[Federal Register Volume 81, Number 223 (Friday, November 18, 2016)]
[Rules and Regulations]
[Pages 81685-81697]
[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

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.

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

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).

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

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

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

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

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

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 http://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

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.

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 http://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 http://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:

------------------------------------------------------------------------
                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