Medical Gas Containers and Closures; Current Good Manufacturing Practice Requirements, 81685-81697 [2016-27838]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 81, Number 223 (Friday, November 18, 2016)]
[Rules and Regulations]
[Pages 81685-81697]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-27838]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 211

[Docket No. FDA-2005-N-0343]
RIN 0910-AC53


Medical Gas Containers and Closures; Current Good Manufacturing 
Practice Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
amending its current good manufacturing practice (CGMP) and labeling 
regulations regarding medical gases. FDA is requiring that portable 
cryogenic medical gas containers not manufactured with permanent gas 
use outlet connections have gas-specific use outlet connections that 
cannot be readily removed or replaced except by the manufacturer. FDA 
is also requiring that portable cryogenic medical gas containers and 
high-pressure medical gas cylinders meet certain labeling, naming, and 
color requirements. These requirements are intended to increase the 
likelihood that the contents of medical gas containers are accurately 
identified and reduce the likelihood of the wrong gas being connected 
to a gas

[[Page 81686]]

supply system or container. FDA is also revising an existing regulation 
that conditionally exempts certain medical gases from certain 
otherwise-applicable labeling requirements in order to add oxygen and 
nitrogen to the list of gases subject to the exemption, and to remove 
cyclopropane and ethylene from the list.

DATES: This rule is effective January 17, 2017. See section V of this 
document for the compliance date of this final rule.

FOR FURTHER INFORMATION CONTACT: J. Patrick Raulerson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6260, Silver Spring, MD 20993-0002, 301-
796-3522.

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits
II. Background
    A. History of the Rulemaking
    B. Summary of Comments to the Proposed Rule
    C. General Overview of the Final Rule
III. Legal Authority
IV. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Description of General Comments and FDA Response
    C. Specific Comments and FDA Response
    V. Compliance Date
VI. Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
VII. Analysis of Environmental Impact
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. References

I. Executive Summary

A. Purpose of the Final Rule

    On April 10, 2006, FDA issued a proposed rule to amend our 
regulations on CGMP to include new or revised requirements for the 
labeling, color, dedication, and design of medical gas containers and 
closures (71 FR 18039). The chief impetus for the proposed rule was a 
number of incidents in which a medical gas container holding a gas 
other than oxygen was erroneously connected to a health care facility's 
oxygen supply system, leading to serious injuries and deaths. In 
addition, FDA recognized that the regulation that conditionally exempts 
certain medical gases from certain otherwise-applicable prescription 
drug labeling regulations did not reflect either industry best 
practices or FDA's current regulatory expectations.
    Following consideration of comments received and further internal 
deliberation, we are finalizing this rule as described in this 
document. The final rule is intended to increase the likelihood that 
the contents of medical gas containers are accurately identified and 
reduce the likelihood of the wrong gas being connected to a gas supply 
system or container. The final rule also modifies the medical gas 
conditional labeling exemption regulation such that it now largely 
reflects existing industry best practices and FDA's current regulatory 
expectations regarding the labeling of medical gases.

B. Summary of the Major Provisions of the Final Rule

    We received approximately 50 comments on the proposed rule. The 
most detailed comments were from industry trade associations. The other 
comments were largely from individual medical gas firms, consultants, 
or other industry stakeholders, and they generally expressed agreement 
with the trade associations' comments. We discuss all significant 
comments in section IV.
    The final rule requires that portable cryogenic medical gas 
containers not manufactured with permanent gas use outlet connections 
have gas-specific use outlet connections that cannot be readily removed 
or replaced except by the manufacturer. The rule further requires that 
portable cryogenic medical gas containers and high-pressure medical gas 
cylinders meet certain labeling, naming, and color requirements. 
Principally, portable cryogenic medical gas containers are required to 
bear a 360[deg] wraparound label identifying the contents of the 
container, and high-pressure medical gas cylinders are required to be 
colored on the shoulder of the container in the FDA-designated color or 
colors associated with the gas or gases held in the container. These 
requirements are intended to increase the likelihood that the contents 
of medical gas containers are accurately identified and reduce the 
likelihood of the wrong gas being connected to a gas supply system or 
container.
    The final rule also revises the medical gas conditional labeling 
exemption regulation to add oxygen and nitrogen to the list of medical 
gases subject to the exemption, and to remove cyclopropane and ethylene 
from the list. The final rule further revises this regulation by adding 
new warning statement content to be included in oxygen labeling and by 
expanding the scope of the regulation to include medically appropriate 
mixtures of medical gases.

C. Legal Authority

    Medical gases are generally regulated as prescription drugs under 
sections 201(g)(1) and 503(b)(1) of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) (21 U.S.C. 321(g)(1) and 353(b)(1)) (though 
oxygen may be dispensed without a prescription for certain uses 
specified at section 576(b)(2) of the FD&C Act (21 U.S.C. 360ddd-
1(b)(2)), and are subject to regulation under section 501(a)(2)(B) of 
the FD&C Act (21 U.S.C. 351(a)(2)(B)). Sections 575 and 576 of the FD&C 
Act (21 U.S.C. 360ddd and 360ddd-1) address the regulation of medical 
gases and designated medical gases. FDA is invoking its authority under 
sections 501(a)(2)(B), 502(f) (21 U.S.C. 352(f)), 576(a), and 701(a) 
(21 U.S.C. 371(a)) of the FD&C Act to create or modify CGMP and 
labeling regulations applicable to medical gases to ensure that they 
meet the requirements of the FD&C Act as to safety and have the 
identity and strength, and meet the quality and purity characteristics, 
that they purport or are represented to possess, and are labeled with 
adequate warnings and instructions for use.

D. Costs and Benefits

    The rule is expected to provide a modest net social benefit 
(estimated benefits minus estimated costs) to society. Costs are 
attributed to coloring medical gas containers, complying with the 
360[deg] wraparound label requirement for portable cryogenic 
containers, and requiring gas-specific use outlet connections on 
portable cryogenic containers to be permanently attached to the valve 
body (e.g., by silver brazing) or attached to the valve body using a 
locking mechanism or other appropriate device so that only the 
manufacturer can readily remove or replace them. Using a standard 10 
year time period, we estimate annualized costs to range between 
$180,000 and $1.5 million using a 3 percent discount rate and between 
$210,000 and $1.8 million using a 7 percent discount rate. Benefits are 
attributed to reducing the probability that medical personnel 
accidentally administer the wrong gas to patients, resulting in serious 
injury or death. We estimate annualized benefits to range between 
$800,000 and $2.8 million using a 3 percent discount rate, and between 
$2.5 million and $8.3 million using a 7 percent discount rate. Together 
we estimate annualized net benefits to range between $620,000 and $1.3 
million using a 3 percent discount rate, and between $2.3 million and 
$6.5 million using a 7 percent discount rate.

[[Page 81687]]

II. Background

A. History of the Rulemaking

    In the Federal Register of April 10, 2006, FDA issued a proposed 
rule to amend our regulations on CGMP to include new requirements for 
the labeling, color, dedication, and design of medical gas containers 
and closures. The chief impetus for issuance of the proposed rule was a 
number of incidents in which a medical gas container holding a gas 
other than oxygen was erroneously connected to a health care facility's 
oxygen supply system, leading to serious injuries and deaths. FDA was 
also concerned with reports of serious injuries attributable to 
contamination of high-pressure medical gas cylinders with residue of 
industrial cleaning solvents, likely as a result of inadequate cleaning 
during conversion of the cylinder from industrial to medical use. For a 
detailed account of these incidents, please refer to the proposed rule 
(71 FR 18039 at 18040-18041).
    Accordingly, FDA proposed certain regulatory requirements intended 
to (1) reduce the likelihood of the wrong gas being attached to a gas 
supply system or container (and in particular to reduce the likelihood 
of a gas other than oxygen being connected to an oxygen supply system), 
(2) make the contents of medical gas containers more easily and 
accurately identifiable, and (3) reduce the risk of contamination of 
medical gases. Additionally, FDA proposed including medical air, 
oxygen, and nitrogen among, and excluding cyclopropane and ethylene 
from, the list of gases that are conditionally exempt from certain 
labeling requirements as described in Sec.  201.161 (21 CFR 201.161). 
FDA solicited written comments on the proposed rule.
    Following publication of the proposed rule, the Food and Drug 
Administration Safety and Innovation Act (FDASIA) was enacted (Pub. L. 
112-144 (July 9, 2012)). Title XI, Subtitle B of FDASIA, ``Medical Gas 
Product Regulation,'' added new sections 575, 576, and 577 to the FD&C 
Act (21 U.S.C. 360ddd, 360ddd-1, and 360ddd-2), creating a new 
certification process for certain ``designated'' medical gases, 
including all of the gases listed at Sec.  201.161 as amended by this 
rule. Section 575 of the FD&C Act defines the term ``designated medical 
gas'' to include oxygen, nitrogen, nitrous oxide, carbon dioxide, 
helium, carbon monoxide, and medical air that meet the standards set 
forth in an official compendium. Section 576 of the FD&C Act permits 
any person to file a request for certification of a medical gas as a 
designated medical gas for certain specified indications. A designated 
medical gas for which a certification is granted is deemed to have in 
effect an approved application under section 505 (New Drug Application) 
or 512 (New Animal Drug Application) of the FD&C Act (21 U.S.C. 355 or 
360b) (see FD&C Act section 576(a)(3)(A)(i)). This approval applies to 
the designated medical gas alone or in combination, as medically 
appropriate, with one or more other designated medical gases for which 
certifications have been granted (Id.).
    Section 576 of the FD&C Act also addresses the labeling and 
prescription drug status of designated medical gases. Section 
576(a)(3)(A)(ii) of the FD&C Act, similar to the conditional labeling 
exemption at Sec.  201.161(a), specifies how the labeling of designated 
medical gases may meet certain generally applicable statutory labeling 
requirements. Specifically, section 576(a)(3)(A)(ii) of the FD&C Act 
provides that the requirements of sections 503(b)(4) of the FD&C Act 
(regarding labeling of a drug as a prescription drug) and 502(f) of the 
FD&C Act (regarding inclusion of adequate directions for use and 
adequate warnings in drug labeling) are deemed to have been met for a 
designated medical gas if the labeling on the final use container for 
the medical gas bears: (1) The information required by section 
503(b)(4); (2) a warning statement concerning the use of the medical 
gas as determined by the Secretary by regulation; and (3) appropriate 
directions and warnings concerning storage and handling. Section 
576(b)(2)(B) of the FD&C Act further provides that, in the case of 
oxygen provided for certain uses specified at section 576(b)(2)(A), the 
requirements of section 503(b)(4) of the FD&C Act are deemed to have 
been met if the labeling bears a warning that the oxygen can be used 
for emergency use only and for all other medical applications a 
prescription is required. Finally, section 576(b) of the FD&C Act 
provides that designated medical gases shall generally be subject to 
the requirements of section 503(b)(1) of the FD&C Act (requiring that 
drugs meeting certain specified conditions be dispensed only upon 
prescription), while also providing that oxygen may be dispensed 
without a prescription for certain specified uses.

B. Summary of Comments to the Proposed Rule

    FDA received approximately 50 written comments on the proposed 
rule. Comments were submitted by trade associations representing the 
medical gas and home health care industries, medical gas firms, medical 
gas industry consultants and other industry stakeholders, and one State 
regulatory body.
    The comments addressed the following topics, among others:
     The appropriate warning statements to be included in 
oxygen and medical air labeling.
     Safety issues associated with converting a gas container 
from industrial to medical use and how best to address them.
     The utility and appropriateness of coloring medical gas 
containers in whole or in part.
     The appropriate content and configuration of wraparound 
labeling on portable cryogenic medical gas containers.
     Estimated costs to comply with the proposed rule and 
whether such costs are justified under a cost-benefit analysis.

C. General Overview of the Final Rule

    This final rule includes many of the provisions of the April 2006 
proposed rule, with certain modifications described in section IV.C of 
this document. In particular, the final rule adds oxygen and nitrogen 
to, and removes cyclopropane and ethylene from, the list of medical 
gases in Sec.  201.161(a) that are conditionally exempt from the 
labeling requirements of Sec.  201.100(b)(2) and (3), and (c)(1). The 
final rule also requires that portable cryogenic medical gas containers 
and high-pressure medical gas cylinders meet certain labeling, naming, 
and coloring requirements as provided in new Sec.  201.328. The final 
rule further requires that portable cryogenic medical gas containers 
not manufactured with permanent gas use outlet connections have gas-
specific use outlet connections that cannot be readily removed or 
replaced except by the manufacturer by amending Sec.  211.94 (21 CFR 
211.94) through the addition of new paragraph (e).
    This final rule also reflects revisions FDA is making to the April 
2006 proposed rule in light of comments received. In addition to other 
changes discussed in section IV.C of this document, FDA is making the 
following significant changes to the proposed rule:
 Revisions to Conditional Labeling Exemptions for Medical Gases
    FDA is making additional revisions to Sec.  201.161 in response to 
concerns raised by comments. First, in response to a comment 
questioning Sec.  201.161(b)'s exclusion of gas mixtures from the scope 
of the Sec.  201.161(a) conditional labeling exemptions applicable to

[[Page 81688]]

certain medical gases, FDA is removing this exclusion. Second, in 
response to comments that oxygen labeling should bear a different 
warning statement from other medical gases listed at Sec.  201.161, 
paragraph (a) of Sec.  201.161 now includes new warning statement 
requirements specific to oxygen. Third, in response to comments that 
medical air labeling should bear a different warning statement from 
other medical gases listed at Sec.  201.161, FDA has determined that 
medical air should be removed from the scope of the final rule, for the 
reasons discussed in section IV.C of this document. Fourth, FDA is also 
revising the regulation such that the warning statement that must be 
included on labeling to qualify for the labeling exemption must contain 
certain specified information, but need not consist of the exact words 
used in the regulation.
    If the labeling on a final use container of a designated medical 
gas (or medically appropriate mixture of designated medical gases) 
includes the information required by section 503(b)(4) of the FD&C Act 
as well as the information required to obtain the conditional labeling 
exemptions provided at Sec.  201.161(a) as revised by this rule, FDA 
will consider such labeling to meet the conditions set forth at section 
576(a)(3)(A)(ii) of the FD&C Act, and, therefore, to have met the 
requirements of sections 503(b)(4) and 502(f) of the FD& C Act.
 Proposed Prohibition on Conversion of Cryogenic Containers and 
High-Pressure Cylinders From Industrial to Medical Use
    In Sec.  211.94(e)(1) of the proposed rule, FDA proposed generally 
prohibiting cryogenic containers and high-pressure cylinders used to 
hold industrial gases from being converted to medical use to minimize 
the risk of contamination of medical gases by industrial contaminants 
or cleaning solvents. As discussed further in section IV.C of this 
document, FDA agrees with comments stating that such a prohibition 
would be unnecessarily costly, as these types of contamination 
incidents appear to be rare and existing regulations regarding cleaning 
and inspection of drug containers and closures are sufficient to 
address this issue. Accordingly, FDA is not finalizing this proposed 
requirement.

III. Legal Authority

    Medical gases are generally regulated as prescription drugs under 
sections 201(g)(1) and 503(b)(1) of the FD&C Act (though oxygen may be 
dispensed without a prescription for certain uses specified at section 
576(b)(2) of the FD&C Act, and are subject to regulation under section 
501(a)(2)(B) of the FD&C Act. Sections 575 and 576 of the FD&C Act 
address the regulation of medical gases and designated medical gases. 
Under sections 501(a)(2)(B), 502(f), and 701(a) of the FD&C Act, FDA 
has the authority to create and modify CGMP and labeling regulations to 
ensure that drugs meet the requirements of the FD&C Act as to safety 
and have the identity and strength, and meet the quality and purity 
characteristics, that they purport or are represented to possess, and 
are labeled with adequate warnings and instructions for use. Medical 
gas containers, closures, and labeling are integral parts of medical 
gas drug products and play a critical role in ensuring that these 
products are safe and have the appropriate identity, strength, quality, 
and purity. Medical gas mix-ups have caused deaths and serious 
injuries. These incidents have occurred despite current regulations and 
guidance addressing the safe handling of medical gases. FDA is 
therefore invoking the authority granted by sections 701(a), 
501(a)(2)(B), 502(f), and 576(a) of the FD&C Act to issue CGMP and 
labeling regulations designed to facilitate the safe use of medical 
gases and to ensure that medical gases are labeled with adequate 
warnings and instructions for use. The specific requirements in these 
regulations will help to ensure the safety of these products.

IV. Comments on the Proposed Rule and FDA Response

A. Introduction

    We describe and respond to comments on the proposed rule in this 
section. We respond to certain comments on the Preliminary Regulatory 
Impact Analysis (PRIA) in the Final Regulatory Impact Analysis (see 
Section VI). For ease of identification, the word ``Comment,'' in 
parentheses, will appear before the comment's description, and the word 
``Response,'' in parentheses, will appear before our response. The 
number assigned to each comment is purely for organizational purposes 
and does not signify the comment's value or importance or the order in 
which it was received. Many of the comments voiced the same or highly 
similar concerns and made the same or highly similar recommendations; 
these comments have been consolidated where possible.

B. Description of General Comments and FDA Response

    (Comment 1) Many comments contend that FDA's proposal does not 
reflect the risk-based principles that have historically been 
enunciated in connection with recent CGMP policy. These comments state 
that risk-based principles focus regulation on critical areas that are 
likely to achieve the greatest public health impact. Thus, these 
comments state that because the impact of FDA's proposed rule is 
disproportionate to and beyond the scope of any public health risk 
associated with medical gases, it is inconsistent with the Agency's 
risk-based approach for CGMP. The comments further contend that the 
incidents cited in the preamble of the proposed rule do not support the 
number of requirements proposed, and that a single requirement in the 
proposed rule--requirement for secure connections on portable 
containers--would have prevented all but one of the fatalities cited in 
the preamble.
    (Response 1) FDA agrees in part with these comments and has, 
following reanalysis of expected costs and benefits, declined to adopt 
certain provisions in the proposed rule and has revised other proposed 
provisions to more efficiently achieve public health objectives. Many 
of the requirements in the final rule are consistent with what we 
understand to be industry practices (Refs. 1-3). We continue to believe 
that medical gas containers and closures, such as portable cryogenic 
containers and high-pressure cylinders, are integral parts of the drug 
product and play a critical role in ensuring that the drug provided to 
the patient has the appropriate identity, strength, quality, and 
purity. Accordingly, we believe that this rule, as finalized, is fully 
consistent with FDA's risk-based approach to CGMP regulation.
    (Comment 2) Many comments contend that FDA significantly 
underestimated the costs to industry imposed by the rule as proposed. 
These comments estimate these potential costs to be in the range of 
$855 million to $1.3 billion, as opposed to FDA's estimate of $950,000 
to $1.2 million. These comments request that the cost assumptions and 
conclusions contained in the preamble to the proposed rule be 
critically reexamined by the Department of Health and Human Services 
and the Office of Management and Budget (OMB).
    (Response 2) We considered these concerns, as appropriate, in 
preparing the Final Regulatory Impact Analysis (see Section VI).

[[Page 81689]]

C. Specific Comments and FDA Response

 Revisions To Labeling Exemptions for Certain Medical Gases 
(Sec.  201.161)
    FDA proposed adding medical air, oxygen, and nitrogen to the list 
of gases conditionally exempted by Sec.  201.161(a) from the labeling 
requirements of Sec.  201.100(b)(2) and (3), and (c)(1). FDA proposed 
these changes because, based on its years of regulatory experience with 
these gases, FDA believed that compliance with Sec.  201.100(b)(2) and 
(3), and (c)(1) would be unnecessary if the warning statement and 
storage and handling directions required to obtain the conditional 
Sec.  201.161(a) labeling exemptions were included in the labeling of 
such gases and the labeling and coloring requirements found in proposed 
Sec.  211.94(e)(4) were met. FDA also proposed removing cyclopropane 
and ethylene from Sec.  201.161(a), as these gases are no longer used 
in medical procedures because they are flammable and pose a risk of 
explosion or fire.
    Comments support these proposed changes to the list of exempted 
gases. Many comments expressed concern, however, over how these 
proposed changes would affect the labeling of oxygen and medical air. 
These concerns are set forth in comments 3 and 4, followed by FDA's 
response.
    (Comment 3) Many comments express significant concerns with FDA's 
proposal to add oxygen to the list of gases at Sec.  201.161(a) without 
providing a warning statement specific to oxygen. The warning statement 
at Sec.  201.161(a)(1) previously provided that the gas may only be 
used by or under the supervision of a licensed practitioner. These 
comments argue that requiring this statement for oxygen could eliminate 
the ability of first responders to administer oxygen without a 
prescription. These comments also note that the labeling on oxygen 
containers that has long been in use by the industry, which provides 
for use without a prescription in certain situations when administered 
by properly trained personnel, would no longer be acceptable and would 
need to be changed. These comments state that further changes are 
needed to address these issues.
    (Comment 4) Many comments further note that the warning statement 
at Sec.  201.161(a) does not include certain warnings currently 
included on oxygen labels. For instance, widely used oxygen labeling 
warns that uninterrupted use of high concentrations of oxygen over a 
long duration without monitoring its effect on oxygen content of 
arterial blood may be harmful and that oxygen should not be used on 
patients who have stopped breathing unless used in conjunction with 
resuscitative equipment.
    (Response to Comments 3 and 4) FDA is further revising Sec.  
201.161(a)(1) in response to these comments.
    Prior to the revisions finalized in this rule, Sec.  201.161(a) 
provided that if the labeling of the medical gases listed in the rule--
carbon dioxide, cyclopropane, ethylene, helium, and nitrous oxide 
intended for drug use--bore a specified warning statement and any 
needed directions concerning the conditions for storage and warnings 
against the inherent dangers in the handling of the specific compressed 
gas, those gases would be exempt from certain otherwise-applicable 
labeling requirements concerning the recommended or usual dosage, the 
drug's route of administration, and adequate directions for use. 
Section 201.161(b) provided that the exemption in Sec.  201.161(a) did 
not apply to any mixture of the gases covered by the regulation with 
oxygen or with each other. In the 2006 proposed rulemaking FDA proposed 
adding oxygen, medical air, and nitrogen, and removing cyclopropane and 
ethylene, from the scope of Sec.  201.161, but proposed no other 
changes to the rule.
    As many comments point out, the warning statement previously 
specified at Sec.  201.161(a)(1) differs significantly from the warning 
statement that has long been in use on oxygen labeling. FDA agrees with 
these comments that this oxygen-specific warning statement is more 
useful and appropriate for oxygen than the general warning statement 
previously specified at Sec.  201.161(a)(1).
    FDA further agrees with these comments that conditioning the Sec.  
201.161(a) labeling exemptions on inclusion of a warning statement 
limiting oxygen to prescription use would be inconsistent with the 
longstanding use of oxygen without a prescription in certain 
situations. It would also be inconsistent with new section 576(b)(2)(B) 
of the FD&C Act which, as discussed in section II.A of this document, 
provides that, in the case of oxygen provided without a prescription 
for certain uses specified at section 576(b)(2)(A), the requirements of 
section 503(b)(4) of the FD&C Act shall be deemed to have been met if 
the labeling bears a warning that the oxygen can be used for emergency 
use only and for all of other medical applications a prescription is 
required.
    Therefore, Sec.  201.161(a)(1)(i) of this final rule provides 
warning statement requirements specific to oxygen, as well as an 
additional warning statement requirement for oxygen that may be 
provided for certain uses without a prescription. FDA believes most 
oxygen containers currently marketed in the United States bear labeling 
that satisfies these new requirements (Ref. 1).
    (Comment 5) Some comments express concerns with FDA's proposal to 
add medical air to the list of gases at Sec.  201.161(a) without 
providing a warning statement specific to medical air. These comments 
point out that widely used medical air labeling indicates that medical 
air may be used without a prescription by properly trained personnel 
for breathing support, while for all other uses a prescription is 
required. These comments note that such labeling would be inconsistent 
with the warning statement previously specified at Sec.  201.161(a)(1), 
which provided that the gas may only be used by or under the 
supervision of a licensed practitioner.
    (Response 5) FDA acknowledges the comments that certain non-
prescription uses of medical air are medically appropriate, and, 
accordingly, that the `prescription only' warning statement at Sec.  
201.161(a)(1)(i) as finalized by this rule is not appropriate for 
medical air. FDA is not finalizing the proposal to add medical air to 
the list of gases at Sec.  201.161, and the question of what 
constitutes an appropriate warning statement for medical air remains 
under consideration by FDA.
    (Comment 6) Many comments note that the proposed rule does not 
address labeling for medical gas mixtures, but rather leaves in place 
Sec.  201.161(b)'s exclusion of gas mixtures from the scope of the 
Sec.  201.161(a) conditional labeling exemptions. These comments 
recommend for the short term that Sec.  201.161(b) remain as currently 
published but that FDA nonetheless permit these medical gas mixtures to 
be labeled consistent with industry practice, which utilizes the 
warning statement previously specified at Sec.  201.161(a)(1).
    (Response 6) FDA notes that, as discussed in section II.A of this 
document, following publication of the proposed rule new section 
576(a)(3)(A)(i) was added to the FD&C Act by FDASIA. This new section 
provides that designated medical gases for which a certification is 
granted are deemed alone or in combination, as medically appropriate, 
with one or more other designated medical gases for which 
certifications have been granted to have in effect an approved 
application.
    Accordingly, FDA is further revising Sec.  201.161(a)(1) in 
response to these

[[Page 81690]]

comments. Specifically, FDA has determined that medically appropriate 
mixtures of the gases listed at Sec.  201.161(a) should be eligible for 
the conditional labeling exemptions provided by Sec.  201.161(a). 
Accordingly, in this final rule FDA is removing the Sec.  201.161(b) 
exclusion and is specifying that the general warning statement 
requirements applicable to the gases listed at Sec.  201.161(a) (other 
than oxygen) are also applicable to medically appropriate mixtures of 
the listed gases (see Sec.  201.161(a)(1)(ii) of this final rule).
    (Comment 7) A comment requests that medical xenon be added to the 
list of exempted gases in Sec.  201.161(a) as it is used clinically as 
a general anesthetic and as a diagnostic and test agent.
    (Response 7) FDA disagrees that medical xenon should be added to 
the list of gases for which the Sec.  201.161(a) conditional labeling 
exemptions are available. Xenon is not a designated medical gas and is 
not otherwise approved for use as a general anesthetic. Certain xenon 
gas radioisotopes have been approved as diagnostic agents, but these 
products have approved prescription drug labeling. Accordingly, it 
would be inappropriate to add xenon gas to the list of gases at Sec.  
201.161(a).
    (Comment 8) Many comments contend that the content in proposed 
Sec.  211.94(e)(4) is misplaced by being located in part 211 (21 CFR 
part 211, CGMP requirements) rather than part 201 (21 CFR part 201, 
labeling requirements). These comments recommend that any proposed 
labeling requirements be included in part 201.
    (Response 8) FDA largely agrees with these comments and is 
reorganizing this content in the final rule. Specifically, the labeling 
content requirements in proposed Sec.  211.94(e)(4) are being finalized 
under new Sec.  201.328, while requirements that medical gas labels and 
coloring materials be resistant to wear and, in the case of labels, not 
susceptible to inadvertent removal, have been retained in Sec.  
211.94(e).
 Requirement for 360[deg] Wraparound Label for Portable 
Cryogenic Medical Gas Containers (Sec.  201.328(a)(1))
    In Sec.  211.94(e)(4) of the proposed rule (renumbered as Sec.  
201.328(a)(1) in this final rule), FDA proposed to require portable 
cryogenic containers to bear 360[deg] wraparound labeling that meets 
naming, lettering, and placement specifications.
    (Comment 9) Many comments expressed concern about the proposed 
requirement that the word ``Medical'' precede the name of the gas on 
the wraparound label. These comments state that there is a risk that 
users would focus on the ``Medical'' designation and ignore the more 
significant information, i.e., the identity of the gas itself (e.g., 
oxygen versus nitrogen). Therefore, these comments recommend removing 
this requirement from the final rule. Some of these comments also state 
that this naming requirement would be inconsistent with the 
``established name'' of the gas, e.g., Oxygen USP or Nitrogen NF (see 
definition of ``established name'' at section 502(e)(3) of the FD&C 
Act). As an alternative, one comment proposes that the rule refer to 
the product name and provide that either the word ``Medical'' may 
precede, or ``USP'' or ``NF'' may follow, the product name.
    (Response 9) FDA proposed adding the word ``Medical'' to the 
wraparound label to distinguish containers labeled with medical gases 
from containers holding industrial gases. This proposed requirement was 
intended to make the contents of the containers more readily and 
accurately identified by persons responsible for handling and 
connecting them to medical gas supply systems in hospitals or other 
health care facilities and thereby reduce the likelihood of medical gas 
mix-ups. However, FDA agrees with the comments that inclusion of the 
word ``Medical'' in the name of the gas would be inconsistent with the 
established names of medical gases.
    Accordingly, as set forth in Sec.  201.328(a)(2), FDA will instead 
require that the portable cryogenic containers bear a label (either the 
wraparound label or a separate label) near the top of the container but 
below the top seam weld that includes the phrase ``For Medical Use,'' 
``Medical Gas,'' or some similar phrase that indicates the gas is for 
medical use in conspicuous lettering.
    FDA has also reconsidered the proposed requirement that gases be 
identified on the wraparound label by their ``standard names.'' Section 
502(e) of the FD&C Act provides that a drug product is misbranded 
unless its label bears the established name of the drug, if there is 
such a name. All of the gases listed at Sec.  201.328(c) have 
established names. Thus, the proposed requirement regarding ``standard 
names'' is not necessary, and we are removing this concept from the 
final rule.
    (Comment 10) A few of the parties providing comments state that 
while they agree with the proposed requirement at Sec.  
211.94(e)(4)(i)(E) that the label be placed ``as close to the top of 
the container as possible but below the top weld seam'', they object to 
the following phrase: ``. . . so that it cannot be easily detached or 
worn'' (Sec.  211.94(e)(4)(i)(F)). These comments express concern that 
if the label is worn or detached by the user, for whatever reason, the 
manufacturer may be considered to be not in compliance with the 
proposed rule requirements, when in fact the firm may have properly 
placed the label.
    (Response 10) FDA agrees that this proposed requirement should be 
revised. The key issue is that the wraparound label be affixed such 
that it is not susceptible to wear or to being inadvertently removed 
during normal use, and FDA is revising this requirement accordingly 
(see Sec.  211.94(e)(2) of this final rule).
    (Comment 11) Many comments note that the minimum lettering height 
requirement for the name of the gas on the wraparound label in the 
proposed rule (2\3/4\ inches) is inconsistent with the industry 
practice (minimum letter height of 2 inches). According to these 
comments, requiring 2\3/4\ inch letters will reduce the number of times 
the name can be fully printed on the label, and will come at a 
considerable expense to those suppliers that currently comply with the 
2-inch industry practice.
    (Response 11) FDA is revising the minimum letter height requirement 
in consideration of these comments. The final rule states that the 
lettering height for the name of the gas on the label must be at least 
2 inches high (see Sec.  201.328(a)(1)(ii) of this final rule).
 Color Requirements for Medical Gas Cylinders (Sec.  
201.328(a)(1)(v) and (b))
    (Comment 12) Many comments support color-coding high-pressure 
cylinders, but are concerned that FDA may be placing undue emphasis on 
this means of identification. These comments contend that health care 
personnel should primarily rely on the label to identify the gas or 
gases in a container, and argue that reliance on color is problematic 
because of the variability of lighting conditions, color fading, and 
potential personnel colorblindness. Other comments state that reliance 
on color coding would appear to contradict training programs that 
industry and FDA have implemented to prevent mix-ups, as the consistent 
and fundamental themes of these training programs has been to emphasize 
that the label should be the primary indicator of a container's 
contents.
    (Response 12) FDA agrees that the wording on the label should be 
used as the primary means of identifying a drug product. Requiring 
color coding of high-pressure cylinders, which we understand is already 
industry practice (Ref. 2), simply provides an additional safeguard to 
facilitate accurate identification of the drug product and

[[Page 81691]]

detection of potential errors. Additionally, Sec.  211.25 addresses the 
need to train qualified personnel in the manufacture, processing, 
packing, or holding of a drug product. Proper training should help 
mitigate against the possibility that users might improperly rely 
solely on the cylinder's color to identify its contents.
    (Comment 13) Many comments recommend removing the requirement of 
``colored in whole'' for non-aluminum high-pressure cylinders. These 
comments state that the current industry practice is to paint the 
shoulder to match the designated color for that medical gas. This is 
based on manufacturer recommendations that some non-aluminum high-
pressure cylinders should not be painted in whole due to concerns about 
concealing defects.
    (Response 13) FDA agrees with these comments. Thus, the final rule 
requires only that high-pressure medical gas cylinders be colored on 
the shoulder portion of the cylinder (see Sec.  201.328(b)), which is 
consistent with what FDA understands to be industry practice (Ref. 2).
    (Comment 14) Many comments dispute FDA's assumption that a large 
majority of high-pressure medical gas cylinders are already in 
compliance with the proposed coloring requirements. These comments note 
that portions of the shoulders of many cylinders are painted white to 
make retest information more visible, and that the upper neck portion 
of many cylinders are not painted a color based on the contents of the 
cylinder.
    (Response 14) The cylinder coloring requirement in the final rule 
(see Sec.  201.328(b)) would not require recoloring of cylinders 
colored in the manner described in the comments. As long as the 
cylinder shoulder is colored in the FDA-designated color or colors, the 
upper neck portion of the cylinder need not be that same color and use 
of white to make retesting information on a portion of the shoulder of 
the cylinder more visible is acceptable.
    (Comment 15) Many comments recommend removal of the requirement 
that high-pressure medical gas cylinders containing mixtures of gases 
be painted in rough proportion to the fractions of gases contained in 
the mixture. These comments express concern that this method may cause 
the end user to ignore the label and rely on color proportions to 
identify the contents of a mixture. Additionally, these comments 
recommend that the following language be incorporated in the 
regulation: ``when color marking consists of 2 or more colors, the 
pattern shall permit a portion of the colors to be seen together when 
viewed from the top,'' which is consistent with industry practice.
    (Response 15) FDA agrees with these comments. Therefore, FDA is 
revising the rule to require that the color for every constituent gas 
be visible when the cylinder is viewed from the top, and to remove the 
proportionality requirement.
    (Comment 16) Many comments recommend removing the proposed 
requirement (at Sec.  211.94(e)(4)(i)(G) in the proposed rule) that if 
the shoulder portion of a portable cryogenic medical gas container is 
colored, the color used must be the FDA-designated color of the gas 
held in the container. These comments point out that painting cryogenic 
containers with dark colors causes increased heat absorption, 
accelerating the rate of product venting, which could lead to unsafe 
conditions. These comments also note that large cryogenic containers 
made from carbon steel are painted in whole (including on the shoulder) 
in a light-reflective color, which would not necessarily correspond to 
the FDA-designated color or colors of the gas or gases held in the 
container.
    (Response 16) FDA agrees with these concerns and is revising the 
proposed coloring requirement for portable cryogenic medical gas 
containers. As set forth in Sec.  201.328(a)(1)(v) of the final rule, a 
portable cryogenic medical gas container may only be colored, in whole 
or in part, in the color or colors designated at Sec.  201.328(c) if 
the gas or gases held in the container correspond to that color or 
those colors. The container may still be colored in a light-reflective 
color such as white (or some other color that is not an FDA-designated 
gas color), or simply not colored at all.
    Finally, FDA is revising color requirements for the wraparound 
label such that they only apply to portable cryogenic medical gas 
containers that hold a single gas (see Sec.  201.328(a)(1)(i) of this 
final rule). FDA believes that multiple colors on a single wraparound 
label--either in the lettering or in the background--may be 
impractical. Firms may still choose to follow the color scheme at Sec.  
201.328(a)(1)(i) for portable cryogenic medical gas containers that 
hold gas mixtures or blends, but will not be required to do so.
 Proposed Prohibition on Conversion of Cryogenic Containers and 
High-Pressure Cylinders From Industrial to Medical Use (Proposed Sec.  
211.94(e)(1))
    In Sec.  211.94(e)(1) of the proposed rule, FDA proposed 
prohibiting cryogenic containers and high-pressure cylinders used to 
hold industrial gases from being converted to medical use, subject to 
limited exceptions.
    (Comment 17) Many comments oppose any requirements to dedicate 
high-pressure cylinders and cryogenic containers to solely one use--
industrial or medical. These comments contend that the root cause of 
the contamination incidents involving high-pressure cylinders discussed 
in the preamble to the proposed rule was the improper cleaning of 
cylinders, regardless of whether the cylinders previously held gases 
intended for medical or industrial use. These comments argue that the 
costs that would be associated with implementing this rule are not 
justified considering that the preamble to the proposed rule identified 
only two contamination incidents leading to injuries. According to 
these comments, these costs would include procuring additional 
containers (and associated assets), tracking individual containers over 
their useful life, marking containers for industrial or medical use, 
and increased distribution expenses. These comments further argue that 
FDA significantly underestimated the costs associated with this 
requirement in the economic analysis provided in the preamble to the 
proposed rule.
    Many comments state that the proposed prohibition on conversion of 
medical gas containers from industrial to medical use is unwarranted 
because existing CGMP requirements, particularly Sec.  211.94(c) 
(requiring cleaning of containers and closures to assure they are 
suitable for their intended use) and Sec.  211.100(a) (requiring 
written procedures for process and production control designed to 
assure drug products have the identity, strength, quality, and purity 
they purport or are represented to possess), are adequate to prevent 
contamination associated with such conversion. These comments further 
argue that the proposed rule is inconsistent with FDA's past advice 
that medical gas assets can be converted from industrial to medical use 
and need not be dedicated to industrial use provided the items in 
question undergo validated cleaning procedures when converted to 
medical use.
    (Response 17) FDA has reevaluated this proposed requirement in 
light of these concerns. FDA has determined that the risk of 
contamination associated with converting gas containers from industrial 
to medical use is relatively low, and can be fully addressed if the 
manufacturer, in compliance with Sec. Sec.  211.84(a), 211.94(c), 
211.100, and other applicable CGMP regulations, employs adequate, 
validated cleaning

[[Page 81692]]

and production control strategies when performing such conversion. FDA 
also agrees with the comments that the proposed requirement to dedicate 
containers to either industrial or medical use would be quite expensive 
to implement, and, in light of our assessment that existing regulations 
are adequate to address this concern, not cost-justified. Accordingly, 
we are removing this requirement from the final rule.
    (Comment 18) One comment states that the incidents dated March 20, 
1998, and March 27, 1996, attributed in the proposed rule to 
contamination likely associated with conversion of high-pressure 
cylinders from industrial to medical use, could have been ignition 
events involving polytetraethylene seals or sealing tape. The comment 
suggests that a more detailed description of these events should be 
provided in order to make clear that the odors and compounds detected 
were from improper cleaning and not from ignition events.
    (Response 18) As stated, FDA has reevaluated the necessity of the 
proposed non-conversion requirement and is removing it from the final 
rule.
 Requirement for Secure Gas-Specific Use Outlet Connections on 
Portable Cryogenic Medical Gas Containers (Sec.  211.94(e)(1))
    In Sec.  211.94(e)(3) of the proposed rule, FDA proposed to require 
that portable cryogenic medical gas containers not manufactured with 
permanent gas use outlet connections have gas-specific use outlet 
connections that cannot be readily removed or replaced except by the 
manufacturer. FDA is finalizing this provision (renumbered as Sec.  
211.94(e)(1)) with certain minor modifications explained in this 
document.
    (Comment 19) Many comments support this requirement, as it would 
have a positive impact on patient safety by making medical gas mix-ups 
less likely. In fact, these comments recommend that the rule be 
extended to other outlets typically found on portable cryogenic medical 
gas containers, namely, the vent outlet and liquid fill/withdrawal 
outlet.
    (Response 19) FDA is not aware of mix-up incidents involving the 
vent outlet valves or with liquid fill/withdrawal outlets, and such 
hypothetical mix-ups do not seem likely, given that the gas use outlet 
connection should be the only connection used to connect a portable 
cryogenic container to a health care facility's gas supply system. 
Accordingly, FDA believes that it is not necessary to extend the secure 
gas-specific use outlet connection requirement to vent outlets or 
liquid fill/withdrawal outlets.
    (Comment 20) Some comments propose that the Agency slightly modify 
the exemption for ``small cryogenic gas containers for use by 
individual patients'' from the proposed definition of ``portable 
cryogenic medical gas containers.'' These comments note that some 
liquid oxygen home units designed for use by individual patients are, 
in fact, also used in certain situations to fill other containers for 
use by patients. These comments are concerned that if the exemption is 
not clarified, these liquid oxygen home units may be subject to the 
secure gas use outlet connection rule if they are used to fill other 
containers. Accordingly, these comments propose that the exemption be 
revised to include ``small cryogenic gas containers designed for use by 
individual patients at their residence, including health care 
facilities'' (emphasis added).
    (Comment 21) Many comments propose that FDA clarify in the rule 
that the requirement for secure gas-specific use outlet connections is 
inapplicable to cryogenic containers that are too large (e.g., tank 
trucks, trailers, rail cars) to be connected to a medical gas supply 
system.
    (Response to Comments 20 and 21) FDA agrees that the definition of 
``portable cryogenic medical gas container'' as used in the rule should 
be clarified. As such, we are clarifying in the final rule that 
cryogenic gas containers not designed to be connected to a medical gas 
supply system, including tank trucks, trailers, rail cars, and liquid 
oxygen home units, are exempt from the secure gas-specific use outlet 
connection requirement.
    (Comment 22) A comment recommends that base units used to fill 
portable containers for use by patients in hospitals and other health 
care facilities, and large cryogenic containers that may be placed on 
trailers along with vaporizers and that are used as emergency backup 
when repairs are performed on the health care facility's permanent 
storage system, also be excluded from the rule. The comment states that 
because these base units and containers remain within the control of 
the medical gas manufacturer, and not the consumer, the risk of an 
improper connection is substantially reduced.
    (Response 22) FDA does not agree that base units used to fill 
portable containers for use by patients in hospitals and other health 
care facilities and large cryogenic containers that may be placed on 
trailers along with vaporizers and that are used as emergency backup 
when repairs are performed on the health care facility's permanent 
storage system should be excluded from the rule. We believe that 
requiring such containers (which are designed to be connected to a 
medical gas supply system) to have secure gas-specific use outlet 
connections will help minimize the likelihood that an incorrect gas is 
connected to a gas distribution system or container.
    (Comment 23) Many comments express concern with the discussion of 
records maintenance in the proposed rule. The PRIA indicated that there 
could be a slight increase in the medical gas industry's container 
closure records maintenance activities under Sec.  211.184 if the 
industry chooses to use locking valves or devices to bring portable 
cryogenic containers into compliance with the secure gas-specific use 
outlet connection requirement. The proposed rule stated that under 
existing Sec.  211.184(b), records of the results of any test or 
examination of a container closure under Sec.  211.82(a) must be 
maintained, and that under existing Sec.  211.184(c), an individual 
inventory record must be maintained for each container closure. FDA 
estimated that about 10 percent of the existing inventory of portable 
cryogenic containers would need to be modified to comply with the 
secure gas-specific use outlet connection requirement, that the 
industry would choose to comply through use of locking valves or 
devices (rather than silver brazing, which is more expensive), and that 
the records maintenance activities associated with this work would 
amount to about 2 minutes per locking device per year, resulting in an 
annualized records maintenance cost of about $54,000 dollars per year. 
The estimate of 2 minutes per locking device per year includes time 
associated with the initial inspection of the locking valve or device 
by the manufacturer (71 FR 18039 at 18048-18049).
    The comments express concern that the proposed rule's reference to 
Sec.  211.184(c) in particular entails a change of policy from FDA's 
historic application of records maintenance regulations to the medical 
gas industry and amounts to a new records maintenance expectation for 
medical gas containers and closures that would cost the industry 
between $376 and $665 million dollars to meet. The comments appear to 
reach this much higher number by assuming that it would be necessary to 
serialize valves and/or permanently mark all valves and connections on 
portable cryogenic containers to meet what they contend

[[Page 81693]]

are FDA's new records maintenance expectations.
    (Response 23) FDA does not believe that serializing or permanently 
marking all valves and connections on portable cryogenic containers is 
necessary to satisfy the requirements of Sec.  211.184. FDA did not 
intend to announce new or heightened records maintenance expectations 
for medical gas container closures in the proposed rule. While FDA 
believes that the records maintenance activities used to arrive at the 
estimate in the PRIA section for the records maintenance costs 
associated with the secure gas-specific use outlet connection 
requirement are appropriate, medical gas manufacturers may employ 
alternative records maintenance procedures to document any work 
performed to bring container closures into compliance with the secure 
gas-specific use outlet connection requirement.
    As discussed in the Final Regulatory Impact Analysis (see Section 
VI), the estimated records maintenance costs associated with the secure 
gas use outlet connections requirements have been revised to range 
between $70 and $3,500. This reduction in estimated costs is largely 
driven by updated information showing that the number of portable 
cryogenic containers in the market is much lower than was thought at 
the time the proposed rule was issued.
 Miscellaneous Comment
    (Comment 24) A comment requests that the final rule include a 
requirement that all personnel handling medical gases have documented 
competency training. This comment states that medical gases are USP 
listed and should be delivered by qualified personnel, such as 
respiratory therapists (who, according to this comment, are the only 
health care professionals specifically educated and competency-tested 
in all aspects of oxygen therapy).
    (Response 24) In Sec.  211.25 individuals engaged in the 
manufacture, processing, packing, or holding of a drug product (which 
would include a medical gas manufacturer's delivery personnel) are 
required to have the education, training, and experience necessary to 
perform assigned functions. Further, we are not aware that actual 
administration of medical gases to patients is part of the function of 
medical gas delivery personnel, so it is not clear why such personnel 
would need to be trained to administer gases to patients. We believe 
the existing regulation (Sec.  211.25) is sufficient to address any 
issues that may arise regarding the qualifications of a medical gas 
manufacturer's delivery personnel.

V. Compliance Date

    This rule is effective January 17, 2017. Affected firms and persons 
are encouraged to comply as soon as possible after the effective date. 
We recognize, however, that while most of the requirements of this 
final rule are already industry practices (Refs. 1-3), such practices 
are not ubiquitous. Accordingly, the compliance date is May 17, 2017. 
We believe it would be reasonable for affected firms and persons to 
fully implement this final rule in that amount of time.
    (Comment 25) FDA received several comments that the 60-day time 
period proposed for implementation of the proposed rule is 
insufficient. These comments state that the proposal will impact every 
portable cryogenic container and request that FDA provide a reasonable 
transition period consistent with FDA precedents.
    (Response 25) FDA agrees, and is establishing a compliance date 
that is 180 days after publication of the final rule in the Federal 
Register, as noted previously. The Agency believes that it would be 
reasonable for affected firms and persons to fully implement the final 
rule in this amount of time. Furthermore, to avoid any contradiction 
with this compliance date, and for purposes of clarity, FDA is removing 
paragraph (c) of Sec.  201.161, which states that regulatory action may 
be initiated with respect to any article shipped within the 
jurisdiction of the FD&C Act contrary to the provisions of this section 
after 60 days following publication of this section in the Federal 
Register.

VI. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). We 
believe that this final rule is not a significant regulatory action as 
defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because the final rule imposes new burdens on small entities, 
we cannot certify that the final rule will not have a significant 
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before issuing ``any rule that includes 
any Federal mandate that may result in the expenditure by State, local, 
and tribal governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any 1 year.'' 
The current threshold after adjustment for inflation is $146 million, 
using the most current (2015) Implicit Price Deflator for the Gross 
Domestic Product. FDA does not expect this final rule to result in an 
expenditure in any year that meets or exceeds this amount.

B. Summary of Costs and Benefits

    This final rule amends the CGMP and labeling regulations for 
medical gases. These amendments include the following: (1) Portable 
cryogenic medical gas containers not manufactured with permanent gas 
use outlet connections must have gas-specific use outlet connections 
that cannot be readily removed or replaced except by the manufacturer; 
(2) portable cryogenic medical gas containers must have a 360[deg] 
wraparound label that clearly identifies the container's contents and 
conforms to certain placement, lettering, and other requirements; (3) 
high-pressure medical gas cylinders (and portable cryogenic medical gas 
containers, if colored) must be colored using an FDA-designated 
standard color (or colors in the case of gas mixtures); (4) the list of 
medical gases that are conditionally exempt from certain otherwise-
applicable labeling requirements has been revised; and (5) the warning 
statements required to be on final use containers to qualify for the 
conditional exemption from certain otherwise-applicable labeling 
requirements have been modified for oxygen and medical air.
    The rule is expected to provide a modest net social benefit 
(estimated benefits minus estimated costs) to society. Costs are 
attributed to coloring medical gas containers, complying with the 
360[deg] wraparound label requirement for portable cryogenic 
containers, and requiring gas-specific use outlet connections on 
portable cryogenic containers to be permanently attached to the valve 
body (e.g., by silver brazing) or attached to the valve body using a 
locking mechanism or other appropriate

[[Page 81694]]

device so that only the manufacturer can readily remove or replace 
them. Using a standard 10 year time period, we estimate annualized 
costs to range between $0.18 million to $1.5 million using a 3 percent 
discount rate and $0.21 million to $1.8 million using a 7 percent 
discount rate. Benefits are attributed to reducing the probability that 
medical personnel accidentally administer the wrong gas to patients, 
resulting in serious injury or death. We estimate annualized benefits 
to approximately range between $0.8 million to $2.8 million using a 3 
percent discount rate, and $2.5 million to $8.3 million using a 7 
percent discount rate. Together we estimate annualized net benefits to 
range between $0.62 million to $1.3 million using a 3 percent discount 
rate, and $2.3 million to $6.5 million using a 7 percent discount rate.
    FDA also examined the economic implications of the rule as required 
by the Regulatory Flexibility Act. If a rule will have a significant 
economic impact on a substantial number of small entities, the 
Regulatory Flexibility Act requires us to analyze regulatory options 
that would lessen the economic effect of the rule on small entities. 
The rule imposes new costs to small entities. We estimate the rule's 
one-time costs to roughly range between 0.0001 percent and 0.13 percent 
of average annual revenues.
    The full analysis of economic impacts is available in the docket 
for this final rule (Ref. 4) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

VII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(j) and (k) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VIII. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by the OMB under the Paperwork Reduction Act of 
1995 (the PRA) (44 U.S.C. 3501-3520). The title, description, and 
respondent description of the information collection provisions are 
shown in this section with an estimate of the third-party disclosure 
and recordkeeping burdens. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Medical Gas Containers and Closures; Current Good 
Manufacturing Practice Requirements.
    Description: The final rule revises FDA's labeling and CGMP 
regulations to include new requirements for the label, color, and 
design of medical gas containers and closures. These requirements are 
intended to make the contents of medical gas containers more readily 
identifiable and to reduce the likelihood that the wrong gas will be 
connected to a medical gas supply system.
    Description of Respondents: Persons and businesses, including small 
businesses and manufacturers, involved in the processing, 
manufacturing, transportation, handling, and administration of 
designated medical gases. FDA's database of establishments that 
manufacture medical gases includes about 2,500 such establishments.
    We estimate the burden for the collection of information as 
follows:
    Third-party disclosure: Table 1 shows the estimated one-time third-
party disclosure burden. Upon implementation of the requirements under 
the final rule, we expect respondents will have realized the associated 
burden. In our subsequent PRA evaluation conducted in connection with 
requesting a renewal of OMB's approval of the information collection 
associated with this rule (assuming that initial approval occurs), we 
will adjust our estimate accordingly.

                                              Table 1--Estimated One-Time Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                   Number of
                 21 CFR sections                    Number of   disclosures per      Total             Average burden per disclosure         Total hours
                                                   respondents     respondent     disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
201.328(a)(1) and (2) and 211.94(e)(2) Portable          2,500               14        35,000  0.10 (6 minutes)............................        3,500
 Cryogenic Medical Gas Container Labels and
 Colors.
201.328(b) and 211.94(e)(2) High-Pressure                2,500              984     2,460,000  0.10 (6 minutes)............................      246,000
 Medical Gas Cylinder Colors.
                                                 -------------------------------------------------------------------------------------------------------
    Total.......................................         2,500              998     2,495,000  0.10 (6 minutes)............................      249,500
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    A gas listed at Sec.  201.161(a) is exempt from certain labeling 
requirements if its labeling bears, among other things, a warning 
statement that conforms to Sec.  201.161(a)(1). Section 
201.161(a)(1)(i) specifies the content to be included in a warning 
statement for oxygen and Sec.  201.161(a)(1)(ii) specifies the content 
to be included in a warning statement for nitrogen, carbon dioxide, 
helium, nitrous oxide, and any medically appropriate combinations of 
any of the gases listed in Sec.  201.161(a). FDA believes most medical 
gases are already labeled in a manner that complies with Sec.  
201.161(a) as finalized. Furthermore, because Sec.  201.161(a) provides 
the warning statement content to be included in medical gas labeling, 
the inclusion of these warning statements on medical gas labeling is 
not considered a ``collection of information'' subject to review under 
the PRA. See 5 CFR 1320.3(c)(2) (providing that ``the public disclosure 
of information originally supplied by the Federal government to the 
recipient for the purpose of disclosure to the public is not included'' 
within the definition of ``collection of information'').
    Under Sec.  201.328(a)(1), each portable cryogenic medical gas 
container must be conspicuously marked with a 360[deg] wraparound label 
identifying its contents. The identity of the medical gas held in the 
container must be printed on the label in one of the following ways: 
Using lettering that appears in the standard color designated for the 
gas in Sec.  201.328(c) and that is printed against a white background, 
or using lettering that appears in white against a background that is 
painted in the standard color for the gas as designated in Sec.  
201.328(c). The lettering for the name of the gas on the label must be 
at least 2 inches high; the name of the gas must be printed 
continuously around the label and be capable of being read around the 
entire container; the label must be on the sidewall of the container, 
as close to the top of the container as possible but below the top weld 
seam; and, if the shoulder portion

[[Page 81695]]

of a portable cryogenic gas container is colored, the color used must 
be the standard color or colors designated in Sec.  201.328(c) for the 
gas or gases held within the container.
    Under Sec.  201.328(a)(2), the 360[deg] wraparound label required 
in Sec.  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 the gas is for medical use. 
Finally, under Sec.  211.94(e)(2), the wraparound label 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, and the wraparound label must 
be reasonably resistant to fading, durable when exposed to atmospheric 
conditions, and not readily soluble in water.
    We estimate that there are approximately 35,000 portable cryogenic 
containers in medical gas service that are subject to the labeling 
requirements at Sec.  201.328(a). As discussed in the Economic Analysis 
of Impacts, FDA conservatively estimates that all manufacturers will 
choose to comply with Sec.  201.328(a) by removing any existing 
wraparound labels from all portable cryogenic containers and replacing 
them with wraparound labels that meet all of the requirements at Sec.  
201.328(a). Thus, on average, each manufacturer would need to add 
labels to (or re-label) approximately 14 containers (35,000 / 2,500). 
FDA estimates that approximately 6 minutes would be required to remove 
any existing wraparound label and attach a new wraparound label to each 
container. Thus, the total burden third-party disclosure burden hours 
associated with Sec.  201.328(a)(1) and (2) is approximately 3,500 
hours (2,500 x 14 x 0.10 hours).
    Section 201.328(a)(1)(v) also provides that a portable cryogenic 
cylinder may only be colored in the color or colors designated in Sec.  
201.328(c) if the gas or gases held within the container correspond to 
that color or those colors. Alternatively, the container may be colored 
in a light-reflective color such as white (or some other color which is 
not an FDA-designated gas color), or simply not colored at all. Based 
on discussions with subject matter experts, we believe that few to no 
cryogenic containers will require recoloring as a result of this 
requirement, and therefore we estimate no third-party disclosure burden 
associated with this requirement.
    Under Sec.  201.328(b), high-pressure medical gas cylinders must be 
colored on the shoulder with the colors designated in Sec.  201.328(c) 
for the gas contained in the cylinder, and such colors must be visible 
when viewed from the top of the cylinder. Under Sec.  211.94(e)(2), the 
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. Based on information contained in the 
Economic Analysis of Impacts (see Section VI), we estimate that as many 
as 10 percent of the estimated 24.6 million high-pressure cylinders in 
medical service will require coloring or recoloring to comply with 
Sec.  201.328(b). Thus, on average, each manufacturer would need to 
color 984 containers (2.46 million / 2,500). We conservatively estimate 
that it will take an average of 6 minutes to color a cylinder. Thus, 
the total third-party disclosure burden hours associated with Sec.  
201.328(b) is approximately 246,000 hours (2,500 x 984 x 0.10 hours).
    Recordkeeping: Table 2 shows the estimated annual recordkeeping 
burden associated with the information collection.

                               Table 2--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                  Number of
       21 CFR Section            Number of       records per      Total annual    Average burden per     Total
                               recordkeepers     recordkeeper       records         recordkeeping        hours
----------------------------------------------------------------------------------------------------------------
211.184 and 211.94(e)(1)               2,500              0.7            1,750    0.033 (2 minutes)          58
 Records Maintenance of
 Secure Gas Use Outlet
 Connection Requirement.....
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    Section 211.94(e)(1) requires that portable cryogenic medical gas 
containers that are not manufactured with permanent gas use outlet 
connections must have gas-specific use outlet connections that are 
attached to the valve body so that they cannot be readily removed or 
replaced except by the manufacturer. A small portion of the existing 
inventory of portable cryogenic containers would need to be modified to 
comply with this requirement, and manufacturers must maintain records 
in accordance with Sec.  211.184 for drug product containers. As 
discussed in the Economic Analysis of Impacts (see Section VI), FDA 
conservatively estimates that manufacturers will need to secure the gas 
use outlets of as many as 1,750 portable cryogenic containers to bring 
them into compliance with the final rule. As a result each manufacturer 
would incur annual recordkeeping under Sec.  211.184 incident to 
bringing, on average, 0.7 containers into compliance with the secure 
gas use outlet connection requirement (1,750 / 2,500). Consistent with 
our estimate in the proposed rule, this should require an average of 2 
minutes (0.033 hours) per container. This results in an annual burden 
of 58 hours (2,500 x 0.7 x 0.033 hours) for 1,750 records.
    The information collection provisions of this final rule have been 
submitted to OMB for review, as required by section 3507(d) of the PRA. 
Before the effective date of this final rule, FDA will publish a notice 
in the Federal Register announcing OMB's decision to approve, modify, 
or disapprove the information collection provisions in this final rule. 
An Agency may not conduct or sponsor, and a person is not required to 
respond to, a collection of information unless it displays a currently 
valid OMB control number.

IX. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we conclude that the rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

[[Page 81696]]

X. References

    The following reference is on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, and is available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; it 
is also available electronically at https://www.regulations.gov. FDA has 
verified the Web site address, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. CGA M-15, Standard for Appropriate and Effective Regulations for 
Medical Gases within 21 CFR parts 201, 2015, and 210/211 (Compressed 
Gas Association 2014, 1st ed), at pages 1, 14-15, 35.
2. CGA C-9, Standard Color Marking of Compressed Gas Containers for 
Medical Use (Compressed Gas Association 2013, 5th ed).
3. CGA Safety Bulletin SB-26, Cylinder Connections on Portable 
Liquid Cryogenic Cylinders (Compressed Gas Association 2014, 4th 
ed).
4. Medical Gas Containers and Closures; Current Good Manufacturing 
Practice Requirements, Final Regulatory Impact Analysis, Final 
Regulatory Flexibility Analysis, and Unfunded Mandates Reform Act 
Analysis, Docket No. FDA-2005-N-0343, available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 211

    Drugs, Labeling, Laboratories, Packaging and containers, 
Prescription drugs, Reporting and recordkeeping requirements, 
Warehouses.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
201 and 211 are amended as follows:

PART 201--LABELING

0
1. The authority citation for part 201 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.


0
2. Revise Sec.  201.161 to read as follows:


Sec.  201.161  Medical gases.

    (a) Oxygen, nitrogen, carbon dioxide, helium, and nitrous oxide 
gases intended for drug use, and medically appropriate combinations of 
any of these gases intended for drug use, are exempted from the 
requirements of Sec.  201.100(b)(2) and (3), and (c)(1), provided that, 
where applicable, the requirements of Sec. Sec.  201.328 and 
211.94(e)(2) of this chapter are met and the labeling bears, in 
addition to any other information required by the Federal Food, Drug, 
and Cosmetic Act, the following:
    (1)(i) In the case of oxygen, a warning statement providing that 
uninterrupted use of high concentrations of oxygen over a long 
duration, without monitoring its effect on oxygen content of arterial 
blood, may be harmful; that oxygen should not be used on patients who 
have stopped breathing unless used in conjunction with resuscitative 
equipment; and, in the case of oxygen that may be provided without a 
prescription for use in the event of depressurization or other 
environmental oxygen deficiency, or for oxygen deficiency or for use in 
emergency resuscitation when administered by properly trained 
personnel, a warning statement providing that oxygen may be used for 
emergency use only when administered by properly trained personnel for 
oxygen deficiency and resuscitation, and that for all other medical 
applications a prescription is required.
    (ii) In the case of nitrogen, carbon dioxide, helium, nitrous 
oxide, and medically appropriate combinations of any of the gases 
listed in paragraph (a) of this section, a warning statement providing 
that the administration of the gas or gas combination (as applicable) 
may be hazardous or contraindicated; and that the gas or gas 
combination (as applicable) should be used only by or under the 
supervision of a licensed practitioner who is experienced in the use 
and administration of the gas or gas combination (as applicable) and is 
familiar with the indications, effects, dosages, methods, and frequency 
and duration of administration, and with the hazards, 
contraindications, and side effects and the precautions to be taken.
    (2) Any needed directions concerning the conditions for storage and 
warnings against the inherent dangers in the handling of the specific 
compressed gas.
    (b) [Reserved]

0
3. Add new Sec.  201.328 to read as follows:


Sec.  201.328  Labeling of medical gas containers.

    (a) Portable cryogenic medical gas containers. For the purposes of 
this section a ``portable cryogenic medical gas container'' is one that 
is capable of being transported and is intended to be attached to a 
medical gas supply system within a hospital, health care entity, 
nursing home, other facility, or home health care setting, or is a base 
unit used to fill small cryogenic gas containers for use by individual 
patients. The term does not include cryogenic containers that are not 
designed to be connected to a medical gas supply system, e.g., tank 
trucks, trailers, rail cars, or small cryogenic gas containers for use 
by individual patients (including portable liquid oxygen units as 
defined at Sec.  868.5655 of this chapter).
    (1) Each portable cryogenic medical gas container must be 
conspicuously marked with a 360[deg] wraparound label identifying its 
contents. Such label must meet the requirements of Sec.  211.94(e)(2) 
of this chapter and the following additional requirements.
    (i) If the container holds a single gas, the name of the gas held 
in the container must be printed on the label in one of the following 
ways:
    (A) Using lettering that appears in the color designated for the 
gas in paragraph (c) of this section and that is printed against a 
white background, or
    (B) Using lettering that appears in white against a background that 
is painted in the color for the gas designated in paragraph (c) of this 
section.
    (ii) The lettering for the name of the gas on the label must be at 
least 2 inches high.
    (iii) The name of the gas must be printed continuously around the 
label and be capable of being read around the entire container.
    (iv) The label must be on the sidewall of the container, as close 
to the top of the container as possible but below the top weld seam.
    (v) A portable cryogenic medical gas container may only be colored 
in the color or colors designated in paragraph (c) of this section if 
the gas or gases held within the container correspond to that color or 
those colors.
    (2) A label on the container (either the 360[deg] wraparound label 
required in paragraph (a)(1) of this section or a separate label) must 
include, in conspicuous lettering, the phrase ``For Medical Use'', 
``Medical Gas,'' or some similar phrase that indicates the gas is for 
medical use.
    (b) High-pressure medical gas cylinders. Each high-pressure medical 
gas cylinder must be colored on the shoulder portion of the cylinder in 
the color or colors designated in paragraph (c) of this section. The 
color or colors must be visible when viewed from the top of cylinder.
    (c) Medical gas colors. The colors required to identify medical 
gases under paragraph (a) and (b) of this section are:

[[Page 81697]]



------------------------------------------------------------------------
                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.
------------------------------------------------------------------------

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED 
PHARMACEUTICALS

0
4. The authority citation for part 211 continues to read as follows:


    Authority:  21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 
U.S.C. 216, 262, 263a, 264.


0
5. Amend Sec.  211.94 by adding new paragraph (e) to read as follows:


Sec.  211.94   Drug product containers and closures.

* * * * *
    (e) Medical gas containers and closures must meet the following 
requirements--(1) Gas-specific use outlet connections. Portable 
cryogenic medical gas containers that are not manufactured with 
permanent gas use outlet connections (e.g., those that have been 
silver-brazed) must have gas-specific use outlet connections that are 
attached to the valve body so that they cannot be readily removed or 
replaced (without making the valve inoperable and preventing the 
containers' use) except by the manufacturer. For the purposes of this 
paragraph, the term ``manufacturer'' includes any individual or firm 
that fills high-pressure medical gas cylinders or cryogenic medical gas 
containers. For the purposes of this section, a ``portable cryogenic 
medical gas container'' is one that is capable of being transported and 
is intended to be attached to a medical gas supply system within a 
hospital, health care entity, nursing home, other facility, or home 
health care setting, or is a base unit used to fill small cryogenic gas 
containers for use by individual patients. The term does not include 
cryogenic containers that are not designed to be connected to a medical 
gas supply system, e.g., tank trucks, trailers, rail cars, or small 
cryogenic gas containers for use by individual patients (including 
portable liquid oxygen units as defined at Sec.  868.5655 of this 
chapter).
    (2) Label and coloring requirements. The labeling specified at 
Sec.  201.328(a) of this chapter must be affixed to the container in a 
manner that does not interfere with other labeling and such that it is 
not susceptible to becoming worn or inadvertently detached during 
normal use. Each such label as well as materials used for coloring 
medical gas containers must be reasonably resistant to fading, durable 
when exposed to atmospheric conditions, and not readily soluble in 
water.

0
6. Amend Sec.  211.125 by adding a sentence to the end of paragraph (c) 
to read as follows:


Sec.  211.125   Labeling issuance.

* * * * *
    (c) * * * Labeling reconciliation is also waived for 360[deg] 
wraparound labels on portable cryogenic medical gas containers.
* * * * *

    Dated: November 15, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-27838 Filed 11-17-16; 8:45 am]
 BILLING CODE 4164-01-P