2016 Medical Gas Container-
Closure Rule  
Questions and Answers 
 
Guidance for Industry 
 
 
(Small Entity Compliance Guide) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2017 
Current Good Manufacturing Practice 
Labeling 
   
2016 Medical Gas Container-
Closure Rule  
 
Questions and Answers
 
Guidance for Industry 
 
 
(Small Entity Compliance Guide) 
 
 
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) 
 
January 2017 
Current Good Manufacturing Practice 
Labeling 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  QUESTIONS AND ANSWERS ....................................................................................... 4 
  Contains Nonbinding Recommendations 
2016 Medical Gas Container-Closure Rule  
Questions and Answers 
1
Guidance for Industry  
 
(Small Entity Compliance Guide) 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to help small businesses better understand and comply with recently 
issued regulations on current good manufacturing practice (CGMP) and labeling for medical 
gases.  On November 18, 2016 (81 FR 81685), FDA published a final rule Medical Gas 
Containers and Closures; Current Good Manufacturing Practice Requirements (Container-
Closure Rule or final rule).  The final rule amends certain CGMP regulations regarding medical 
gases to increase the likelihood that the contents of medical gas containers are accurately 
identified on labeling and by container coloring and to reduce the likelihood of the wrong gas 
being connected to a supply system by requiring gas-specific outlet connections.  The final rule 
also revises an existing labeling regulation (21 CFR 201.161) that exempts listed medical gases 
from certain otherwise-applicable labeling requirements under specified conditions (including 
meeting the applicable medical gas labeling and container closure requirements and including 
certain warning statement(s)). 
 
FDA has prepared this guidance in accordance with section 212 of the Small Business 
Regulatory Enforcement Fairness Act (Public Law 104-121, as amended by Public Law 110-28)2 
to assist small entities in complying with the Container-Closure Rule. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
                                                 
1 This guidance has been prepared by the Office of Regulatory Policy in cooperation with the Office of 
Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER) at the Food and Drug 
Administration.  
2 5 U.S.C. 601 (note). 
  1  Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
In the Federal Register of April 10, 2006 (71 FR 18039), FDA issued a proposed rule addressing 
certain CGMP and labeling regulations for medical gases.  FDA proposed changes to these 
regulations to include new or revised requirements for the labeling, color, dedication, and design 
of medical gas containers and closures.  The main reason for proposing these changes was to put 
into regulation certain industry best practices intended to reduce errors and increase patient 
safety.3  FDA also proposed changes to a regulation (21 CFR 201.161) that provides certain 
medical gases a conditional exemption from several of the labeling requirements that ordinarily 
apply to prescription drugs.  The existing regulation did not reflect either industry best practices 
or FDAs current regulatory expectations regarding the labeling of medical gases, and the list of 
gases covered by the regulation needed to be updated.  FDA received and considered numerous 
public comments on the proposed rule. 
 
In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) was enacted.4  
Among other things, this law established a new certification process5 for certain designated 
medical gases.6 
 
In the Federal Register of November 18, 2016 (81 FR 81685), FDA published the final 
Container-Closure Rule, which is the subject of this guidance.  The citations to the Code of 
Federal Regulations (CFR) in this guidance refer to the CFR as amended by this final rule. 
 
The final Container-Closure Rule revises CGMP regulations to: 
 
  Require portable cryogenic medical gas containers7 not manufactured with permanent gas 
use outlet connections to have gas-specific use outlet connections that cannot be readily 
                                                 
3 There were 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, leading to serious injuries and deaths.  For a 
detailed account of these incidents, please refer to the proposed rule (71 FR 18039 at 1804018041). 
4 Pub. L. 112144 (July 9, 2012).  See Title XI, Subtitle B of FDASIA, Medical Gas Product Regulation, adding 
new sections 575, 576, and 577 to the FD&C Act (21 U.S.C. 360ddd, 360ddd1, and 360ddd2). 
5 See section 576 of the FD&C Act.  For a more detailed discussion of these provisions, please see the preamble to 
the Container-Closure Rule (81 FR 81685 at 81687-81688). 
6 Designated medical gases include, for example, Oxygen USP, Carbon Dioxide USP, Nitrogen NF, Nitrous Oxide 
USP, and Helium USP (see section 575(1) of the FD&C Act).  Designated medical gases for which certifications are 
granted, as well as medically appropriate combinations of certified designated medical gases, are deemed to have 
approved applications (under section 505 or 512 of the FD&C Act) for selected indications (see section 576(a)(3)(i) 
of the FD&C Act).   For more information, see the draft guidance for industry Certification Process for Designated 
Medical Gases.  When final, this guidance will represent the FDAs current thinking on this topic.  For the most 
recent version of a guidance, check the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.     
   
Most of these designated medical gases, along with medically appropriate combinations of them, are now included 
in FDAs regulation providing for conditional labeling exemptions for medical gases, 21 CFR 201.161 (before the 
Container-Closure Rule was finalized, the regulation did not include oxygen, nitrogen, or medically appropriate 
combinations of medical gases).  Two designated medical gases  medical air and carbon monoxide  are not 
covered by the revised regulation at this time.  
 
  2  Contains Nonbinding Recommendations 
removed or replaced except by the manufacturer (see  211.94 (e)(1) (21 CFR 
211.94(e)(1))).  
 
  Require that labeling on portable cryogenic medical gas containers meet certain 
placement and durability requirements ( 211.94(e)(2)). 
 
  Waive labeling reconciliation requirements for 360 wraparound labels (described below) 
on portable cryogenic medical gas containers (21 CFR 211.125(c)). 
 
The final rule also adds a new medical gas labeling regulation that: 
 
  Sets forth the FDA-designated color scheme for medical gas containers ( 201.328(c) (21 
CFR 201.328(c)); see Question Q4 in section III of this guidance for the list of colors). 
 
  Requires that portable cryogenic medical gas containers bear 360 wraparound labeling 
so that the name of the gas can be clearly seen from any vantage point; this labeling must 
meet specific requirements regarding coloring, lettering, position on the container, and 
identification of contents as medical gas(es) (see  201.328(a)(1) and (a)(1)(i)-(v)).  
 
  Requires that labeling for portable cryogenic medical gas containers include, in 
conspicuous lettering, the phrase For Medical Use, Medical Gas, or some similar 
phrase that indicates the gas is for medical use.  This phrase may be included either on 
the 360 wraparound label required by  201.328(a)(1) and described above, or on  a 
separate label ( 201.328(a)(2)). 
 
  Requires that high-pressure medical gas containers be colored on the shoulder portion in 
an FDA-designated color associated with the gas contained in the cylinder ( 201.328(b); 
see Question Q4 in section III of this guidance for the list of colors).   
 
  Prohibits a portable cryogenic medical gas container from being colored in the FDA-
designated color or colors unless the gas(es) held in the container correspond(s) to that 
color or those colors ( 201.328(a)(1)(v)).  It is permissible for such containers not to be 
colored, or to be colored in a light-reflective color such as white.    
 
In addition, the final rule makes the following changes to a regulation providing conditional 
labeling exemptions for listed medical gases: 
 
  Revises the list of gases that are exempt from otherwise-applicable prescription drug 
labeling requirements by adding oxygen and nitrogen (which are commonly used medical 
gases), by removing cyclopropane and ethylene (which are no longer considered 
appropriate for medical use), and by including medically appropriate combinations of 
medical gases (see  201.161(a) (21 CFR 201.161(a)). 
                                                                                                                                                             
7 Cryogenic containers are specialized containers used to hold a low-temperature, low-pressure liquid product.  The 
term portable cryogenic medical gas container is defined in 21 CFR 201.328(a) and is discussed in section III of 
this guidance (see Question Q5).   
  3  Contains Nonbinding Recommendations 
 
  Adds a new oxygen-specific warning statement to the regulation (see  201.161(a)(1)(i)).   
It is FDAs understanding that this warning statement is consistent with most existing 
oxygen labeling. 
 
The final rule is effective on January 17, 2017, but affected persons and firms have until May 17, 
2017, the final rules Compliance Date, to bring their medical gas containers and labeling into 
compliance with the final rules requirements.   
 
 
III.  QUESTIONS AND ANSWERS 
 
Q1.  Will I have to change my medical gas containers or labeling because of the 
new regulations? 
 
For most companies, no.  Based on information FDA received from industry stakeholders and 
FDA inspections, we believe that most medical gas manufacturers and transfillers are already in 
compliance with the new requirements in the Container-Closure Rule.  This is because these new 
requirements largely codify industry practices that have been widespread for at least a decade 
(and in some cases, much longer).   
 
However, covered persons and entities should review the final rule to be sure that their medical 
gas containers and labeling comply with the requirements of this final rule.  If they are not in 
compliance already, covered entities should take steps to bring their containers and labeling into 
compliance by May 17, 2017, the final rules Compliance Date. 
 
Q2.  What entities are covered by the final rule? 
 
The requirements apply to medical gas manufacturers, including transfillers, and distributors.  
We note that the requirements generally do not apply to end users of medical gases (e.g., 
hospitals, nursing homes, emergency medical technician (EMT) units, fire departments), unless 
those entities also engage in medical gas manufacturing or distributing.  For medical gases, FDA 
considers the term manufacturer to include any person or firm that manufactures a medical gas, 
which includes cascading, distributing, filling, mixing, purifying, separating, transferring, or 
transfilling medical gases. 
 
Firms that are not sure whether their activities are covered by the final rule are encouraged to 
contact FDA staff for more information. 
 
Q3.  What do medical gas manufacturers and transfillers (and other covered 
entities) need to do to comply with these rule changes? 
 
Medical gas manufacturers and other covered entities should confirm that all containers and 
labeling comply with the final rule requirements described above in section II of this guidance 
and set forth in  201.328 and 211.94(e).  It is FDAs understanding that most medical gas 
  4  Contains Nonbinding Recommendations 
containers and labeling already meet these requirements, but it is important to confirm that your 
containers and labeling are in compliance. 
 
Medical gas manufacturers and other covered entities should also confirm that the labeling of 
oxygen, nitrogen, carbon dioxide, helium, nitrous oxide, and medically appropriate combinations 
of any of these gases includes warning statements consistent with the requirements set forth in 
the final rule (see  201.161(a)(1)).  
 
These changes are not expected to require any action on the part of most medical gas 
manufacturers and transfillers, as it is FDAs understanding that these gases have, consistent 
with industry best practices, long been labeled in a manner consistent with the requirements of  
201.161(a).  Additionally, because cyclopropane and ethylene (the two gases now removed from 
the list) have not been considered appropriate for medical use for many years, FDA does not 
expect that any action will be required by most medical gas manufacturers or transfillers with 
regard to these gases.  However, as previously noted, it is important to confirm that your 
containers and labeling are in compliance. 
 
Q4.  What is the required color-coding scheme for identifying medical gas 
containers? 
 
There are separate coloring requirements for portable cryogenic medical gas containers and high-
pressure medical gas containers, although the color associated with each medical gas is the same 
regardless of the type of container (see Table 1, below). 
 
A portable cryogenic medical gas container may only be colored, in whole or in part, in the color 
or colors designated in  201.328(c) if the gas or gases held in the container correspond to that 
color or those colors ( 201.328(a)(1)(v)).  The container may instead be colored in a light 
reflective color such as white or simply not colored at all.  Also see Question Q6. 
 
Each high-pressure medical gas cylinder must be colored on the shoulder portion of the cylinder 
in the color or colors designated in  201.328(c) that correspond to the gas or gases held in the 
container, and the color or colors must be visible when viewed from the top of cylinder ( 
201.328(b)).  Also see Question Q7.   
 
The FDA-designated colors identifying medical gases in portable cryogenic medical gas 
containers and high-pressure medical gas containers are: 
 
Table 1.  FDA-designated colors for medical gases. 
 
Medical gas                          Color 
   
Medical Air     Yellow 
Carbon Dioxide   Gray 
Helium     Brown 
Nitrogen   Black 
Nitrous Oxide    Blue 
  5  Contains Nonbinding Recommendations 
Oxygen      Green 
Mixture or Blend     Colors corresponding to 
each component gas 
 
( 201.328(c)).   It is FDAs understanding that this color scheme has been in use by the majority 
of medical gas manufacturers and transfillers for many years. 
 
Q5.  How is portable cryogenic medical gas container defined? 
 
The term portable cryogenic medical gas container means a container that is capable of being 
transported and is intended to be attached to a medical gas supply system within a hospital, 
health care entity, nursing home, other facility, or home health care setting, or that is a base unit 
used to fill small cryogenic gas containers for use by individual patients ( 201.328(a) and 
211.94(e)(1)).    
 
Cryogenic containers that are not designed to be connected to a medical gas supply system (e.g., 
tank trucks, trailers, rail cars, or small cryogenic gas containers for use by individual patients, 
such as certain portable liquid oxygen units8) are not considered portable cryogenic medical gas 
containers for purposes of the new requirements ( 201.328(a) and 211.94(e)(1)), though other 
CGMP and labeling requirements continue to apply to these containers, as they did before 
issuance of the final rule. 
 
Q6.  What new requirements for portable cryogenic medical gas containers are 
established by this final rule? 
 
The Container-Closure Rule sets forth new CGMP and labeling requirements for gas use outlet 
connections, 360 wraparound labeling (and, e.g., its placement, coloring, and lettering), for 
medical use labeling, and other labeling information, as described below.   
 
Gas-Specific Use Outlet Connections 
 
Portable cryogenic medical gas containers that are not manufactured with permanent gas use 
outlet connections (e.g., those that have been silver-brazed) must have gas-specific use outlet 
connections that are attached to the valve body so that they cannot be readily removed or 
replaced (without making the valve inoperable and preventing the containers use) except by the 
manufacturer ( 211.94(e)(1)).   
 
360 Wraparound Labeling 
 
  Each portable cryogenic medical gas container must be conspicuously marked with a 
360 wraparound label identifying its contents ( 201.328(a)).  
 
                                                 
8 This includes portable liquid oxygen units as defined in 21 CFR 868.5655 (see  201.328(a) and 211.94(e)(1)). 
  6  Contains Nonbinding Recommendations 
  The 360 wraparound labeling must be affixed to the container in a manner that does not 
interfere with other labeling and such that it is not susceptible to becoming worn or 
inadvertently detached during normal use ( 211.194(e)(2)).  
 
  Each label, as well as materials used for coloring medical gas containers, must be 
reasonably resistant to fading, durable when exposed to atmospheric conditions, and not 
readily soluble in water ( 211.94(e)(2)). 
 
  Labeling reconciliation requirements are waived for 360 wraparound labels on portable 
cryogenic medical gas containers (21 CFR 211.125(c)). 
 
  The 360 wraparound label must meet the label placement and durability requirements 
described above, and meet the following additional requirements (see  201.328(a) and 
(a)(i)-(v)): 
 
Name of Gas (Color of Lettering and Label) 
 
  If the container holds a single gas, the name of the gas held in the 
o
container must be printed on the label in one of the following ways: 
  Using lettering that appears in the color designated for the gas 
(see  201.328 (c); also addressed in Question Q4 of this 
guidance) and that is printed against a white background, or  
  Using lettering that appears in white against a background that 
is painted in the color for the gas (see  201.328(c); also 
addressed in Question Q4 of this guidance). 
 
  There are no specific color requirements for the 360 wraparound label for 
o
portable cryogenic medical gas containers containing a medically 
appropriate combination of gases.  There are, however, requirements 
addressing the color of the container itself.  See Question Q4 of this 
guidance. 
 
Name of Gas (Size of Lettering) 
 
  The lettering for the name of the gas on the label must be at least 2 inches 
o
high. 
 
Name of Gas (Continuous Printing and Readability) 
 
  The name of the gas must be printed continuously around the label (e.g., 
o
Oxygen USP Oxygen USP Oxygen USP...) and be readable around the 
entire container. 
 
 
 
 
  7  Contains Nonbinding Recommendations 
Placement of Label 
 
  The label must be on the sidewall of the container, as close to the top of 
o
the container as possible but below the top weld seam. 
 
Container Coloring (Must Correspond to Gas Inside the Container, But White or 
Uncolored Containers Permissible) 
 
  If you color a portable cryogenic medical gas container, it may only be 
o
colored in the color or colors designated at  201.328(c) if the gas or gases 
held within the container correspond(s) to that color or those colors.  Such 
containers may also be not colored at all, or colored in a light-reflective 
color such as white.    
 
For Medical Use Labeling 
 
  A label on the container (either the 360 wraparound label required in  201.328(a)(1) or 
a separate label) must include, in conspicuous lettering, the phrase For Medical Use, 
Medical Gas, or some similar phrase that indicates that the gas is for medical use ( 
201.328(a)(2)). 
 
  The for medical use labeling (whether included as part of the 360 wraparound labeling 
or otherwise) that is required for portable cryogenic medical gas containers must be 
affixed to the container in a manner that does not interfere with other labeling and such 
that it is not susceptible to becoming worn or inadvertently detached during normal use ( 
211.94(e)(2)).  
 
Q7.  What new requirements for high pressure medical gas cylinder coloring are 
established by this final rule? 
 
Each high-pressure medical gas cylinder must be colored on the shoulder portion of the cylinder 
in the color or colors designated in the color-coding system (see  201.328(b) and (c); also see 
Question Q4 in this guidance).  The color or colors must be visible when viewed from the top of 
cylinder. 
 
Q8.  Where can I get more information, if needed? 
 
Questions regarding compliance with the Container-Closure Rule should be directed to 
CDERCompliance@fda.hhs.gov.  Questions regarding other medical gas issues should be 
directed to CDER-OPQ-Inquiries@fda.hhs.gov. 
 
 
  8