Medical Gases — Current Good Manufacturing Practice: Draft Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Medical Gases —
Current Good
Manufacturing Practice
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with
the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) at cder-quality-
policy@fda.hhs.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Veterinary Medicine (CVM)
Office of Inspections and Investigations (OII)
Office of Combination Products (OCP) in the Office of the Commissioner
November 2025
Pharmaceutical Quality/Manufacturing Standards (CGMP)
Revision 2

Medical Gases —
Current Good
Manufacturing Practice
Guidance for Industry
Additional copies are available from:
Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
Phone: 855-543-3784 or 301-796-3400
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Policy and Regulations Staff
Center for Veterinary Medicine
Food and Drug Administration
5001 Campus Dr., College Park, MD 20740-3835
https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Veterinary Medicine (CVM)
Office of Inspections and Investigations (OII)
Office of Combination Products (OCP) in the Office of the Commissioner
November 2025
Pharmaceutical Quality/Manufacturing Standards (CGMP)
Revision 2

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TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
A. 	Definition of Medical Gas and Designated Medical Gas ............................................................ 2
B. 	CGMP Statutory and Regulatory Requirements ........................................................................ 2
III. 	ORGANIZATION AND PERSONNEL ......................................................................... 3
A. 	Quality Unit Responsibilities ........................................................................................................ 3
B. 	Quality Agreements With Suppliers ............................................................................................ 4
C. 	Personnel Qualifications and Responsibilities............................................................................. 5
IV. 	BUILDINGS AND FACILITIES .................................................................................... 5
V. 	EQUIPMENT .................................................................................................................... 6
A. 	Equipment Maintenance and Cleaning........................................................................................ 6
B. 	Automatic, Mechanical, and Electronic Equipment ................................................................... 7
1. Equipment Qualification .................................................................................................................. 7
2. Equipment Calibration..................................................................................................................... 7
3. Computerized Systems ..................................................................................................................... 8
VI. 	CONTROL OF INCOMING DMG, COMPONENTS, AND MEDICAL GAS
CONTAINERS AND CLOSURES.................................................................................. 9
A. 	Receipt of Incoming DMGs and Components ............................................................................. 9
1. Certificate of Analysis ...................................................................................................................... 9
2. Supplier Qualification.................................................................................................................... 10
B. 	Medical Gas Containers and Closures ....................................................................................... 10
1. General Requirements ................................................................................................................... 10
2. Prefill Inspections .......................................................................................................................... 11
VII. 	PRODUCTION AND PROCESS CONTROLS........................................................... 14
A. 	Charge-In of Components and Incoming DMGs ...................................................................... 15
B. 	Sampling and Testing of In-Process Materials.......................................................................... 15
C. 	Vacuum Evacuation of High-Pressure Cylinders ..................................................................... 15
D. 	Filling Procedure Checks ............................................................................................................ 16
1. Temperature and Pressure Readings ............................................................................................. 16
2. Valve Assembly Leak Testing ......................................................................................................... 16
3. Heat-of-Compression Check .......................................................................................................... 17
VIII. 	PACKAGING AND LABELING CONTROL............................................................. 17
A. 	Materials Examination and Usage ............................................................................................. 17
B. 	Labeling Issuance ......................................................................................................................... 18

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C. 	Packaging and Labeling Operations .......................................................................................... 18
IX. 	HOLDING AND DISTRIBUTION ............................................................................... 19
X. 	LABORATORY CONTROLS ...................................................................................... 20
A. 	Instrument Calibration ............................................................................................................... 20
B. 	Testing and Release for Distribution.......................................................................................... 20
C. 	Test Method and Alternative Test Method Validation............................................................. 21
D. 	Stability Testing and Expiration Dating .................................................................................... 22
XI. 	RECORDS ....................................................................................................................... 23
A. 	General Requirements ................................................................................................................. 23
1. Record Retention and Availability ................................................................................................. 23
2. Maintenance of Written Records ................................................................................................... 23
3. Equipment Calibration, Checks, and Inspections .......................................................................... 24
4. Computer Validation Data............................................................................................................. 24
5. Process Validation Data ................................................................................................................ 24
B. 	Equipment Cleaning and Use Log .............................................................................................. 24
C. 	Records for Components, Medical Gas Containers and Closures, and Labeling .................. 25
D. 	Master Production and Control Records................................................................................... 25
E. 	Batch Production and Control Records ..................................................................................... 25
F. 	Production Record Review.......................................................................................................... 27
G. 	Laboratory Records ..................................................................................................................... 27
H. 	Distribution Records.................................................................................................................... 29
I. 	Complaint Files ............................................................................................................................ 29
XII. 	RETURNED AND SALVAGED MEDICAL GASES ................................................. 30
XIII. 	ADAPTERS ..................................................................................................................... 31
GLOSSARY................................................................................................................................. 32

Contains Nonbinding Recommendations
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1
Medical Gases — Current Good Manufacturing Practice	1
Guidance for Industry1
2
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
I. 	INTRODUCTION	14
15
This guidance is intended to assist manufacturers2 of medical gases in complying with current	16
good manufacturing practice (CGMP) requirements. CGMP requirements, when adequately put	17
into practice, help to ensure that medical gases meet appropriate quality standards, and prevent	18
mix-ups, deviations, failures, and errors.3	
19
20
On June 18, 2024, FDA established new and revised regulations tailored to medical gases,4	
21
including CGMP requirements codified in part 213 (21 CFR part 213). Before these	22
requirements were implemented, medical gas manufacturers were subject to the CGMP	23
regulations for finished pharmaceuticals in parts 210 and 211 (21 CFR parts 210 and 211). The	24
draft guidance for industry Current Good Manufacturing Practice for Medical Gases (June	25
2017) described how to comply with those requirements. This guidance revises and replaces the	26
2017 draft and describes how to comply with the CGMP requirements for medical gases in part	27
213. This revision includes among its recommendations clarification on ensuring the reliability	28
of a supplier’s capabilities; protection against container closure leaks; appropriate cleaning and	29
maintenance of buildings, facilities, and equipment used in medical gas manufacture; prevention	30
of labeling and product mix-ups; circumstances requiring stability testing, expiration testing, or	31
both; and handling of returned and salvaged medical gases.	32
33
1 This guidance has been prepared by the Center for Drug Evaluation and Research, in cooperation with the Center
for Veterinary Medicine, the Office of Inspections and Investigations, and the Office of Combination Products in the
Office of the Commissioner at the Food and Drug Administration.
2 The Glossary defines many of the terms for purposes of this guidance. Words or phrases found in the Glossary
appear in bold italics at first mention.
3 For more information about CGMP regulations, see FDA’s Facts About Current Good Manufacturing Practice
(CGMP) web page at https://www.fda.gov/drugs/pharmaceutical-quality-resources/facts-about-current-good-
manufacturing-practice-cgmp.
4 See 89 FR 51738.

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In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	34
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	35
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	36
the word should in Agency guidances means that something is suggested or recommended, but	37
not required.	38
39
40
II. 	BACKGROUND	41
42
A. 	Definition of Medical Gas and Designated Medical Gas	43
44
This guidance applies to medical gases as defined in section 575(2) of the Federal Food, Drug,	45
and Cosmetic Act (FD&C Act) (21 U.S.C. 360ddd(2)). In this section, the term medical gas	46
means a drug that is manufactured or stored in a liquefied, nonliquefied, or cryogenic state and	47
administered as a gas. Medical gases include designated medical gases (DMGs) as defined in	48
section 575(1) of the FD&C Act; medically appropriate combinations of DMGs; medical gases	49
that are approved under an application submitted to FDA under section 505 of the FD&C Act (21	50
U.S.C. 355) for administration to humans or under section 512 of the FD&C Act (21 U.S.C.	51
360b) for administration to animals; and any marketed unapproved drugs that are medical gases.	52
Additionally, some medical gases are marketed as part of a combination product, such as a	53
medical gas marketed with a device constituent part.5	
54
55
Section 575(1) of the FD&C Act defines a DMG as any of the following gases that meet the	56
standards in an official compendium:6 oxygen, nitrogen, nitrous oxide, carbon dioxide, helium,	57
carbon monoxide, and medical air. The United States Pharmacopeia and National Formulary	58
(USP-NF) is the applicable compendium for DMGs. Section 575(1)(H) of the FD&C Act	59
authorizes FDA to add to the list of DMGs any other medical gas it deems appropriate.	60
61
The term medical gas does not include gases that are used as excipients in drug products that are	62
not medical gases (e.g., a propellant for an inhalation drug); gases that serve as processing aids in	63
drug manufacturing (e.g., a nitrogen overlay to prevent oxidation of an active pharmaceutical	64
ingredient during manufacturing); or gases that do not meet the definition of a drug under section	65
201(g)(1) of the FD&C Act (21 U.S.C. 321(g)(1)) (e.g., gases for food or industrial applications,	66
gases used for device testing and verification activities, or gases used to clean or purge medical	67
gas containers or medical gas pipelines). Gases that are not medical gases are outside the scope	68
of this guidance.	69
70
B. 	CGMP Statutory and Regulatory Requirements	71
72
Under section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)), a drug, including a	73
medical gas, is deemed to be adulterated if “the methods used in, or the facilities or controls used	74
5 A combination product is a product comprised of two or more different types of products (i.e., a combination of a
drug, device, and/or biological product with one another), as described in 21 CFR Part 3. A constituent part is a
drug, device, or biological product that is part of a combination product (see 21 CFR 4.2).
6 See section 201(j) of the FD&C Act.

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for, its manufacture, processing, packing, or holding do not conform to or are not operated or	75
administered in conformity with current good manufacturing practice.” Section 501 of the	76
FD&C Act states that “the term current good manufacturing practice includes the	77
implementation of oversight and controls over the manufacture of drugs to ensure quality,	78
including managing the risk of and establishing the safety of raw materials, materials used in the	79
manufacturing of drugs, and finished drug products.” To implement oversight and controls,	80
FDA strongly encourages medical gas manufacturers to establish an effective pharmaceutical	81
quality system (PQS).7 An effective PQS enables the manufacturer’s quality unit to use	82
information obtained about the product and the process to assess risks to manufacturing	83
performance and drug quality and to identify opportunities to address those risks through	84
changes to manufacturing practices.8 This approach reflects the principle that quality should be	85
built into the product; testing alone cannot ensure product quality.	86
87
The regulations implementing the statutory requirements for medical gas are located in part 213.	88
They cover the same categories as the general CGMP drug regulations in parts 210 and 211 for	89
finished pharmaceuticals but reflect differences in how medical gases are manufactured,	90
processed, packed, and held. Differences include the fact that generally, medical gases are	91
manufactured, stored, combined, and distributed under pressure in closed systems, which reduce	92
the risk of contamination (e.g., dust, dirt, moisture, and unacceptable levels of impurities); are	93
not expected to expire or chemically degrade under ordinary storage conditions; and are	94
marketed in containers and closures that are typically reused many times.	95
96
CGMP requirements for combination products are addressed in 21 CFR part 4, subpart A. The	97
combination product CGMP requirements that apply to each constituent part apply to the	98
combination product they constitute. Because of the different CGMP requirements, a	99
streamlined approach to demonstrate CGMP compliance while avoiding unnecessary	100
redundancies is available to combination products, as described in part 4A. The medical gas	101
final rule (see footnote 4) amended certain requirements in part 4A to reflect the new CGMP	102
requirements for medical gases under part 213. The amendments to part 4A include the CGMP	103
requirements applicable to a combination product that includes a drug constituent part that is a	104
medical gas (see 21 CFR 4.3(e)) and how certain combination products that include a drug	105
constituent part that is a medical gas can comply with the CGMP requirements, including use of	106
a streamlined approach (see 21 CFR 4.4).	107
108
109
III. 	ORGANIZATION AND PERSONNEL	110
111
A. 	Quality Unit Responsibilities	112
113
The quality unit is responsible for quality oversight throughout manufacturing. Specifically, the	114
quality unit has the responsibility and authority to approve or reject all components, medical gas	115
7 See the International Council for Harmonisation (ICH) guidance for industry Q10 Pharmaceutical Quality System
(April 2009). We update guidances periodically. For the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
8 See the ICH guidance for industry Q9(R1) Quality Risk Management (May 2023).

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containers and closures, in-process materials, packaging material, labeling, and medical gases,	116
and the authority to review production records to ensure that no errors have occurred or, if errors	117
have occurred, that they have been fully investigated (§ 213.22(a)). Quality unit responsibilities	118
also include approving or rejecting medical gases manufactured, processed, packed, or held	119
under contract by another company (§ 213.22(a)). To fulfill its responsibilities, the quality unit	120
must have available to them adequate laboratory facilities for the testing and approval or	121
rejection of components, medical gas containers and closures, packaging materials, in-process	122
materials, and medical gases (§ 213.22(b)). The quality unit is also responsible for approving or	123
rejecting all procedures or specifications impacting on the identity, strength, quality, and purity	124
of the medical gas (§ 213.22(c)). The quality unit’s responsibilities and procedures must be in	125
writing, and its procedures must be followed (§ 213.22(d)).	126
127
A quality unit’s size and complexity can vary with the size and number of operations for which	128
the quality unit is responsible. For example, a manufacturer that fills only oxygen and has very	129
few employees might have only one person as the quality unit. However, larger manufacturers	130
with establishments at several locations might employ a corporate quality structure to oversee	131
their staff at multiple locations or opt for a separate quality unit at each establishment. Either	132
arrangement may satisfy the requirements of § 213.22 as long as all responsibilities of the quality	133
unit are fulfilled.	134
135
Production personnel and the quality unit should remain independent. Some medical gas	136
manufacturing establishments, however, have limited personnel, and in such cases, the	137
individuals assigned quality unit responsibilities can also perform other functions (§ 213.22(e)).	138
These individuals, regardless of their production functions or other roles, implement the controls	139
and review the results of manufacture to ensure that product quality standards established by the	140
manufacturer are met. Appropriate written controls must be in place to ensure any other	141
functions are performed separately from quality unit responsibilities and that such other	142
functions do not interfere with the quality unit’s responsibilities or subordinate the quality unit’s	143
responsibilities to any other unit (§ 213.22(e)). For example, in instances where there are limited	144
personnel, it would not be appropriate for personnel to check their own work.	145
146
Each person who performs quality unit functions must be adequately trained and experienced in	147
all quality unit tasks assigned (§ 213.25(a)). For additional information see section III.C.,	148
Personnel Qualifications and Responsibilities. In addition, FDA recommends that each person	149
who is part of the quality unit be identified by function and title in written procedures to ensure	150
that quality unit responsibilities are fulfilled.	151
152
B. 	Quality Agreements With Suppliers	153
154
The quality unit’s procedures should provide for written quality agreements with suppliers of	155
goods and services to ensure compliance with CGMP. The quality agreement should clearly	156
describe the provided goods or services, quality specifications, and communication mechanisms	157
between the contracting parties.9 FDA recommends that CGMP responsibilities and the	158
9 For more information on quality agreements, see the guidance for industry Contract Manufacturing Arrangements
for Drugs: Quality Agreements (November 2016). The term quality specifications refers to any quality controls
(e.g., drug specifications, process parameters, responsibilities) established to ensure quality during manufacturing.

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communication processes for reporting complaints and changes that could be critical to drug	159
quality be defined in written quality agreements with suppliers. For example, timely	160
communications about process changes are important because such changes could affect the	161
composition of the gas supplied.	162
163
C. 	Personnel Qualifications and Responsibilities	164
165
Under § 213.25(a), all personnel engaged in the manufacture, processing, packing, or holding of	166
a medical gas, including production personnel, repackers, transfillers, and those driving to	167
customer sites to distribute medical gas, must have sufficient education, training, and experience,	168
or any combination thereof, necessary to perform their assigned functions. Section 213.25(a)	169
specifies the following:	170
171
• 	Such training must be in both the particular operations that the employee performs and in	172
CGMP requirements related to their assigned functions.	173
174
• 	The CGMP training must be conducted by qualified individuals on a continuing basis and	175
with sufficient frequency to assure that employees remain familiar with CGMP	176
requirements applicable to their job functions. To comply with this requirement, FDA	177
recommends that CGMP training be provided at least annually.	178
179
• 	Manufacturers must maintain written documentation, for each employee, of the	180
completion of employee training, including the date of the training, the type of training,	181
and the results of any completion criteria, such as test results.	182
183
Similarly, any consultants hired to advise on medical gas manufacturing must have the necessary	184
education, training, and experience, or any combination thereof, to advise on the subject for	185
which they are retained (§ 213.34).	186
187
Manufacturers must have an adequate number of qualified personnel to perform the manufacture,	188
processing, packing, or holding of each medical gas (§ 213.25(b)). What would constitute	189
adequate personnel would depend in part on the size and complexity of the performed	190
operations. Additionally, any personnel entering limited-access areas of a manufacturing facility	191
(e.g., certain storage areas) must be authorized to avoid improper manufacture or mishandling of	192
medical gas (§ 213.25(c)).	193
194
195
IV. 	BUILDINGS AND FACILITIES	196
197
The standard industry practice of manufacturing multiple gases at the same facility and refilling	198
labeled medical gas containers underscores the importance of building and facility design as a	199
control method for proper operation. Buildings and facilities must be of adequate design,	200
including adequate space, for the orderly placement of equipment and materials to prevent mix-	201
ups between components, incoming DMGs, medical gas containers and closures, labeling, in-	202
process materials, and medical gases (§ 213.42(a)(1)). For example, the design should include	203

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sufficient lighting for personnel to read labels. The design and construction must also allow for	204
adequate cleaning, maintenance, and proper operations (§ 213.42(a)(2)).	205
206
Manufacturers must perform operations within specifically defined areas of adequate size to	207
prevent contamination or mix-ups during manufacturing (§ 213.42(b)(1)). For example, because	208
facilities may reuse labeled medical gas containers, filled and unfilled containers with identical	209
labeling may only be distinguishable if they are in well-defined areas. Manufacturers must	210
design the flow of components, incoming DMGs, medical gas containers and closures, labeling,	211
in-process, materials, and medical gases through the buildings and facilities in a manner to	212
prevent contamination and mix-ups (§ 213.42(b)(2)). Manufacturers must maintain	213
establishments in a clean condition, as specified in written procedures, so as to assure the safety,	214
identity, strength, quality, and purity of the medical gas (§ 213.42(c)).	215
216
Outdoor spaces and delivery truck beds can be appropriate areas to conduct certain operations	217
(e.g., storage and handling) for medical gases in pressurized containers. For example, industrial	218
and medical gases could be physically separated in the warehouse or in the delivery truck. To	219
separate these areas from other spaces as required under § 213.42(b)(1), manufacturers should	220
use identifiers such as signage, floor demarcation, physical dividers, or tagging.	221
222
223
V. 	EQUIPMENT	224
225
Equipment used in the manufacture, processing, packing, or holding of a medical gas must be of	226
appropriate design and adequate size and be suitably located to facilitate operations for its	227
intended use and any necessary cleaning and maintenance (§ 213.63). In addition, equipment	228
must be constructed so that surfaces that contact components, in-process materials, or medical	229
gases are not reactive, additive, or absorptive (§ 213.65(a)), and any substances required for	230
manufacturing operations, such as lubricants or coolants, do not come into contact with	231
components, containers, closures, in-process materials, or medical gases (§ 213.65(b)).	232
233
A. 	Equipment Maintenance and Cleaning	234
235
Under § 213.67 manufacturers are required to establish, maintain, and follow written procedures	236
for adequate cleaning and maintenance of equipment used in the manufacture, processing,	237
packing, or holding of medical gases. These procedures must include, but are not limited to the	238
following:	239
240
• 	Assignment of responsibility for cleaning and maintaining equipment	241
242
• 	Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules	243
244
• 	A description in sufficient detail of the methods, equipment, and materials used in	245
cleaning and maintenance operations, and the methods of disassembling and	246
reassembling equipment as necessary to assure proper cleaning and maintenance	247
248
• 	Removal or obliteration of previous batch identification	249

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250
• 	Protection of clean equipment from contamination before use	251
252
• 	Inspection of equipment for cleanliness immediately before use	253
254
FDA recommends that medical gas manufacturers ensure that personnel can access all equipment	255
that must be cleaned, and tailor their equipment maintenance, cleaning, and inspection	256
procedures to match the type and complexity of the particular operation and to prevent	257
malfunctions or contamination.	258
259
Manufacturers should ensure equipment used in the manufacture of medical gases (e.g.,	260
manifolds, pigtails, valve assemblies, hoses, gauges) is cleaned or verified as clean (e.g.,	261
ensuring no residual cleaning agents are present) before initial use and after potential exposure to	262
a contaminant. Closed pressurized systems used for filling medical gases (e.g., manifolds) can	263
be considered acceptable without cleaning between batches, unless exposed to a contaminant.	264
To prevent contamination, manufacturers should ensure that open ends are appropriately covered	265
(e.g., with physical caps) and that valves that are critical for preventing contamination are	266
properly maintained and cleaned. Because industrial and medical gases can be filled on the same	267
manifold rack, there should be procedures in place and followed to prevent cross-contamination.	268
269
B. 	Automatic, Mechanical, and Electronic Equipment	270
271
Automatic, mechanical, and electronic equipment must be routinely calibrated, inspected, and	272
checked according to a written program designed to ensure proper performance (§ 213.68(a)).	273
274
1. 	Equipment Qualification	275
276
Manufacturers should perform equipment qualification to verify that equipment used in medical	277
gas manufacturing is installed, operates, and performs as intended. FDA recommends that	278
equipment be qualified for the anticipated temperatures and pressures used during filling.	279
Manufacturers should also qualify manifold valves to ensure they are appropriately designed to	280
prevent mix-ups during filling operations and shown to prevent contamination of the medical	281
gas. Similarly, other valves that are critical to the prevention of drug contamination, such as	282
check valves used in filling systems, should be qualified for the particular use.	283
284
2. 	Equipment Calibration	285
286
Manufacturers can calibrate equipment by either following the equipment manufacturer’s	287
recommended calibration schedule or a schedule based on the medical gas manufacturer’s	288
experience using the equipment (e.g., the manufacturer’s frequency of use). Medical gas	289
manufacturers can reference the equipment manufacturer’s instruction manual in their written	290
procedures if the manual is available for on-site use.	291
292
FDA recommends that manufacturers do the following:	293
294

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• 	Check the performance of vacuum gauges daily to ensure that the needle on the gauge	295
returns to zero when there is no vacuum or pressure (above atmospheric pressure).	296
297
• 	Calibrate vacuum and pressure gauges at least annually against an established standard	298
(e.g., a standard from the National Institute of Standards and Technology). Low-pressure	299
gauges and flow meters used in filling portable cryogenic medical gas containers do not	300
require calibration, but manufacturers should ensure that they function properly for their	301
intended use.	302
303
• 	Calibrate thermometers according to the equipment manufacturer’s instructions. If the	304
instructions do not specify frequency, calibration should be conducted at least annually.	305
306
3. 	Computerized Systems	307
308
Manufacturers must appropriately validate computerized systems that record, store, or use data in	309
the manufacturing, processing, and holding of medical gases (e.g., computerized systems used in	310
test analyses) (e.g., § 213.68(b)). The validation should address the intended use of the	311
computerized system, and the extent of validation studies should be commensurate with the risk	312
posed by the automated system.10 In addition, manufacturers must maintain a backup file of any	313
data entered into the computer system unless certain data, such as calculations performed in	314
connection with laboratory analysis, are eliminated by computerization or automated processes	315
(§ 213.68(c)).	316
317
Manufacturers must use appropriate change controls whenever modifications are made to	318
computer systems so that changes do not adversely affect data integrity11 or product quality, and	319
records of such modifications must be maintained (§ 213.68(d)).12 Appropriate personnel with	320
expertise should assess the potential impact these changes could have on quality both before the	321
change is approved and after the change is implemented, as well as any need for revalidation.	322
323
Manufacturers should enable audit trail functions for computerized systems to capture changes	324
and maintain complete data about CGMP activities. This information is important for the	325
manufacturer to trace CGMP activities throughout the supply chain when retrospective review or	326
investigation is warranted.	327
10 To comply with the requirement in § 213.68(b) when using commercially available software (e.g., off-the-shelf
software), the medical gas manufacturer, as the party with regulatory responsibility, should assess the adequacy of
the off-the-shelf software and must ensure it is validated, so that the software specifications conform to user needs
and intended uses. See sections 6.1 through 6.3 of the guidance for industry and FDA staff General Principles of
Software Validation (January 2002). Although the guidance focuses on the validation of medical device software, it
states that “this document is based on generally recognized software validation principles and, therefore, can be
applied to any software.”
11 See the guidance for industry Data Integrity and Compliance With Drug CGMP: Questions and Answers
(December 2018).
12 For FDA’s current thinking on the use of computerized systems for maintaining electronic records, see the
guidance for industry Part 11, Electronic Records; Electronic Signatures—Scope and Application (August 2003).

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328
329
VI. 	CONTROL OF INCOMING DMG, COMPONENTS, AND MEDICAL GAS	330
CONTAINERS AND CLOSURES	331
332
Manufacturers must control and assess the quality of incoming DMGs, components, containers,	333
and closures as specified in §§ 213.80, 213.82, and 213.84 because materials of poor quality can	334
adversely affect the quality and safety of the medical gas. Materials can contain impurities (e.g.,	335
caused by poor air quality conditions in air separation units or inadequate purification during	336
manufacturing), or a change to the manufacturing process could affect quality (e.g., an	337
adjustment in a manufacturing step could alter the composition of a supplied gas). Any rejected	338
incoming DMGs, components, and medical gas containers and closures must be handled in	339
accordance with § 213.89, which requires rejected items to be identified and quarantined to	340
prevent their use in manufacturing or processing operations for which they are unsuitable. In	341
addition, manufacturers must document and assess the data on rejected material and take	342
appropriate corrective action (§ 213.192(a)).	343
344
A. 	Receipt of Incoming DMGs and Components	345
346
Upon receipt of each shipment of each incoming DMG, the manufacturer must perform an	347
identity test (§ 213.82(b)). The manufacturer must also perform either full compendial testing on	348
the gas and record the results, or verify and record that a signed certificate of analysis (COA)	349
from the supplier accompanied the shipment (§ 213.82(a)(1)). For incoming DMGs, if the	350
supplier is not the original manufacturer, the supplier must include complete information from	351
the original manufacturer’s COA (§ 213.82(a)(2)). Manufacturers must sample, test, and	352
approve or reject each component, as appropriate, prior to use either by performing testing for	353
conformance with written specifications or by an identity test on the component accompanied by	354
an acceptable COA from the supplier (§ 213.84(c)).	355
356
1. 	Certificate of Analysis	357
358
For incoming DMGs, if a manufacturer relies on the supplier’s COA, the COA must include (i)	359
the supplier’s name; (ii) the name of the incoming DMG; (iii) the lot number (also referred to as	360
control number or batch number) or other unique identification number; (iv) the actual	361
analytical result obtained for strength, as well as the results of other performed tests; (v)	362
identification of the test method(s) used for analysis; (vi) the incoming DMG’s new drug	363
application (NDA) and/or new animal drug application (NADA) number; and (vii) the supplier	364
representative’s signature and the date of signature (§ 213.82(a)(1)).	365
366
For a component, if a manufacturer relies on the supplier’s COA, it should include the following	367
data: (i) the supplier’s name; (ii) the name of the component; (iii) the lot number or other unique	368
identification number; (iv) the type of test or examination to evaluate conformance with written	369
procedures and specifications; (v) the method(s) used; (vi) specification limits; (vii) all test	370
results; and (viii) the supplier representative’s signature and the date of signature.	371
372

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10
2. 	Supplier Qualification	373
374
Reliance on information provided in a COA requires a high degree of confidence in the supplier.	375
For both incoming DMGs and components, when the manufacturer is relying on a supplier’s	376
COA to verify that the incoming DMG or components meet specifications beyond identity	377
testing, the manufacturer must establish and maintain a program to ensure the reliability of the	378
supplier’s capabilities through appropriate assessment and testing procedures (§§ 213.82(a)(2),	379
213.84(a), and 213.84(c)). To establish the reliability of the supplier’s analyses, the	380
manufacturer, a contract-testing laboratory, or another third party can perform testing at	381
appropriate intervals. Manufacturers can begin the supplier qualification process, for example,	382
by fully testing several batches and examining the provided gas, containers, and closures.	383
Written procedures should address how to qualify and approve suppliers and to periodically	384
verify the qualifications of approved suppliers. This can be done by conducting audits (e.g., on-	385
site for the initial audit and, as needed, remotely for subsequent audits), analyzing trends in the	386
quality of received goods, testing, and evaluating the timeliness of the supplier’s responses to	387
complaints.	388
389
B. 	Medical Gas Containers and Closures	390
391
1. 	General Requirements	392
393
The quality unit must examine medical gas containers and closures, including valves, for	394
conformance with appropriate written procedures and specifications, and approve or reject them,	395
before manufacturing or filling (§§ 213.22(a), 213.84(a) and (c) and 213.89). A manufacturer	396
should reexamine a medical gas container or closure when it is exposed to adverse storage	397
conditions that could cause deterioration or contamination of the medical gas. Manufacturers	398
must also protect against container and closure leaks (§ 213.84(b)). This includes performing	399
leak tests on containers and closures and investigating any container closure defects identified	400
either during production or upon receipt of a leak complaint (§ 213.198(a)). Valve replacements	401
(e.g., due to a valve defect) should be performed as part of a planned program, with mitigation	402
strategies, and investigated as a deviation. See section VIII.D.2., Valve Assembly Leak Testing	403
for a discussion of leak testing.	404
405
Medical gas containers and closures must at all times be handled and stored in a manner to	406
prevent contamination and mix-ups (§ 213.80(b)). Accordingly, high-pressure cylinders exposed	407
to the elements and hoses used to fill cryogenic containers should have caps or other protective	408
means to prevent contamination. Medical gas containers and closures must not be reactive,	409
additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of a medical	410
gas beyond the official or established requirements and must provide adequate protection against	411
foreseeable external factors and use that can cause deterioration or contamination (§ 213.94(a)	412
and (b)). Medical gas containers and closures must also be clean for their intended use	413
(§ 213.94(c)). Thus, medical gas containers and closures should be cleaned before initial use and	414
after exposure to a contaminant. To comply with the requirements in §§ 213.84 and 213.94(c),	415
manufacturers should implement appropriate cleaning and retesting procedures when converting	416
a container’s use from industrial grade gas to medical gas, or if there is reason to believe there	417
was previous industrial use.	418

Contains Nonbinding Recommendations
Draft — Not for Implementation
11
419
Portable cryogenic containers that are not manufactured with permanent gas-specific use outlet	420
connections (e.g., those that have been silver-brazed) must have gas-specific use outlet	421
connections that are attached to the valve body so that they cannot be readily removed or	422
replaced (without making the valve inoperable and preventing the container’s use) except by the	423
manufacturer (§ 213.94(e)(1)). If a gas-specific use outlet connection can be readily removed	424
and replaced, a container holding one gas could be inadvertently connected to the supply system	425
for another type of gas, which could cause serious injury or death because of the gas mix-up.	426
427
Manufacturers should not use vapor recovery systems during carbon dioxide delivery unless the	428
manufacturer has adequately addressed potential contamination in a risk management program.	429
Contaminants present in the gaseous head space of the storage tank or container could be drawn	430
into the tank or container, thereby contaminating the carbon dioxide.	431
432
2. 	Prefill Inspections	433
434
Prefill inspections ensure that containers and closures are acceptable for use before filling begins.	435
This section addresses prefill inspections that evaluate containers and closures used to hold	436
incoming medical gases and store medical gases. Prefill inspections, like filling and postfilling	437
inspections, are a significant step in the manufacturing, processing, packing, or holding of the	438
medical gas produced and, therefore, must be properly documented (§ 213.189(b)). Medical gas	439
containers and closures that are rejected must be quarantined and assessed (§§ 213.84 and	440
213.89). Manufacturers should address the problem by repairing, cleaning, or replacing	441
unsuitable parts and then reinspecting.	442
443
a. 	External inspection of the container	444
445
Manufacturers should examine each container for dents, burns, dings, oil, grease, and other signs	446
of damage or contamination that can cause a container to be unsafe for use.	447
448
b. 	External inspection of valves, inlets, outlets, gauges, and connectors	449
450
Manufacturers should inspect each container’s valve assembly, connectors, and fittings to ensure	451
that they are appropriate for the medical gas. Manufacturers should examine valves, inlets,	452
outlets, gauges, and connectors for signs of damage (including fire damage), unusual wear,	453
corrosion, or the presence of debris, oil, or grease. This inspection should cover connections that	454
are brazed, welded, or equipped with a locking device. Manufacturers must ensure that portable	455
cryogenic medical gas containers and small cryogenic gas containers for use by individual	456
patients have a working gauge sufficient to assist the user in determining whether the container	457
contains an adequate supply of medical gas for continued use (§ 213.94(e)(2)).	458
459
c. 	Label inspection	460
461
Product labels on medical gas containers may be reused if they are legible, properly affixed to the	462
container, and otherwise meet all applicable requirements (§ 213.122(h)). Labels that are obsolete,	463
outdated, or that do not meet applicable requirements must be destroyed (§ 213.122(e)).	464

Contains Nonbinding Recommendations
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12
465
Manufacturers must ensure that the labeling specified for portable cryogenic medical gas	466
containers in § 201.328(a) (21 CFR 201.328(a)) is affixed to the container in a manner that does	467
not interfere with (e.g., obscure) other labeling and that each label, as well as materials used for	468
coloring medical gas containers, are reasonably resistant to fading, durable when exposed to	469
atmospheric conditions, and not readily soluble in water (§ 213.94(e)(3)).	470
471
Portable cryogenic medical gas containers must be conspicuously marked with a 360°	472
wraparound label identifying their contents (§ 201.328(a)(1)). The wraparound label must be	473
placed on the sidewall of the container as close to the top portion of the container as possible, but	474
below the top weld seam (§ 201.328(a)(1)(iv)). The name of the gas must be printed	475
continuously around the 360° wraparound label so that it can be read around the entire container	476
(e.g., Oxygen USP, Oxygen USP, Oxygen USP) (§ 201.328(a)(1)(iii)), and the lettering for the	477
name of the gas on the label must be at least 2 inches high (§ 201.328(a)(1)(ii)). For containers	478
that hold a single gas, either the lettering or the label’s background must be in the appropriate	479
color (e.g., green for oxygen) with contrasting background or lettering (i.e., lettering in the	480
designated color against a white background, or white lettering on a background of the	481
designated color) (§ 201.328(a)(1)(i)).13	
482
483
The 360° wraparound label or a separate label on the portable cryogenic medical gas container	484
must include, in conspicuous lettering, the phrase For Medical Use, Medical Gas, or some	485
similar phrase that indicates the gas is for medical use (§ 201.328(a)(2)).	486
487
Although permanently mounted cryogenic containers are not required to have a 360° label, any	488
content labeling should be easily readable from all readily accessible viewing angles.	489
490
d. 	Color code inspection	491
492
The shoulder of each high-pressure medical gas cylinder must be colored in the color or colors	493
that correspond to the gas held in the cylinder; furthermore, the shoulder’s color or colors must	494
be visible when viewed from the top of the cylinder (§ 201.328(b)). The FDA-designated colors	495
identifying medical gases in high-pressure medical gas containers and portable cryogenic	496
medical gas containers are (§ 201.328(c)):	497
498
13 There are no specific color requirements for the 360° wraparound label for portable cryogenic medical gas
containers containing a mixture of gases. As discussed in this guidance, however, there are requirements under
§ 201.328(a)(1)(v) addressing the color of the cryogenic container itself.

Contains Nonbinding Recommendations
Draft — Not for Implementation
13
Labeling of Medical Gas Containers1	
499
Medical Gas 	Color
Medical Air 	Yellow
Carbon Dioxide 	Gray
Helium 	Brown
Nitrogen 	Black
Nitrous Oxide 	Blue
Oxygen 	Green
Mixture or Blend2 	Colors corresponding to each component gas 3
1 Adapted from 21 CFR 201.328(c)	500 2 The terms mixture and blend refer to combinations of medical gases.	501 3 For example, green and gray for a blend of oxygen and carbon dioxide.	502
503
Unlike high-pressure cylinders, portable cryogenic medical gas containers are not required to be	504
colored in whole or in part. Portable cryogenic medical gas containers can be colored in a light-	505
reflective color (e.g., white), any color that is not an FDA-designated gas color, or no color.	506
However, if a manufacturer chooses to color a portable cryogenic container in an FDA-	507
designated color, it may only be colored, in whole or in part, with the color corresponding to the	508
gas or gases held in the container (§ 201.328(a)(1)(v)).	509
510
Manufacturers should not rely solely or primarily on color coding to identify medical gases; the	511
label should be used as the primary means of identifying the medical gas. Color coding provides	512
an additional safeguard to facilitate accurate identification and detection of potential errors.	513
514
A container filled with a DMG or medically appropriate combination of DMGs can bear a	515
statement identifying the name of the owner of the container or the address to which the	516
container should be returned after use. If the owner of the medical gas container is not the	517
manufacturer, packer, or distributor, it must be clearly stated on the container (§ 201.328(d)).	518
519
e. 	Inspection of high-pressure cylinders	520
521
For high-pressure cylinders, manufacturers should include the following as part of prefill	522
inspections:	523
524
• 	Examination of the U.S. Department of Transportation (DOT) requalification date	525
• 	Hammer or dead-ring test	526
• 	Odor inspection	527
• 	Venting or blow-down of cylinders	528
529
Manufacturers should examine each high-pressure cylinder for the DOT date stamped on the	530
cylinder before use to verify that each cylinder conforms with DOT requirements under 49 CFR	531
180.209 for the requalification and marking of cylinders. If the DOT requalification date has	532
been exceeded, the manufacturer should quarantine the cylinder until either DOT requirements	533
have been satisfied, or the cylinder is removed from inventory.	534
535

Contains Nonbinding Recommendations
Draft — Not for Implementation
14
Manufacturers should also conduct a hammer or dead-ring test to provide information about	536
internal corrosion of steel cylinders that could lead to cylinder failure. The test consists of	537
lightly tapping the cylinder sidewall with a hammer-like instrument and listening to the sound	538
produced. A clear bell tone indicates that the cylinder is clean and free of internal corrosion. A	539
dull ring indicates the possibility of internal corrosion and warrants further investigation.	540
Manufacturers should not perform a hammer or dead-ring test on aluminum or composite	541
cylinders because the test would not indicate internal corrosion and could damage the cylinder	542
wall.	543
544
Manufacturers can use an odor test to detect the presence of a foreign gas or odor remaining in	545
the container. This test should not be performed on carbon dioxide, nitrous oxide, or toxic or	546
corrosive gases for safety reasons. This test should not be confused with odor testing conducted	547
as part of finished product testing, which may be included in a USP-NF monograph. If a	548
cylinder is empty at atmospheric pressure, manufacturers can introduce Nitrogen NF into the	549
cylinder at a predetermined pressure (i.e., a pressure that is high enough to introduce gas into the	550
container) and perform an odor test on the resulting gas. Residual pressure valves prevent the	551
cylinder from emptying completely and prevent backflow. A prefill odor test on a cylinder with	552
a qualified residual pressure valve is not necessary if the cylinder has residual pressure.	553
Manufacturers should document verification of residual pressure on the batch record.	554
555
High-pressure cylinders that manufacturers receive for refilling should be vented or blown down	556
to remove gas remaining in the cylinders. Manufacturers can omit this step if the cylinder is	557
equipped with a qualified residual pressure valve and has residual pressure. Manufacturers	558
should address the continued suitability of medical gas containers and closures after extended	559
storage by having procedures in place to ensure that they (1) are not exposed to conditions that	560
render them unfit for use, and (2) have successfully completed prefill tests.	561
562
563
VII. 	PRODUCTION AND PROCESS CONTROLS	564
565
Under § 213.100(a) manufacturers are required to have written procedures for production and	566
process controls designed to assure that medical gases have the identity, strength, quality, and	567
purity they purport or are represented to have. This regulation requires manufacturers to design a	568
process, including operations and controls, so that products meet these attributes, and is therefore	569
the foundation for process validation.14 For example, validation of automated filling systems	570
provides assurance that filling will be done properly. This regulation also requires that the	571
procedures, and any changes, be drafted, reviewed, and approved by the appropriate	572
organizational units and reviewed and approved by the quality unit.	573
574
During production, if contamination is found, or it seems likely that contamination occurred, the	575
manufacturer must quarantine the batch or lot of medical gas in which the contamination was	576
found until an investigation has been completed (§§ 213.84, 213.89, 213.110(c)). Given that	577
products with a USP monograph must meet the monograph standards if tested or be considered	578
14 For more information on FDA recommendations regarding process validation generally, see the guidance for
industry Process Validation: General Principles and Practices (January 2011).

Contains Nonbinding Recommendations
Draft — Not for Implementation
15
adulterated under section 501(b) of the FD&C Act, any tests for detecting contaminants in	579
medical gas should be equivalent to, or better than, USP compendial methods and suitable for	580
their intended use.15 For additional information, see section X.C., Test Method and Alternative	581
Test Method Validation.	582
583
When monitoring medical gas production, adverse trends of errors or deviations can indicate a	584
drift in the state of control, which warrants an appropriate investigation and an effective	585
corrective and preventative action (CAPA).16 Manufacturers should pay particular attention to	586
critical defects (e.g., leaking units, contamination) and assess whether marketed units were	587
potentially impacted.	588
589
A. 	Charge-In of Components and Incoming DMGs	590
591
Under § 213.101(a), a batch must be formulated with the intent to provide 100 percent of the	592
labeled or established amount of each medical gas unless a monograph or formulary specifies a	593
range. Where a monograph or formulary specifies a range for the contents of a medical gas, the	594
medical gas must be formulated with the intent to provide an amount within that specified range.	595
596
Under § 213.101(b) components and incoming DMGs added to in-process supply or final	597
product containers must be weighed or measured as appropriate. In-process and final product	598
containers must identify (1) the name of the component or DMG, or if there are multiple, the	599
name and percentage of each component or DMG; and (2) the unique lot number assigned.	600
601
B. 	Sampling and Testing of In-Process Materials	602
603
During production, in-process materials must be tested for identity, strength, quality, and purity	604
as appropriate, and the quality unit must approve or reject the in-process materials	605
(§ 213.110(a)). In-process control procedures and tests or examinations on appropriate samples	606
of in-process materials of each batch must be established to monitor output and to validate the	607
performance of manufacturing processes that can cause variability in the quality of the medical	608
gas (§ 213.110(b)). For example, in-process controls could include validation of processes to	609
remove contaminants. Manufacturers must identify and quarantine any rejected in-process	610
materials to prevent their use in manufacturing or processing operations for which they are	611
unsuitable (§ 213.110(c)).	612
613
C. 	Vacuum Evacuation of High-Pressure Cylinders	614
615
For cylinders that are not equipped with a residual pressure valve with backflow prevention,	616
FDA recommends vacuum evacuation to remove residual gases if cylinders are reused. FDA	617
recommends manufacturers use 25 or more inches of mercury vacuum to evacuate the residual	618
gases. If using less than 25 inches of vacuum (e.g., when compensating for altitude),	619
15 USP-NF General Notices, Section 5.60, Impurities and Contaminants in Official Articles is an example of an
appropriate reference for a contaminant test method.
16 To identify an adverse trend, we recommend that the quality unit establish appropriate alert and action limits to
ensure investigation expansion to reassess process design and control.

Contains Nonbinding Recommendations
Draft — Not for Implementation
16
manufacturers should maintain data demonstrating sufficient evacuation). Changes to the	620
amount of vacuum used must be documented (§§ 213.184, 213.186, and 213.189) and available	621
for inspection (§ 213.180(a)), and the changes should be scientifically justified.	622
623
Manufacturers must maintain records of their testing or examination of any problems that occur	624
with container evacuation, such as the inability to adequately empty the cylinder of residual	625
gases (§ 213.184).	626
627
D. 	Filling Procedure Checks	628
629
When filling medical gas containers, filling to a predetermined and acceptable temperature or	630
pressure limit, along with the required finished product testing at § 213.165, indicates that the	631
medical gas or medical gas mixture in the container is the amount17 and type indicated by the	632
label and required by the final product specifications. Manufacturers should include the	633
following checks:	634
635
1. 	Temperature and Pressure Readings	636
637
A medical gas in a container will increase in pressure as the temperature of the gas rises.	638
Overfilled containers can reach dangerously high pressures if exposed to elevated temperatures,	639
even if the pressure at room temperature is at a safe level. To ensure that high-pressure	640
containers filled with DMG(s) in a gaseous state are filled correctly (i.e., contents as indicated on	641
the label), the manufacturer can attach a thermometer to one container per manifold-filling	642
sequence, or to each container if filling one at a time, and adjust the final filling pressure	643
according to a temperature/pressure chart or temperature/pressure calculations (Boyle’s Law) to	644
achieve proper content (expressed on the label in liters or cubic feet based on the filled pressure	645
at 70°F as required under 21 CFR 201.51(b)(1)).	646
647
The manufacturer must record the temperature and/or pressure readings on the batch production	648
record as part of the required documentation that each significant step in the manufacture,	649
processing, packing, or holding of the medical gas produced was accomplished (§ 213.189(b)).	650
See section XI.E., Batch Production and Control Records.	651
652
2. 	Valve Assembly Leak Testing	653
654
Manufacturers must take appropriate actions to identify and protect against container and closure	655
leaks, which include leak testing at the time of fill and after fill but prior to release (§ 213.84(b)).	656
Leak testing, performed at additional time points, may be warranted (e.g., if leaks are detected	657
after leaving the manufacturer) to provide sufficient assurance of the durability and suitability of	658
the container closure system throughout its period of use.	659
660
In the event the manufacturer receives a complaint involving a possible leak in a medical gas	661
container or closure, that complaint must be reviewed, evaluated, and investigated in accordance	662
with § 213.192 (§ 213.198(a)). An appropriate investigation includes a determination of the	663
17 For requirements related to the measure of contents for DMGs, see 21 CFR 201.51(b), which explains how net
quantity must be expressed on the label, depending on container type.

Contains Nonbinding Recommendations
Draft — Not for Implementation
17
source of a leak. Based on the results of the investigation, additional leak testing, such as upon	664
pickup, could be warranted as part of an appropriate corrective action to prevent recurrence.	665
666
During leak testing, manufacturers should test each valve assembly for leaks by spraying or	667
brushing an appropriate leak detection solution on and around the entire assembly.18 The	668
solution should be safe for use with the particular medical gas, leave no residue that is	669
flammable, and be noncorrosive to the valve assembly. Among other things, it should not	670
contain hydrocarbons, ammonia, ethylene glycol, or halide ions. Solutions containing soap are	671
not recommended because they can corrode the valve stem and leave a residue. Manufacturers	672
should perform this test while the cylinder is under pressure with the cylinder valve open. If	673
bubbles appear in the solution, there is a leak. If leaks are detected, the cylinder must be	674
removed from service and quarantined until repaired (see §§ 213.84(a) and 213.89).	675
676
3. 	Heat-of-Compression Check	677
678
During or immediately after filling a high-pressure cylinder, manufacturers should perform a	679
heat-of-compression check by lightly touching the exterior of the cylinder or an alternative	680
method that verifies temperature change. A warm cylinder indicates that the cylinder is filling	681
properly; a cool or cold cylinder indicates that the cylinder is not filling properly. Manufacturers	682
should investigate, in accordance with § 213.192, any cool or cold cylinders.	683
684
685
VIII. 	PACKAGING AND LABELING CONTROL	686
687
A. 	Materials Examination and Usage	688
689
To ensure the quality and legibility of medical gas labels, in particular because labels may be	690
reused (§ 213.122(h)), manufacturers must do the following:	691
692
• 	Representatively sample, and examine or test, labeling and packaging materials upon	693
receipt and before use in packaging or labeling of a medical gas (§ 213.122(a)).	694
695
• 	Approve and release for use any labeling or packaging materials that meet appropriate	696
written specifications and reject any labeling or packaging materials that do not meet	697
specifications to prevent their use in operations for which they are unsuitable	698
(§ 213.122(b)). We note that previous lot numbers on any labeling must be removed or	699
obliterated as part of equipment maintenance and cleaning requirements (§ 213.67(a)(4)).	700
701
• 	Maintain records of each shipment of each different labeling and packaging material,	702
indicating receipt, examination, and whether accepted or rejected (§ 213.122(c)).	703
704
• 	Store labels and other labeling materials for each different medical gas, strength, or	705
quantity of contents with suitable identification to avoid mix-ups (§ 213.122(d)). Labels	706
18 See ASTM International, 2021, G188-05 (Reapproved 2021), Standard Specification for Leak Detector Solutions
Intended for Use on Brasses and Other Copper Alloys.

Contains Nonbinding Recommendations
Draft — Not for Implementation
18
and labeling materials can be stored in the same cabinet provided they are adequately	707
separated and identified. Labels for nonmedical purposes (e.g., industrial gas) should be	708
stored in a separate area.	709
710
• 	Secure labeling by limiting access to authorized personnel (§ 213.122(d)).	711
712
• 	Destroy obsolete and outdated labeling (§ 213.122(e)).	713
714
• 	Include one of the following special control procedures:	715
716
- 	Dedicate labeling and packaging lines to each different strength of each different	717
medical gas (§ 213.122(f)(1))	718
719
- 	Use appropriate electronic or electromechanical equipment to conduct a	720
100 percent examination for correct labeling during or after completion of	721
finishing operations (§ 213.122(f)(2))	722
723
- 	Use visual inspection to conduct a 100-percent examination for correct labeling	724
during or after completion of labeling operations for hand-applied labeling, which	725
must be independently verified by a second person (§ 213.122(f)(3))	726
727
• 	Monitor any printing devices on, or associated with, manufacturing lines used to imprint	728
labeling on the unit label or case for conformance with the print specified in the batch	729
production record (§ 213.122(g)).	730
731
B. 	Labeling Issuance	732
733
Manufacturers must strictly control labeling issued for use in medical gas operations to prevent	734
labeling and product mix-ups (§ 213.125(a) (21 CFR 125(a)). Appropriate controls include	735
labeling reconciliation (§ 213.125(b)) and the discarding of all excess lot number stickers or	736
decals that are unused (§ 213.125(c)). FDA recommends that labeling be issued for use in	737
medical gas labeling operations by authorized personnel only.	738
739
Manufacturers must reconcile the number of labels issued, used, and returned and evaluate any	740
discrepancies outside narrow preset limits based on historical operating data (§ 213.125(b)) and	741
investigate those discrepancies (§ 213.192).	742
743
Labeling reconciliation is waived for cut or roll labeling if manufacturers perform a 100 percent	744
examination for correct labeling in accordance with § 213.122(f)(2) and is also waived for 360°	745
wraparound labels on portable cryogenic medical gas containers (§ 213.125(b)).	746
747
C. 	Packaging and Labeling Operations	748
749
Manufacturers must handle packaging and labeling operations in a manner that assures that	750
correct labels, labeling, and packaging materials are used for medical gases (§ 213.130).	751
Measures include the following:	752

Contains Nonbinding Recommendations
Draft — Not for Implementation
19
753
• 	Physically or spatially separating labeling and packaging operations for medical gas from	754
operations on other products (e.g., gases for industrial use) (§ 213.130(a)).	755
756
• 	Identifying any filled, unlabeled containers that have been set aside for future labeling	757
operations to prevent mislabeling (§ 213.130(b)). Each container does not need to be	758
individually identified. This requirement can be met by having signage for an area	759
designated to store these containers.	760
761
• 	Identification of a batch medical gas with a lot or control number (§ 213.130(c)). A	762
separate sticker or decal can be used to meet the requirement as long as the sticker or	763
decal remains adhered to the container and is legible. The sticker or decal should be	764
readily visible and should not obscure required drug information. Manufacturers should	765
consider as a batch each (1) manifold filling sequence, (2) uninterrupted filling	766
sequence, and (3) filled rail tank car, trailer, and cryogenic container. For continuous	767
manufacturing operations, a batch is the amount of medical gas produced in a unit of time	768
(e.g., in 24 hours) or quantity in a manner that assures its having uniform character and	769
quality within specified limits (§ 213.3(b)(9)), with the unit of time or quantity defined by	770
the manufacturer.	771
772
• 	Inspection of packaging and labeling facilities immediately before use to assure that all	773
medical gases have been removed from previous operations and any packaging or	774
labeling materials unsuitable for subsequent operations have been identified and removed	775
(§ 213.130(d) and (e)).	776
777
If a manufacturer includes an expiration date on the medical gas product labeling, it must appear	778
on the labeling in accordance with 21 CFR 201.17. The date must be supported by a stability	779
testing program as described in § 213.166. See section X.D., Stability Testing and Expiration	780
Dating for additional information and requirements.	781
782
783
IX. 	HOLDING AND DISTRIBUTION	784
785
Manufacturers must establish and follow written procedures describing medical gas distribution	786
(§ 213.150(a)). These procedures must include a system by which the distribution of each lot	787
can be readily determined to facilitate its recall if necessary (§ 213.150(a)). The procedures	788
should explain (1) who would evaluate distribution information, (2) how a recall would be	789
initiated, (3) who would be informed about the recall, (4) what would be done with the recalled	790
product, and (5) how these steps would be accomplished.	791
792
Manufacturers must also establish and follow written procedures describing the warehousing of	793
medical gas, including quarantine before release by the quality unit (§ 213.150(b)).	794
795
796

Contains Nonbinding Recommendations
Draft — Not for Implementation
20
X. 	LABORATORY CONTROLS	797
798
Laboratory control requirements in § 213.160 include establishment of scientifically sound and	799
appropriate specifications, standards, sampling plans, and test procedures designed to assure that	800
components, medical gas containers and closures, in-process materials, labeling, and medical	801
gases conform to appropriate standards of identity, strength, quality, and purity (§ 213.160(b)).	802
These laboratory control mechanisms must be drafted by the appropriate organizational unit,	803
reviewed and approved by the quality unit, followed, documented at the time of performance,	804
and any deviations from the written specifications, standards, sampling plans, test procedures, or	805
other laboratory control mechanisms recorded and justified (§ 213.160(a)). For example, to	806
comply with this requirement, manufacturers must record and justify changes made to the	807
analytical method, such as a different column length or a different carrier gas (§ 213.160(a)).	808
809
A. 	Instrument Calibration	810
811
Laboratory controls must include a written program for the calibration, or verification of	812
calibration, for instruments, apparatus, gauges, and recording devices at suitable intervals in	813
accordance with an established written program containing specific directions, schedules, limits	814
for accuracy and precision, and provisions for remedial action in the event accuracy and/or	815
precision limits are not met (§ 213.160(b)(4)). Under this requirement, any downstream	816
entities19 that do not perform their own calibration must verify calibration. It is of particular	817
importance that instruments measuring a quality characteristic are calibrated to ensure proper	818
performance.	819
820
If using a calibration gas, manufacturers should verify that it is traceable to a nationally	821
recognized standard and that it ensures the appropriate level of precision and accuracy. The	822
COA for the calibration gas should be specific to the cylinder of calibration gas received and	823
should contain the following:	824
825
• 	Name and address of the supplier	826
• 	Name of the calibration gas	827
• 	Lot number or unique identification number	828
• 	Description of the analytical method used to assay the calibration gas	829
• 	Analytical results expressed quantitatively (e.g., 99.9 percent nitrogen)	830
• 	Statement that the calibration gas is traceable to a nationally recognized standard	831
• 	Responsible person’s signature and the date signed	832
833
B. 	Testing and Release for Distribution	834
835
For each batch of medical gas, there must be an appropriate laboratory determination of	836
satisfactory conformance to final specifications for the medical gas, including the identity and	837
strength, before release (§ 213.165(a)). An appropriate laboratory determination would include	838
19 Downstream entities are entities that manufacture, process, pack, or hold medical gases, including firms that
combine, commingle, refill, or distribute DMGs and medically appropriate combinations of DMGs but are
downstream from the manufacturer that initially manufactures the medical gas.

Contains Nonbinding Recommendations
Draft — Not for Implementation
21
meeting the standards listed in an applicable compendium (e.g., a USP-NF monograph for	839
certified DMGs,20 relevant general USP NF chapters21) or the specifications established in an	840
application approved under section 505 or section 512 of the FD&C Act.	841
842
Written procedures must describe the method of sampling and testing, including the number of	843
units per batch that will be sampled and tested and the acceptance criteria (§ 213.165(b)). The	844
method of sampling must be suitable and verified under actual conditions of use (§ 213.165(c)).	845
Test results that fail to meet specifications must be rejected (§ 213.165(d)). Samples can be	846
retested, but retesting is not recommended until the manufacturer has conducted a thorough	847
investigation according to established written procedures.22	
848
849
For cylinders filled on a multiple-outlet manifold, at least one high-pressure cylinder from each	850
manifold filling sequence should be tested for identity and strength.	851
852
For cylinders filled individually, one high-pressure cylinder per uninterrupted filling sequence	853
should be tested for identity and strength.	854
855
For mixtures containing two gases, each high-pressure cylinder in a batch should be tested for	856
both the identity and strength of one of the gases, and one cylinder from each batch should be	857
tested for the identity of the second gas. For mixtures containing three gases, each high-pressure	858
cylinder in a batch should be tested for both the identity and strength of two of the gases, and one	859
cylinder from each batch should be tested for the identity of the third gas. If mixtures contain	860
oxygen, each cylinder in the batch should be tested for the identity and strength of the oxygen.	861
862
C. 	Test Method and Alternative Test Method Validation	863
864
The manufacturer must demonstrate that test methods are accurate, sensitive, specific, and	865
reproducible under actual conditions of use (§ 213.165(c)) and must be approved by the quality	866
unit (§ 213.22(c)). Validation and documentation must be accomplished as described in	867
§ 213.194(a)(2).	868
869
Because USP-NF monograph drug products must meet USP-NF monograph standards (section	870
501(b) of the FD&C Act), FDA recommends that manufacturers use the test methods in the	871
appropriate USP-NF monograph for the medical gas. For USP-NF test methods, a full test	872
method validation study is unnecessary, as long as the referenced method is not modified. Data	873
that verify that the USP-NF test method is accurate and reliable for testing the particular product	874
(i.e., suitable for its intended purpose) should be generated on the appropriate equipment and	875
20 See section 576(a)(2)(A) and (B) of the FD&C Act (21 U.S.C. 360ddd-1(a)(2)(A) and (B)) (a certification will not
be granted if the Secretary finds that the medical gas is not a DMG, or if the request does not contain required
information or otherwise lacks sufficient information to permit the Secretary to determine that the medical gas is a
DMG); section 575(1) of the FD&C Act (defining each DMG as a gas that “meets the standards set forth in an
official compendium”).
21 See footnote 15.
22 See the guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical
Production (May 2022).

Contains Nonbinding Recommendations
Draft — Not for Implementation
22
readily available. If a medical gas manufacturer relies on the equipment manufacturer’s study,	876
the medical gas manufacturer should retain a copy of the study, including the protocol and data.	877
878
Manufacturers that use approved test methods that are not USP-NF monograph methods must	879
maintain a copy of the full and complete test method validation (§ 213.165(c)). When a test is	880
approved as part of an NDA submitted under section 505(b)(1) and approved under section	881
505(c) of the FD&C Act, an abbreviated new drug application (ANDA) submitted and approved	882
under section 505(j) of the FD&C Act, a NADA submitted under section 512(b)(1) and approved	883
under section 512(c)(1) of the FD&C Act, or an abbreviated new animal drug application	884
(ANADA) submitted under section 512(b)(2) and approved under section 512(c)(2) of the FD&C	885
Act, it becomes the approved analytical test method for the medical gas.	886
887
For drug products with a USP-NF monograph, a manufacturer can establish alternative test	888
methods, as long as the USP-NF monograph standards are met or exceeded. Alternative test	889
methods must be validated (§§ 213.160(b) and 213.165(c)). The validation can be performed in	890
accordance with USP-NF General Chapter <1225> Validation of Compendial Procedures, and	891
the validation study should include data comparing it to the official test method.23	
892
893
The suitability of all testing methods must be verified under the actual conditions of use	894
(§ 213.165(c)). For example, paramagnetic oxygen analyzers can give inaccurate readings when	895
used at high altitudes unless special adjustments are made. The results of these tests must be	896
fully documented (§ 213.165(c)).	897
898
Certain changes made to instrumentation can be substantive enough to be considered changes to	899
the test method itself; these changes would require additional documentation of the accuracy and	900
reliability of the method or a new validation study (see § 213.194(b)).	901
902
D. 	Stability Testing and Expiration Dating	903
904
For medical gases marketed under applications submitted under section 505 or section 512 of the	905
FD&C Act, any stability testing performed and any expiration dating established must be in	906
accordance with § 213.166(b), subject to the conditions established in their approved	907
applications, if any. For example, if an approved application states that both stability testing and	908
expiration dating are conditions for the safe and effective use of the medical gas, the	909
manufacturer must have a stability program to assess the stability characteristics of the medical	910
gas and the integrity of its container closure (§ 213.166(b)(1)). The stability program must	911
include the appropriate sample size, test intervals, container closure systems, and storage	912
conditions for samples retained for testing, and the results of the stability testing would be the	913
basis for determining appropriate storage conditions and any expiration date included on the	914
label (§ 213.166(b)(1)).	915
916
If an approved application does not require stability testing or expiration dating for the safe and	917
effective use of a medical gas, but the manufacturer nonetheless chooses to include an expiration	918
date on the labeling, the expiration date must be based on the results of a stability program as	919
described in § 213.166(b)(1). Similarly, stability testing and expiration dating are not required	920
23 See the guidance for industry Analytical Procedures and Methods Validation for Drugs and Biologics (July 2015).

Contains Nonbinding Recommendations
Draft — Not for Implementation
23
for DMGs, but if a manufacturer of a DMG chooses to include an expiration date on the label,	921
the date should be determined by stability testing.	922
923
Manufacturers must evaluate stability periodically to ensure that the medical gas continues to	924
meet the standards for identity, strength, quality, and purity stated on the labeling to support the	925
expiration date (§ 213.166(b)(3)).	926
927
928
XI. 	RECORDS	929
930
This section discusses general records requirements and requirements related to records	931
maintenance for equipment cleaning and use; components, containers and closures, and labeling;	932
master production and control; batch production and control; laboratory records; distribution	933
records; record review; and complaint files.	934
935
A. 	General Requirements	936
937
1. 	Record Retention and Availability	938
939
Manufacturers must maintain all records required under part 213 for at least 3 years after the	940
distribution of the batch of medical gas, except as otherwise provided in this part (§ 213.180(c)).	941
942
All records must be readily available for authorized inspection during the retention period at the	943
establishment where the activities described in such records occurred (§ 213.180(a)). Records	944
must be originals or accurate copies of original records that are legible and stored to prevent	945
deterioration or loss (§ 213.180(b)). Electronic records that can be immediately retrieved satisfy	946
this requirement.24	
947
948
2. 	Maintenance of Written Records	949
950
Manufacturers must maintain written records so that data therein can be used for evaluating, at	951
least annually, the quality standards of each medical gas to determine the need for changes in	952
specifications or manufacturing or control procedures (§ 213.180(d)). There must be written	953
procedures for the review of the following:	954
955
• 	A representative number of batches, whether approved or rejected, and where applicable,	956
records associated with the batch (§ 213.180(d)(1))	957
958
• 	Complaints, recalls, returned or salvaged medical gases, and investigations conducted	959
under § 213.192 for each medical gas (§ 213.180(d)(2))	960
961
Also, under § 213.180(e), the manufacturer must have written procedures to notify responsible	962
officials of the firm, in writing, of any recalls, reports of inspectional observations by FDA,	963
regulatory actions related to good manufacturing practices brought by FDA, or investigations	964
24 Electronic records are subject to the requirements of 21 CFR part 11. See the guidance for industry Part 11,
Electronic Records; Electronic Signatures—Scope and Application.

Contains Nonbinding Recommendations
Draft — Not for Implementation
24
resulting from adverse event complaints. Manufacturers should use these records to identify	965
potential product quality issues and opportunities for continuous process improvement. This can	966
be done on a company-wide or site-by-site basis.	967
968
3. 	Equipment Calibration, Checks, and Inspections	969
970
Manufacturers must keep records of calibration, checks, and inspections of automatic,	971
mechanical, and electronic equipment used in the manufacture, processing, packing, and holding	972
of medical gas (§ 213.68(a)). See section V.B.2., Equipment Calibration for more information	973
about equipment calibration.	974
975
4. 	Computer Validation Data	976
977
Manufacturers must have documentation that their automated, mechanical, and electronic	978
equipment—including computers used in the manufacturing or holding of a gas—demonstrates	979
proper performance as required under § 213.68(a) through (d), including data after modifications	980
are made to computer systems.	981
982
5. 	Process Validation Data	983
984
Records required under part 213 include process validation records. Such data must show that	985
the manufacturer has production and process controls designed to assure that medical gases have	986
the identity, strength, quality, and purity that they purport or are represented to possess as	987
required under § 213.100.	988
989
B. 	Equipment Cleaning and Use Log	990
991
Under § 213.182, manufacturers must retain cleaning records for major equipment cleaning,	992
nonroutine maintenance, and equipment use, including the date, time, product, and lot number of	993
each batch processed.	994
995
Manufacturers must document the work on individual equipment logs, which are separate	996
cleaning or maintenance records that are not associated with specific batch records. The people	997
who perform and double-check cleaning and maintenance must date and either sign or initial the	998
log indicating that the work was performed, with entries made in chronological order	999
(§ 213.182). If using equipment dedicated to the manufacture of a single medical gas, and lots or	1000
batches follow in numerical order and are manufactured in numerical sequence, individual	1001
equipment logs are not required. However, records for cleaning, maintenance, and use would be	1002
required as a part of the batch record (§ 213.182). If automated equipment is used in cleaning	1003
and maintenance in accordance with § 213.68, only the person verifying the cleaning and	1004
maintenance needs to date and sign or initial the use log.	1005
1006

Contains Nonbinding Recommendations
Draft — Not for Implementation
25
C. 	Records for Components, Medical Gas Containers and Closures, and	1007
Labeling	1008
1009
Records associated with component, container and closure systems, and labeling requirements	1010
covered in §§ 213.84, 213.122, and 213.130 must include the following (§ 213.184):	1011
1012
• 	Results of any test or examination performed on components, containers, and container	1013
closure systems, including those performed as required by §§ 213.84 or 213.122, and the	1014
conclusions derived from the results	1015
1016
• 	Documentation of the examination and review of labels and labeling for conformity with	1017
established specifications in accordance with §§ 213.122 and 213.130	1018
1019
• 	Disposition of rejected medical gas components, containers and closures, and labeling	1020
1021
D. 	Master Production and Control Records	1022
1023
Master production and control records for each medical gas must be prepared, dated, and signed	1024
to assure uniformity from batch to batch. The manufacturer must have written procedures for the	1025
preparation of these records that must include the following (§ 213.186):	1026
1027
• 	The name and strength of the medical gas	1028
1029
• 	A complete list of components and any incoming DMGs used in manufacturing	1030
designated by names or codes sufficiently specific to indicate any special quality	1031
characteristic	1032
1033
• 	A description of the medical gas containers and closures, packaging materials, and labels	1034
1035
• 	Complete manufacturing and control instructions, sampling and testing procedures,	1036
specifications, special notations, and precautions to be followed	1037
1038
E. 	Batch Production and Control Records	1039
1040
Batch production and control records must be prepared for each batch of medical gas produced	1041
(§ 213.189(a)).	1042
1043
The records must contain documentation that each significant step in batch manufacture,	1044
processing, packing, or holding was accomplished, including:	1045
1046
• 	Dates of each significant step, including in-process and laboratory tests as applicable	1047
(§ 213.189(b)(1)). Manufacturers should not use a single entry to indicate that all	1048
significant manufacturing, processing, packing, and holding steps have been performed.	1049
1050
• 	Description of the container for the medical gas, including the number and size of the	1051
containers filled as applicable (§ 213.189(b)(2)).	1052

Contains Nonbinding Recommendations
Draft — Not for Implementation
26
1053
• 	Specific identification of each component and its source or in-process material used as	1054
applicable (§ 213.189(b)(3)).	1055
1056
• 	Measures of components used in the course of processing, as applicable	1057
(§ 213.189(b)(4)).	1058
1059
• 	Testing results, including in-process test results and finished product test results	1060
(§ 213.189(b)(5)).	1061
1062
• 	Dated signature or initials of each person performing and directly supervising or checking	1063
each significant step in the operation (§ 213.189(b)(6)).	1064
1065
• 	Inspection of the packaging and labeling area before and after use (§ 213.189(b)(7)).	1066
1067
• 	Complete labeling control records, including specimens or copies of all labeling used and	1068
label application and reconciliation records as appropriate (§ 213.189(b)(8)).	1069
Considering that all written, printed, and graphic matter upon or accompanying an article	1070
is labeling,25 any accompanying labeling (e.g., booklets, brochures) is to be part of the	1071
complete labeling control records. Manufacturers should consider the following:	1072
1073
- 	A photocopy or printed digital image can be an alternative to a label specimen.	1074
Manufacturers should include a specimen of the specific lot number labeling (e.g.,	1075
lot number sticker) in the batch record.	1076
1077
- 	At the time a container is transferred from one entity to another, each entity is	1078
responsible for the labeling on or accompanying the container. This labeling	1079
should be part of the complete labeling control records. For example,	1080
§ 201.328(d) states that a container filled with a DMG or medically appropriate	1081
combination of DMGs may bear a statement identifying the name of the owner of	1082
the container or the address to which the container should be returned after use	1083
and that this statement may appear on a separate sticker or decal. In addition, this	1084
regulation requires that if the owner of the medical gas container is not the	1085
manufacturer, packer, or distributor of the medical gas, this fact must be clearly	1086
stated on the container. The above information is considered labeling and	1087
therefore is expected to be part of complete labeling control records.	1088
1089
- 	Labeling control records maintained by original manufacturers that fill bulk	1090
trailers may or may not include a finished product label. These manufacturers	1091
should maintain both product and lot-specific labeling.	1092
1093
• 	Any investigation made according to § 213.192 (§ 213.189(b)(9)).	1094
1095
25 Section 201(m) of the FD&C Act defines the term labeling to mean “all labels and other written, printed, or
graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.”

Contains Nonbinding Recommendations
Draft — Not for Implementation
27
Batch production records should reflect actual production practices and conditions at the time of	1096
manufacture. Transfiller pumper or filler logs can serve as batch production records if they	1097
contain the relevant information specified in § 213.189.	1098
1099
In addition, FDA recommends that batch records maintained by transfillers, including curbside	1100
vendors, document the following information:	1101
1102
• 	Findings from the transfiller’s inspections conducted prefill, during fill, and postfill	1103
• 	Number and size of the containers filled	1104
• 	Final temperature and pressure results	1105
• 	Other inspection results	1106
1107
All required batch record information should be easily located and traceable to each specific	1108
batch manufactured. Manufacturers need not maintain batch production records as one	1109
document. Each lot number should be traceable in records for batch manufacturing, labeling,	1110
testing, and release. Manufacturers that use computer-controlled equipment during manufacture	1111
should establish and follow procedures to maintain, review, and approve the manufacturing data.	1112
1113
A checkmark or other symbol should not be used in place of an actual value, such as for	1114
temperature and pressure readings, or results from purity and identity testing.	1115
1116
FDA recommends that records of nonconforming medical gas describe the rejection relative to	1117
the rest of the batch to ensure that the scope of the investigation is appropriate. For example,	1118
medical gases rejected for container or manifold leaks during filling must be documented	1119
(§§ 213.84, 213.165, and 213.189) and investigated (§ 213.192), and the scope of the	1120
investigation should extend to other batches of medical gas that could have been associated with	1121
the same failure.	1122
1123
F. 	Production Record Review	1124
1125
The quality unit must review and approve all manufacturing production and control records,	1126
including those for packaging and labeling, before a batch is released or distributed	1127
(§ 213.192(a)). Unexplained discrepancies or the failure of a batch to meet its specifications,	1128
including any test results falling outside of specifications, must be investigated (by the quality	1129
unit) and corrective actions taken (e.g., removing a faulty cylinder from circulation)	1130
(§ 213.192(a)).	1131
1132
Manufacturers must maintain written records of investigations that include conclusions and	1133
follow-up information (§ 213.192(a)). In the event that filling occurs when the quality unit	1134
official(s) is temporarily not on site, the quality unit may review and approve production and	1135
control records within one business day after fill (§ 213.192(b)).	1136
1137
G. 	Laboratory Records	1138
1139
Laboratory records related to the manufacturer of a medical gas must include complete data	1140
derived from all tests necessary to ensure compliance with established specifications and	1141

Contains Nonbinding Recommendations
Draft — Not for Implementation
28
standards, including examinations and assays (§ 213.194(a)). These records include the	1142
following:	1143
1144
• 	Description of the sample, batch or lot number to be tested; date the sample was taken;	1145
and date the sample was tested (§ 213.194(a)(1)).	1146
1147
• 	The test method, the test result, how the results compare with established standards of	1148
identity, strength, quality, and purity for the component, container, in-process materials	1149
(as applicable), and medical gas tested; a record of any calculations performed and any	1150
calculated results; and the unit of measurement of the result. It would not be necessary to	1151
provide the actual calculation where the result is evident through use of simple addition	1152
and subtraction (§ 213.194(a)(2)).	1153
1154
• 	Where applicable, any graphs, charts, and spectra from laboratory instrumentation,	1155
properly identified to show the specific component, in-process material, or medical gas	1156
for each lot tested (§ 213.194(a)(3)). If the analytical equipment only provides a direct	1157
reading, recording the result for each test would fulfill the requirement.	1158
1159
• 	Initials or signature of the person who performs each test and a second person showing	1160
that the original records have been reviewed for accuracy, completeness, and compliance	1161
with established standards (§ 213.194(a)(4)).	1162
1163
In addition, manufacturers must maintain complete records of the following:	1164
1165
• 	Any modification of an established test method, including the reason for the modification	1166
and the data to verify that the modification produced results that are at least as accurate	1167
and reliable for the material being tested as the established method (§ 213.194(b)).	1168
1169
• 	Any testing and standardization of laboratory reference standards, reagents, and standard	1170
solutions (e.g., a reference gas or calibration gas used as a standard) (§ 213.194(c)).	1171
1172
• 	Periodic calibration or verification of calibration of laboratory instruments, apparatus,	1173
gauges, and recording devices required by § 213.160(b)(4) (§ 213.194(d)). For example,	1174
medical gas equipment calibrated by a supplier before it arrives at the laboratory can be	1175
verified rather than performed again.	1176
1177
• 	Stability testing performed in accordance with § 213.166 (§ 213.194(e)).	1178
1179
When a chromatographic method specified in the USP-NF (e.g., the assay method for Nitrogen	1180
NF) is used for testing, the chromatographic system must meet all system suitability	1181
requirements listed in the monograph (see section 501(b) of the FD&C Act). If the USP-NF	1182
monograph lacks specific suitability requirements, manufacturers should use USP-NF General	1183
Chapter <621> Chromatography as a reference.	1184
1185

Contains Nonbinding Recommendations
Draft — Not for Implementation
29
H. 	Distribution Records	1186
1187
Distribution records must contain the product name, the lot or batch number, consignee’s name	1188
and address, shipping date, and quantity shipped (§ 213.196). For medically appropriate	1189
combinations of DMGs, the distribution record must include the percentage of each gas in the	1190
combination (§ 213.196). Record maintenance according to written procedures is critical for	1191
batch traceability, particularly in the event a safety-related problem leads to a product recall.	1192
1193
I. 	Complaint Files	1194
1195
Under § 213.198(a), the quality unit must review all written and oral complaints involving the	1196
possible failure of a medical gas to meet any of its specifications. The quality unit must also	1197
determine the need for an investigation in accordance with § 213.192, as well as determine	1198
whether the complaint contains an event reportable under 21 CFR part 230. For example, any	1199
complaint involving a possible leak of a container or closure must be reviewed, evaluated, and	1200
investigated in accordance with § 213.192. Further, if multiple complaints indicate an adverse	1201
trend, it is important that the investigation extend to evaluating state of process control and	1202
ensure appropriate CAPAs to resolve any operational problems.	1203
1204
Manufacturers must maintain written records of each complaint concerning a medical gas. These	1205
records must include (§ 213.198(b)) the following:	1206
1207
• 	Name of the gas	1208
• 	Lot or batch number	1209
• 	Name of the complainant	1210
• 	Date the complaint was received	1211
• 	Nature of the complaint	1212
• 	Response provided to the complainant	1213
• 	Findings of any investigation and follow-up	1214
1215
In addition to the name of the complainant, FDA recommends that manufacturers list any known	1216
contact information and the date of the FDA response to the complainant. The description of the	1217
nature of the complaint should contain sufficient information to facilitate investigative follow-up	1218
and identify adverse trends or patterns (e.g., a higher-than-expected rate of valve replacement	1219
indicating a recurring container closure defect). If the manufacturer conducts an investigation, a	1220
record of the findings should include the following:	1221
1222
• 	Nature of the complaint and date the complaint was received	1223
1224
• 	Action initially taken, including dates and the identity of the person taking the action	1225
1226
• 	Follow-up action taken, which can include both corrective action and preventative	1227
measures to address the complaint	1228
1229
• 	Whether other batches of medical gas were potentially affected	1230
1231

Contains Nonbinding Recommendations
Draft — Not for Implementation
30
• 	Outcome regarding the problem(s) raised by the complainant	1232
1233
If an investigation was not conducted, there must be a record of the reason an investigation was	1234
found to be unnecessary and the name of the responsible person making such a determination	1235
(§ 213.198(b)).	1236
1237
1238
XII. 	RETURNED AND SALVAGED MEDICAL GASES	1239
1240
The requirements pertaining to the handling of returned medical gas are in 21 CFR 213.204. If	1241
the conditions under which a returned gas had been held, stored, or shipped before or during their	1242
return casts doubt (e.g., is unknown) on the safety, identity, strength, quality, or purity of the gas,	1243
or if the condition of the gas, its container, carton, or labeling, as a result of storage or shipping,	1244
casts doubt on the safety, identity, strength, quality, or purity of the gas, then the manufacturer	1245
must destroy the returned gas. However, the returned gas does not need to be destroyed if the	1246
manufacturer can prove through examination, testing, or other investigations that the gas meets	1247
appropriate standards. If the reason a medical gas was returned is because of a quality issue or	1248
implicates associated batches, the manufacturer must conduct an investigation as required under	1249
§ 213.192. FDA recommends that manufacturers vent or completely evacuate the container	1250
holding returned gas.	1251
1252
FDA does not consider gas remaining in high-pressure cylinders or cryogenic containers that are	1253
returned for refilling in the normal course of business to be returned medical gas. In these cases,	1254
a small amount of gas is expected to remain in a returned container and can be reused if the	1255
medical gas meets specifications.	1256
1257
Manufacturers must have written procedures for the holding, testing, and use of returned medical	1258
gases and must maintain records of returned medical gases that include the following	1259
(§ 213.204):	1260
1261
• 	Name of the returned medical gas	1262
• 	Lot number (or control number or batch number)	1263
• 	Reason for the return	1264
• 	Quantity returned	1265
• 	Date of disposition	1266
• 	Ultimate disposition of the returned gas	1267
1268
The requirements pertaining to the salvaging of medical gas are in 21 CFR 213.208.	1269
Manufacturers may salvage medical gases that have been improperly stored and return the	1270
medical gas to the marketplace unless the container was subjected to adverse conditions that	1271
impact the identity, strength, quality, and purity of the medical gas, or the integrity of the	1272
container closure. Examples of such adverse conditions include natural disasters, facility	1273
structural damage, and changes in external factors such as temperature. In these instances,	1274
manufacturers must demonstrate through laboratory tests that the gases continue to meet all	1275
applicable standards of identity, strength, quality, and purity, and that the adverse conditions did	1276

Contains Nonbinding Recommendations
Draft — Not for Implementation
31
not compromise the integrity of the container closure system. Manufactures must have written	1277
procedures for the holding, testing, and use of salvaged medical gases.	1278
1279
1280
XIII. 	ADAPTERS	1281
1282
For safety reasons, FDA recommends avoiding the use of adapters of any kind to circumvent the	1283
specific medical gas valves and connections associated with a medical gas.	1284
1285
In limited circumstances, such as when filling medical gas mixtures, manufacturers can use	1286
adapters (e.g., to reduce or expand the connection size for a specific medical gas while still	1287
maintaining the connection system). Manufacturers should have written procedures detailing	1288
system checks and controls to prevent mix-ups or contamination when using adapters, and to	1289
promptly identify and quarantine compromised gases if a mix-up or contamination should occur.	1290
1291

Contains Nonbinding Recommendations
Draft — Not for Implementation
32
GLOSSARY	1292
1293
The following terms are defined for the purposes of this guidance:	1294
1295
Air separation units: Air separation units separate atmospheric air into constituent gases of	1296
oxygen, nitrogen, and argon through a purification process of precleaning, compression, cooling,	1297
and fractional distillation of liquefied air.	1298
1299
Batch: A specific quantity of a medical gas or other material that is intended to have uniform	1300
character and quality, within specified limits, and is produced according to a single	1301
manufacturing order during the same cycle of manufacture.1	
1302
1303
Component: Any ingredient intended for use in the manufacture of a medical gas, including	1304
those that may not appear in such gas. It does not include an incoming designated medical gas.2	
1305
1306
Designated medical gas (DMG): A drug that is manufactured or stored in a liquefied,	1307
nonliquefied, or cryogenic state; is administered as a gas; and is defined in section 575(1) of the	1308
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360ddd(1)).3	
1309
1310
In-process material: Any material fabricated, compounded, blended, or derived by chemical	1311
reaction that is produced for, and used in, the preparation of the medical gas.4	
1312
1313
Incoming DMG: A DMG received from one source that, after receipt, is commingled with the	1314
same gas from another source, used in a medically appropriate combination of DMGs or in the	1315
production of another medical gas, or further distributed.5	
1316
1317
Lot: A batch, or a specific identified portion of a batch, having uniform character and quality	1318
within specified limits; or, in the case of a medical gas produced by continuous process, it is a	1319
specific identified amount produced in a unit of time or quantity in a manner that assures its	1320
having uniform character and quality within specified limits.6	
1321
1322
Lot number, control number, or batch number: Any distinctive combination of letters,	1323
numbers, or symbols, or any combination of them, from which the complete history of the	1324
manufacture, processing, packing, holding, and distribution of a batch or lot of medical gas or	1325
other material can be determined.7	
1326
1327
Manufacturer: Any person or firm that manufactures, processes, packs, or holds a medical gas,	1328
which includes packaging and labeling operations, testing, and quality control.8	
1329
1 See 21 CFR 213.3(b)(2).
2 See 21 CFR 213.3(b)(4).
3 See 21 CFR 213.3(b)(5).
4 See 21 CFR 213.3(b)(7).
5 See 21 CFR 213.3(b)(8).
6 See 21 CFR 213.3(b)(9).
7 See 21 CFR 213.3(b)(10).
8 This definition is based on the definition of manufacture, processing, packing, or holding of medical gases in
21 CFR 213.3(b)(11).

Contains Nonbinding Recommendations
Draft — Not for Implementation
33
1330
Medical gas: A drug that is manufactured or stored in a liquefied, nonliquefied, or cryogenic	1331
state and administered as a gas.9	
1332
1333
Original manufacturer: The person that initially produces a DMG by chemical reaction,	1334
physical separation, compression of atmospheric air, purification (e.g., reprocessing an industrial	1335
gas into a medical gas), or other means.10	
1336
1337
Portable cryogenic medical gas containers: Containers that are capable of being transported	1338
and are intended to be attached to a medical gas supply system within a hospital, health care	1339
entity, nursing home, other facility, or home health care setting, or is used to fill small cryogenic	1340
gas containers for use by individual patients. The term excludes cryogenic containers that are	1341
not designed to be connected to a medical gas supply system, e.g., tank trucks, trailers, rail cars,	1342
or small cryogenic gas containers for use by individual patients (including portable liquid oxygen	1343
units, as defined in 21 CFR 868.5655).11	
1344
1345
Quality unit: Any person or persons designated with the authority and responsibility for overall	1346
quality management and other responsibilities as defined in 21 CFR 213.22.12	
1347
1348
Strength: The concentration of the medical gas (for example, weight/weight, weight/volume, or	1349
unit dose/volume basis); and/or the potency, that is, the therapeutic activity of the medical gas as	1350
indicated by appropriate laboratory tests or by adequately developed and controlled clinical data	1351
(expressed, for example, in terms of units by reference to a standard).13	
1352
1353
Transfillers: Transfillers manufacture medical gas by transferring a finished medical gas, either	1354
in a liquid or gaseous state, from one container to another, including a container that contains the	1355
same medical gas. Manufacturers that combine different medical gases are considered both	1356
transfillers and original manufacturers.	1357
1358
Uninterrupted filling sequence: A single, continuous filling sequence with no breaks or	1359
shutdowns occurring during the filling operation. This sequence uses the same personnel,	1360
equipment, and batch of component(s).	1361
1362
9 See section 575(2) of the FD&C Act; 21 CFR 213.3(b)(12).
10 See 21 CFR 213.3(b)(13).
11 See 21 CFR 213.94(e)(1); 21 CFR 201.328(a).
12 See 21 CFR 213.3(b)(14).
13 See 21 CFR 213.3(b)(15).