viii) Storage of medical gases after 

release; and 

(ix) Control and laboratory operations. 

(2) The flow of components, incoming 

designated medical gases, medical gas 

containers and closures, labeling, inprocess 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 

§ 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. 

§ 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. 

§ 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 § 213.180. 

§ 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 

§ 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. 

§ 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. 

§ 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 § 213.89. 


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(b) Firms shall take appropriate 

actions to protect against container and 

closure leaks, which shall include 

performing leak tests on containers and 

closures at the time of fill and after fill 

but prior to release. 

(c) Each component shall be sampled, 

tested, and approved or rejected as 

appropriate prior to use. This 

requirement can be met by performing 

testing for conformance with written 

specifications or by an identity test on 

the component accompanied by an 

acceptable certificate of analysis from 

the supplier, provided that the firm 

establishes and maintains a program to 

ensure the reliability of the supplier’s 

capabilities through appropriate 

assessment and testing procedures. 

§ 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. 

§ 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 

§ 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 § 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 § 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 

§ 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. 

§ 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 inprocess 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. 

§ 213.110 Sampling and testing of inprocess 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 

§ 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 


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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. 

§ 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 

§ 213.192. Labeling reconciliation is 

waived for cut or roll labeling if a 100- 

percent examination for correct labeling 

is performed in accordance with 

§ 213.122(f)(2). Labeling reconciliation 

is also waived for 360° 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 § 201.161(c)(3) of this 

chapter) are exempt from this section. 

§ 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° 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 § 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 

§ 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 

§ 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, 


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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. 

§ 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 

§ 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. 

§ 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 § 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 

§ 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 

§ 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. 

§ 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 doublechecking the cleaning and maintenance 

(or, if the cleaning and maintenance is 

performed using automated equipment 

under § 213.68, just the person verifying 

the cleaning and maintenance done by 

the automated equipment) shall date 

and sign or initial the log indicating that 

the work was performed. Entries in the 

log shall be in chronological order. 

§ 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 § 213.84 or 

§ 213.122) and the conclusions derived 

therefrom. 


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(b) Documentation of the examination 

and review of labels and labeling for 

conformity with established 

specifications in accordance with 

§§ 213.122 and 213.130. 

(c) The disposition of rejected 

components, medical gas containers and 

closures, and labeling. 

§ 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. 

§ 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 inprocess 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 § 213.192. 

§ 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. 

§ 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, inprocess 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 

§ 213.160(b)(4). 

(e) Complete records shall be 

maintained of all stability testing 

performed in accordance with 

§ 213.166. 

§ 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. 

§ 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 § 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 


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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 

§ 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 § 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. 

§ 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. 

■ 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 

§ 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. 

§ 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. 

§ 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 


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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 

§ 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. 

§ 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 

§ 20.45 of this chapter (FDA’s public 

information regulations). 

§ 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 


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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 

§ 230.50. The updated information must 

be submitted no later than 30 calendar 

days after the date the change occurred. 

§ 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 § 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. 

§ 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. 

§ 230.100 FDA review of submissions. 

(a) In reviewing a submission 

pursuant to § 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 § 230.100(b), 

FDA will notify the applicant in writing 

that the submission is denied and 

provide the basis for FDA’s 

determination. 

§ 230.105 When a submission is deemed 

granted. 

Unless FDA makes one of the findings 

described in § 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. 

§ 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 

§§ 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 wellcontrolled investigations as defined in 

§ 314.126 of this chapter, that the 

designated medical gas will have the 

effect it is purported or represented to 


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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 

§§ 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 

§ 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. 

§ 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 § 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 

§ 230.220 or 230.230 constitutes an 

admission that the designated medical 

gas caused or contributed to an adverse 

effect. 

§ 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 


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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 § 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 

§ 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 


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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. 

§ 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 

■ 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. 

■ 27. In § 314.1, redesignate paragraph 

(c) as paragraph (d) and add new 

paragraph (c) to read as follows: 

§ 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) §§ 314.50 through 314.72; 

(2) § 314.80 except paragraph (g); 

(3) § 314.81(a), (b)(1), and (b)(2); 

(4) § 314.90; 

(5) Subpart C; 

(6) §§ 314.100 through 314.162; 

(7) Subpart H; and 

(8) Subpart I. 

* * * * * 

PART 514—NEW ANIMAL DRUG 

APPLICATIONS 

■ 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. 

■ 29. In § 514.1, add an eighth sentence 

to the end of paragraph (a) to read as 

follows: 

§ 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 


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chapter: §§ 514.1(b) through 514.8, 

514.12, and 514.15; and Subpart B. 

* * * * * 

■ 30. Amend § 514.80 by: 

■ a. In the intro text table adding a new 

entry after the sixth row. 

■ b. Adding a new paragraph (a)(6). 

The additions read as follows. 

§ 514.80 Records and reports concerning 

experience with approved new animal 

drugs. 

The following table outlines the 

purpose for each paragraph of this 

section: 

Purpose 21 CFR paragraph and title 

*******

Does this section apply to designated medical gases subject to the certification requirements 

under part 230?.

514.80(a)(6). 

******

(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 


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