requirements in Sec.  213.180 differ from the requirements in Sec.
211.180. Paragraph (a) would provide that all records that would be
required under part 213, or copies of such records, be readily
available for authorized inspection during the retention period and are
subject to copying as part of such an inspection. The records would be
able to be kept at either the establishment where the activities
described in such records occurred or at another location from which
the records can be immediately retrieved. Retrieval via computer or
other electronic means would meet this requirement. Per paragraph (b),
all records would have to be legible, stored to prevent deterioration
or loss, and either original or accurate reproductions of original
records. Paragraph (c) would require that all records that would be
required to be maintained in compliance with part 213 be maintained

for at least 3 years from the date the batch of medical gas is
distributed, except where otherwise provided. This timeframe is the
same as that used in Sec.  211.180(a) for over-the-counter drugs
lacking expiration dating.
    Paragraph (d) would require that written records required under
part 213 be maintained so that their data can be used for evaluating,
at least annually, the quality standards of each medical gas to
determine the need for changes in specifications or manufacturing or
control procedures. Written procedures would also have to be
established and followed for such evaluations. The procedures would
also be required to include provisions for a review of a representative
number of batches, whether approved or rejected, and, where applicable,
records associated with the batch, and a review of complaints, recalls,
returned or salvaged medical gases, and investigations conducted under
Sec.  213.192 for each gas. Under paragraph (e), firms would be
required to develop written procedures for notifying responsible firm
officials of any recalls, reports of inspectional observations by FDA,
regulatory actions related to good manufacturing practice taken by FDA,
or any investigations resulting from adverse event complaints.
    Proposed Sec.  213.182 would require that there be a written record
of major equipment cleaning, maintenance (except routine maintenance
such as lubrication and adjustments), and use. These records would be
required, as part of individual equipment logs, to show the date, time,
product, and lot number of each batch processed. Individual equipment
logs would not be required for equipment dedicated to one product, but
lots or batches would have to follow in numerical order and be
manufactured in numerical sequence in such a case. Also, where
dedicated equipment is employed, the records of cleaning, maintenance,
and use would be required to be part of the batch record. The
individuals performing and double-checking the cleaning and maintenance
(or, if the cleaning and maintenance is performed using automated
equipment under Sec.  213.68, just the person verifying such cleaning
and maintenance) would have to date and sign or initial the log
indicating the work was performed. Entries in the log would be required
to be in chronological order. While FDA recognizes that cleaning of a
closed, pressurized system is not always appropriate, when it is
applicable, it is essential to maintain adequate records of such
cleaning.
    FDA proposes in Sec.  213.184 a more limited set of recordkeeping
requirements for components, medical gas containers and closures, and
labeling than those described in Sec.  211.184. The records would
include the results of any test or examination performed (including
those performed pursuant to Sec. Sec.  213.84 and 213.122) and the
conclusions derived from the test or examination; documentation of the
examination and review of labels and labeling for conformity with
established specifications in accordance with Sec. Sec.  213.122 and
213.130; and the disposition of rejected components, containers,
closures, and labeling. Medical gas containers are generally reused
many times before they are taken out of service. FDA believes that the
proposed requirements in Sec. Sec.  213.84, 213.122, and 213.130 to
evaluate containers and labeling are appropriate and sufficient to
assure the quality of containers and the accuracy and legibility of
their labels.
    In Sec.  213.186, FDA proposes master production and control
recordkeeping requirements that are more tailored to medical gases than
the current requirements in Sec.  211.186. Paragraph (a) would require
that master production and control records for each medical gas be
prepared, dated, and signed to assure uniformity from batch to batch.
Paragraph (a) would also require that the preparation of such records
be described in a written procedure, and that such written procedure be
followed. Paragraph (b) proposes to require certain information for
each master production and control record. The records would be
required to include: The product name and strength; a list of all
components and any incoming designated medical gases used in
manufacturing designated by names or codes sufficiently specific to
indicate any special quality characteristics; a description of the
containers, closures, and packaging materials and labels; and complete
manufacturing and control instructions, sampling and testing
procedures, specifications, special notations, and precautions to be
followed.
    These proposed requirements differ from the requirements in Sec.
211.186 because of the differences in manufacturing and distribution of
medical gases. For example, because medical gas manufacturing generally
includes some venting of gas, measuring calculated excess of component,
theoretical weight, and theoretical yield is infeasible.
    In lieu of the requirements found in Sec.  211.188, FDA proposes
Sec.  213.189, which would impose batch production and control
recordkeeping requirements for each batch of medical gas produced.
Paragraph (a) would require batch production and control records to be
prepared for each batch of medical gas produced. Paragraph (b) would
require that batch production and control records include documentation
that each significant step in the manufacturing, processing, packing,
and holding process was accomplished, including:
     Dates and times of each significant step, including in-
process and laboratory tests as applicable. This documentation would
include any prefill, filling, or post-filling inspections, which are
essential to assuring product meets applicable standards.
     A description of the container for the medical gas,
including the number and size of the containers filled as applicable.
The containers used in manufacturing and filling operations can vary
significantly, so documenting the containers is important for tracking
purposes.
     Specific identification of each component and its source
or in-process material used as applicable.
     Measures of components used in the course of processing as
applicable.
     Testing results, including any in-process test results and
finished product test results.
     Dated signature or initials of the persons performing and
directly supervising or checking each significant event in the
operation.
     Inspection of the packaging and labeling area before and
after use.
     Complete labeling control records, including specimens or
copies of all labeling used and label application and reconciliation
records as appropriate. Because labeling does not always need to be
applied due to the reuse of labels, documentation of these labeling
control activities is important to help prevent mix-ups and the
incorrect application of labeling.
     Any investigation made according to Sec.  213.192.
    Proposed Sec.  213.192 would contain production record review
requirements for medical gases. Under paragraph (a), manufacturing
production and control records, including those for packaging and
labeling, would need to be reviewed and approved by the quality unit to
determine compliance with all established, approved written procedures
before release or distribution of a batch. The quality unit would also
be required to review production records to determine whether errors or
unexplained discrepancies have occurred prior to batch release. If any

errors or unexplained discrepancies have occurred, or a batch or any
component of the batch fails to meet specifications, the firm would be
required to conduct thorough investigations and take appropriate
corrective actions. FDA further proposes to require a written record of
the investigation, including the conclusions and followup. However, for
entities that fill at a delivery site, paragraph (b) would require that
production and control records be reviewed and approved by the quality
unit to determine compliance with all established, approved written
procedures within 1 business day after fill. FDA believes this
additional time is needed for reviewing such records associated with
filling at a delivery site because delivery personnel typically conduct
such filling at multiple locations. As such, it is impractical for the
quality unit to be present at the time of filling, and the
characteristics of the gas are not expected to change during the
filling process. Therefore, the Agency believes it is appropriate for
the quality unit to review production and control records shortly after
delivery is completed.
    FDA recognizes that, because containers and labels are reused many
times for medical gases, firms are generally unable to trace the
history of a cylinder's use or identify the root cause of a cylinder-
related problem. Nevertheless, if an error or unexplained discrepancy
associated with a cylinder is identified, or if a cylinder is found not
to meet any of its specifications, FDA believes it is necessary for the
firm to conduct a thorough investigation to identify the problem and
take appropriate corrective action, such as taking a faulty cylinder
out of circulation. FDA believes this proposal would establish
production record review requirements that would assure that medical
gases meet the requirements of the FD&C Act as to safety and have the
identity, strength, quality, and purity they are purported or
represented to possess.
    FDA is also proposing Sec.  213.194, which would impose laboratory
recordkeeping requirements. Paragraph (a) would require that laboratory
records related to the manufacture of a medical gas include complete
data derived from all tests necessary to ensure compliance with
established specifications and standards, including examinations and
assays. Laboratories would have to keep a complete record of all data
created in the course of each test, including the records described in
paragraphs (a)(1) through (4), as follows:
     A description of the sample, the batch or lot number to be
tested, the date the sample was taken, and the date the sample was
tested.
     The test method used, the test result, how the results
compare with established standards of identity, strength, quality, and
purity for the component, container, in-process materials (as
applicable), and medical gas tested, a record of any calculations
performed and any calculated results, and the unit of measurement of
the result. It would not be necessary to provide the actual calculation
where the result is evident through use of simple addition and
subtraction (for example 100 - 0.1 = 99.9).
     Where applicable, any graphs, charts, and spectra from
laboratory instrumentation, properly identified to show the specific
component, in-process material, or medical gas for each lot tested.
     The initials or signature of the person performing the
test as well as a second person showing that the original records have
been reviewed for accuracy, completeness, and compliance with
established standards.
    Paragraph (b) would require that complete records be maintained of
any modification of an established test method. These records would
need to include the reason for the modification and data to verify that
the modification produced results that are at least as accurate and
reliable for the material being tested as the established method.
Paragraph (c) would require that complete records be maintained of any
testing and standardization of laboratory reference standards,
reagents, and standard solutions. These requirements are the same as
those that currently apply to medical gases under Sec.  211.194(b) and
(c).
    Paragraph (d) would require that complete records be maintained of
the periodic calibration or verification of calibration of laboratory
instruments, apparatus, gauges, and recording devices that would be
required by Sec.  213.160(b)(4). This paragraph differs from Sec.
211.194(d) in that it would allow for verification of calibration. It
is FDA's understanding that it is common for some medical gas equipment
to be calibrated by a supplier or other entity prior to arrival at the
laboratory.
    Paragraph (e) would require that complete records be maintained of
all stability testing performed in accordance with proposed Sec.
213.166. This requirement is consistent with the current requirement in
Sec.  211.194(e). As described above, only a subset of medical gases
are expected to be subject to stability testing requirements, but for
such gases, documentation of stability testing is essential to ensuring
that the gas will maintain its stability for the expected timeframe.
    Under proposed Sec.  213.196, distribution records would be
required to contain the name of the product, the lot or batch number,
the consignee's contact information, and the date and quantity shipped.
FDA believes that including the lot or batch number is essential to
properly tracking and tracing product in the event a safety issue is
discovered. Information about the dosage form, as required in Sec.
211.196, is not necessary for medical gases because the dosage form is
always ``gas.'' For medical air and medically appropriate combinations
of designated medical gases, the distribution record would also need to
include the percentage of each gas. FDA believes that this information
is essential to prevent mix-ups because the concentration of each
component would be clearly determined.
    Proposed Sec.  213.198 contains proposed requirements for complaint
files that are similar to those requirements that currently apply to
medical gases under Sec.  211.198. Paragraph (a) would require that
written procedures be established and followed for the receipt and
handling of all written and oral complaints concerning a medical gas.
These procedures would have to include a quality unit review of any
complaint involving the possible failure of a medical gas to meet its
specification as well as an investigation to determine the cause of the
failure. An out-of-specification medical gas (for example, a
combination containing higher quantities of oxygen than intended) could
result in serious patient harm if administered. These procedures would
also be required to include provisions for determining the need for an
investigation under Sec.  213.192 and determining whether the complaint
represents an event that would need to be reported under proposed part
230.
    Paragraph (b) would require that a written record of each complaint
be maintained. This record would have to include the name of the
medical gas, the lot or batch number, the name of the complainant, the
date the complaint was received, the nature of the complaint, and the
response to the complaint. It would also be required to include the
findings of any investigation and followup. If an investigation is not
conducted, the record would need to include the reason that an
investigation was found not to be necessary and the name of the
responsible person making such a determination.

    Paragraph (c) would require the maintenance of complaint files in a
manner such that they would be readily available for inspection by the
firm or by FDA during an inspection. Complaint files would be required
to be maintained for at least 1 year after the date that the complaint
was received or for at least 3 years after distribution of the medical
gas, whichever is longer. This proposed record retention period is the
same as that used in Sec.  211.180(a) for certain over-the-counter
drugs lacking expiration dating and would facilitate review and
evaluation by the firm of information that is received after the event,
thus facilitating the firm's ability to observe trends over time.
12. Returned and Salvaged Medical Gases
    Subpart K contains proposed requirements for returned and salvaged
medical gases. FDA proposes in Sec.  213.204 to require that returned
medical gases be identified as such and held. Moreover, if the
conditions under which the returned gases have been held, stored, or
shipped before or during their return, or if the condition of the gas,
its container, carton, or labeling, as a result of storage or shipping,
cast doubt on its safety, identity, strength, quality, or purity, the
returned medical gas would need to be destroyed unless examination,
testing, or other investigations prove the gas meets appropriate
standards of safety, identity, strength, quality, or purity. These
requirements would apply to situations in which a distributed medical
gas is sent back to a firm due to a quality issue. Firms would need to
maintain certain records of returned medical gases. Further, if the
reason for a medical gas being returned implicates associated batches,
an appropriate investigation pursuant to proposed Sec.  213.192 would
need to be conducted. Procedures for holding, testing, and use of
returned medical gases would need to be in writing and followed.
Proposed Sec.  213.204 would not apply to the routine refilling of a
cryogenic medical gas containers in the normal course of business
unless the container was returned for a quality issue.
    Proposed section 213.204 is largely the same as current Sec.
211.204, with an added provision regarding routine refilling. FDA
believes that the current requirements for returned drug product are
appropriate for medical gases. However, the proposed routine refilling
provision would be essential to address the fact that small amounts of
gas are expected to remain in a returned container that will be reused.
This situation is uncommon for other types of drug products, but
medical gas containers are generally reusable, and complete purging of
a container is impracticable. Another notable difference compared to
Sec.  211.204 is the omission of reprocessing requirements, as it is
FDA's understanding that reprocessing of returned medical gases does
not occur. Generally, gases are reused if they meet specifications;
otherwise, they are vented. FDA requests comment on this issue.
    Section 213.208 would allow the salvaging of medical gases that
have been subjected to improper storage conditions unless the gas's
container has been subjected to adverse conditions that impact the
identity, strength, quality, and purity of the medical gas, or the
integrity of the container closure. These requirements would apply to
situations in which a medical gas has been subject to improper storage
conditions under the control of a firm responsible for the manufacture,
processing, packing, or holding of the gas. Scenarios in which this may
arise include natural disasters, facility structural damage (such as a
building collapse), or exposure to smoke in the event of a fire. If
there is a question whether the medical gas has been subjected to
improper storage conditions, salvaging would only be permitted if there
is evidence from laboratory tests that the gas meets all applicable
standards of identity, strength, quality and purity, and the closure is
not compromised. Section 213.208 also would require that firms maintain
and follow written procedures for the holding, testing, and use of
salvaged medical gases. While medical gases in sealed containers are
generally considered unlikely to be affected by adverse conditions,
such as natural disasters or significant changes in temperature,
humidity, or pressure, a medical gas container could be damaged by such
circumstances. Therefore, it is essential for firms to evaluate any
containers potentially affected by adverse conditions.
13. Notable Part 211 Provisions FDA Does Not Propose To Include in Part
213
    In this section, FDA discusses existing CGMP provisions of note
that the Agency has not proposed for inclusion in part 213. In the
proposed CGMP requirements described above in this section, FDA
addressed some individual requirements in part 211 that the Agency has
not proposed for inclusion in part 213, but this section addresses some
other sets of requirements that are outside the scope of the above
discussion. We specifically request public comment on these areas.
    The requirements in Sec.  211.28(a), (b), and (d) regarding
personnel responsibilities are not included in this proposed rule.
Medical gases are generally manufactured, stored, combined, and
distributed under pressure in closed systems. Therefore, the risk of
contamination is generally lower than for other drugs. FDA believes
that the other requirements that would be established by this proposed
rule would sufficiently address the risk of contamination in medical
gases.
    FDA is not proposing to include certain buildings and facilities
requirements from part 211, subpart C, in proposed part 213, subpart C
(specifically Sec. Sec.  211.44 through 211.58) because they are not
relevant to the manufacture, processing, packing, and holding of
medical gases, or because the proposed requirements in Sec.  213.42
sufficiently address these issues. For example, FDA believes that
specific lighting requirements are not necessary because the risk of
lightbulbs breaking and contaminating the gas inside a closed
manufacturing system is remote. Moreover, FDA believes that the level
of lighting at a facility would be sufficiently addressed by the
requirements in Sec.  213.42 to ensure that the design, space, and
placement of equipment in a facility help protect against mix-ups (for
example, we interpret this to mean that, among other things, employees
have sufficient light to read labels). Similarly, specific ventilation
requirements are not necessary because the closed manufacturing system
for medical gases is generally unaffected by external factors such as
air quality in the facility. Other specific requirements in part 211
regarding plumbing, sewage, and sanitation are also unnecessary because
the risk of contamination is extremely low and because the proposed
requirements in part 213 would adequately address these concerns.
    The current requirements for filters in Sec.  211.72 are also not
included in this proposed rule. Because medical gases are not
administered as injectable drugs, the requirements in Sec.  211.72 are
not relevant. FDA seeks comment on the need for filter requirements.
    Because medical gases are generally not expected to expire or
degrade under ordinary storage conditions, FDA does not believe it is
necessary to include in this proposed rule the requirements in Sec.
211.86 regarding using the oldest approved stock first or Sec.  211.87
regarding retesting product that has been stored for long periods of
time or whose containers have been exposed to air.

    FDA is not proposing to include a calculation of yield requirement
similar to Sec.  211.103. Gas loss is expected during manufacturing and
can be variable even under normal operating conditions. The
requirements proposed in part 213 would be sufficient to determine that
the medical gas in the container is the amount and type indicated by
the label and required by the final product specifications. Therefore,
such a requirement would not provide useful information to firms or
FDA.
    FDA is not proposing to include an equipment identification
requirement similar to Sec.  211.105. Because equipment used for
medical gas manufacturing is expected to be specific to the gas being
manufactured, there is typically no changeover of machinery for firms
to track. Accordingly, FDA does not believe such a requirement is
necessary to assure the safety, identity, strength, quality, and purity
of medical gases.
    FDA is not proposing to include time limitations on production
similar to Sec.  211.111 because medical gases are generally not
expected to expire or degrade under ordinary storage conditions. FDA
also is not proposing to include requirements regarding the control of
microbiological contamination similar to Sec.  211.113 because the risk
of contamination is extremely low for these products.
    FDA is not proposing to include a requirement similar to Sec.
211.115, which establishes requirements for reprocessing. The Agency is
not aware that reprocessing occurs for medical gases. Rather, it is
FDA's understanding that gases not meeting specifications generally
would be vented. However, as mentioned above, we welcome comment on
this issue, including any example scenarios in which medical gases are
reprocessed.
    FDA is not proposing to include the drug product inspection
requirements in Sec.  211.134. Because cylinders are reused many times,
FDA believes that the labeling inspection provisions in proposed Sec.
213.122(f) would assure proper product labeling.
    FDA is not proposing to include the reserve sampling requirements
in Sec.  211.170 because the requirements in Sec.  211.170 are not
appropriate for medical gases. The proposed sampling requirements
elsewhere in part 213 would be sufficient to address sampling for in-
process and finished medical gases.
14. Proposed Revisions to 21 CFR Part 4 CGMP Requirements
    FDA recognizes that some medical gases are marketed as part of a
combination product. For example, a medical gas may be marketed with a
device constituent part (for example, a portable liquid oxygen unit or
a pressure regulator). However, a gas cylinder with a simple on/off
valve (i.e., without a pressure regulator) would generally not be
considered a device. Combination products are subject to part 4,
subpart A (21 CFR part 4, subpart A), which clarifies the application
of CGMP regulations to combination products and provides a streamlined
approach to demonstrate CGMP compliance for facilities that manufacture
co-packaged or single-entity combination products.
    FDA intends to amend part 4, subpart A to reflect the new
requirements for medical gases under part 213 and clarify how to comply
with part 4, as amended. FDA proposes to include in 21 CFR 4.2 a
definition of the term ``medical gas'' consistent with the definition
in proposed part 213, as well as a definition of ``medical gas CGMPs''
that refers to part 213.
    FDA also proposes to revise Sec.  4.3(a) (21 CFR 4.3(a)) to account
for combination products that contain a medical gas. For such products,
part 213 would apply rather than parts 210 and 211, as described in
proposed new Sec.  4.3(e).
    FDA proposes to include in Sec.  4.4(b) (21 CFR 4.4(b)) specific
provisions for combination products that include a medical gas as a
drug constituent part to enable use of a streamlined approach for
designing and implementing a CGMP operating system that complies with
CGMP requirements for medical gas-device combination products akin to
the streamlined approaches available for other drug-device combination
products. FDA believes that when a manufacturer of a medical gas-device
combination product demonstrates that its CGMP operating system
complies with part 213 in full, the provisions from part 820 (21 CFR
part 820), with which manufacturers must demonstrate compliance, should
be the same as those currently listed in Sec.  4.4(b)(1) because part
213 covers the same general areas as part 211, and FDA is not aware of
device characteristics that would necessitate a different approach. If
a medical gas-device combination product manufacturer demonstrates that
its CGMP operating system complies with part 820 in full, FDA believes
that the following proposed requirements from part 213 would be
appropriate to ensure that critical aspects of medical gas production
are addressed:
     Section 213.84. Testing and approval or rejection of
components, containers, and closures.
     Section 213.94. Medical gas containers and closures.
     Section 213.122. Materials examination and usage criteria.
     Section 213.165. Testing and release for distribution.
     Section 213.166. Stability testing and expiration dating
for medical gases marketed under applications submitted under section
505 or 512 of the FD&C Act.
     Section 213.204. Returned medical gases.
     Section 213.208. Salvaging of medical gases.
    FDA proposes to make other conforming edits as needed, such as
revising Sec.  4.4(e) to include a reference to part 213, and to
clarify (where appropriate) throughout part 4, subpart A the
requirements for medical gases.
    FDA specifically seeks comment on this proposal, including: (1)
Which part 213 provisions should be included in the list of provisions
for combination products containing a medical gas as a drug constituent
part for which the CGMP operating system has been shown to comply with
part 820; (2) whether the part 820 provisions listed in Sec.  4.4(b)(1)
should be revised for combination products containing a medical gas as
a drug constituent part to include other 820 requirements or to remove
certain existing references to part 820 call-outs; and (3) whether it
is appropriate to permit manufacturers to have the option of choosing
to demonstrate compliance with part 213 in full along with the part 820
call-out provisions or compliance with part 820 in full along with the
part 213 call-out provisions.
    The Agency believes that part 4, subpart A helps ensure appropriate
implementation of CGMP requirements for combination products while
avoiding unnecessary redundancy in CGMP operating systems for these
products, and that, given the benefits of the approach in part 4,
subpart A, it should include combination products that contain a
medical gas. FDA expects that sponsors of medical gases submitted under
section 505 of the FD&C Act with a delivery system are already aware
that they are producing a combination product, and as such should
already be familiar with the requirements in part 4, subpart A. For
firms that combine a designated medical gas or medically appropriate
combination of designated medical gases with a finished, off-the-shelf
device, FDA expects that the burden for complying with the device CGMP
requirements would be relatively low. In some cases, firms may be able
to leverage information from their device supplier to demonstrate
compliance

with device call-outs. Additionally, some device provisions are not
expected to apply in all cases; some class I devices are exempt from
the design control requirements in 21 CFR 820.30, and the installation
and servicing requirements in 21 CFR 820.170 and 820.200, respectively,
are not applicable to all devices.

C. Proposed Certification and Annual Reporting Provisions

    The proposed rule would establish, within new part 230, regulations
setting forth the requirements for obtaining certification of a
designated medical gas pursuant to section 576 of the FD&C Act. Since
the passage of FDASIA, many applicants have sought marketing
authorization for a designated medical gas under section 576 of the
FD&C Act, and this proposed rule would codify that process in FDA's
regulations while also providing additional clarity where necessary. As
proposed, part 230 would contain the requirements for filing a
certification request for a designated medical gas for human use,
animal use, or both. FDA is also proposing to make certain provisions
in parts 314 and 514 inapplicable to designated medical gases, given
that part 230 would apply instead.
    Sections 575 and 576 of the FD&C Act also authorize FDA to deem
certain medical gases not listed in section 575(1)(A) through (G) to be
designated medical gases (FD&C Act section 575(1)(H)) and to certify
designated medical gases or medically appropriate combinations of such
gases for certain indications for use not listed in section
576(a)(3)(A)(i)(I) through (VII) (FD&C Act section
576(a)(3)(A)(i)(VIII)). The Agency is not proposing regulations
implementing these provisions as part of this rulemaking because the
Agency does not expect to deem additional medical gases to be
designated medical gases at this time. In addition, the Agency does not
expect to certify designated medical gases for indications beyond those
currently described in section 576 of the FD&C Act at this time. If, in
the future, FDA decides it would be appropriate to deem additional
medical gases to be designated medical gases or to certify designated
medical gases or medically appropriate combinations of such gases for
additional indications for use, FDA expects to undertake such actions
without the need for further rulemaking.
    FDA also notes that section 575(1)(F) of the FD&C Act provides that
carbon monoxide is a designated medical gas if it ``meets the standards
set forth in an official compendium.'' Section 201(j) of the FD&C Act
defines ``official compendium'' to include the U.S. Pharmacopeia (USP),
the official Homeopathic Pharmacopeia of the United States (HPUS), the
official National Formulary (NF), or any supplement to any of them.
There is currently no monograph in the USP or NF for carbon monoxide.
There is a HPUS monograph for carbon monoxide, though it is
inapplicable to carbon monoxide as a designated medical gas for use in
lung diffusion testing. FDA does not intend to object to the marketing
of carbon monoxide for use in lung diffusion testing as long as the
product conforms to one of the alternatives in the Center for Drug
Evaluation and Research's Manual of Policies and Procedures 5310.7 Rev.
1, Acceptability of Standards from Alternative Compendia (BP/EP/JP)
(Ref. 10). This proposed approach is consistent with the draft policy
described in the draft guidance for industry entitled ``Certification
Process for Designated Medical Gases'' (Ref. 1). If and when a
monograph entitled ``Carbon Monoxide'' is added to the USP or NF, FDA
expects original manufacturers that wish to continue marketing carbon
monoxide to promptly submit a certification request.
1. Definitions
    Proposed Sec.  230.3(b)(2) defines the term ``applicant.'' An
applicant is proposed to be defined as any person or entity who submits
a certification request for a designated medical gas under part 230,
including supplements. This is generally the original manufacturer. An
applicant would also include any person or entity who owns a granted
certification for a designated medical gas under part 230. This
definition is generally consistent with FDA's use of the term
``applicant'' with regard to NDAs and ANDAs (see 21 CFR 314.3(b)), as
well as NADAs and ANADAs (see 21 CFR 514.3).
    FDA also proposes to define ``certification request'' as a
submission under section 576 of the FD&C Act requesting certification
of a medical gas as a designated medical gas. After a certification
request is deemed to be granted, a designated medical gas is deemed,
alone or in combination, as medically appropriate, with another
designated medical gas or gases for which a certification or
certifications have been granted, to have in effect an approved
application under section 505 or 512 of the FD&C Act, subject to all
applicable postapproval requirements, for the applicable indications
for use described in section 576(a)(3)(A)(i)(I) through (VIII) of the
FD&C Act.
    FDA proposes to define ``FDA or Agency'' to mean the Food and Drug
Administration, consistent with other Agency regulations.
2. General Requirements for All Certification Submission Types
    Proposed Sec.  230.50 would establish the general requirements
related to designated medical gas certification requests. The
requirements would apply to all submission types. Proposed Sec.
230.50(a)(1) would provide that the certification process described in
part 230, subpart B applies to designated medical gases for the
indications described in section 576(a)(3)(A)(i) of the FD&C Act.
Currently, manufacturers who intend to market medical gases that do not
meet the definition of designated medical gas, or who intend to market
designated medical gases for indications not described in section
576(a)(3)(A)(i) of the FD&C Act, must obtain approval of that medical
gas under part 314 or part 514, or both, as applicable. For example, if
an applicant intends to market nitrous oxide for a use other than
analgesia (see section 576(a)(3)(A)(i)(III) of the FD&C Act), the
certification process in proposed part 230 would not be available for
that drug product at this time. If FDA deems additional indications for
use appropriate under section 576(a)(3)(A)(i)(VIII) of the FD&C Act,
the certification process could extend to designated medical gases for
those uses. However, as of the date of this proposed rule, FDA has not
deemed any additional indications for use to be appropriate for any
designated medical gases.
    Also in Sec.  230.50(a)(1), FDA proposes to require any person who
seeks to initially introduce or deliver for introduction a designated
medical gas into interstate commerce to file a request for
certification. An applicant would be required to identify its intention
to market their designated medical gas for human use, animal use, or
both. If a certification is deemed to be granted, a designated medical
gas, alone or in combination, as medically appropriate, with another
designated medical gas or other designated medical gases for which a
certification or certifications have been granted, would be deemed to
have in effect, for the uses described in section 576(a)(3)(A)(i) of
the FD&C Act:
     An approved application under section 505 of the FD&C Act,
if the applicant requested certification solely for human use;
     an approved application under section 512 of the FD&C Act,
if the

applicant requested certification solely for animal use; or
     approved applications under sections 505 and 512 of the
FD&C Act, if the applicant requested certification for both human and
animal use.
    (See section 576(a)(3)(A)(i); see also proposed Sec.  230.105.)
Applicants should submit one request per designated medical gas,
regardless of how many of their facilities manufacture or will
manufacture that designated medical gas. Persons who receive a
designated medical gas from an applicant or another person and fill the
gas into containers, including via liquid to liquid at a delivery site,
are not expected to submit certification requests under part 230
because the gas they are handling should be the subject of a granted
certification held by another entity. (See also proposed Sec.  213.82.)
    Proposed Sec.  230.50(a)(2) would describe the relationship between
the proposed certification requirements in part 230 and parts 314 and
514. Proposed Sec.  230.50(a)(2) would provide that any person that
proposes to market a medical gas that is a new drug for human use must
obtain approval under part 314, and any person that proposes to market
a medical gas that is a new animal drug for animal use must obtain
approval under part 514, unless the medical gas meets the definition of
a designated medical gas, and the medical gas is proposed to be
marketed, alone or in combination (as medically appropriate), with
another designated medical gas or gases for which a certification or
certifications have been granted, for a use described under section
576(a)(3)(A)(i) of the FD&C Act. ``New drug'' and ``new animal drug''
are defined in section 201(p) and (v) of the FD&C Act.
    Proposed Sec.  230.50(b) would outline the information that must be
submitted in a certification request. In addition, though not a
proposed requirement in this proposed rule, FDA recommends that the
applicant include a cover letter describing the purpose of the
submission (e.g., original certification, amendment to supply
additional information requested by FDA). Such cover letters often
provide context and information that would be helpful to the Agency as
it processes certification requests. Under Sec.  230.50(b)(1), the
certification request would need to include the name, address,
telephone number, and email address of the person or entity requesting
certification. If the address of the entity requesting certification is
not in the United States, the certification request would need to
contain the name and address of, and be countersigned by, an attorney,
agent, or other authorized official who resides or maintains a place of
business within the United States. Under Sec.  230.50(b)(2), the
certification request would also need to identify the type of
submission as one of the following:
     Original certification request: An initial request for
certification by an applicant for certification of a medical gas as a
designated medical gas.
     Amendment to a pending submission: A submission related to
a pending submission that revises existing information or provides
additional information, including responses to Information Request
Letters.
     Resubmission: A complete submission that has been revised
and submitted again following a previous denial (if the applicant
chooses to resubmit its submission, it would need to provide a written
response to all deficiencies identified in FDA's denial letter, along
with other information required for certification requests; this would
help assure that past deficiencies are addressed before applicants
resubmit, thus promoting the efficient use of Agency resources)
     Supplement to a granted certification: Any submission that
contains a change to a certification that was previously granted.
     Other: Any submission that does not fit into one of the
other categories described in this list.
    Under Sec.  230.50(b)(3), the applicant would also need to include
a description of the designated medical gas. Each designated medical
gas certification request would need to include the name of the gas, as
well as a certification statement that the designated medical gas meets
the appropriate compendial standard. FDA intends to develop a
designated medical gas certification form which would include a
certification statement. The Agency anticipates the form would have OMB
approval prior to the finalization of any proposed rule.
    Under Sec.  230.50(b)(4), applicants would also be required to
include certain facility information in the certification request,
including the name and address of the facility or facilities where the
designated medical gas will be initially produced. FDA uses the term
``facility'' in this proposed provision to be consistent with the
terminology in section 576(a)(1)(C) of the FD&C Act, which requires
that a certification request include ``[t]he name and address of the
facility or facilities where the medical gas is or will be
manufactured.'' For purposes of this proposed regulation, the term
``facility'' would be synonymous with the term ``establishment'' as it
is used in part 207 (21 CFR part 207). Other facilities that only
perform subsequent activities such as transfilling, mixing, or filling
at a delivery site would not be considered ``facilities'' for purposes
of this proposed regulation. Applicants would also need to include a
brief description of the manufacturing or processing activities
performed at each facility listed in the certification, which would
include chemical reaction, physical separation, compression of
atmospheric air, purification of a gas, or other activities to produce
a designated medical gas. Applicants would also need to include an FDA
Establishment Identifier (FEI), if one exists, and a Unique Facility
Identifier (UFI) in accordance with the requirements of part 207 and
section 510 of the FD&C Act (21 U.S.C. 360). If an applicant intends to
open a new facility to manufacture the designated medical gas, FDA
recognizes that the applicant may not have an FEI at the time of the
certification request, as FEIs are generally assigned upon registration
of a new establishment. However, for existing facilities, including the
FEI in the certification request will assist FDA in monitoring its
establishment inventory. Regarding the UFI, inclusion of this
information will assist the Agency in linking certification requests to
registration information required by section 510(b)(1) of the FD&C Act
and 21 CFR 207.25(e). FDA's preferred UFI is the Data Universal
Numbering System (DUNS) number (Ref. 11). Firms can acquire a DUNS
number at no cost. For amendments and supplements, only changes to the
list of facilities would need to be submitted.
    Under proposed Sec.  230.50(b)(5), the applicant would be required
to certify in its certification request that its methods, facilities,
and controls used in manufacturing, processing, packing, and holding of
the designated medical gas, as applicable, are adequate to ensure the
gas's safety, identity, strength, quality, and purity. This
certification would be met by completing a field on the certification
form referenced above. This information is critical to determining
whether the medical gas manufactured at the facility is a designated
medical gas because it meets applicable compendial standards (FD&C Act
section 576(a)(1)(D)). Designated medical gases generally have narrow
compendial standards, and requiring an applicant to certify that it
employs appropriate methods, facilities, and controls would help ensure
consistent, quality manufacture of a gas that meets such standards.
    Lastly, under Sec.  230.50(b)(6), if the Agency deems any other
information

appropriate to determine whether the gas meets the definition of a
designated medical gas, the applicant would be required to provide that
additional information as well. This would generally be in the form of
a written request by FDA for the additional information. The applicant
may also provide other information that the applicant believes will
assist the Secretary in evaluating the request.
    Though FDA is not proposing changes to its registration and listing
regulations as they apply to designated medical gases, FDA notes that
firms must also comply with applicable registration and listing
requirements in section 510 of the FD&C Act and part 207. For example,
firms must register establishments and list designated medical gases,
or update existing registration and listing information, pursuant to
part 207, subparts B and D.
    Proposed Sec.  230.50(c) would describe the requirements for
submitting a certification request. Applicants would be required to
submit a signed, completed request for certification either in an
electronic format that FDA can process, review, and archive, or in hard
copy by submitting two paper copies to the Center for Drug Evaluation
and Research (CDER) Central Document Room. FDA encourages submission of
certification requests through the NextGen Portal at https://edm.fda.gov. FDA intends to assign an NDA or NADA number (or both, if
the applicant has expressed its intent to market the medical gas for
human and animal use) for reference purposes when an original
certification request is filed. If certification is granted, the
applicant should use these application numbers in all further
submissions to the Agency. If certification is not granted, and the
applicant resubmits their certification request in the future, the
previously assigned NDA and/or NADA number would continue to be the
relevant application number(s).
    Section 230.65 would allow applicants to withdraw a certification
request that has not been deemed granted. An applicant could notify FDA
that it withdraws its certification request at any time prior to the
certification being deemed granted. Withdrawal of a certification
request would not preclude refiling. If a certification request is
withdrawn, FDA would retain the certification request, and if the
applicant requests a copy via Freedom of Information Act (FOIA)
request, FDA would provide it pursuant to the fee schedule in FDA's
public information regulations.
3. Supplements and Other Changes to a Granted Certification
    Section 230.70(a) of the proposed rule would require an applicant
to submit a supplement if any information in the certification request
has changed after the request has been deemed granted, including, but
not limited to, the addition of a new facility manufacturing the
designated medical gas, a change in contact information, or a change in
the corporate name. FDA anticipates these are the most common types of
information in the request that might change after certification has
been deemed granted.
    Under proposed Sec.  230.70(b), the supplement would need to
include a signed, completed request for certification form with the
updated information in compliance with the requirements of Sec.
230.50, and would need to be submitted no later than 30 calendar days
after the date the change occurred. FDA proposes that supplements may
be submitted after the fact because the Agency does not anticipate that
the types of changes submitted in a supplement would need to be
approved before the change occurs.
4. Change in Ownership of a Certification That Has Been Granted
    Proposed Sec.  230.72 would address situations in which a
designated medical gas certification that has been granted undergoes a
change in ownership, for example, due to a merger or acquisition.
Proposed Sec.  230.72 would expressly allow for the transfer of
ownership of such a certification. When a transfer occurs, both the new
and former owners would be required to submit certain information to
FDA. Under proposed paragraph (a), the former owner would be required
to submit a letter or other document explaining that all rights to the
certification have been transferred to the new owner. Under proposed
paragraph (b), the new owner would be required to submit a supplement
under Sec.  230.70 signed by the new owner describing any changes in
the conditions in the granted certification, and a letter or other
document identifying the date the transfer of ownership is effective.
5. Annual Report
    Proposed Sec.  230.80(a) would require applicants to submit an
annual report each year within 60 calendar days of the anniversary of
the date the certification was deemed granted. Section 576(a)(2) of the
FD&C Act provides that a certification request is deemed to be granted
unless, within 60 days of its filing, FDA denies the request based on
certain findings; FDA interprets the period of 60 days in this
provision to mean a period of 60 calendar days. The applicant would be
required to submit a signed, completed annual report form either in an
electronic format that FDA can process, review, and archive, or in hard
copy by submitting two paper copies to CDER's Central Document Room.
The annual report would be required to contain the following
information from the prior 12 months, pursuant to proposed Sec.
230.80(b):
     A summary of any significant new information that might
affect the safety, effectiveness, or labeling of the designated medical
gas. The applicant would also be required to include any actions it has
taken or intends to take as a result of this information.
     The applicant would need to include the National Drug Code
(NDC) numbers, the quantities distributed for domestic use, and the
quantities distributed for foreign use. The disclosure of financial or
pricing data would not be required.
     Any changes to the applicant's name or contact
information. This information would need to be submitted in a
supplement no later than 30 calendar days after the change occurred
pursuant to proposed Sec.  230.70, but the Agency believes that
receiving all current information consolidated in an annual report will
help FDA keep track of applicants and ensure that the Agency has
current information.
     The applicant would need to include a list of current
facilities, and a list of facilities that were used since the previous
annual report (or since the certification was deemed granted) but are
no longer in use.
    This information would be critical to allow FDA to evaluate all
changes to the product and its manufacturing since the most recent
report and determine whether any changes have the potential to alter
the identity of the gas such that it no longer meets the applicable
compendial standard or the definition of a designated medical gas.
6. FDA Review of Certification Submissions
    Under proposed Sec.  230.100(a), as part of its review, FDA would
consider information submitted with the certification submission along
with any other available, relevant information of which FDA becomes
aware. Such information could include information obtained from State
or Federal officials, FDA inspection reports, or any other source. Per
Sec.  230.100(b), FDA proposes the following grounds for denying a
submission:

     The medical gas that is the subject of the submission is
not a designated medical gas. For example, FDA currently would deny a
certification request for oxygen that fails to meet the standards for
Oxygen, USP.
     The submission does not contain the required information
or otherwise appears to lack sufficient information to determine that
the medical gas is a designated medical gas. This may occur if the
applicant fails to certify that the medical gas meets the applicable
compendial standards, or if FDA obtains evidence that the medical gas
fails to meet applicable compendial standards.
     The applicant's methods, facilities, and controls used for
the manufacture, processing, and handling of the designated medical
gas, as applicable, are not adequate to ensure its safety, identity,
strength, quality, and purity, or
     Denying the request is otherwise necessary to protect the
public health.
    Under proposed Sec.  230.100(c), within 60 calendar days of filing
of a certification submission, FDA could contact the applicant to
request additional information regarding the submission if it
determines that the submission is missing required information, that
FDA needs such information to determine whether the medical gas is a
designated medical gas, or that FDA determines such information is
necessary to protect the public health. This proposed provision would
help applicants correct or complete their submission, or decide to
withdraw, in a timely and efficient manner. Section 576(a)(2) of the
FD&C Act provides that a certification request is deemed to be granted
unless, within 60 days of its filing, FDA denies the request based on
certain findings; FDA interprets the date of filing under this
provision to mean the date that the certification request is received
by the Agency. Upon receipt of an amendment to a pending certification
request, this 60-day period would restart to allow FDA sufficient time
to review new information received. FDA may find that the submission
lacks sufficient information if, within the 60-day review period, FDA
is unable to contact the applicant to obtain and evaluate the missing
information or if FDA is able to contact the applicant but is not
provided with the additional information within the 60-day review
period.
    Proposed Sec.  230.100(d) would provide that, within 60 calendar
days of filing of a submission, if FDA makes one of the findings
described in proposed Sec.  230.100(b), FDA will notify the applicant
in writing that the submission is denied and provide the basis for
FDA's determination.
7. When a Certification Submission Is Deemed Granted
    Proposed Sec.  230.105 would provide that, unless FDA makes one of
the findings described in Sec.  230.100(b) and notifies the applicant
within 60 calendar days of filing that the submission is denied,
certification is deemed to be granted and the designated medical gas
will be deemed to have in effect an approved application under section
505 or 512 of the FD&C Act, or both, for the indications specified in
section 576(a)(3)(A)(i) of the FD&C Act. FDA would notify the applicant
in writing and intends to post the letter on the Agency's website. The
designated medical gas for which a certification is deemed granted
would be subject to all applicable postapproval requirements. If,
however, FDA has not responded during the 60-day review time period,
the applicant may begin marketing their designated medical gas unless
and until FDA withdraws or revokes approval.
8. Withdrawal or Revocation of Approval of an Application for a
Designated Medical Gas
    Proposed Sec.  230.150 describes requirements concerning withdrawal
or revocation of approval of an application for a designated medical
gas. Proposed paragraph (a) addresses withdrawal of approval. FDA
proposes that it will notify the applicant and afford an opportunity
for a hearing on a proposal to withdraw approval of the application
under the procedure in Sec.  314.200 (21 CFR 314.200), Sec.  514.200
(21 CFR 514.200), or both, as applicable, for any of the grounds listed
in proposed paragraph (a)(1). FDA proposes that if the Secretary of the
Department of Health and Human Services has suspended approval on a
finding that there is an imminent hazard to public health, FDA will
initiate the withdrawal process. Additionally, FDA proposes that it
will initiate the withdrawal process if it makes any of the following
findings:
     Clinical or other experience, tests, or other scientific
data show that the designated medical gas is unsafe for use under the
conditions of use upon the basis of which the application was approved;
     New evidence of clinical experience not available to FDA
until after the application was approved, or tests by new methods, or
tests by methods not deemed reasonably applicable when the application
was approved, evaluated together with the evidence available when the
application was approved, reveal that the designated medical gas is not
shown to be safe for use under the conditions of use upon the basis of
which the application was approved;
     Upon the basis of new information before FDA with respect
to the designated medical gas, evaluated together with the evidence
available when the application was approved, that there is a lack of
substantial evidence from adequate and well-controlled investigations
as defined in 21 CFR 314.126, that the designated medical gas will have
the effect it is purported or represented to have under the conditions
of use prescribed, recommended, or suggested in its labeling; or
     The application contains any untrue statement of a
material fact.
    In Sec.  230.150(a)(2), FDA proposes that it may notify the
applicant and afford an opportunity for a hearing on a proposal to
withdraw approval of the application under the procedure in Sec.
314.200, Sec.  514.200, or both, as applicable, if FDA makes any of the
following findings:
     The applicant has failed to establish a system for
maintaining required records, or has repeatedly or deliberately failed
to maintain required records or to make required reports applicable to
designated medical gases, including under sections 505(k) and 512(l) of
the FD&C Act, part 230, and part 213, or that the applicant has refused
to permit access to, or copying or verification of, its records;
     On the basis of new information before FDA, evaluated
together with the evidence available when the application was approved,
the methods used in, or the facilities and controls used for, the
manufacture, processing, and packing of the designated medical gas are
inadequate to ensure and preserve its identity, strength, quality, and
purity and were not made adequate within a reasonable time after
receipt of written notice from the Agency;
     On the basis of new information before FDA, evaluated
together with the evidence available when the application was approved,
the labeling of the designated medical gas, based on a fair evaluation
of all material facts, is false or misleading in any particular, and
the labeling was not corrected by the applicant within a reasonable
time after receipt of written notice from the Agency; or
     The applicant has failed to comply with the notice
requirements of section 510(j)(2) of the FD&C Act (pertaining to the
requirements regarding product listing updates).
    Section 576(a)(4)(A) of the FD&C Act makes clear that the authority
to

withdraw or suspend approval under section 505(e) applies to designated
medical gases that are deemed to have in effect approved applications
under section 505 or 512. FDA believes the grounds proposed in Sec.
230.150(a)(1) and (2) are consistent with the bases for withdrawing an
application under section 505(e) of the FD&C Act.
    Under proposed Sec.  230.150(a)(3), FDA would also withdraw
approval if the applicant requests its withdrawal because the
designated medical gas subject to the application is no longer being
marketed, provided none of the conditions listed in proposed paragraphs
(a)(1) or (a)(2) applies. FDA proposes to consider such a written
request for withdrawal to be a waiver of an opportunity for hearing
otherwise provided for in this section. Such withdrawal, when requested
by the applicant, would be without prejudice to refiling.
    Under proposed paragraph (a)(4), FDA could notify an applicant that
it believes a potential problem associated with a designated medical
gas is sufficiently serious that the designated medical gas should be
removed from the market and may ask the applicant to waive the
opportunity for hearing otherwise provided under this section, to
permit FDA to withdraw approval, and to remove voluntarily the product
from the market. If the applicant agrees, FDA would not make a finding
under paragraph (a), but would withdraw approval in a notice published
in the Federal Register that contains a brief summary of FDA's and the
applicant's views of the reasons for withdrawal.
    Proposed paragraph (a)(5) provides that, if FDA withdraws an
approval, the Agency will publish a notice in the Federal Register
announcing the withdrawal of approval. This is consistent with the
Agency's current practice to announce withdrawn approvals.
    Under proposed paragraph (b), FDA could revoke the grant of a
certification if FDA determines, after providing the applicant with
notice and opportunity for an informal hearing in accordance with 21
CFR part 16, that the request for certification contains any material
omission or falsification. This is intended to implement section
576(a)(4)(B) of the FD&C Act. FDA proposes corresponding edits to 21
CFR 16.1(b)(2) to include reference to this provision.
9. Proposed Changes to Part 314
    FDA proposes carving out designated medical gases from certain
provisions in part 314 for which a corresponding provision specific to
designated medical gases is proposed to be added to part 230. FDA also
proposes carving out designated medical gases from certain provisions
of part 314 that are not relevant to designated medical gases. Proposed
new Sec.  314.1(c) (21 CFR 314.1(c)) would list the provisions that FDA
proposes no longer apply to designated medical gases.
    A number of provisions in part 314 would continue to apply to
designated medical gases.\7\ Section 314.80(g) (21 CFR 314.80(g)),
regarding the electronic submission of safety reports, would continue
to apply. FDA anticipates that the electronic format for submission of
human drug individual case safety reports (ICSRs) will be the same as
for other human drugs, and that existing guidance will be appropriate
for human designated medical gas ICSRs.
---------------------------------------------------------------------------

    \7\ FDA has described its intention to issue a proposed rule
that, among other things, would amend part 314 to modernize
postmarketing safety reporting requirements for drugs (see RIN 0910-
AI61 on Fall 2021 Unified Agenda of Regulatory and Deregulatory
Actions), and FDA intends to update proposed Sec.  314.1(c) to
address any new or modified provisions added by that rulemaking that
would not apply to designated medical gases.
---------------------------------------------------------------------------

    The following provisions in Sec.  314.81 (21 CFR 314.81) also would
continue to apply:
     Sec.  314.81(b)(3), which addresses submission of
advertisements and promotional labeling, special reports upon written
request from the Agency, notification of permanent discontinuance or an
interruption in manufacturing, and the requirements for withdrawing an
approved drug product from sale;
     Sec.  314.81(c), which addresses submitting information
related to multiple applications and patient identification
requirements; and
     Sec.  314.81(d), which authorizes FDA to withdraw approval
of an application for failure to make reports required under Sec.
314.81.
    FDA is not aware of any reason to exempt applicants from these
requirements, though the Agency requests comment on the burden
associated with complying with these provisions.
    Subparts E and G of part 314 would also continue to apply. FDA has
not identified any reason to establish different requirements and
procedures for hearings, imports and exports, drug master files, or
public disclosure of Agency records related to designated medical
gases.
10. Proposed Changes to Part 514
    Similarly, FDA proposes carving out designated medical gases from
provisions in part 514 for which a provision specific to designated
medical gases is proposed to be added to part 230. FDA also proposes
carving out provisions that do not apply to certification requests for
designated medical gases. Proposed revisions to Sec.  514.1(a) list the
provisions that FDA proposes no longer apply to designated medical
gases. FDA proposes that the data confidentiality requirements, hearing
procedures, and judicial review process would continue to apply because
FDA has not identified any reason to establish different procedures for
designated medical gases. Within Sec.  514.80, FDA proposes revisions
to the table and to paragraph (a) to further explain that NADAs for
designated medical gases are not subject to the reporting requirements
in Sec.  514.80 and are instead subject to part 230.

D. Proposed Postmarketing Quality and Safety Reporting Provisions

    Also within part 230, FDA proposes new postmarketing safety
reporting requirements for designated medical gases.
1. Definitions
    Proposed Sec.  230.3(a) would incorporate relevant definitions from
sections 201 and 575 of the FD&C Act. Additionally, FDA proposes
several additional definitions in Sec.  230.3(b) related to
postmarketing safety reports along with the definitions described in
section V.C. above. FDA proposes to define ``adverse event'' to mean
any untoward medical occurrence associated with the use of a designated
medical gas in humans or animals, whether or not it is considered
related to the designated medical gas. This would include adverse
events occurring in the course of the use of a designated medical gas,
adverse events occurring from overdose (whether accidental or
intentional), adverse events occurring from abuse, adverse events
occurring from discontinuation (such as physiological withdrawal), and
any failure of expected pharmacological action.
    The proposed definitions of ``ICSR'' and ``ICSR attachments'' would
be generally consistent with the definitions of those terms in Sec.
314.80(a). FDA proposes to define ``ICSR'' to mean a description of an
adverse event related to an individual patient or subject. The Agency
proposes to define ``ICSR attachment'' to mean documents related to the
adverse event described in an ICSR, such as medical records, hospital
discharge summaries, or other documentation.
    FDA proposes to define ``life-threatening adverse event'' to mean
any

adverse event that places the patient, in the view of the initial
reporter, at immediate risk of death from the adverse event as it
occurred. This term would not include an adverse event that, had it
occurred in a more severe form, might have caused death.
    The proposed definition of ``minimum data set for an ICSR for an
adverse event'' is generally consistent with the list of minimum data
elements for a postmarketing ICSR described in the 2001 draft guidance
for industry ``Postmarketing Safety Reporting for Human Drug and
Biological Products Including Vaccines'' (Postmarketing Safety
Reporting Draft Guidance) (Ref. 12). FDA proposes that a minimum data
set for an ICSR for an adverse event include the following four
elements: (1) An identifiable patient, (2) an identifiable reporter,
(3) a suspect designated medical gas, and (4) an adverse event.
    FDA proposes to define ``nonapplicant'' in a manner that is
generally consistent with how the term is described in Sec.
314.80(c)(1)(iii). A nonapplicant would be defined as anyone other than
the applicant whose name appears on the label of a designated medical
gas container as a manufacturer, packer, or distributor.
    FDA proposes to include a definition of ``serious adverse event.''
Under this proposed definition, an adverse event would be considered
serious if it results in: Death; a life-threatening adverse event;
inpatient hospitalization or prolongation of existing hospitalization;
a persistent or significant incapacity or substantial disruption of the
ability to conduct normal life functions; or a congenital anomaly/birth
defect. Important medical events that may not result in one of the
above outcomes may be considered serious adverse events when, based
upon appropriate medical judgment, they may jeopardize the patient or
study subject and may require medical or surgical intervention to
prevent one of the outcomes listed above. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of product
dependency or product abuse. Additional examples in animals include
severe hypersensitivity reactions or respiratory distress.
2. Field Alert Reports
    Section 230.205 contains the proposed requirements for field alert
reporting for distributed designated medical gases and articles.
Applicants would be required to submit a field alert report (FAR) to
the FDA district office that is responsible for their facility
concerning (a) information concerning any incident that causes the
designated medical gas or its labeling to be mistaken for, or applied
to, another article; and (b) information concerning any bacteriological
contamination, or significant chemical, physical, or other change or
deterioration in the designated medical gas, or failure of one or more
distributed batches to meet established specifications. FARs would be
required to be submitted within 3 working days of receipt by the
applicant. FDA considers working days to be any day from Monday through
Friday, excluding U.S. Federal holidays (Ref. 13). The Agency seeks
comment on the appropriateness of the 3-day reporting period. FDA would
accept receipt of a FAR by telephone or other rapid communication if
the applicant promptly follows up in writing. Email is an appropriate
method for rapid communication as well as followup. Proposed Sec.
230.205 would also contain requirements for identifying a FAR
submission.
    Proposed Sec.  230.205 is generally consistent with the FAR
requirements in Sec.  314.81(b)(1). FDA proposes to establish Sec.
230.205 to clarify that designated medical gases for both human and
animal use would need to follow the same FAR requirements. FDA is not
aware of any reason to establish different requirements for designated
medical gases for animal use.
3. General Reporting Requirements for Designated Medical Gas Adverse
Events
    Proposed Sec.  230.210 would contain general requirements for
reporting adverse events related to designated medical gases.
    Proposed Sec.  230.210(a) would require applicants and
nonapplicants to promptly review all safety information that the
applicant or nonapplicant receives or otherwise obtains from any source
(including both foreign and domestic sources). Examples of such sources
would include safety information from commercial marketing experience,
reports in the published scientific and medical literature, unpublished
scientific papers, and reports from regulatory authorities (this would
include domestic and foreign authorities).
    As described below in sections V.D.4 and V.D.5, applicants and
nonapplicants would be required to submit safety reports for designated
medical gases pursuant to Sec. Sec.  230.220 (for human use) and
230.230 (for animal use). Applicants and nonapplicants for a designated
medical gas with both an approved NDA and an approved NADA would be
subject to both the human reporting requirements in Sec.  230.220 and
the animal reporting requirements in Sec.  230.230. However, both sets
of reporting requirements would not apply at the same time for a given
event. For example, if an adverse event associated with the use of a
designated medical gas in a human patient occurs, the proposed
requirements in Sec.  230.220 would apply, but the proposed
requirements in Sec.  230.230 would not. Conversely, if an adverse
event associated with the use of a designated medical gas in an animal
patient occurs, the proposed requirements in Sec.  230.230 would apply,
but the proposed requirements in Sec.  230.220 would not. In addition,
if an adverse event occurs in a human from exposure during use of the
gas in an animal patient, the proposed requirements in Sec.  230.230
would apply, but those in Sec.  230.220 would not. FDA considers an
applicant responsible for information known to its employees,
affiliates, and contractors. FDA would similarly consider a
nonapplicant responsible for information known to its employees,
affiliates, and contractors.
    Under proposed Sec.  230.210(b)(1), reports or information
submitted by applicants or nonapplicants (and any release by FDA of
such reports or information) under Sec.  230.220 or 230.230 would not
necessarily reflect a conclusion that the report or information
constitutes an admission that the designated medical gas caused or
contributed to an adverse effect. Additionally, under proposed Sec.
230.210(b)(2), applicants and nonapplicants would not need to admit,
and they could deny, that the report or information submitted under
Sec.  230.220 or Sec.  230.230 constitutes an admission that the
designated medical gas caused or contributed to an adverse effect.
4. Human Designated Medical Gas ICSR Requirements
    Proposed Sec.  230.220 would contain requirements for submission of
ICSRs associated with the use of a designated medical gas in humans.
Under proposed Sec.  230.220(a)(1), both applicants and nonapplicants
would be required to submit each ICSR associated with the use of a
designated medical gas in humans described in Sec.  230.220(b) to FDA
as soon as possible, but no later than 15 calendar days from the date
when the applicant or nonapplicant has both met the reporting criteria
in paragraph (b) and acquired a minimum data set for an ICSR for that
adverse event.
    The proposed timeframe for reporting adverse events under Sec.
230.220(a)(1) is

15 calendar days. In contrast to Sec.  314.80(c)(1)(iii), which
describes circumstances under which a nonapplicant can elect to submit
adverse drug experience reports to the applicant instead of FDA, FDA
proposes in Sec.  230.220 to require both applicants and nonapplicants
to report adverse events involving designated medical gases directly to
FDA. There are a large number of downstream entities that would meet
the definition of ``nonapplicant'' and that combine, distribute, and
fill designated medical gases, compared to a small number of upstream
entities that would meet the definition of ``applicant.'' These
downstream nonapplicants may receive designated medical gases from
multiple sources, including multiple applicants, and the gases may be
commingled within a single tank. Therefore, FDA anticipates that it
would be challenging for a downstream nonapplicant to trace the suspect
gas to a specific upstream applicant if the nonapplicant becomes aware
of a safety issue.
    FDA also proposes that the 15-day period would be triggered upon
the applicant both meeting the reporting criteria described in proposed
Sec.  230.220(b) and acquiring a minimum data set for an ICSR for an
adverse event. This proposed requirement would help ensure that a
minimum level of information is obtained prior to submission of the
report so that the Agency has a more complete picture of the incident.
Lastly, FDA is not proposing to include a requirement that an adverse
event be unexpected to be subject to the proposed reporting
requirement. Because designated medical gases are not required to be
studied in clinical trials, which are commonly conducted for other
drugs, to be certified under section 576 of the FD&C Act, designated
medical gas applicants are not expected to generate the type of
labeling information about expected adverse events that sponsors of
other types of drugs typically generate during product development.
Thus, we expect that the applicants and nonapplicants for designated
medical gases that would have reporting obligations under this proposed
rule would not be able to determine whether an adverse event was
unexpected.
    FDA is not proposing a requirement for periodic safety reporting
for designated medical gases of the type required under Sec.
314.80(c)(2). This would codify FDA's current approach with regard to
the submission of periodic adverse drug experience reports as described
in the March 2015 Compliance Program Guidance Manual 7356.002E, (Ref.
14). We do not believe it is necessary to incorporate such a
requirement in the proposed postmarket safety reporting regulations
that would apply to designated medical gases, but we welcome comment on
this issue.
    Proposed Sec.  230.220(a)(2) would provide that applicants and
nonapplicants should not resubmit ICSRs that they obtained from the FDA
Adverse Event Reporting System database or that FDA forwarded to them.
This is generally consistent with Sec.  314.80(b). FDA encourages
applicants and nonapplicants not to resubmit such ICSRs. Duplicative
reports can divert Agency resources away from other safety priorities
and, if not identified as duplicates, may obscure signal
identification.
    Under proposed Sec.  230.220(a)(3), applicants and nonapplicants
would be required to submit to FDA new information they receive or
otherwise obtain that is related to a previously-submitted ICSR or an
ICSR that was sent to the applicant by FDA. Such information would need
to be submitted within 15 calendar days after the applicant or
nonapplicant receives or otherwise obtains the new information. If an
applicant or nonapplicant receives or otherwise obtains new information
related to a previously submitted ICSR, they would have to submit the
information to FDA under this proposed rule. For example, if a
physician submits information to an applicant about an adverse event
related to the applicant's designated medical gas, the applicant
submits an ICSR based on that information, and the physician updates
the applicant in the future, any new information would need to be
submitted to FDA as new information within 15 calendar days. This
proposed requirement is important to ensure that FDA becomes aware of
any new information that arises about the adverse event.
    Proposed paragraph (b) would describe two types of ICSRs that must
be submitted to FDA. First, applicants and nonapplicants would be
required to report serious adverse events received. This would include
ICSRs for serious adverse events reported to the applicant or
nonapplicant spontaneously (such as reports initiated by patients,
consumers, and healthcare professionals) as well as ICSRs for serious
adverse events obtained from published scientific and medical journals
either as case reports or as the result of a formal clinical trial.
Unlike the safety reporting requirements in part 314, FDA is not
proposing to include a requirement that the event be unexpected.
Designated medical gases do not have traditional product labels that
most human drugs and animal drugs bear, and their applicants generally
have not conducted traditional clinical trials that would typically
generate robust adverse reaction information. Therefore, required
serious adverse events must be submitted regardless of expectedness.
    In proposed Sec.  230.220(b)(1)(iii), FDA proposes to include one
exception to the requirement that serious adverse events be reported
within 15 calendar days. ICSRs would not be required for reports of a
patient death in cases where the patient was administered oxygen,
unless the applicant or nonapplicant is aware of evidence to suggest
that the death was caused by the administration of oxygen. FDA
recognizes that oxygen is commonly administered during end-of-life care
or to patients with a life-threatening disease or who are otherwise in
critical condition. Accordingly, FDA believes that unless there is
evidence to suggest that the administration of oxygen caused a
patient's death, such reports are unlikely to reflect an underlying
safety signal.
    Second, FDA proposes that, upon notification by FDA, an applicant
would be required to submit, in a timeframe established by FDA, ICSRs
for any adverse events that would not be required under proposed Sec.
230.220(b)(1). FDA would specify the adverse events to be reported as
well as the reason for requiring its reporting to the Agency. For
example, FDA might take such action if it identifies a potential safety
signal that would not otherwise be reported under Sec.  230.220(b)(1),
but the Agency needs additional information to fully evaluate the
safety signal, including its seriousness and scope.
    Under the proposed requirements in Sec.  230.220, ICSRs would not
need to be submitted for fires associated with oxygen use if the
patient did not also experience a reportable adverse event. Applicants
and nonapplicants who become aware of patients who experience a
reportable adverse event associated with a fire related to oxygen use
(such as burns or smoke inhalation) would be required to submit an
ICSR. Because it is well-known that oxygen accelerates combustion and
that smoking near an oxygen source can cause a fire, FDA believes it is
unnecessary to receive reports in which the patient does not experience
an adverse event.
    Proposed paragraph (c) would describe the process for completing
and submitting an ICSR. Under paragraph (c)(1), FDA proposes to require
submission of ICSRs and ICSR attachments in electronic format that

FDA can process, review, and archive, as described in Sec.
314.80(g)(1). Should this proposed rule be finalized, FDA would
incorporate designated medical gases into existing guidances on
electronic submission of postmarketing safety reports under Sec.
314.80(g)(1), as designated medical gases would be expected to use the
same electronic reporting mechanism. Under Sec.  230.220(c)(1)(ii),
applicants and nonapplicants would be able to request in writing a
temporary waiver of the requirements in Sec.  230.220(c)(1)(i), as
described in Sec.  314.80(g)(2) (see also Ref. 15). Further, FDA would
grant such waivers on a limited basis and for good cause shown.
    Under proposed paragraph (c)(2), FDA proposes additional reporting
requirements. Proposed paragraph (c)(2) would direct applicant and
nonapplicants to submit each ICSR only once and would require
applicants and nonapplicants to submit a separate ICSR for each patient
who experiences an adverse event reportable under paragraph (b). FDA
also proposes to require that adverse event terms described in an ICSR
be coded using standardized medical terminology (e.g., the Medical
Dictionary for Regulatory Activities). The use of standardized medical
terminology facilitates sharing of regulatory information
internationally for human medical products (Ref. 16). Additionally, the
use of standardized medical terminology will facilitate electronic
transmission of safety information in a format that FDA can process,
review, and archive, as required under Sec.  314.80(g)(1). ICSRs
submitted under Sec.  230.220 would be required to contain at least the
minimum data set for an ICSR for an adverse event. The applicant or
nonapplicant would need to actively seek the minimum data set in a
manner consistent with proposed paragraph (f) and document and maintain
records of their efforts. Inclusion of the minimum data set would
similarly facilitate electronic transmission of safety information in
the necessary format for FDA to process, review, and archive. Proposed
paragraph (c)(2) would also require that the applicant or nonapplicant
complete all known, available elements of an ICSR described in proposed
paragraph (d). For adverse events, applicants and nonapplicants would
be required to actively seek any information needed to complete all
applicable elements, consistent with the written procedures that would
be required under proposed paragraph (f), and to document and maintain
records of their efforts to obtain the missing information. However, if
an adverse event is reportable under proposed Sec.  230.220(b) but the
ICSR is missing certain elements listed in paragraph (d) (i.e.,
elements other than the required minimum data set), FDA would still
receive and review the ICSR. Lastly, proposed paragraph (c)(2) would
require an applicant or nonapplicant to submit the following types of
supporting documentation in an ICSR, if available:
     A copy of the autopsy report if the patient died, or a
hospital discharge summary if the patient was hospitalized (to be
submitted as an ICSR attachment in the manner specified); and
     A copy of the published article for each ICSR of an
adverse event obtained from published scientific and medical literature
(to be submitted as an ICSR attachment in the manner specified).
    FDA seeks comment on the burden associated with complying with
these proposed requirements. These proposed requirements also include
required timeframes, translation of foreign language documents, and
cross-referencing in the case of multiple ICSRs related to the same
article.
    Proposed paragraph (d) would describe the information to be
included in an ICSR. This is generally the same list as in Sec.
314.80(f), with a few exceptions. First, FDA is not proposing to
require that the applicant or nonapplicant state whether the product is
a combination product. Second, FDA does not propose to require the
submission to include an expiration date because designated medical
gases are not generally expected to have an expiration date under
proposed part 213. Third, FDA does not propose to require the applicant
or nonapplicant to state whether the product is a prescription or
nonprescription product. With the exception of oxygen for limited uses
identified in section 576(b)(2)(A) of the FD&C Act, all designated
medical gases are for prescription use, and the Agency expects that to
continue to be the case. Fourth, FDA has proposed to combine the
contact information in Sec.  314.80(f)(5)(i) and (ii) into one bullet.
Fifth, we propose to clarify in Sec.  230.220(d)(5)(iv) that the
applicant or nonapplicant would be required to submit the NDA and/or
NADA number for their certification. Lastly, FDA proposes to require
that the applicant or nonapplicant state whether the ICSR is an
expedited report, rather than stating whether the ICSR is a 15-day
alert report.
    Proposed paragraph (e) would contain recordkeeping requirements.
Applicants and nonapplicants would be required to maintain records of
information related to adverse events under proposed Sec.  230.220 for
up to 10 years from the initial receipt of information. These records
would need to be maintained regardless of whether the information was
submitted to FDA. The records would also need to include raw data,
correspondence, and any other information relating to the evaluation
and reporting of adverse event information that is received or
otherwise obtained by the applicant or nonapplicant. These proposed
requirements are generally consistent with the requirements in Sec.
314.80(j). FDA also proposes that, upon written notice, the applicant
or nonapplicant would need to submit any or all of these records to FDA
within 5 calendar days after receipt of the notice. Applicants and
nonapplicants would also need to permit authorized FDA employees to
access, copy, and verify these established and maintained records, at
reasonable times. These proposed requirements will help facilitate the
review of new and emergent safety issues, including of potential safety
signals that may be associated with nonserious adverse events, which
would not be required to be reported to FDA under proposed paragraph
(b)(1).
    Proposed paragraph (f) would require that applicants and
nonapplicants develop written procedures to fulfill their obligations
under proposed Sec.  230.220 for the surveillance, receipt, evaluation,
and reporting of adverse event information. This proposed requirement
is generally consistent with existing requirements in Sec.  314.80(b)
and is appropriate for designated medical gases. Additionally, we
propose to specify that these procedures would need to address employee
training and the obtaining and processing of adverse event information
from other applicants and nonapplicants. Employee training is important
to ensure that all personnel who may receive or handle adverse event
information on the company's behalf fully understand their
responsibilities. Processing adverse event information from other
parties is also critical because of the many layers of distribution
typical for designated medical gases.
    Proposed paragraph (g) would contain proposed patient privacy
provisions. Rather than including patient names and addresses in
reports under proposed Sec.  230.220, proposed paragraph (g) would
recommend that applicants and nonapplicants assign a unique code to
identify patients. Proposed paragraph (g) would recommend that
applicants and nonapplicants include the name of the reporter from whom
the information was received as part of the initial reporter
information, even if the patient

is the reporter. As set forth in FDA's public information regulations
in part 20, FDA generally may not disclose the names of patients,
individual reporters, healthcare professionals, hospitals, and
geographical identifiers submitted to FDA in adverse event reports.
This is similar to the patient privacy provisions for other drugs in
Sec.  314.80(i), though FDA proposes to expand these requirements to
nonapplicants.
5. Animal Designated Medical Gas Adverse Event Reporting Requirements
    Proposed Sec.  230.230 would contain requirements for submission of
adverse event reports related to the use of a designated medical gas in
animals. Proposed Sec.  230.230(a) would govern the types of reports
that would be required to be submitted to FDA.
    Under proposed Sec.  230.230(a)(1), applicants and nonapplicants
must submit adverse event reports to FDA as soon as possible but no
later than within 15 calendar days of first receiving the information.
Reports are required for serious adverse events the applicant or
nonapplicant receives from others as well as reports from published
literature, regardless of whether the applicant or nonapplicant
believes the event is related to the designated medical gas. FDA
proposes an exception to the reporting requirements for the death of an
animal that was administered oxygen, unless the applicant or
nonapplicant becomes aware of evidence to suggest that the
administration of oxygen caused the death. As is the case with human
use of oxygen, FDA expects that oxygen will be administered to animals
that are in critical condition. For such animals, death is expected to
be a common outcome, so unless evidence suggests a causal relationship
between oxygen and the death, FDA does not believe that adverse event
reporting in that instance will shed new light on the safety of oxygen.
    Proposed Sec.  230.230(a)(2) would require that applicants and
nonapplicants report adverse events that do not qualify for serious
adverse event reporting under paragraph (a)(1) if notified by FDA to do
so. This proposed requirement would allow FDA to obtain information
regarding other safety signals if the Agency determines additional
information is necessary to help protect animal or public health.
    As is the case for designated medical gases for human use, FDA
would like to clarify that the proposed rule would not require
submission of reports for fires associated with oxygen use if the
animal patient did not experience an adverse event. Fires associated
with oxygen use would be required to be reported if the animal patient
experiences an adverse event. Because it is known that oxygen
accelerates combustion and that smoking or open flames near an oxygen
source can cause a fire, FDA believes it is not necessary to receive
reports in which the animal patient did not experience a serious
adverse event.
    Proposed Sec.  230.230(a)(3) would state that applicants and
nonapplicants should not resubmit any adverse event reports obtained
from FDA's adverse event reporting database or that FDA forwards to the
applicant or nonapplicant, in order to minimize duplication.
    The format of adverse event reporting for animal use is addressed
in proposed Sec.  230.230(b). FDA proposes to require submission in an
electronic format, and that data in electronic submissions conform to
the data elements in Form FDA 1932 and the Agency's technical documents
on how to provide electronic submissions (e.g., method of transmission
and processing, media, file formats, preparation and organization of
files). The proposed rule would allow FDA to issue updated technical
documents, as necessary. The most current information on submitting
postmarketing safety reports to the Center for Veterinary Medicine
(CVM) in electronic format can be found on CVM's web page at https://www.fda.gov/IndustryReportAnimalAE (see, e.g., ``Instructions for
Electronic Submission of Mandatory Adverse Event Reports to FDA CVM'')
(Ref. 17). As in the corresponding provision for designated medical
gases for human use, under proposed 230.230(b)(2), applicants and
nonapplicants would be able to request in writing a temporary waiver of
the electronic reporting requirements.
    Proposed paragraph (c) contains recordkeeping requirements.
Applicants and nonapplicants must maintain records of information
related to adverse event reports for up to 5 years from the initial
receipt of information. These records must be maintained regardless of
whether the information was submitted to FDA. The records must also
include raw data, correspondence, and any other information relating to
the evaluation and reporting of such information that is received or
otherwise obtained by the applicant or nonapplicant. These proposed
requirements are generally consistent with the requirements in proposed
230.220(e), though FDA proposes a retention period of 5 years,
consistent with other animal safety reporting requirements. FDA also
proposes to require that, upon written notice, the applicant or
nonapplicant must submit these records to FDA within 5 calendar days
after receipt of the notice. Because applicants and nonapplicants would
not be required to submit nonserious adverse event reports, retaining
the ability to collect records not submitted to the Agency would help
FDA address questions that arise as FDA evaluates safety signals.
Applicants and nonapplicants must also permit authorized FDA employees
to access, copy, and verify these established and maintained records,
at reasonable times. These proposed requirements will help facilitate
the review of new and emergent safety issues.
6. Part 4 Postmarketing Safety Reporting Requirements
    As mentioned above, some medical gases are marketed as part of a
combination product. The Agency believes some clarification is needed
regarding the applicability of the postmarketing safety reporting
requirements in part 4, subpart B to such medical gases.
    Because proposed part 230 would only apply to designated medical
gases, medical gases under applications submitted under section 505 of
the FD&C Act would continue to be subject to the postmarketing safety
reporting requirements in part 314. Additionally, if the medical gas is
part of a combination product that received marketing authorization
(e.g., under an application submitted under section 505 of the FD&C
Act), the requirements in part 4, subpart B currently apply. FDA
proposes no changes for such products with regard to safety reporting
requirements.
    As proposed in this section, new part 230 would apply to applicants
and nonapplicants of designated medical gases subject to the
certification requirements in section 576 of the FD&C Act. As explained
in 21 CFR 4.100, part 4, subpart B does not apply to combination
products that have not received marketing authorization. Therefore,
part 4, subpart B would not apply to designated medical gases that are
part of a combination product that did not receive marketing
authorization. However, other reporting requirements may apply, e.g.,
the medical device reporting requirements in 21 CFR part 803 if such
combination product includes a device constituent part. Further, if
proposed part 230 is finalized, the safety reporting requirements
therein would apply to such combination product that includes a
designated medical gas.

VI. Proposed Effective Date

    FDA proposes that any final rule based on this proposal become
effective 18 months after publication in the Federal Register. The
Agency anticipates that some proposed requirements will result in
changes to cylinders as they are returned from service, and that it may
take some time for firms to make required changes to all cylinders. We
believe that 18 months is an appropriate amount of time to enable firms
to make such changes. FDA solicits comment on this proposed compliance
date.

VII. Preliminary Economic Analysis of Impacts

    We have examined the impacts of the proposed 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 proposed 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 this proposed rule would more specifically tailor the
current good manufacturing practice requirements for medical gases, add
new oxygen labeling requirements, clarify the medical gas certification
process, and clarify adverse event reporting requirements, this rule
would create small net cost savings for small entities, and we propose
to certify that the proposed 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 proposing ``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 one year.'' The current threshold after adjustment
for inflation is $165 million, using the most current (2021) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.
    This proposed rule, if finalized, would establish, within part 213,
CGMP regulations specific to medical gases. These proposed regulations
include many of the same categories of requirements as the general drug
CGMP regulations but are tailored to reflect differences in how medical
gases are manufactured, packaged, labeled, stored, and distributed.
This proposed rule, if finalized, would make limited changes to the
labeling requirements of part 201 including requiring that a ``no
smoking'' statement, a ``no vaping'' statement, and graphic warning
symbol be added to oxygen designated medical gas containers to reduce
the risk of fire. This proposed rule, if finalized, would codify and
clarify the process for obtaining a certification to market designated
medical gases. Recommendations for how to request a certification for
designated medical gases are currently included in a draft guidance.
This proposed rule, if finalized, would establish new postmarketing
safety reporting regulations for designated medical gases that would
address human and animal use and more specifically reflect the
development, manufacturing, and distribution of designated medical
gases.
    The costs of this proposed rule, if finalized, would be primarily
driven by new labeling requirements, regulatory clarification leading
to firms becoming compliant with existing requirements, and added CGMP
requirements including a requirement for portable cryogenic containers
to have a working gauge.
    The cost savings of this proposed rule, if finalized, would be
primarily driven by removing CGMP requirements that would not apply to
medical gases, such as removing certain building and facility
requirements, or modifying CGMP requirements so that they would be more
well-tailored to medical gases, which may streamline inspections.
    Table 1 summarizes the estimated benefits and costs of the proposed
rule, if finalized. The annualized benefits would range from $0.00
million to $6.48 million with a primary estimate of $3.24 million over
a 10-year span at a 7 percent discount rate. Annualized at a 3 percent
discount rate these benefits would range from $0.00 million to $6.86
million with a primary estimate of $3.43 million. The annualized costs
would range from $1.38 million to $4.95 million with a primary estimate
of $3.03 million at a 7 percent discount rate. Annualized at a 3
percent discount rate these costs would range from $1.23 million to
$4.77 million with a primary estimate of $2.88 million.
    The present value of the estimated benefits would range from $0.00
million to $51.98 million with a primary estimate of $26.02 million at
a 7 percent discount rate and from $0.00 million to $65.37 million with
a primary estimate of $32.73 million at a 3 percent discount rate. The
present value of the estimated costs would range from $11.06 million to
$39.71 million with a primary estimate of $24.33 million at a 7 percent
discount rate and from $11.74 million to $45.49 million with a primary
estimate of $27.49 million at a 3 percent discount rate.

                                  Table 1--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                          Primary       Low        High    ------------------------------------
               Category                  estimate    estimate    estimate      Year      Discount     Period                      Notes
                                                                              dollars    rate (%)     covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $millions/          $3.24       $0.00       $6.43        2020           7          10  Most benefits are cost savings to
     year.                                    3.43        0.00        6.86        2020           3          10   industry while the remaining are cost
                                                                                savings for FDA due to a more
                                                                                streamlined inspection process.
    Annualized Quantified.............  ..........  ..........  ..........  ..........           7  ..........
                                        ..........  ..........  ..........  ..........           3  ..........
                                       -----------------------------------------------------------------------------------------------------------------
    Qualitative.......................  ..........  ..........  ..........  ..........  ..........  ..........
--------------------------------------------------------------------------------------------------------------------------------------------------------

Costs:
    Annualized Monetized $millions/           3.03        1.38        4.95        2020           7          10
     year.                                    2.88        1.23        4.77        2020           3          10
    Annualized Quantified.............  ..........  ..........  ..........  ..........           7  ..........
                                        ..........  ..........  ..........  ..........           3  ..........
                                       -----------------------------------------------------------------------------------------------------------------
    Qualitative.......................  ..........  ..........  ..........  ..........  ..........  ..........
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized Monetized        ..........  ..........  ..........  ..........           7  ..........
     $millions/year.                    ..........  ..........  ..........  ..........           3  ..........
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
                                       -----------------------------------------------------------------------------------------------------------------
    Other Annualized Monetized          ..........  ..........  ..........  ..........           7  ..........
     $millions/year.                    ..........  ..........  ..........  ..........           3  ..........
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: None.............................................................................................................
    Small Business: Not significant.....................................................................................................................
    Wages: None.........................................................................................................................................
    Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    FDA conducted a regulatory flexibility analysis of the impact of
the proposed rule on small entities. Approximately 41 percent of
domestic entities that would be affected by the proposed rule are small
according to Small Business Administration (SBA) size standards. We
estimate that the highest single year cost for a firm could be as high
as 0.788 percent while the average costs to receipts ratio is 0.007
percent. Therefore, our analysis of the impact of the proposed rule on
small entities suggests that small firms will not be significantly
affected by the proposed regulation, if finalized.
    We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. The full
preliminary analysis of economic impacts is available in the docket for
this proposed rule (Ref. 18) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h), (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.

IX. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that
are subject to review by OMB under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3521). A description of these provisions is given in
the Description section of this document with an estimate of the annual
reporting, recordkeeping, and third-party disclosure burden. Included
in the burden 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.
    FDA invites comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
    Title: Current Good Manufacturing Practice, Certification,
Postmarketing Safety Reporting, and Labeling Requirements for Certain
Medical Gases.
    Description: This rulemaking is amending existing regulations and
establishing new regulatory requirements pertaining to medical gases.
    Description of Respondents: Respondents to this information
collection are entities who manufacture, process, pack, label, or
distribute certain medical gases.

1. Product Jurisdiction and Combination Products; OMB Control No. 0910-
0523--Revision

    FDA recognizes that some medical gases are marketed as part of a
combination product. For example, a medical gas may be marketed with a
device constituent part (for example, a portable liquid oxygen unit or
a pressure regulator). Combination products are subject to information
collection provisions found in 21 CFR parts 3 and 4, which prescribe
content and format requirements associated with marketing applications,
together with applicable recordkeeping and reporting requirements.
    FDA proposes to revise provisions in part 4 to account for
combination products that contain a medical gas, as FDA proposes
medical gases to be subject to proposed part 213, and to clarify (where
appropriate) applicable medical gases requirements throughout part 4.
We believe that the revisions impose no new burden associated with
information collection currently approved under OMB control number
0910-0523 and invite comment on our assumptions.

2. Labeling Requirements for Prescription Drugs; OMB Control No. 0910-
0572--Revision

    We estimate the burden of the information collection as follows:

                                               Table 2--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                   Number of
        Activity; proposed CFR section            Number of     disclosures per     Total annual        Average burden  per disclosure       Total hours
                                                 respondents     respondent \2\   disclosures \2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Labeling of bulk or transport containers used           1,696               2.36            4,000  0.1 (6 minutes)........................           400
 to hold designated medical gases; Sec.
 201.161(b).
On the container label, identify the owner of           1,696               2.36            4,000  0.1 (6 minutes)........................           400
 a designated medical gas container or a
 container of a medically appropriate
 combination of designated medical gases. If
 the container owner is not the manufacturer,
 packer, or distributor of the gas, identify
 that information on the label; Sec.
 201.328(d).
                                              ----------------------------------------------------------------------------------------------------------
    Total....................................  ..............  .................            8,000  .......................................           800
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with the information collection.
\2\ Totals have been rounded to the nearest whole number.

    Regulations in part 201 govern the statement of ingredients and
declaration of net quantity of contents with regard to prescription
drug product labeling.
    The proposed revisions to the regulations would require that firms
identify bulk or transport containers with the name of the product
contained therein and that containers be accompanied by documentation
that identifies the product as meeting applicable compendial standards.
Bulk or transport containers are excluded from the proposed definition
of final use containers. Because these large containers are removed
from the point of care and we do not expect that patients and
healthcare practitioners will use them directly to administer
designated medical gas, FDA does not believe that firms' bulk or
transport containers need to bear the information that we would require
under proposed Sec.  201.161(a). However, to prevent mix-ups, it is
essential that the identity of the gas inside such containers is
evident to individuals who handle and transport the containers. FDA
expects that these proposed requirements will help prevent mix-ups and
ensure that recipients of medical gases in bulk or transport containers
are provided information indicating that such gases meet applicable
compendial standards.
    Based on our experience with similar information collection, we
estimate that 1,696 firms will label 4,000 containers and assume firms
will expend 6 minutes (0.1 hours) to identify the containers with the
name of the product and place documentation that identifies the product
as meeting applicable compendial standards, totaling 400 hours
annually.
    Proposed Sec.  201.328(d) would provide that the owner of a
designated medical gas container or a container of a medically
appropriate combination of designated medical gases may be identified
on the container. This statement may appear on a separate sticker or
decal on the container (that is, it need not be contiguous with other
labeling on the container), but if the container owner is not the
manufacturer, packer, or distributor of the gas, that information shall
be clearly stated. FDA recognizes the complex distribution system for
designated medical gases and medically appropriate combinations of
designated medical gases and the importance of each entity in the
distribution chain being clearly identified so that patients and
healthcare professionals can contact the appropriate entity if
necessary. We intend for this provision to help ensure that appropriate
entities can be contacted about quality issues or adverse events. In
addition, the proposed labeling requirement would facilitate the return
of cylinders to owners who may not also be medical gas manufacturers.
FDA proposes that including the container owner's information will not
cause the container owner to be a ``relabeler'' for purposes of FDA's
registration and listing requirements.
    Based on our experience with similar information collection, we
estimate that 1,696 firms will identify on a designated medical gas
container or a container of a medically appropriate combination of
designated medical gases the name of the container owner who may not
also be the manufacturer, packer, or distributor of the gas. We assume
firms would include this label on 4,000 containers and will expend 6
minutes (0.1 hours) to perform this activity, totaling 400 hours
annually.

3. Current Good Manufacturing Practice for Medical Gases; OMB Control
No. 0910-NEW

    We estimate the burden of the information collection as follows:

                                                   Table 3--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                   Number of
                                                  Number of       records per     Total annual
        Activity; proposed CFR section          recordkeepers     recordkeeper     records \2\       Average burden  per recordkeeping       Total hours
                                                                      \2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
New Start Up SOP; Sec.   213.42..............            1,696                1           1,696  13.......................................        22,048
SOP Maintenance; Sec.   213.42...............            1,696                1           1,696  0.65 (39 minutes)........................         1,102
New Start Up SOP; Sec.   213.208.............            1,696                1           1,696  13.......................................        22,048
SOP Maintenance Sec.   213.208...............            1,696                1           1,696  0.65 (39 minutes)........................         1,102
Documentation of completion of training; Sec.            1,696               10          16,960  0.083 (5 minutes)........................         1,408
   213.25(a).
Consultants' records of sufficient education,            1,696            0.336             571  0.5 (30 minutes).........................           286
 training, and experience, or any combination
 thereof; Sec.   213.34.
Firms' records of equipment maintenance and              1,696          43.7676          74,230  0.25 (15 minutes)........................        18,557
 cleaning; Sec.   213.67(c).
Maintain records for modifications to                    1,696            6.734          11,420  0.25 (15 minutes)........................         2,855
 automatic, mechanical, and electronic
 equipment; Sec.   213.68(d).

Receipt and storage of incoming designated               1,380              417         575,460  0.25 (15 minutes)........................       143,865
 medical gases; Sec.   213.82(a).
Records of rejected components; Sec.   213.89            1,380             24.2          33,400  0.083 (5 minutes)........................         2,772
Maintain records for each shipment received              1,696          43.7676          74,230  0.25 (15 minutes)........................        18,558
 of each different labeling and packaging
 material indicating receipt, examination,
 and whether accepted or rejected; Sec.
 213.122(c).
Document results of inspections in the batch             1,696           67.334         114,200  0.25 (15 minutes)........................        28,550
 production records; Sec.   213.130(e).
Maintain written records so that data therein            1,696             0.27             457  0.25 (15 minutes)........................           114
 can be used for evaluating, at least
 annually, the quality standards of each
 medical gas to determine the need for
 changes in specifications or manufacturing
 or control procedures; Sec.   213.180(d).
Maintain record of equipment cleaning and use            1,696             1.76           2,969  0.16 (10 minutes)........................           475
 log maintenance; Sec.   213.182.
Maintain records for components, medical gas             1,696            2.626           4,454  0.33 (19.8 minutes)......................         1,470
 containers and closures, and labeling; Sec.
  213.184.
Maintain master production and control                   1,696           13.467          22,840  2........................................        45,680
 records; Sec.   213.186.
Maintain batch production and control                    1,696           21.883          37,115  1.3 (78 minutes).........................        48,250
 records; Sec.   213.189.
Maintain record of the investigation; Sec.               1,696             2.69           4,568  1........................................         4,568
 213.192(a).
Maintain laboratory records; Sec.                        1,696           33.667          57,100  0.5 (30 minutes).........................        28,550
 213.194(b) through (e).
Maintain distribution records; Sec.   213.196            1,696           33.667          57,100  0.25 (15 minutes)........................        14,275
Maintain written records of each complaint;              1,696            6.733          11,420  1........................................        11,420
 Sec.   213.198(b).
                                              ----------------------------------------------------------------------------------------------------------
    Total....................................  ...............  ...............       1,105,278  .........................................       417,953
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with the information collection.
\2\ Totals have been rounded to the nearest whole number.

    FDA proposes to establish part 213 setting forth CGMP requirements
applicable to medical gases. If finalized, part 213 would apply to
firms that manufacture a medical gas and would also establish
requirements applicable to firms that subsequently combine, commingle,
refill, or distribute medical gases.
    The proposed regulations include recordkeeping requirements
pertaining to personnel qualifications and responsibilities of persons
who are engaged in the manufacturing, processing, packing, or holding
of a medical gas.
    Provisions under proposed Sec.  213.42(c) include recordkeeping to
document the development and implementation of written procedures to
ensure that firms maintain a clean condition for any building used to
manufacture, process, pack, or hold a medical gas so as to ensure the
safety, identity, strength, quality, and purity of the gas. Firms would
need to develop written procedures that apply to maintaining and
cleaning buildings. Based on available data, we estimate 1,696 firms
will each develop and implement written procedures to maintain and
clean buildings. We assume it will take 13 hours to perform this
activity, totaling 22,048 hours annually. Firms would also maintain
these procedures. Based on available data, we estimate 1,696 firms
would each maintain written procedures to maintain and clean buildings.
We assume it will take 39 minutes (0.65 hours) to perform this
activity, totaling 1,102 hours annually.
    Similarly, under proposed Sec.  213.208, firms would be required to
develop and implement written procedures for the holding, testing, and
use of salvaged medical gases. Based on available data, we estimate
1,696 firms will develop and implement written procedures for the
holding, testing, and use of salvaged medical gases. We assume it will
take 13 hours for firms to perform this activity, totaling 22,048 hours
annually. Based on available data, 1,696 firms will prepare written
procedures (1 procedure each) for the holding, testing, and use of
salvaged medical gases. We assume it takes 0.65 hours to perform this
activity, totaling 1,102 hours annually.
    The proposed regulations would provide that employee training be
included in the firm operations. Recordkeeping would be established to
demonstrate that qualified individuals conduct training on a continuing
basis and with sufficient frequency to allow employees to remain
familiar with applicable requirements. Based on available data, we
estimate that 1,696 firms will prepare written documentation pertaining
to employee training. We assume 10 employees per firm will create
16,960 records (10 records per firm) and that it will take 5 minutes
(0.083 hours) to prepare the records, for a total of 1,408 hours
annually.