Current Good 
Manufacturing Practice 
for Medical Gases 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Frank Perrella 301-796-3265. 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2017 
Pharmaceutical Quality/Manufacturing Standards (CGMP) 
 
Revision 1  
Current Good 
Manufacturing Practice 
for Medical Gases 
Guidance for Industry 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
   
June 2017 
Pharmaceutical Quality/Manufacturing Standards (CGMP) 
 
Revision 1
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  STATUTORY AND REGULATORY REQUIREMENTS .......................................... 2 
III.  ORGANIZATION AND PERSONNEL ......................................................................... 3 
A.  Quality Unit .................................................................................................................................... 3 
1. Responsibilities ................................................................................................................................ 3 
2. Quality Agreements With Suppliers ................................................................................................. 4 
3.  Supplier Qualifications .................................................................................................................... 4 
B.  Personnel Qualifications ................................................................................................................ 4 
IV.   BUILDINGS AND FACILITIES .................................................................................... 5 
V.  EQUIPMENT .................................................................................................................... 5 
A.  Filling Equipment Qualification ................................................................................................... 5 
B.  Equipment Cleaning and Maintenance........................................................................................ 6 
C.  Equipment Calibration .................................................................................................................. 6 
D.  Computerized Systems .................................................................................................................. 7 
VI.  COMPONENTS, CONTAINERS, AND CONTAINER CLOSURE SYSTEMS ....... 8 
A.  Components .................................................................................................................................... 8 
B.  Containers and Container Closure Systems ................................................................................ 8 
1. General ............................................................................................................................................ 8 
2. Prefill Inspections ............................................................................................................................ 9 
C.  Stock Rotation .............................................................................................................................. 12 
VII.  PRODUCTION AND PROCESS CONTROLS ........................................................... 12 
A.  Sampling and Testing .................................................................................................................. 12 
B.  Vacuum Evacuation of High-Pressure Cylinders ..................................................................... 12 
C.  Filling Procedure Checks ............................................................................................................ 13 
1. Temperature and Pressure Readings ............................................................................................. 13 
2. Valve Assembly Leak Testing ......................................................................................................... 13 
3.  Heat-of-Compression Check .......................................................................................................... 14 
D.  Calculation of Yield ..................................................................................................................... 14 
VIII.  PACKAGING AND LABELING CONTROLS .......................................................... 14 
A.  Materials Examination and Usage ............................................................................................. 14 
B.  Labeling Control .......................................................................................................................... 14 
C.  Packaging and Labeling Operations .......................................................................................... 15 
D.   Expiration Dating ........................................................................................................................ 16 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
IX.  HOLDING AND DISTRIBUTION ............................................................................... 16 
X.  LABORATORY CONTROLS ...................................................................................... 16 
A.  General Requirements and Recommendations ......................................................................... 16 
B.  Calibration of Instruments.......................................................................................................... 17 
C.  Medical Gas Sampling and Testing ............................................................................................ 17 
1. Cylinders Filled on a Multiple-Outlet Manifold ............................................................................ 18 
2. Cylinders Filled Individually ......................................................................................................... 18 
3. Mixtures ......................................................................................................................................... 18 
4. Medical Gas From Suppliers ......................................................................................................... 18 
D.  Test Method and Alternative Test Method Validation ............................................................. 19 
E.  Stability Testing ........................................................................................................................... 19 
F.  Reserve Samples ........................................................................................................................... 20 
XI.  RECORDS AND REPORTS ......................................................................................... 20 
A.  General Requirements and Recommendations ......................................................................... 20 
1. Record Retention ............................................................................................................................ 20 
2. Record Review ............................................................................................................................... 20 
3. Equipment Calibration, Checks, and Inspections .......................................................................... 20 
4. Computer Validation Data ............................................................................................................. 21 
5. Process Validation Data ................................................................................................................ 21 
B.  Equipment Cleaning and Use Logs ............................................................................................ 21 
C.  Component, Container, Container Closure System, and Labeling Records .......................... 22 
D.  Master Production and Control Records................................................................................... 22 
E.  Batch Production and Control Records ..................................................................................... 23 
F.  Production Record Review and Investigations Records........................................................... 24 
G.  Laboratory Records ..................................................................................................................... 25 
H.  Distribution Records .................................................................................................................... 26 
I.  Complaint Files ............................................................................................................................ 26 
J.  Certificate of Analysis.................................................................................................................. 27 
XII.  RETURNED MEDICAL GAS....................................................................................... 27 
XIII.  ADAPTERS ..................................................................................................................... 27 
XIV.  GLOSSARY..................................................................................................................... 27 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1    Current Good Manufacturing Practice for Medical Gases 
1
2  Guidance for Industry  
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   
14  I.  INTRODUCTION 
15   
16  This guidance is intended to assist manufacturers of medical gases in complying with applicable 
17  current good manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211).2 Medical 
18  gases are generally regulated as finished pharmaceuticals and are subject to CGMP requirements 
19  regardless of the processing stage. Compliance with applicable CGMP requirements helps to 
20  ensure the safety, identity, strength, quality, and purity of medical gases. Medical gases that are 
21  not manufactured, processed, packed, or held according to applicable CGMP requirements can 
22  cause serious injury or death.3 
23   
24  Pursuant to its review of Federal drug regulations under the Food and Drug Administration 
25  Safety and Innovation Act (FDASIA),4 FDA determined, in part, that additional guidance 
26  regarding the application of certain regulations to medical gases would be useful.5 This 
27  document provides such additional guidance regarding CGMP regulations. This guidance is 
28  expected to reduce the regulatory compliance burden for the medical gas industry by providing 
                                                 
1 This guidance has been prepared by the Office of Pharmaceutical Quality and the Office of Compliance in the 
Center for Drug Evaluation and Research in cooperation with the Office of Regulatory Affairs at the Food and Drug 
Administration. 
2 In this guidance, the term manufacturer includes any person or firm that manufactures a medical gas, which 
includes producing, cascading, distributing, filling, mixing, purifying, separating, transferring, and transfilling 
medical gases. See section XIV, Glossary, for definitions of different types of manufacturers.  
3 A number of injuries and deaths have resulted from medical gases not being produced or handled properly. For 
example, there have been a number of incidents in which a medical gas container holding a gas other than oxygen 
was erroneously connected to a health care facilitys oxygen supply system. For further details regarding several of 
these incidents, see proposed rule Medical Gas Containers and Closures; Current Good Manufacturing Practice 
Requirements (71 FR 18039, April 10, 2006).  
4 Public Law 112-144, 126 Stat. 993 (July 9, 2012); see section 1112(a)(2).  
5 See FDA, 2015, Report to Congress: Review of Federal Drug Regulations With Regard to Medical Gases, 
available at 
http://www.fda.gov/downloads/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/
UCM453727.pdf. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
29  clear, up-to-date, detailed recommendations regarding CGMP issues that have been the subject 
30  of industry questions. 
31   
32  This guidance supersedes the draft guidance for industry Current Good Manufacturing Practice 
33  for Medical Gases issued in May 2003.6  
34   
35  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
36  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
37  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
38  the word should in Agency guidances means that something is suggested or recommended, but 
39  not required. 
40   
41  II.  STATUTORY AND REGULATORY REQUIREMENTS 
42   
43  This guidance applies to medical gases that meet the definition of a drug under section 201(g)(1) 
44  of the Federal Food, Drug, and Cosmetic Act (FD&C Act),7 including those that are recognized 
45  in the United States Pharmacopeia-National Formulary (USP-NF). Gases that do not meet the 
46  definition of a drug, including gases intended for industrial applications or nondrug medical 
47  applications (e.g., a calibration gas used as a standard), are outside the scope of this guidance. 
48  Medical gasesincluding those that are marketed pursuant to a new drug application (NDA) 
49  submitted under section 505 of the FD&C Act or the certification process described in section 
50  576 of the FD&C Act8are generally considered finished drug products. 
51   
52  A medical gas that meets the definition of a drug (referred to in this guidance as simply a 
53  medical gas) is deemed to be adulterated under section 501(a)(2)(B) of the FD&C Act if the 
54  methods used in, or the facilities or controls used for, its manufacture, processing, packing, or 
55  holding do not conform to or are not operated or administered in conformity with current good 
56  manufacturing practice.9 Section 501 of the FD&C Act states that the term current good 
57  manufacturing practice includes the implementation of oversight and controls over the 
58  manufacture of drugs to ensure quality, including managing the risk of and establishing the 
59  safety of raw materials, materials used in the manufacturing of drugs, and finished drug 
60  products.  
61   
62  Medical gases that are subject to applicable CGMP requirements at 21 CFR parts 210 and 211, 
63  and manufacturers of such medical gases, must meet these requirements to comply with section 
64  501(a)(2)(B) of the FD&C Act (see 21 CFR 210.1(b)). Manufacturers that solely produce gases 
65  for industrial or nondrug medical applications are not subject to these CGMP requirements. 
66   
                                                 
6 See 68 FR 24005 (May 6, 2003). 
7 See 21 U.S.C. 321(g)(1) for the definition of drug under the FD&C Act. See 21 U.S.C. 360ddd(2) for the definition 
of medical gas and 21 U.S.C. 360ddd(a) for the definition of designated medical gas.  
8 21 U.S.C. 360ddd-1. 
9 21 U.S.C. 351(a)(2)(B). 
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  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
67  Manufacturers of medical gases need only comply with those CGMP requirements applicable to 
68  the operations in which they are engaged (see  210.2(b)). 
69   
70  III.  ORGANIZATION AND PERSONNEL 
71   
72  A.  Quality Unit 
73   
74  The establishment of an effective quality system reflects the principle that quality should be built 
75  into the product; testing alone cannot ensure product quality. 21 CFR 211.22 provides that the 
76  quality control unit (hereinafter quality unit) has the authority needed to create, monitor, and 
77  implement a quality system.10 The quality units responsibilities and procedures must be in 
78  writing and its procedures must be followed ( 211.22(d)). 
79   
80  Manufacturers must have a quality unit with the responsibility and authority to approve or reject 
81  all components, drug product containers, closures, in-process materials, packaging material, 
82  labeling, and drug products and the authority to review production records to ensure that no 
83  errors have occurred or, if errors have occurred, that they have been fully investigated. The 
84  quality unit is also responsible for approving or rejecting drug products manufactured, processed, 
85  packed, or held under contract by another company ( 211.22(a)). 
86   
87  1.  Responsibilities 
88   
89  A quality units size and complexity can vary with the size of the operation. For example, a 
90  manufacturer that fills only oxygen and has very few employees might only have one person as 
91  the quality unit, whereas a larger manufacturer with several locations might have a corporate 
92  quality unit responsible for multiple locations. Either arrangement can satisfy the requirements of 
93   211.22. Staff at each manufacturing facility must follow procedures and specifications that are 
94  approved by the appropriate quality unit ( 211.22(c)).  
95   
96  As described in FDAs guidance on maintaining a quality system,11 production personnel and the 
97  quality unit typically remain independent. Some medical gas manufacturing sites, however, have 
98  limited personnel, and the individuals assigned to the quality unit also perform production 
99  functions. These individuals implement all the controls and review the results of manufacture to 
100  ensure that product quality standards established by the manufacturer have been met, regardless 
101  of their production functions or other roles. FDA considers this approach to comply with CGMP 
102  requirements provided that each individual who performs quality unit functions is adequately 
103  trained and experienced in all quality unit tasks assigned ( 211.25). FDA recommends that all 
                                                 
10 For purposes of this guidance, the term quality unit is synonymous with the term quality control unit. For the 
definition of quality control unit, see  210.3(b)(15). We note that FDA also takes this approach in its guidance for 
industry Contract Manufacturing Arrangements for Drugs: Quality Agreements. We update guidances periodically. 
To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
11 See the ICH guidance for industry Q10 Pharmaceutical Quality System and the guidance for industry Quality 
Systems Approach to Pharmaceutical CGMP Regulations. 
3 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
104  individuals who are part of the quality unit be identified by function and title in written 
105  procedures to ensure that the appropriate quality unit responsibilities are fulfilled.12 
106   
107  2.  Quality Agreements With Suppliers 
108   
109  The quality units procedures should call for written quality agreements with suppliers of goods 
110  and services that clearly describe the goods or services to be provided, quality specifications, and 
111  communication mechanisms between the contracting parties; this assists in ensuring drug quality 
112  and safety.13 Timely communication about process changes that could affect the composition of 
113  the gas supplied or about changes in tank cleaning services, for example, can prevent 
114  contamination. Therefore, FDA recommends that written quality agreements with suppliers 
115  define CGMP responsibilities and the communication processes for reporting complaints and 
116  changes that could be critical to drug quality. 
117   
118  3.   Supplier Qualifications 
119   
120  Written procedures should explain how manufacturers qualify and approve suppliers.14 
121  Manufacturers should determine supplier qualifications to ensure that quality standards are met 
122  and that purchased gases, including feeder gases, have an accurate and complete certificate of 
123  analysis (COA). If using a suppliers COA, manufacturers must conduct at least one specific 
124  identity test and establish the reliability of the suppliers analyses through appropriate validation 
125  of the suppliers test results at appropriate intervals (see  211.84(d)). Such periodic testing may 
126  be performed by the manufacturer, a third party, or a contract-testing laboratory. Manufacturers 
127  can begin the supplier qualification process, for example, by fully testing several batches and 
128  examining the gas, containers, and closures provided.15 Manufacturers should periodically verify 
129  the qualification of approved suppliers by conducting audits (on-site or remote), analyzing trends 
130  in the quality of received goods, testing, and evaluating the timeliness of supplier responses to 
131  complaints. 
132   
133  B.  Personnel Qualifications 
134   
135  All personnel, including those working on the manufacturing floor or driving to customer sites to 
136  distribute medical gas, must have the education, training, and experience necessary to perform 
137  their assigned functions ( 211.25(a) and (b)). Inadequately trained personnel could 
138  inadvertently fill the wrong gas into a storage tank or connect the wrong gas to a gas supply 
139  system, which can result in serious injury or death.16 
                                                 
12 For quality unit requirements, see  211.22. 
13 For more information on quality agreements, see the guidance for industry Contract Manufacturing Arrangements 
for Drugs: Quality Agreements.  
14 Designated medical gases must be certified (see sections 575 and 576 of the FD&C Act). For more information on 
certification of designated medical gases, see the draft guidance for industry Certification Process for Designated 
Medical Gases. When final, this guidance will represent FDAs current thinking on this topic. 
15 In this guidance, the terms batch and lot are interchangeable. 
16 See footnote 3. 
4 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
140   
141  Personnel, including drivers, who connect portable cryogenic containers to gas supply systems 
142  must be trained appropriately in the specifics of those supply systems. Drivers who deliver 
143  multiple gases (including multiple medical gases or both medical and industrial gases) must be 
144  trained to accurately identify each gas and distinguish among them. Personnel must be trained in 
145  CGMP requirements on a continuing basis and with sufficient frequency to provide assurance 
146  that they remain familiar with the applicable requirements ( 211.25(a)). FDA recommends that 
147  CGMP training be provided annually and that manufacturers keep training records that include 
148  time and attendance entries. 
149   
150  IV.   BUILDINGS AND FACILITIES 
151   
152  The standard industry practice of refilling labeled medical gas containers underscores the 
153  importance of building and facility design as a control method for proper operation. For example, 
154  because facilities reuse labeled medical gas containers, filled and unfilled cylinders with 
155  identical labeling may only be distinguishable if they are quarantined in well-defined areas. 
156  Buildings must have a sufficient number of adequately sized areas for organized sequential 
157  operations, including well-defined areas for incoming medical gases, containers, manufacturing 
158  equipment, rejected containers and container closure systems, filling, and quarantine, as well as 
159  finished product that is ready for distribution ( 211.42, 211.89). Outdoor spaces and delivery 
160  truck beds may be appropriate areas to conduct certain operations (e.g., storage and handling) for 
161  medical gases in pressurized containers. For example, industrial and medical gases could be 
162  separated physically in the warehouse or in the delivery truck. To separate these areas from other 
163  spaces ( 211.42(c)), manufacturers should use identifiers such as signage, floor demarcation, or 
164  tagging.  
165   
166  V.  EQUIPMENT 
167   
168  A.  Filling Equipment Qualification 
169   
170  Automatic, mechanical, and electronic equipment, or other types of equipment, must be checked 
171  according to a written program designed to ensure proper performance ( 211.68(a)). Equipment 
172  qualification helps ensure proper performance. FDA recommends the following: 
173   
174    Equipment should be qualified at the temperature and pressures used during filling. 
175   
176    Manifold valves should be qualified for use (e.g., appropriately designed to prevent mix-
177  ups during medical gas filling operations and shown to prevent contamination of medical 
178  gas). 
179   
180    Other valves that are critical to the prevention of drug contamination, such as check 
181  valves used in filling systems, should be qualified for use. 
182     
5 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
183  B.  Equipment Cleaning and Maintenance 
184   
185  21 CFR  211.67 requires that equipment be adequately cleaned and maintained. FDA 
186  recommends that medical gas manufacturers: 
187   
188    Ensure that equipment used in the manufacture of medical gases (e.g., manifolds, pigtails, 
189  valve assemblies, hoses, gauges) is cleaned before initial use and after exposure to a 
190  contaminant (e.g., industrial gas impurities).  
191   
192    Tailor their equipment cleaning and maintenance procedures to match the type and 
193  complexity of the particular operation, as appropriate. 
194   
195  Closed pressurized systems used for filling medical gases (e.g., manifolds) need not be cleaned 
196  between batches, unless exposed to a contaminant. To prevent contamination ( 211.80(b)), 
197  manufacturers should ensure that open ends are appropriately covered (e.g., with physical caps).  
198   
199  Components and drug product containers and closures must at all times be handled and stored in 
200  a manner to prevent contamination ( 211.80(b)). Accordingly, high-pressure cylinders exposed 
201  to the elements and hoses used to fill cryogenic containers must have caps or other protective 
202  means to prevent contamination ( 211.80(b)). 
203   
204  Valves that are critical to the prevention of drug contamination, such as manifold or check valves 
205  used in supply systems, must be properly maintained ( 211.67). 
206   
207  Industrial and medical gases can sometimes be filled at different times on the same manifold 
208  rack. This practice is acceptable as long as processes and procedures are in place and followed to 
209  prevent any possible contamination caused by backflow from the industrial cylinders into the 
210  medical cylinders or from residual industrial gas in the manifold. 
211    
212  For reporting requirements and recommendations, see section XI.B, Equipment Cleaning and 
213  Use Logs.  
214   
215  C.  Equipment Calibration 
216   
217  Manufacturers must establish an appropriate schedule or frequency for equipment calibration 
218  ( 211.68). This can be done using either the equipment manufacturers recommended 
219  calibration schedule or a schedule based on the medical gas manufacturers own historical data. 
220  Medical gas manufacturers can reference the equipment manufacturers instruction manual in 
221  their written procedures if the manual is available for use on-site. Medical gas manufacturers that 
222  use automated, mechanical, or electronic equipment such as computer systems must ensure these 
223  systems are routinely calibrated, inspected, or checked according to a written program designed 
224  to ensure proper performance ( 211.68(a)).  
225   
226  FDA recommends that manufacturers: 
227   
6 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
228    Check the performance of vacuum gauges daily to ensure that the needle on the gauge 
229  returns to zero when there is no vacuum or pressure (above atmospheric pressure).  
230   
231    Calibrate vacuum and pressure gauges annually against an established standard (e.g., a 
232  standard from the National Institute of Standards and Technology). Low-pressure gauges 
233  and flow meters used in filling cryogenic home containers do not require calibration, but 
234  manufacturers should ensure that they function properly for their intended use. 
235     
236    Calibrate thermometers according to the equipment manufacturers instructions at least 
237  annually. 
238   
239    Calibrate handheld oxygen analyzers based on the equipment manufacturers instructions 
240  or a schedule based on the gas manufacturers own historical data.  
241   
242  See section XI.A.3 for records requirements related to equipment calibration, checks, and 
243  inspections. 
244   
245  D.  Computerized Systems 
246     
247  Computerized systems, including hardware and software, used in the manufacturing, processing, 
248  and holding of medical gases must be validated for their intended use (e.g.,  211.63, 211.68(a) 
249  and (b)).17 The depth and scope of the validation depend on the complexity and significance of 
250  the computerized system.  
251   
252  Automated filling systems must be validated to provide assurance that the filling is done properly 
253  ( 211.68, 211.100). 
254   
255  Computerized or automated systems must have sufficient controls to prevent unauthorized access 
256  or changes to master production control records or other records and to ensure records or data are 
257  accurate ( 211.68(b)). In addition, any change to a computerized or automated system should be 
258  made according to approved procedures, and any changes should be documented.18 A risk 
259  assessment should be performed to determine the potential of the computerized system to affect 
260  product quality, safety, and record integrity. Manufacturers can use an audit trail as part of these 
261  systems to address risk. 
262   
263  For examples of the validation of medical gas air separation unit (ASU) automated and computer 
264  controls, see the Compressed Gas Associations Guideline for Validation of Air Separation Unit 
265  and Cargo Tank Filling for Oxygen USP and Nitrogen NF (CGA P-8.2, 5th ed., 2013). 
266   
                                                 
17 For more information about validation, see the guidance for industry Process Validation: General Principles and 
Practices. 
18 For FDAs current thinking on the use of computerized systems for maintaining electronic records, see the 
guidance for industry Part 11, Electronic Records; Electronic SignaturesScope and Application.  
7 
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267  VI.  COMPONENTS, CONTAINERS, AND CONTAINER CLOSURE SYSTEMS 
268   
269  A.  Components 
270   
271  Manufacturers must control and assess the quality of components (i.e., any ingredient intended 
272  for use in the manufacture of a drug product) as specified in  211.80, 211.82, 211.84, and 
273  211.110. Recommendations for control of incoming components include the following: 
274   
275    ASUs should assess the air quality when validating the manufacturing process to 
276  determine when it should be reassessed and to determine which air quality conditions 
277  could require additional testing. 
278   
279    Original manufacturers that use a feeder gas as their raw material should perform an 
280  initial and periodic characterization of the feeder gas (e.g., fingerprinting) for any 
281  impurities that could affect the finished product safety and quality. They should also 
282  assess levels of impurities in the feeder gas to ensure that the manufacturing process is 
283  capable of adequate purification (i.e., remains valid under normal processing conditions). 
284  Furthermore, original manufacturers should maintain written agreements with suppliers 
285  of feeder gas so that they are informed of any changes that suppliers make that might 
286  affect the composition of the feeder gas. (See also section III.A.2, Quality Agreements 
287  With Suppliers.) 
288   
289  B.  Containers and Container Closure Systems 
290   
291  1.  General 
292   
293  The quality unit must examine, reexamine as appropriate, and approve or reject containers and 
294  container closure systems ( 211.22, 211.84, 211.87). A manufacturer should reexamine a 
295  container or container closure system when, for example, it is stored for an extended period or 
296  exposed to adverse environmental conditions. Rejected containers and container closure systems 
297  must be identified and quarantined ( 211.89). After customers use containers and container 
298  closure systems and send them back for refilling, manufacturers must store them under 
299  quarantine until they have been tested or examined, as appropriate ( 211.82(b)). 
300   
301  Containers and container closure systems must be clean and must not be reactive, additive, or 
302  absorptive so as to alter the safety, identity, strength, quality, or purity of a medical gas beyond 
303  the official or established requirements ( 211.94(a) and (c)). Thus, containers and container 
304  closure systems should be cleaned before initial use and after exposure to a contaminant. In 
305  addition, if converting a containers use from industrial grade gas to medical gas, or if there is 
306  reason to believe there was previous industrial use, manufacturers must implement appropriate 
307  cleaning and retesting procedures ( 211.84, 211.94(c)).  
308   
309  Portable cryogenic containers that are not manufactured with permanent gas-specific use outlet 
310  connections (e.g., those that have been silver-brazed) must have gas-specific use outlet 
311  connections that are attached to the valve body so that they cannot be readily removed or 
312  replaced (without making the valve inoperable and preventing the containers use) except by the 
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Draft  Not for Implementation 
313  manufacturer ( 211.94(e)(1)). If the gas-specific use outlet connection can be readily removed 
314  and replaced, a container holding a gas other than oxygen could be inadvertently connected to an 
315  oxygen supply system, causing serious injury or death. 
316   
317  Manufacturers should not use vapor recovery systems during carbon dioxide delivery. It is 
318  possible that toxic contaminants or impurities present in the gaseous head space of the storage 
319  tank or container could be drawn into the tank or container, thereby contaminating the carbon 
320  dioxide. 
321   
322  2.  Prefill Inspections  
323   
324  Manufacturers should conduct prefill inspections to provide assurance that containers and 
325  container closure systems are acceptable for use before filling begins. This section addresses 
326  prefill inspections that evaluate containers and container closure systems used to hold incoming 
327  medical gases and store medical gases and finished product containers and container closure 
328  systems. Any prefill inspections performed must be properly documented ( 211.184(b)). 
329  Containers and container closure systems that fail prefill inspections must be quarantined until 
330  the container, container closure system, or valve has been repaired, cleaned, or replaced, as 
331  appropriate, and determined to pass reinspection ( 211.84, 211.89). 
332   
333  a.  External inspection  
334   
335  i.  Container 
336   
337  Manufacturers should carefully examine each container for dents, burns, dings, oil, grease, and 
338  other signs of damage or contamination that can cause a container to be unsafe for use. Any 
339  container found to have any of these conditions must be quarantined until its suitability has been 
340  determined ( 211.82, 211.84, 211.89). 
341   
342  ii.  Valves, inlets, outlets, and connectors  
343   
344  Manufacturers should carefully inspect each containers valve assembly, connectors, and fittings 
345  to ensure that they are appropriate for the medical gas. The valves, inlets, outlets, gauges, and 
346  connectors should be examined carefully for signs of damage (including fire damage), unusual 
347  wear, corrosion, or the presence of debris, oil, or grease. This inspection should cover any 
348  connections that are brazed, welded, or equipped with a locking device. 
349   
350  b.  Label inspection 
351   
352  Manufacturers should examine the labeling on each container for legibility and accuracy and 
353  should remove and replace damaged labels. Product labels on medical gas containers can be 
354  reused. Labels that are obsolete or outdated must be removed ( 211.122(e)).  
355   
356  Each portable cryogenic container must be conspicuously marked with a 360 wraparound label 
357  identifying its contents ( 201.328(a)(1)). The wraparound label must be placed on the sidewall 
358  of the container as close to the top portion of the container as possible, but below the top weld 
359  seam ( 201.328(a)(1)(iv)). The name of the gas must be printed continuously around the 360 
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360  wraparound label so that it can be read around the entire container (e.g., Oxygen USP, Oxygen 
361  USP, Oxygen USP) ( 201.328(a)(1)(iii)), and the lettering for the name of the gas on the label 
362  must be at least 2 inches high (201.328(a)(1)(ii)). For containers that hold a single gas, either 
363  the lettering or the labels background must be in the appropriate color (e.g., green for oxygen) 
364  with contrasting background or lettering (e.g., lettering in the designated color against a white 
365  background, or white lettering on a background of the designated color) ( 201.328(a)(1)(i)).19  
366   
367  The 360 wraparound label or a separate label on the portable cryogenic medical gas container 
368  must include, in conspicuous lettering, the phrase For Medical Use, Medical Gas, or some 
369  similar phrase that indicates the gas is for medical use ( 201.328(a)(2)). 
370   
371  The 360 wraparound label and, if separate, the For Medical Use label required for portable 
372  cryogenic medical gas containers must be affixed to the container in a manner that does not 
373  interfere with other labeling and such that it is not susceptible to becoming worn or inadvertently 
374  detached during normal use ( 211.94(e)(2)). Each label, as well as materials used for coloring 
375  medical gas containers, must be reasonably resistant to fading, durable when exposed to 
376  atmospheric conditions, and not readily soluble in water ( 211.94(e)(2)). 
377   
378  Although permanently mounted cryogenic containers are not required to have a 360 label, such 
379  containers should include content labeling that is easily readable from all sides. 
380   
381  c.  Color code inspection 
382   
383  The shoulder of each high-pressure medical gas cylinder must be colored in the color or colors 
384  that correspond to the gas held in the cylinder; furthermore, the shoulders color or colors must 
385  be visible when viewed from the top of the cylinder ( 201.328(b)). The FDA-designated colors 
386  identifying medical gases in high-pressure medical gas containers and portable cryogenic 
387  medical gas containers are ( 201.328(c)):  
388   
Medical Gas  Color 
Medical Air  Yellow 
Carbon Dioxide  Gray 
Helium  Brown 
Nitrogen  Black 
Nitrous Oxide  Blue 
Oxygen  Green 
Mixture or Blend*   Colors corresponding to each component gas** 
389  * The terms mixture and blend refer to combinations of medical gases. 
390  **For example, green and gray for a blend of oxygen and carbon dioxide. 
391   
                                                 
19 There are no specific color requirements for the 360 wraparound label for portable cryogenic medical gas 
containers containing a mixture of gases. As stated above, however, there are requirements addressing the color of 
the cryogenic container itself. 
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392  Unlike high-pressure cylinders, portable cryogenic medical gas containers are not required to be 
393  colored in whole or in part (see below for a discussion of the label requirements for portable 
394  cryogenic medical gas containers). However, a portable cryogenic container may only be 
395  colored, in whole or in part, in the FDA-designated colors in the chart above if the gas or gases 
396  held in the container correspond to those colors ( 201.328(a)(1)(v)). Alternatively, these 
397  containers can be colored in a light-reflective color (e.g., white) that is not one of the FDA-
398  designated colors in the chart above. 
399   
400  Manufacturers should not rely solely or primarily on color coding to identify medical gases; the 
401  label should be used as the primary means of identifying the product. Color coding provides an 
402  additional safeguard to facilitate accurate identification and detection of potential errors. 
403   
404  d.  Prefill inspection of high-pressure cylinders  
405   
406  When inspecting high-pressure cylinders, manufacturers should conduct the following prefill 
407  inspections (in addition to the previously mentioned prefill inspections). 
408   
409  i.  Inspection of high-pressure cylinders for the DOT requalification date 
410   
411  Manufacturers should examine each high-pressure cylinder for the U.S. Department of 
412  Transportation (DOT) date stamped on the cylinder before use to verify that each cylinder 
413  conforms with DOT requirements for requalification and marking of cylinders (see, e.g., 49 CFR 
414  180.209). If the DOT requalification date has been exceeded, the cylinder should be quarantined 
415  until either DOT requirements have been satisfied or the cylinder is removed from inventory. 
416   
417  ii.  Hammer or dead-ring test 
418   
419  Manufacturers should conduct a hammer or dead-ring test to provide information about internal 
420  corrosion of steel cylinders. The test consists of lightly tapping the cylinder sidewall with a 
421  hammer-like instrument. The hammer or dead-ring test should not be performed on aluminum or 
422  composite cylinders because the test would not indicate internal corrosion and could damage the 
423  cylinder wall.  
424   
425  iii.  Odor inspection  
426   
427  Manufacturers can use an odor test to detect the presence of any foreign gas or odor remaining in 
428  the container. This test should not be performed on carbon dioxide, nitrous oxide, or toxic or 
429  corrosive gases for safety reasons. This test should not be confused with finished product testing, 
430  for which an odor test may be included in a USP-NF monograph. 
431   
432  If a cylinder is empty (at atmospheric pressure), manufacturers can introduce Nitrogen NF into 
433  the cylinder at a predetermined pressure and perform an odor test on the resulting gas. 
434   
435  Residual pressure valves prevent the cylinder from emptying completely and also prevent 
436  backflow. A prefill odor test on a cylinder with a qualified residual pressure valve is not 
437  necessary if the cylinder has residual pressure. Manufacturers should document verification of 
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438  residual pressure on the batch record. For batch records and reporting requirements and 
439  recommendations, see section XI.E, Batch Production and Control Records.  
440   
441  iv.  Venting or blow down of cylinders  
442   
443  High-pressure cylinders that are received for refilling should be vented or blown down 
444  appropriately to remove any gas remaining in the cylinders. Manufacturers can omit this step if 
445  the cylinder is equipped with a qualified residual pressure valve and has residual pressure. 
446   
447  C.  Stock Rotation 
448   
449  Medical gas containers and container closure systems are typically reused over a period of years 
450  and undergo prefill testing. Accordingly, FDA does not intend to object if medical gas 
451  manufacturers do not comply with the containers and container closure systems requirements in 
452   211.86 for stock rotation and use of the oldest containers and container closure systems first. 
453  Manufacturers should address the continued suitability of containers and container closure 
454  systems after extended storage by having procedures in place to ensure that they (1) are not 
455  exposed to conditions that may render them unfit for use, and (2) have undergone prefill tests. 
456   
457  VII.  PRODUCTION AND PROCESS CONTROLS 
458   
459  A.  Sampling and Testing 
460   
461  Control procedures must be established to monitor output and to validate the performance of 
462  manufacturing processes that may cause variability in the quality of the medical gas ( 211.110). 
463  For example, to address variation in the quality of feeder gas or atmospheric air, original 
464  manufacturers should validate the process to remove contaminants.  
465   
466  B.  Vacuum Evacuation of High-Pressure Cylinders 
467   
468  For those cylinders that are not equipped with a residual pressure valve with backflow 
469  prevention, FDA recommends vacuum evacuation to remove residual gases when cylinders are 
470  being reused. FDA recommends manufacturers use 25 or more inches of mercury vacuum for 
471  high-pressure cylinders to vacuum evacuate the residual gases. If using less than 25 inches of 
472  vacuum, manufacturers should have data on file demonstrating that the amount of vacuum 
473  evacuation sufficiently removes all residual gases from high-pressure cylinders.  
474   
475  Manufacturers must maintain records of any problems that occur with container evacuation, such 
476  as the inability to adequately empty the cylinder of residual gases ( 211.84, 211.184). Data 
477  regarding changes to the amount of vacuum used must be available for inspection ( 211.84, 
478  211.94, 211.100, 211.184), and such changes should be scientifically justified. 
479     
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480  C.  Filling Procedure Checks 
481   
482  Components must be weighed or measured as appropriate ( 211.101(b)). When filling high-
483  pressure cylinders, manufacturers should include the following checks to demonstrate the 
484  presence of gas in the container and to ensure net content is delivered.  
485   
486  1.  Temperature and Pressure Readings  
487   
488  A medical gas in a high-pressure cylinder increases in pressure as the temperature of the gas 
489  rises. Overfilled cylinders can reach dangerously high pressures if exposed to elevated 
490  temperatures, even if the pressure at room temperature is safe. To ensure that high-pressure 
491  cylinders are filled correctly (i.e., contents as indicated on the label), the manufacturer can attach 
492  a thermometer to one cylinder per manifold-filling sequence, or to each cylinder if filling one at 
493  a time, and adjust the final filling pressure according to a temperature/pressure chart. 
494  Manufacturers should use temperature/pressure charts or temperature/pressure calculations 
495  (Boyles Law) to adjust filling pressure, thereby achieving proper content. This is usually stated 
496  as the pressure at 70F with appropriate tolerances.  
497   
498  The manufacturer must record the actual temperature and/or pressure readings on the batch 
499  production record ( 211.188(b)). For batch records and reporting requirements and 
500  recommendations, see section XI.E, Batch Production and Control Records. 
501   
502  2.  Valve Assembly Leak Testing 
503   
504  During filling operations, manufacturers should test each valve assembly for leaks by spraying or 
505  brushing an appropriate leak detection solution on and around the entire assembly.20 The solution 
506  should be safe for use with oxygen, leave no residue that is flammable, and be noncorrosive to 
507  the valve assembly. That is, it should not contain hydrocarbons, ammonia, ethylene glycol, or 
508  halide ions. Solutions containing soap are not recommended because they can corrode the valve 
509  stem and leave a residue. Manufacturers should perform this test while the cylinder is under 
510  pressure with the cylinder valve open. If bubbles appear, there is a leak. 
511   
512  Once the cylinders are filled and disconnected, manufacturers should perform a second valve 
513  assembly leak test. If any leaks are detected, the cylinder must be removed from service and 
514  quarantined until repaired ( 211.82, 211.89). 
515   
516  Performing these two tests helps ensure that the contents of high-pressure cylinders will not leak 
517  during storage or shipment. 
518     
                                                 
20 See ASTM International, 2011, G188-05 (2011), Standard Specifications for Leak Detector Solutions Intended for 
Use on Brasses and Other Copper Alloys. 
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519  3.   Heat-of-Compression Check 
520   
521  During or immediately after filling high-pressure cylinders, manufacturers should perform a 
522  heat-of-compression check by lightly touching the exterior of each cylinder or by following an 
523  alternative method that verifies temperature change. A warm cylinder indicates that the cylinder 
524  is filling properly; a cool or cold cylinder indicates that the cylinder may not be filling properly. 
525  Manufacturers should investigate cool or cold cylinders. 
526   
527  D.  Calculation of Yield 
528   
529  Medical gas loss is expected during manufacturing and can be variable even under normal 
530  operating conditions. Accordingly, FDA does not intend to object if medical gas manufacturers 
531  do not comply with the requirements in  211.103 for calculation of actual yield and percentages 
532  of theoretical yield. Filling to a predetermined and acceptable temperature or pressure limit, 
533  along with finished product testing, is sufficient to determine that the medical gas or medical gas 
534  mixture in the container is the amount and type indicated by the label and required by the final 
535  product specifications (see  211.134, 211.165). 
536   
537  VIII.  PACKAGING AND LABELING CONTROLS 
538   
539  A.  Materials Examination and Usage 
540   
541  According to  211.122(a), (d), and (e) and 211.125(b), manufacturers must:  
542   
543    Representatively sample new labels and other labeling materials and compare them for 
544  accuracy to the master label before use in labeling of a medical gas. 
545   
546    Secure labeling by limiting access to authorized personnel.  
547   
548    Destroy obsolete and outdated labeling. 
549   
550  Different medical gas labels should be stored separately. They can be stored in the same cabinet 
551  provided they are adequately separated to prevent mix-ups (see  211.130). Industrial gas labels 
552  should be stored in a separate area.  
553   
554  Only labeling that meets appropriate written specifications may be approved and released for use 
555  ( 211.122(b)). Previous lot numbers on any labeling must be removed or obliterated 
556  ( 211.67(b)(4)). 
557   
558  See section VI.B.2.c for more information about prefill label inspections. 
559   
560  B.  Labeling Control 
561   
562  Manufacturers must strictly control labeling issued for use in medical gas operations 
563  ( 211.125(a)). To prevent mix-ups, manufacturers should compare the number of labels issued 
564  with the number of labels applied.  
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565   
566  For cut labeling that does not use a dedicated product labeling and packaging operation, 
567  manufacturers must use appropriate electronic or electromechanical equipment or visual 
568  inspection to conduct a 100-percent examination for correct labeling or any automated technique 
569  that physically prevents incorrect labeling from being processed by labeling and packaging 
570  equipment ( 211.122(g)). 
571   
572  Label reconciliation is waived for 360 wraparound labels on portable cryogenic medical gas 
573  containers ( 211.125(c)).  
574   
575  FDA recommends that all labeling be issued for use in medical gas labeling operations by 
576  authorized personnel only. 
577   
578  C.  Packaging and Labeling Operations 
579   
580  Manufacturers should consider as a batch each (1) manifold filling sequence, (2) uninterrupted 
581  filling sequence, and (3) filled rail tank car, trailer, and cryogenic container.21 For continuous 
582  manufacturing operations (including ASUs), manufacturers should designate a batch as the 
583  amount of medical gas produced in 24 hours or less. Each batch must be assigned a lot or control 
584  number from which the history of the manufacture and control of the batch may be determined 
585  ( 210.3(b)(11), 211.130(c)).  
586   
587  Transfillers receiving shipments of medical gas into a storage tank should assign a new lot 
588  number to the contents of the storage tank each time it is refilled, regardless of whether it 
589  contains previously received medical gas.  
590   
591  Manufacturers should ensure that for each container, the labeling accurately identifies the 
592  contents of the container and that any other required or included information in labeling is 
593  accurate. This is particularly important given that medical gas containers and labels are typically 
594  reused many times. Labels should be affixed to the container in a manner that does not interfere 
595  with other labeling and will not be susceptible to wear or inadvertent detachment during normal 
596  use. For portable cryogenic container labeling requirements, see  211.94(e)(2). 
597   
598  A separate sticker or decal may be used to identify the lot number for a batch of medical gas, as 
599  long as the sticker remains adhered to the container and is legible. The sticker should be readily 
600  visible and should not obscure required drug information. A separate sticker can also be used for 
601  the containers net content information. 
602   
603  For information about prefill label inspections, see section VI.B.2.c and for labeling records, see 
604  sections XI.C and XI.E. 
605   
                                                 
21 Under  210.3, batch means a specific quantity of a drug or other material that is intended to have uniform 
character and quality, within specified limits and is produced according to a single manufacturing order during the 
same cycle of manufacture. 
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606  D.   Expiration Dating 
607   
608  Medical gases have unique stability characteristics. Accordingly, FDA does not intend to object 
609  if manufacturers of designated medical gases do not comply with the expiration dating 
610  requirements in  211.137(a) for those gases (see also section X.E, Stability Testing). The 
611  containers and closures should, however, be verified as capable of holding gas at the appropriate 
612  pressure before release for distribution (see section VII). If a manufacturer labels a medical gas 
613  with an expiration date, it must be supported by stability studies ( 211.137(b)).  
614   
615  IX.  HOLDING AND DISTRIBUTION 
616   
617  Manufacturers must establish and follow written procedures describing medical gas distribution 
618  ( 211.150). These procedures must include a system by which the distribution of each batch can 
619  be readily determined to facilitate its recall if necessary ( 211.150(b)). 
620   
621  The procedures should explain (1) who would evaluate distribution information, (2) how a recall 
622  would be initiated, (3) who would be informed about the recall, and (4) what would be done with 
623  the recalled product. 
624    
625  Because of the nature of medical gas manufacturing and the stability characteristics of the gases, 
626  FDA does not intend to object if medical gas manufacturers do not establish and follow written 
627  procedures to distribute their oldest stock first (as required by  211.150(a)), provided that 
628  manufacturers establish a system to manage and handle medical gas stock in an orderly manner 
629  and have procedures in place. These procedures should ensure that the components, containers, 
630  and container closure systems (1) are used in a timely manner, (2) are not exposed to conditions 
631  that may render them unfit for use, and (3) have undergone prefill and other testing as required 
632  before distribution.  
633   
634  X.  LABORATORY CONTROLS 
635   
636  A.  General Requirements and Recommendations 
637   
638  Manufacturers must follow the laboratory control requirements in subpart I of part 211, follow 
639  and document the laboratory controls at the time of performance, and record and justify any 
640  deviations from the written specifications, standards, sampling plans, test procedures, and other 
641  laboratory control mechanisms ( 211.160(a)). For example, manufacturers must record and 
642  justify changes made to the analytical method, such as a different column length or a different 
643  carrier gas. 
644   
645  Designated medical gases that have been certified must meet the standards set forth in an 
646  applicable compendium.  
647   
648  The manufacturing processes used for industrial grade gas could result in a gas with higher levels 
649  of impurities than permitted in gas for medical use or impurities not specified in the relevant 
650  USP-NF monograph. Accordingly, FDA does not recommend converting industrial grade gas to 
651  medical gas. However, if a manufacturer chooses to convert industrial grade gas to medical gas, 
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652  such conversion requires testing in addition to testing for conformance to the applicable USP-NF 
653  monograph (see section VI.A, Components, for discussion of characterizing a feeder gas). 
654   
655  When the likelihood of contamination has been identified during prefill inspections or filling 
656  operations, the manufacturer must quarantine the medical gas until an investigation has been 
657  completed ( 211.84, 211.89, 211.110(d), 211.192). The medical gas may not be released 
658  unless the investigation shows that the medical gas is not contaminated and that it meets product 
659  specifications ( 211.84). Manufacturers should use tests suitable for detecting such 
660  contaminants as well as the tests provided in the approved application or USP-NF monograph.22 
661   
662  B.  Calibration of Instruments 
663   
664  Laboratory controls must include a written program for calibration of instruments, apparatus, 
665  gauges, and recording devices at suitable intervals ( 211.160(b)(4)).  
666   
667  Manufacturers should verify that the calibration gas is traceable to a nationally recognized 
668  standard and that it ensures the appropriate level of precision and accuracy. The COA for the 
669  calibration gas should be specific to the cylinder of calibration gas received and should contain 
670  the following: 
671   
672    Name and address of the supplier. 
673    Name of the calibration gas. 
674    Lot number or unique identification number. 
675    Description of the analytical method used to assay the calibration gas. 
676    Analytical results expressed quantitatively (e.g., 99.9 percent nitrogen). 
677    Statement that the calibration gas is traceable to a nationally recognized standard. 
678    Responsible persons signature and the date signed. 
679   
680  See section V.C. for additional information about equipment calibration. 
681   
682  C.  Medical Gas Sampling and Testing  
683   
684  For each batch of medical gas, there must be an appropriate laboratory determination of 
685  satisfactory conformance to final specifications for the medical gas, including testing for identity 
686  and strength, before release ( 211.165(a)). Written procedures must describe (1) sampling and 
687  testing plans that include the number of units per batch that will be sampled and tested, (2) the 
688  acceptance criteria for sampling and testing, and (3) actions to be taken if test results are outside 
689  of specifications ( 211.165).  
690   
691  FDA recommends that manufacturers document conformance to specification(s) in a COA for 
692  each batch of medical gas filled. See section XI.J for more information about COAs. When test 
                                                 
22 Refer to USP-NF General Notices, Section 5.60, Impurities and Foreign Substances, available at 
http://www.usp.org/usp-nf/development-process/policies-guidelines/usp-nf-general-notices. 
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693  results do not meet specifications, retesting is not recommended until a thorough investigation 
694  has been performed according to established written procedures.23  
695   
696  1.  Cylinders Filled on a Multiple-Outlet Manifold 
697   
698  At least one high-pressure cylinder from each manifold filling sequence should be tested for 
699  identity and strength.  
700   
701  2.  Cylinders Filled Individually 
702   
703  One high-pressure cylinder per uninterrupted filling sequence should be tested for identity and 
704  strength.  
705   
706  3.  Mixtures 
707   
708  For mixtures containing two gases, each high-pressure cylinder should be tested for both the 
709  identity and strength of one of the gases, and one cylinder from each batch should be tested for 
710  the identity of the second gas.  
711   
712  For mixtures containing three gases, each high-pressure cylinder should be tested for both the 
713  identity and strength of two of the gases, and one cylinder from each batch should be tested for 
714  the identity of the third gas.  
715   
716  Note: For mixtures containing oxygen, each cylinder should be tested for the identity and 
717  strength of the oxygen. 
718   
719  4.  Medical Gas From Suppliers 
720   
721  Manufacturers receiving a batch of medical gas from suppliers should test for conformance to 
722  established specifications after receipt or before the manufactured lot is released (e.g., for further 
723  processing or transfilling). This can be done either by sampling directly from the storage tank or 
724  by testing one container from the first batch of medical product filled.  
725   
726  If manufacturers receive and maintain supplier COAs, the manufacturers must conduct specific 
727  identity testing ( 211.84(d)(2)) and should conduct purity testing. FDA does not intend to object 
728  if Oxygen USP transfillers delivering to sites that only receive Oxygen USP do not conduct at 
729  least one specific identity test, as long as they witness the identity testing that their oxygen 
730  suppliers conduct. Employees who witness oxygen testing must have appropriate training 
731  ( 211.25) and should record that they have witnessed the testing and document the method used 
732  and identity of the person who performed the test.  
733     
                                                 
23 
See the guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical 
Production.  
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734  D.  Test Method and Alternative Test Method Validation  
735   
736  When a test is approved as part of an NDA or an abbreviated new drug application, it becomes 
737  the approved analytical test method or manufacturing method for the medical gas.  
738   
739  Manufacturers must use approved analytical test methods for the medical gas they manufacture 
740  ( 211.22(d)). USP-NF monograph drug products must meet USP-NF monograph standards 
741  (section 501(b) of the FD&C Act; 21 U.S.C. 351(b)), and manufacturers should use the test 
742  methods in the appropriate USP-NF monograph. For USP-NF test methods, a full test method 
743  validation study is unnecessary ( 211.194). Data that verify that the USP-NF test method is 
744  accurate and reliable should be generated on the appropriate equipment and maintained at the 
745  manufacturing site. If a medical gas manufacturer relies on the equipment manufacturers study, 
746  the medical gas manufacturer should retain a copy of the actual study, including the protocol and 
747  data. 
748   
749  Manufacturers that use approved test methods that are not USP-NF monograph methods must 
750  maintain a copy of the full and complete test method validation ( 211.165).  
751   
752  For USP-NF monograph drug products, a manufacturer can establish alternative test methods, as 
753  long as the USP-NF monograph standards are met or exceeded. Alternative test methods must be 
754  validated ( 211.160(b), 211.165(e)). The validation can be performed in accordance with USP-
755  NF General Chapter <1225> Validation of Compendial Procedures, and the validation study 
756  should include data comparing it to the official test method.24  
757   
758  FDA recommends that methods be validated under the same conditions in which they will be 
759  used. If the testing environment is considerably different, manufacturers should conduct 
760  additional on-site tests, such as with a small number of standard gases, to demonstrate that 
761  method performance has not been affected by local conditions. For example, paramagnetic 
762  oxygen analyzers can give inaccurate readings when used at high altitudes unless special 
763  adjustments are made. The results of these tests should be fully documented. 
764   
765  Certain changes made to instrumentation may be substantive enough to be considered changes to 
766  the test method itself; these changes would require additional documentation of the accuracy and 
767  reliability of the method or a new validation study (see  211.194(b)). 
768   
769  E.  Stability Testing 
770   
771  If an expiration date is assigned to a batch, manufacturers must establish, document, and follow a 
772  stability testing program ( 211.137, 211.166). If an expiration date is not assigned to a 
773  designated medical gas, supporting stability studies are not needed (see section VIII.D, 
774  Expiration Dating). 
775    
                                                 
24 See the guidance for industry Analytical Procedures and Methods Validation for Drugs and Biologics. 
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776  F.  Reserve Samples 
777   
778  Per  211.170, reserve samples for compressed medical gases need not be retained. 
779   
780  XI.  RECORDS AND REPORTS 
781   
782  Manufacturers must maintain a number of records, including but not limited to those described 
783  by  211.68 and subpart J of part 211. This section reviews some of these requirements and also 
784  provides recommendations regarding records and reports. 
785    
786  A.  General Requirements and Recommendations 
787   
788  1.  Record Retention 
789   
790  For products with an expiration date, any required production, control, or distribution record 
791  must be retained for 1 year after the expiration date of the batch ( 211.180(a)). If the batch of 
792  medical gas is not labeled with an expiration date, the aforementioned records should be 
793  maintained for at least 3 years after the batch distribution date. FDA also recommends that 
794  manufacturers retain training records and COAs for at least 3 years.  
795   
796  All records required under part 211, or copies of such records, must be readily available for 
797  authorized inspection during the retention period at the establishment where the activities 
798  described in such records occurred ( 211.180(c)). Records can be kept on paper or 
799  electronically.25  
800   
801  2.  Record Review 
802   
803  Manufacturers must review a representative number of batch records, complaint files, 
804  investigations, recalls, and returned products annually to determine the need for changes in drug 
805  product specifications for manufacturing or control procedures ( 211.180(e)). In addition, 
806  manufacturers should use these records to identify potential product quality issues and 
807  opportunities for continuous process improvement. This can be done on a companywide or site-
808  by-site basis. 
809   
810  3.  Equipment Calibration, Checks, and Inspections  
811   
812  Manufacturers must keep records of calibration, checks, and inspections of electronic equipment 
813  used in the manufacture, processing, and holding of medical gas ( 211.68(a)). See section V.C. 
814  for more information about equipment calibration.  
815     
                                                 
25 Electronic records are subject to the requirements of 21 CFR part 11 (see the guidance for industry Part 11, 
Electronic Records; Electronic SignaturesScope and Application). 
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816  4.  Computer Validation Data  
817   
818  Manufacturers (including ASUs) must have documentation that their automated, mechanical, and 
819  electronic equipmentincluding computers used in the manufacturing or holding of a gas
820  demonstrates proper performance ( 211.68(a)).  
821    
822  5.  Process Validation Data  
823    
824  Manufacturers must have process validation records showing that their operational and process 
825  control procedures ensure that medical gases have the identity, strength, quality, and purity that 
826  they purport or are represented to possess ( 211.100). (For more information on FDA 
827  recommendations regarding process validation, see the guidance for industry Process Validation: 
828  General Principles and Practices.) 
829   
830  B.  Equipment Cleaning and Use Logs 
831   
832  For medical gases that are manufactured using closed pressurized systems and equipment, the 
833  system and equipment generally does not need to be cleaned between batches, unless exposed to 
834  a contaminant. See section V.B, Equipment Cleaning and Maintenance. 
835   
836  Manufacturers should retain records of cleaning pressurized systems and equipment before 
837  commissioning for production use. 
838   
839  When cleaning or maintenance is required, manufacturers should document the work on separate 
840  cleaning or maintenance records that are not associated with specific batch records. The people 
841  who perform cleaning and maintenance and those who verify it must date and sign or initial the 
842  log indicating that the work was performed ( 211.182). If automated equipment is used in 
843  cleaning and maintenance in accordance with  211.68(c), only the person verifying the cleaning 
844  and maintenance needs to date and sign or initial the log. 
845   
846  If using equipment dedicated to a single medical gas, manufacturers may keep control records 
847  for cleaning, maintaining, and using the equipment as a part of the batch records, provided that 
848  batches of the medical gas follow in numerical order and are manufactured in numerical 
849  sequence ( 211.182).  
850   
851  Equipment logs, including maintenance records, are critical for original manufacturers (including 
852  ASUs) because of the complex nature of the manufacturing equipment and associated 
853  maintenance requirements (e.g., carbon beds, dryer beds, distillation units).  
854   
855  Manufacturers should maintain cleaning and use logs for their filling equipment used on- or off-
856  site.  
857   
858  See also section V.B. Equipment Cleaning and Maintenance. 
859     
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860  C.  Component, Container, Container Closure System, and Labeling Records 
861   
862  Records must include the following ( 211.184): 
863   
864    The identity and quantity of each shipment or each batch of newly purchased 
865  components, containers, or container closure systems. The records must contain the 
866  suppliers name, lot number if known, and date of receipt. Manufacturers should also 
867  maintain records of the serial numbers of newly purchased containers or container closure 
868  systems. Original manufacturers (including ASUs) that use a feeder gas or atmospheric 
869  air as a component should maintain records of the periodic testing they conduct. (See 
870  section VI.A for testing recommendations.) 
871   
872    The results of any test or examination performed on components, containers, and 
873  container closure systems. (See section VI for testing requirements and 
874  recommendations.)  
875   
876    Documentation of the examination of labels and labeling for conformity with established 
877  specifications. (See section VIII for labeling requirements and recommendations.) 
878   
879    The disposition of rejected medical gas components, containers, container closure 
880  systems, and labeling. 
881   
882  Medical gas loss is expected during storage and manufacturing, and medical gas is subject to 
883  release testing (see section X.C, Medical Gas Sampling and Testing). Therefore, because of the 
884  expected loss, FDA does not intend to object if the requirement at  211.184(c) regarding 
885  reconciliation of individual inventory records is not met with respect to medical gases that are 
886  components of the finished drug product. 
887   
888  Quality agreement records should be maintained with the other required records and available for 
889  FDA review. See section III.A.2 for more information about quality agreements. 
890   
891  D.  Master Production and Control Records 
892   
893  Master production and control records are necessary to ensure uniformity from batch to batch. 
894  These required records must be prepared, dated, and signed by one person and independently 
895  checked, dated, and signed by a second person ( 211.186(a)). These records must include 
896  ( 211.186(a) and (b)): 
897   
898    A description of the medical gas containers, container closure systems, and packaging 
899  materials, including a specimen or copy (e.g., electronic copy) of each label and labeling.  
900   
901    Complete manufacturing and control instructions, sampling and testing procedures, 
902  specifications, special notations, and precautions to be followed. 
903     
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904  E.  Batch Production and Control Records 
905   
906  Batch production and control records must be prepared for each batch of medical gas produced 
907  and must include complete information related to the production and control of each batch 
908  ( 211.188). These records must include but are not limited to: 
909   
910    A reproduction of the appropriate master production or control record, checked for 
911  accuracy, dated, and signed. 
912    
913    Documentation that each significant step in batch manufacture, processing, packing, or 
914  holding was accomplished, including: 
915   
916    Date of performance. 
o
917   
918    Lot number or other unique identification number. 
o
919   
920    In-process and batch test results. 
o
921   
922    Description of medical gas containers and container closure systems. 
o
923   
924    Any sampling performed. 
o
925   
926    Identification of the people performing and directly supervising or checking each 
o
927  significant step. 
928   
929    Any investigation made according to  211.192. 
o
930   
931    Results of examinations made according to  211.134. 
o
932   
933  Batch production records must clearly and accurately reflect actual production practices and 
934  conditions at the time of manufacture ( 211.188). Transfiller pumpers or fillers logs can be 
935  used as batch production records if they contain all relevant information as specified in 
936   211.188 and in section XI.D, Master Production and Control Records.  
937   
938  In addition to the requirements listed above, FDA recommends that batch records maintained by 
939  transfillers, including curbside vendors, also document: 
940   
941    Prefill inspections. 
942    Number and size of the cylinders or cryogenic containers filled. 
943    Filling inspections. 
944    Postfill inspections. 
945    Final temperature and pressure results or other inspection results. 
946   
947  Manufacturers need not store and maintain batch production records as one document; however, 
948  all the required batch record information should be easily located and traceable to each specific 
949  batch manufactured. Continuous processing logs can designate lot numbers and entries (e.g., 
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950  initials, dates) demonstrating that each significant step in the operation has been checked. 
951  Manufacturers that use computer-controlled equipment during manufacture should establish and 
952  follow procedures to maintain, review, and approve the manufacturing data. 
953   
954  Manufacturers must not use a single entry to indicate that all of the significant manufacturing, 
955  processing, packing, and holding steps have been performed ( 211.188(b)). A checkmark or 
956  other symbol should not be used in place of an actual value, such as for temperature and pressure 
957  readings, purity, and identity results.  
958   
959  FDA recommends that manufacturing records identifying nonconforming medical gas describe 
960  the rejection relative to the rest of the batch to ensure that the scope of the investigation is 
961  appropriate. Medical gases rejected for container leaks and medical gases rejected for manifold 
962  leaks during filling must be documented ( 211.165, 211.188) and investigated ( 211.192). 
963  The scope of the investigation into a manifold leak must extend to other batches of medical gas 
964  that may have been associated with the same failure ( 211.192).  
965   
966  Complete labeling control records, including specimens or copies of all labels used, and 
967  examination results must be included in the batch record ( 211.188(b)(8)). A photocopy or 
968  printed digital image can be an appropriate alternative to a label specimen. A specimen of the 
969  specific lot number labeling (e.g., lot number sticker) should also be included in the batch record. 
970  Labeling control records maintained by original manufacturers (including ASUs) that fill bulk 
971  trailers may or may not include a finished product label; however, these manufacturers should 
972  maintain both product and lot-specific labeling.  
973   
974  Each lot number should be traceable in records for batch manufacturing, labeling, testing, and 
975  release. 
976   
977  F.  Production Record Review and Investigations Records 
978   
979  The quality unit must review and approve all medical gas production and control records, 
980  including those for packaging and labeling, before a batch is released or distributed ( 211.192). 
981  Unexplained discrepancies or the failure of a batch to meet its specifications, including any test 
982  results outside of established limits, must be thoroughly investigated, whether or not the batch 
983  has already been distributed ( 211.192). Manufacturers must maintain records of investigations, 
984  which must include conclusions and follow-up information ( 211.180, 211.192). 
985   
986  For original manufacturers (including ASUs): 
987   
988    FDA recommends that third-party consignees (e.g., trucking company staff) not perform 
989  the quality unit release of a medical gas.  
990   
991    If filling occurs when the quality unit is not on site, the quality unit is responsible for 
992  review and approval before distribution ( 211.192). 
993   
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994  For curbside vendors of oxygen, the quality unit must review documentation associated with the 
995  off-site filling operation, including records of all inspections and maintenance procedures 
996  performed ( 211.22(a)). 
997   
998  G.  Laboratory Records 
999   
1000  Laboratory records must include complete data derived from all tests necessary to ensure 
1001  compliance with established specifications and standards, including examinations and assays 
1002  ( 211.194). These records include the following: 
1003   
1004    Description of the sample, lot number, location from which the sample was obtained, date 
1005  the sample was taken, and date received for testing. 
1006    
1007    Statement of each method used to test the sample.  
1008   
1009    Complete record of all data created in the course of each testincluding graphs, charts, 
1010  and spectra from laboratory instrumentationproperly identified to show the specific 
1011  medical gas and the batch tested. If the analytical equipment only provides a direct 
1012  reading, visual observation and subsequent recording of the specific result for each test 
1013  would fulfill the data requirements.  
1014   
1015    Record of all calculations performed in connection with the test, including units of 
1016  measure, conversion factors, and equivalency factors. 
1017   
1018    Statement of the test results and how the results compare with established standards of 
1019  identity, strength, quality, and purity for the component (e.g., feeder gas), in-process 
1020  materials (as applicable), and finished product (see section XI.J, Certificate of Analysis). 
1021   
1022    Initials or signature of the person who performs each test and the dates the tests were 
1023  performed. 
1024   
1025    Initials or signature of a second person showing that the original records have been 
1026  reviewed for accuracy, completeness, and compliance with established standards. 
1027   
1028  In addition, manufacturers must maintain complete records of: 
1029   
1030    Any modification of an established method employed in testing, including justification. 
1031   
1032    Any testing and standardization of laboratory reference standards, reagents, and standard 
1033  solutions (e.g., a reference gas or calibration gas used as a standard). 
1034   
1035    The periodic calibration of laboratory instruments, apparatus, gauges, and recording 
1036  devices required by  211.160(b)(4). 
1037   
1038  When testing is done by a chromatographic method specified in the USP-NF (e.g., the assay 
1039  method for Nitrogen NF), the chromatographic system must meet all system suitability 
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1040  requirements listed in the monograph (see section 501(b) of the FD&C Act). If the USP-NF 
1041  monograph lacks specific suitability requirements, manufacturers should use USP-NF General 
1042  Chapter <621> Chromatography as a reference.  
1043   
1044  H.  Distribution Records 
1045   
1046  Distribution records must contain the product name and strength, dosage form description, 
1047  consignees name and address, shipping date, and quantity shipped ( 211.196). For medical 
1048  gases, distribution records do not need to contain lot numbers. Instead, manufacturers can use the 
1049  name of the medical gas, consignees name and address, shipping date, and quantity shipped to 
1050  comply.  
1051   
1052  Record maintenance according to written procedures is critical for batch traceability, particularly 
1053  during a product recall. See section IX of this guidance and  211.150 for more information. 
1054   
1055  I.  Complaint Files 
1056   
1057  Manufacturers must maintain written records of each complaint in a file designated for medical 
1058  gas complaints ( 211.198(b)). Manufacturer complaint records must include, if known 
1059  ( 211.198(a) and (b)):  
1060   
1061    Medical gas name and lot number. 
1062   
1063    Complainants name and contact information (and, if appropriate, title). 
1064   
1065    Full description of the nature of the complaint.26 
1066   
1067    Any evaluation to determine if the complaint is also an adverse event. 
1068   
1069    Response provided to the complainant, which should include the date the response was 
1070  sent. 
1071   
1072  The quality unit must review and, as needed, investigate all written and oral complaints 
1073  involving the possible failure of a medical gas to meet any of its specifications ( 211.192, 
1074  211.198(a)). When an investigation is conducted, the written record must include the 
1075  investigation findings and follow-up ( 211.198(b)(2)). These records should include the 
1076  following: 
1077   
1078    Date the complaint was received. 
1079   
1080    Action initially taken, including dates and identity of the person taking the action. 
1081   
                                                 
26 The description should facilitate investigative follow-up and identify adverse trends or patterns (e.g., a recurring 
container or container closure defect). 
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1082    Follow-up action taken, including any investigation or corrective action and whether 
1083  other batches of product were potentially affected. 
1084   
1085    Final outcome regarding the issues raised by the complaint. 
1086   
1087  J.  Certificate of Analysis 
1088   
1089  When manufacturers use COAs to demonstrate medical gas conformance to applicable 
1090  specifications, the COAs should contain the following information: 
1091   
1092    Manufacturer name and complete address. 
1093    Supplier name and complete address (if available). 
1094    Product name (e.g., Oxygen USP). 
1095    An air liquefaction statement, as appropriate. 
1096    Lot number or other unique identification number. 
1097    Analytical results for all USP-NF monographs or other testing (e.g., impurities).  
1098    Test method used to perform the analysis.  
1099    Manufacturer or supplier signature and date. 
1100    
1101  See also section III.A.2, Quality Agreements With Suppliers. 
1102   
1103  XII.  RETURNED MEDICAL GAS  
1104   
1105  For the purposes of this guidance, FDA does not consider gas remaining in high-pressure 
1106  cylinders or cryogenic containers that are returned for refilling to be returned medical gas. 
1107   
1108  For medical gas that is returned, FDA recommends that the container be vented. 
1109   
1110  Medical gases that have been improperly stored must not be salvaged and returned to the 
1111  marketplace ( 211.208). 
1112    
1113  XIII.  ADAPTERS 
1114   
1115  For safety reasons, FDA recommends avoiding the use of adapters of any kind to circumvent the 
1116  specific medical gas valves and connections associated with a specific medical gas.  
1117    
1118  On rare occasions and only under strict control, adapters can be used to fill mixtures of medical 
1119  gases. However, manufacturers should have written procedures detailing system checks and 
1120  controls to prevent mix-ups or contamination, and to promptly identify and quarantine 
1121  compromised gases if a mix-up or contamination should occur.  
1122   
1123  XIV.  GLOSSARY 
1124   
1125  The following terms are defined for the purposes of this guidance.  
1126   
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1127  Air separation units (ASUs): ASUs separate atmospheric air into constituent gases of oxygen, 
1128  nitrogen, and argon through a purification process of precleaning, compression, cooling, and 
1129  fractional distillation of liquefied air. ASUs are original manufacturers. 
1130   
1131  Chemical synthesizers: Chemical synthesizers or processors produce medical gas by chemical 
1132  reaction (e.g., nitrous oxide by thermal degradation of ammonium nitrate) or by reprocessing 
1133  feeder gas. Feeder gas is often the waste stream of other industrial manufacturing operations, 
1134  which is then purified and treated to manufacture a medical gas. 
1135   
1136  Cryogenic medical gas containers: Containers used to hold a low-temperature, low-pressure 
1137  liquid product. They can be divided into: 
1138   
1139    Cryogenic medical gas home containers: Containers designed to hold liquid oxygen at 
1140  a patients residence. 
1141   
1142    Portable medical gas cryogenic containers: Containers that are capable of being 
1143  transported and are intended to be connected to a medical gas supply system within a 
1144  hospital, health care entity, nursing home, other facility, or home health care setting, or 
1145  that are base units used to fill small cryogenic containers for use by individual patients. 
1146  The term does not include cryogenic containers that are not designed to be connected to a 
1147  medical gas supply system (e.g., tank trucks, trailers, rail cars) or small cryogenic gas 
1148  containers for use by individual patients, such as portable liquid oxygen containers, as 
1149  defined in 21 CFR 868.5655. 
1150    
1151  Designated medical gas: A drug that is manufactured or stored in a liquefied, 
1152  nonliquefied, or cryogenic state; is administered as a gas; and is identified in section 575(1) of 
1153  the FD&C Act (e.g., Oxygen USP, Carbon Dioxide USP, Nitrogen NF, Nitrous Oxide USP, 
1154  Helium USP, Medical Air USP). 
1155   
1156  Manufacturer: Any person or firm that manufactures a medical gas, which includes producing, 
1157  cascading, distributing, filling, mixing, purifying, separating, transferring, and transfilling 
1158  medical gases. This includes original manufacturers.  
1159   
1160  Original manufacturer: The original manufacturer of the medical gas, that is, the person or 
1161  entity that initially produces the gas by chemical reaction, physical separation, compression of 
1162  atmospheric air, or other means, including ASUs and chemical synthesizers or processors as well 
1163  as transfillers who manufacture medical gas by mixing other gases. 
1164   
1165  Transfillers: Transfillers manufacture medical gas by transferring the gas, either in a liquid or 
1166  gaseous state, from a larger container into smaller containers. Manufacturers who combine 
1167  different medical gases are considered both transfillers and original manufacturers. 
1168   
1169  Uninterrupted filling sequence: A single, continuous filling sequence with no breaks or 
1170  shutdowns occurring during the filling operation. This procedure uses the same personnel, 
1171  equipment, and batch of component.  
28