Under proposed Sec.  213.34, records demonstrating that consultants
have sufficient education, training, and experience, or any combination
thereof, to advise on the subject for which they are retained will be
required. Based on available data, we estimate that 1,696 firms will
maintain 571 records of consultants' education, training, and
experience, or any combination thereof and assume it will take 30
minutes (0.5 hours) to perform this activity, totaling 286 hours
annually.
    Based on available data, we estimate that 1,696 firms will maintain
74,230 records of equipment maintenance and cleaning and assume it will
take 15 minutes (0.25 hours) to perform this activity, totaling 18,557
hours annually.
    Based on available data, we estimate 1,696 firms will develop and
implement 11,420 written procedures for automatic, mechanical, and
electronic equipment and assume firms will expend 15 minutes (0.25
hours) to perform this activity, totaling 2,855 hours annually.
    As provided for in the proposed regulations, if an incoming
designated medical gas is obtained from a supplier other than the
original manufacturer, the shipment would also need to include specific
information. To ensure the reliability of appropriate assessment and
testing, firms will be required to establish and maintain a program to
ensure the reliability of the supplier's capabilities through
appropriate assessment and testing procedures. Based on assumptions
found in our Preliminary Regulatory Impact Analysis (PRIA), we estimate
that 1,380 firms would verify and document records upon receipt of a
designated medical gas. We assume firms will maintain

575,460 records (417 records each (1 delivery per week of oxygen for 1
year (52 deliveries) plus 1 delivery per night of nitrogen for 1 year
(365 deliveries)). We further assume firms will expend 15 minutes (0.25
hours) each (104 hours in total for each firm) to perform this
activity, totaling approximately 143,865 hours annually.
    Proposed Sec.  213.89 would require that firms identify and control
rejected components, containers, and closures under a quarantine system
designed to prevent their use in operations for which they are
unsuitable. Proposed Sec.  213.89 also applies to incoming designated
medical gases. Quarantine systems would not need to include physical
quarantining because other methods can adequately ensure that
unsuitable products are not used. Based on assumptions found in section
II.F.4.b of the PRIA, we estimate that 1,380 downstream firms would
need to assess and document 33.4 million medical gas components,
containers, and closures annually. We assume that firms would reject 0
to 0.1 percent of all containers. These firms will maintain a total of
33,400 records of rejected components and we assume will expend 5
minutes (0.083 hours) to perform this activity, totaling 2,772 hours
annually.
    Under proposed Sec.  213.122(c), firms would need to maintain
records for each shipment received of each different labeling and
packaging material indicating receipt, examination, and whether
accepted or rejected. Based on available data, we estimate 1,696 firms
will prepare 74,230 records to document each shipment received of each
different labeling and packaging material indicating receipt,
examination, and whether accepted or rejected. We assume it will take
15 minutes (0.25 hours) to perform this activity, totaling 18,558 hours
annually.
    Under proposed 213.130(e), firms would need to document results of
inspections concerning packaging and labeling in the batch production
records. Based on available data, we estimate 1,696 firms will document
results of inspections in the batch production records in approximately
114,200 records. We assume it will take 15 minutes (0.25 hours) per
record to perform this activity, totaling 28,550 hours annually.
    As described in section V.B.11 of this document and proposed Sec.
213.180(d), firms would need to maintain written records so that data
therein 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. Based on
available data, we estimate 1,696 firms will prepare 457 records. We
assume it will take 15 minutes (0.25 hours) to perform this activity,
totaling 114 hours annually.
    Under proposed Sec.  213.182 and as described in section V.B.11 of
this document, firms would need to maintain a written record of major
equipment cleaning, maintenance (except routine maintenance such as
lubrication and adjustments), and use. Based on available data, we
estimate 1,696 firms will prepare 2,969 records documenting major
equipment cleaning, maintenance (except routine maintenance such as
lubrication and adjustments), and use. We assume it will take 10
minutes (0.16 hours) to perform this activity, totaling 475 hours
annually.
    As described in section V.B.11 of this document and under proposed
Sec.  213.184, firms would need to maintain certain records concerning
components, medical gas containers and closures, and labeling. Based on
assumptions found in our PRIA, we estimate 1,696 firms will prepare
4,454 records for components, medical gas containers and closures, and
labeling. We assume firms will expend 19.8 minutes (0.33 hours) to
perform this activity, totaling 1,470 hours annually.
    As discussed in section V.B.11 of this document and estimates for
the number of firms calculated throughout the PRIA, under proposed
Sec.  213.186, to ensure uniformity from batch to batch, firms would
need to prepare, date, and sign master production and control records
for each medical gas. Based on data from existing information
collection requests and estimates for the number of firms calculated
throughout the PRIA, we estimate 1,696 firms will prepare and maintain
approximately 22,840 master production and control records and assume
it will require 2 hours for firms to perform this activity, totaling
45,680 hours annually.
    Under proposed Sec.  213.189 and as described in section V.B.11 of
this document, firms would need to maintain batch production and
control records. These records would need to include documentation that
the firm has accomplished each significant step in the manufacturing,
processing, packing, or holding of the medical gas produced. Based on
data from existing information collection requests and estimates for
the number of firms calculated throughout the PRIA, we estimate 1,696
firms will prepare and maintain 37,115 batch production and control
records. We assume it will require 78 minutes (1.3 hours) for firms to
perform this activity, totaling 48,250 hours annually.
    Section V.B.11 of this document and proposed Sec.  213.192(a)
describe production record review. Per paragraph (a), firms would need
to maintain a written record of the investigation and include the
conclusions and followup. Based on data from existing information
collection requests and estimates for the number of firms calculated
throughout the PRIA, we estimate 1,696 firms will prepare and maintain
4,568 laboratory records and that it will require 1 hour for firms to
perform this activity, totaling 4,568 hours annually.
    Under proposed Sec.  213.194(b) through (e) and as described in
section V.B.11 of this document, firms would need to maintain certain
laboratory records. Based on available data, we estimate 1,696 firms
will prepare and maintain 57,100 laboratory records and assume it will
require 30 minutes (0.5 hours) for firms to perform this activity,
totaling 28,550 hours annually.
    As described in section V.B.11 of this document, proposed Sec.
213.196 describes certain proposed requirements for distribution
records. Based on available data, we estimate 1,696 firms will prepare
and maintain 57,100 distribution records and assume it will require 15
minutes (0.25 hours) for firms to perform this activity, totaling
14,275 hours annually.
    As discussed under proposed Sec.  213.198(b), firms would be
required to maintain written records of each complaint regarding
medical gases. Our full discussion is shown in section V.B.11 of this
document. Based on assumptions found in our PRIA, we estimate 1,696
firms will maintain 11,420 records of complaints. We assume it will
require approximately 1 hour for firms to perform this activity,
totaling 11,420 hours annually.

4. Certification Process and Postmarketing Quality and Safety
Reporting; OMB Control No. 0910-NEW

                                  Table 4--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
 Activity; proposed CFR section      Number of     responses per   Total annual   Average burden    Total hours
                                    respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
Submission of certification                    5               1               5               3              15
 requests and certification form
 that includes any resubmissions
 and amendments to pending
 requests; Sec.   230.50........
Submission of supplements to                   4               1               4               3              12
 certification requests and
 other changes; Sec.   230.70...
Submission of requests to                      2               2               4               2               8
 transfer ownership of
 certification, including new
 address and the owner's
 submission of any change in the
 conditions in the granted
 certification; Sec.   230.72...
Annual reports; Sec.   230.80...              50            2.16             108               2             216
Field alert reports; Sec.                  1,380           0.002               3               8              24
 230.205........................
CDER: Submission of ICSRs (Sec.            1,430            0.12             172               6           1,032
  230.220(a) through (d)).......
CDER's maintenance of records              1,430            0.48             686              16          10,976
 for human designated medical
 gas ICSR requirements (Sec.
 230.220(e))....................
CVM's recordkeeping requirements           1,696          0.0044             7.5               5            37.5
 related to adverse event
 reports (Sec.   230.230(c))....
CVM: Submission of adverse event           1,696          0.0044             7.5               5            37.5
 reports; Sec.   230.230........
CVM: Waiver request from                   1,696          0.0044             7.5               5            37.5
 electronic submission
 requirement; Sec.   230.230....
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............         1,004.5  ..............        12,395.5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Totals have been rounded to the nearest whole number.

    Proposed Sec.  230.50 (see section V.C.2 of this document) would
establish the general requirements for requesting a designated medical
gas certification for all submission types and would outline the
information that must be included in certification request submissions.
    The proposed regulations would require applicants to include
facility information in certification requests. Such information would
include, among others, name and address of the original manufacturing
facility or facilities where the gas is or will be manufactured.
    Proposed section 230.50 would also provide for the submission of
additional information if FDA deems it appropriate to determine whether
a medical gas meets the definition of a designated medical gas. This
information would generally be in the form of a written request by FDA
for the additional information.
    Based on assumptions found in our PRIA, we estimate that five
respondents will submit a total of five certification requests
annually, including certification forms for original and resubmissions.
We assume each certification request will require 3 hours to prepare
and submit, totaling 15 hours annually.
    Under proposed Sec.  230.65, applicants would be allowed 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 before the certification is deemed granted. Upon an
applicant's withdrawal of a certification request, FDA would retain the
certification request, and if the applicant requests a copy via FOIA
request, FDA would provide it pursuant to the fee schedule in FDA's
public information regulations. Since the passage of FDASIA, FDA has
received several certification requests but has not received any
withdrawal requests. FDA has no other data on which to provide a burden
estimate. Therefore, the Agency does not expect to receive withdrawal
requests except in exceedingly rare situations.
    Proposed Sec.  230.70, as discussed in section V.C.3 of the
proposed rule would require applicants to submit a supplement if any
information in the granted certification has changed. The proposed
regulation would prescribe information to be included in a supplement
submission.
    Based on our experience with similar information collection, we
estimate four applicants will submit supplements and assume, each
submission will require 3 hours to prepare, totaling 12 hours annually.
    Proposed Sec.  230.72 would govern changes in ownership of a
granted certification. An example of when a change in ownership could
occur is during a merger or acquisition. Upon a change in ownership,
the regulations would require that both the new and previous owner
notify FDA.
    Based on related submissions received by FDA over the last few
years and averaged accordingly, we estimate two respondents will submit
four letters or other supporting documents, and assume it will take 2
hours to complete this task, totaling 8 hours annually.
    To assist respondents with the proposed submission requirements
associated with proposed Sec.  230.80 (annual reports), we are
developing an annual report form.
    Based on our records and informal requests received upon announcing
this rulemaking, we estimate that 50 applicants will submit to FDA 108
annual reports (a total of 108 reports). We assume firms will expend 2
hours to perform this activity, totaling 216 hours annually.
    Our estimate associated with proposed requirements in Sec.  230.205
for field alert reporting for designated medical gases is based on our
experience with similar reports that FDA received in 2019 and 2020.
    We estimate that 1,380 applicants and nonapplicants will submit to
FDA three FARs. We assume respondents will expend approximately 8 hours
to perform this activity, totaling 24 hours annually.
    Proposed Sec.  230.210 would require that applicants and
nonapplicants promptly review all safety information that the applicant
or nonapplicant receives or otherwise obtains from any source
(including both foreign and domestic sources). Applicants and
nonapplicants would generate reports from their review and submit them
under proposed Sec. Sec.  230.220 and 230.230.
    As described under proposed Sec.  230.220(a) through (d) (see
section V.D.4 of this document), firms would be required to submit
ICSRs associated with the use of a designated medical gas in humans.
    Proposed Sec.  230.220 (see section V.D.4 of this document) 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),
applicants and nonapplicants would be required to submit each ICSR as
soon as possible, but no later than 15 calendar days from the date the
applicant or nonapplicant has met the reporting criteria under proposed
Sec.  230.220(b) and acquired a

minimum data set for an ICSR for that adverse event.
    Under proposed Sec.  230.220(a)(3), applicants and nonapplicants
would submit new information they receive or otherwise obtain about a
previously submitted ICSR to FDA. The proposed regulation would
prescribe reporting schedules to ensure FDA becomes aware of any new
information that arises about the adverse event.
    Based on assumptions found in our PRIA and a review of safety
report data, we estimate that 1,430 applicants and nonapplicants will
submit to FDA 172 ICSRs annually. We assume it will take 6 hours for
respondents to perform this activity, totaling 1,032 hours annually.
    Proposed Sec.  230.220(b) would describe the types of ICSRs that
applicants and nonapplicants would need to report for human use. Under
proposed Sec.  230.220(b)(1), applicants and nonapplicants would be
required to submit ICSRs for serious adverse events. Under proposed
Sec.  230.220(b)(2), FDA proposes to require an applicant to report to
FDA, in a timeframe established by FDA, ICSRs for any adverse events
that would not be required under proposed Sec.  230.220(b)(1) upon
notification by FDA.
    Proposed Sec.  230.220(e) would prescribe content and format
requirements for records pertaining to human designated medical gas
adverse events. For a period of 10 years from the initial receipt of
information, each applicant or nonapplicant would be required to
maintain records of information relating to adverse events, whether or
not submitted to FDA. These records would need to include raw data,
correspondence, and any other information relating to evaluating and
reporting adverse event information that is received or otherwise
obtained by the applicant or nonapplicant. Upon written notice by FDA,
the applicant or nonapplicant would need to submit any and all of these
records to FDA within 5 calendar days after receipt of the notice. The
applicant or nonapplicant would need to permit any authorized FDA
employee, at reasonable times, to access, copy, and verify the
established and maintained records described in this section.
    Based on available data, we estimate that 1,430 manufacturers will
create 686 records pertaining to human designated medical gas
requirements and that it would take approximately 16 hours to perform
this activity, totaling 10,976 hours.
    Proposed Sec.  230.220(c) and (d) would include additional
requirements for the content and format of ICSRs.
    Based on available data, we assume all firms (1,696) will
distribute designated medical gases for human and animal use and invite
comment on our assumption.
    Under proposed Sec.  230.230(a)(1), an applicant or nonapplicant
would need to submit serious adverse events related to the use of a
designated medical gas in animals to FDA as soon as possible but no
later than 15 calendar days from first receiving the information. The
applicant or nonapplicant would need to submit the report to FDA in
electronic format as described under proposed Sec.  230.230(b)(1) of
this section, unless the applicant or nonapplicant obtains a waiver
under proposed Sec.  230.230(b)(2) of this section or FDA requests the
report in an alternate format.
    Under proposed Sec.  230.230(a)(2), upon notification by FDA,
applicants and nonapplicants would need to submit reports of adverse
events associated with the use of a designated medical gas in animals
that do not qualify for reporting under proposed Sec.  230.230(a)(1) of
this section. The notice would specify the adverse events to be
reported and the reason for requiring the reports.
    We estimate approximately 7.5 records will be submitted per year
and estimate that it will take approximately 5 hours to perform this
activity, totaling 37.5 hours. We also estimate that approximately 7.5
reports will be maintained yearly and estimate it will take 5 hours to
perform this activity, totaling 37.5 hours.
    Under proposed Sec.  230.230(b)(2), an applicant or nonapplicant
could request, in writing, a temporary waiver of the electronic
submission requirements under proposed Sec.  230.230(b)(1). An
applicant or nonapplicant would need to provide the initial request by
telephone or email to CVM's Division of Veterinary Product Safety, with
prompt written followup submitted as a letter to the granted
certification or certifications. FDA would grant waivers on a limited
basis for good cause shown. If FDA grants a waiver, the applicant or
nonapplicant would need to comply with the conditions for reporting
specified by FDA upon granting the waiver.
    We estimate approximately 7.5 waiver requests will be submitted
annually and estimate it will take 5 hours to perform this activity,
totaling 37.5 hours annually.
    To ensure that comments on information collection are received, OMB
recommends that written comments be through reginfo.gov (see
ADDRESSES). All comments should be identified with the title of the
information collection.
    In compliance with the PRA (44 U.S.C. 3407(d)), we have submitted
the information collection provisions of this proposed rule to OMB for
review. These information collection requirements will not be effective
until FDA publishes a final rule, OMB approves the information
collection requirements, and the rule goes into effect. FDA will
announce OMB approval of these requirements in the Federal Register.

X. Federalism

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

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the proposed rule does not contain policies that would
have a substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.

XII. References

    The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of

the date this document publishes in the Federal Register, but websites
are subject to change over time.

*1. Food and Drug Administration (FDA) draft guidance for industry
``Certification Process for Designated Medical Gases,'' November
2015, available at https://www.fda.gov/media/85013/download.
*2. FDA, Medical Gas Regulation Public Workshops, available at
https://www.fda.gov/drugs/news-events-human-drugs/medical-gas-regulation-public-workshops.
3. Lacasse, Y., M. L[eacute]gar[eacute], and F. Maltais, ``E-
cigarette Use in Patients Receiving Home Oxygen Therapy,'' Canadian
Respiratory Journal, vol. 22, no. 2, 83-85, March/April 2015.
https://downloads.hindawi.com/journals/crj/2015/215932.pdf.
*4. Benowitz, N.M., ``E-cigarette Explosion in a Patient Room,''
PSNet, April 2019. https://psnet.ahrq.gov/web-mm/e-cigarette-explosion-patient-room.
5. Fire & Rescue NSW, ``Fire Research Report--E-Cigarette Fire Risks
and Reported Incidents,'' January 30, 2015. https://www.icao.int/safety/dangerousgoods/dgpwg15/dgpwg.15.ip.004.2.en.app.pdf.
6. Rudy, S.F. and E.L. Durmowicz, ``Electronic Nicotine Delivery
Systems: Overheating, Fires and Explosions,'' Tobacco Control,
26:10-18, 2017. https://tobaccocontrol.bmj.com/content/tobaccocontrol/26/1/10.full.pdf.
*7. FDA, Response to petition submitted by Compressed Gas
Association, Docket No. 87P-0167/CP1, September 19, 1996.
*8. FDA, Public Health Advisory, ``Guidance for Hospitals, Nursing
Homes, and Other Health Care Facilities,'' March 2001, available at
https://www.fda.gov/media/70999/download.
*9. Kreiter, P., T.G. Bizjak, and R.L. Friedman, ``Preventing
Patients From Receiving Leaking or Empty Containers of Medical Gas:
A Review of Inspectional Findings From 2003 to 2021,'' CDER Office
of Manufacturing Quality, December 2021, U.S. Food and Drug
Administration.
*10. CDER, Manual of Policies and Procedures 5310.7 Rev. 1,
``Acceptability of Standards from Alternative Compendia (BP/EP/
JP),'' available at https://www.fda.gov/media/72412/download.
*11. FDA guidance for industry ``Specification of the Unique
Facility Identifier (UFI) System for Drug Establishment
Registration,'' November 2014, available at https://www.fda.gov/media/89926/download.
*12. FDA draft guidance for industry ``Postmarketing Safety
Reporting for Human Drug and Biological Products Including
Vaccines,'' March 2001, available at https://www.fda.gov/media/73593/download.
*13. FDA guidance for industry ``Field Alert Report Submission--
Questions and Answers,'' July 2021, available at https://www.fda.gov/media/114549/download.
*14. FDA, Compliance Program Guidance Manual 7356.002E, ``Compressed
Medical Gases,'' March 15, 2015, available at https://www.fda.gov/media/75194/download.
*15. FDA draft guidance for industry ``Providing Submissions in
Electronic Format--Postmarketing Safety Reports,'' June 2014,
available at https://www.fda.gov/media/71176/download.
16. International Council on Harmonization, MedDRA, available at
https://www.ich.org/page/meddra.
*17. FDA, Veterinary Adverse Event Reporting for Manufacturers,
available at https://www.fda.gov/IndustryReportAnimalAE.
*18. FDA, Preliminary Regulatory Impact Analysis: Current Good
Manufacturing Practice, Certification, Postmarketing Safety
Reporting, and Labeling Requirements for Certain Medical Gases,
available at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

List of Subjects

21 CFR Part 4

    Biologics, Drugs, Human cells and tissue-based products, Medical
devices.

21 CFR Part 16

    Administrative practice and procedure.

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 210

    Drugs, Packaging and containers.

21 CFR Part 211

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

21 CFR Part 213

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

21 CFR Part 230

    Administrative practice and procedure, Animal drugs, Drugs,
Reporting and recordkeeping requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 514

    Administrative practice and procedure, Animal drugs, Confidential
business information, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, the
Food and Drug Administration proposes to amend chapter I of title 21 of
the Code of Federal Regulations as follows:

PART 4--REGULATION OF COMBINATION PRODUCTS

0
1. The authority citation for part 4 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360b-
360f, 360h-360j, 360l, 360hh-360ss, 360aaa-360bbb, 360ddd, 360ddd-1,
371(a), 372-374, 379e, 381, 383, 394; 42 U.S.C. 216, 262, 263a, 264,
271.

0
2. Revise Sec.  4.2 to read as follows:

Sec.  4.2  How does FDA define key terms and phrases in this subpart?

    The terms listed in this section have the following meanings for
purposes of this subpart:
    Biological product has the meaning set forth in Sec.  3.2(d) of
this chapter. A biological product also meets the definitions of either
a drug or device as these terms are defined under this section.
    Combination product has the meaning set forth in Sec.  3.2(e) of
this chapter.
    Constituent part is a drug, device, or biological product that is
part of a combination product.
    Co-packaged combination product has the meaning set forth in Sec.
3.2(e)(2) of this chapter.
    Current good manufacturing practice operating system means the
operating system within an establishment that is designed and
implemented to address and meet the current good manufacturing practice
requirements for a combination product.
    Current good manufacturing practice requirements means the
requirements set forth under Sec.  4.3(a) through (e).
    Device has the meaning set forth in Sec.  3.2(f) of this chapter. A
device that is a constituent part of a combination product is
considered a finished device within the meaning of the QS regulation.
    Drug has the meaning set forth in Sec.  3.2(g) of this chapter and
includes medical gas as defined in section 575(2) of the Federal Food,
Drug, and Cosmetic Act. Medical gas includes designated medical gases
as defined in section 575(1) of the Federal Food, Drug, and Cosmetic
Act and medical gases approved under section 505 of the Federal Food,
Drug, and Cosmetic Act. A drug other than a medical gas that is a
constituent part of a combination product is considered a drug product
within the meaning of the drug current good manufacturing practice
regulations (CGMPs). A drug that is a medical gas

that is a constituent part of a combination product is considered a
medical gas within the meaning of the medical gas CGMPs.
    Drug CGMPs refers to the current good manufacturing practice
regulations set forth in parts 210 and 211 of this chapter.
    HCT/Ps refers to human cell, tissue, and cellular and tissue-based
products, as defined in Sec.  1271.3(d) of this chapter. An HCT/P that
is not solely regulated under section 361 of the Public Health Service
Act may be a constituent part of a combination product. Such an HCT/P
is subject to part 1271 of this chapter and is also regulated as a
drug, device, and/or biological product.
    Manufacture includes, but is not limited to, designing,
fabricating, assembling, filling, processing, testing, labeling,
packaging, repackaging, holding, and storage.
    Medical gas CGMPs refers to the current good manufacturing practice
regulations set forth in part 213 of this chapter.
    QS regulation refers to the quality system regulation in part 820
of this chapter.
    Single-entity combination product has the meaning set forth in
Sec.  3.2(e)(1) of this chapter.
    Type of constituent part refers to the category of the constituent
part, which can be either a biological product, a device, or a drug, as
these terms are defined under this section.
0
3. Amend Sec.  4.3 by revising paragraphs (a), (c), and (d), and adding
paragraph (e) as follows:

Sec.  4.3  What current good manufacturing practice requirements apply
to my combination product?

* * * * *
    (a) The current good manufacturing practice requirements in parts
210 and 211 of this chapter apply to a combination product that
includes a drug constituent part other than a medical gas;
* * * * *
    (c) The current good manufacturing practice requirements among the
requirements (including standards) for biological products in parts 600
through 680 of this chapter apply to a combination product that
includes a biological product constituent part to which those
requirements would apply if that constituent part were not part of a
combination product;
    (d) The current good tissue practice requirements including donor
eligibility requirements for HCT/Ps in part 1271 of this chapter apply
to a combination product that includes an HCT/P; and
    (e) The current good manufacturing practice requirements in part
213 of this chapter apply to a combination product that includes a drug
that is a medical gas.
0
4. Amend Sec.  4.4 by:
0
a. Revising paragraphs (b)(1) introductory text, (b)(2) introductory
text, and (e);
0
b. Redesignating paragraphs (b)(3) and (b)(4) as (b)(4) and (b)(5),
respectively; and
0
c. Adding new paragraph (b)(3).
    The revisions and addition read as follows:

Sec.  4.4  How can I comply with these current good manufacturing
practice requirements for a co-packaged or single-entity combination
product?

* * * * *
    (b) * * *
    (1) If the combination product includes a device constituent part
and a drug constituent part, and the current good manufacturing
practice operating system has been shown to comply with the drug CGMPs
or the medical gas CGMPs, as applicable, the following provisions of
the QS regulation must also be shown to have been satisfied; upon
demonstration that these requirements have been satisfied, no
additional showing of compliance with respect to the QS regulation need
be made:
* * * * *
    (2) If the combination product includes a device constituent part
and a drug constituent part other than a medical gas, and the current
good manufacturing practice operating system has been shown to comply
with the QS regulation, the following provisions of the drug CGMPs must
also be shown to have been satisfied; upon demonstration that these
requirements have been satisfied, no additional showing of compliance
with respect to the drug CGMPs need be made:
* * * * *
    (3) If the combination product includes a device constituent part
and a drug constituent part that is a medical gas, and the current good
manufacturing practice operating system has been shown to comply with
the QS regulation, the following provisions of the medical gas CGMPs
must also be shown to have been satisfied; upon demonstration that
these requirements have been satisfied, no additional showing of
compliance with respect to the medical gas CGMPs need be made:
    (i) Section 213.84 of this chapter. Testing and approval or
rejection of components, containers, and closures.
    (ii) Section 213.94 of this chapter. Medical gas containers and
closures.
    (iii) Section 213.122 of this chapter. Materials examination and
usage criteria.
    (iv) Section 213.165 of this chapter. Testing and release for
distribution.
    (v) Section 213.166 of this chapter. Stability testing and
expiration dating for medical gases marketed under applications
submitted under section 505 or section 512 of the Federal Food, Drug,
and Cosmetic Act.
    (vi) Section 213.204 of this chapter. Returned medical gases.
    (vii) Section 213.208 of this chapter. Salvaging of medical gases.
* * * * *
    (e) The requirements set forth in this subpart and in parts 210,
211, 213, 820, 600 through 680, and 1271 of this chapter listed in
Sec.  4.3, supplement, and do not supersede, each other unless the
regulations explicitly provide otherwise. In the event of a conflict
between regulations applicable under this subpart to combination
products, including their constituent parts, the regulations most
specifically applicable to the constituent part in question shall
supersede the more general.

PART 16--REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION

0
5. The authority citation for part 16 continues to read as follows:

    Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394,
467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.

0
6. In Sec.  16.1, revise paragraph (b)(2) by numerically adding an
entry for ``Sec.  230.150(b)'' to read as follows:

Sec.  16.1  Scope.

* * * * *
    (b) * * *
    (2) * * *
    Sec.  230.150(b), relating to revocation of the grant of a
certification for a designated medical gas.
* * * * *

PART 201--LABELING

0
7. The authority citation for part 201 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 343, 351, 352, 353, 355, 358,
360, 360b, 360ccc, 360ccc-1, 360ddd, 360ddd-1, 360ee, 360gg-360ss,
371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

0
8. In Sec.  201.1, revise paragraph (b) to read as follows:

Sec.  201.1  Drugs; name and place of business of manufacturer, packer,
or distributor.

* * * * *
    (b) As used in this section, and for purposes of section 502(a) and
(b)(1) of

the Federal Food, Drug, and Cosmetic Act, the manufacturer of a drug
product is the person who performs all of the following operations that
are required to produce the product:
    (1) Mixing,
    (2) Granulating,
    (3) Milling,
    (4) Molding,
    (5) Lyophilizing,
    (6) Tableting,
    (7) Encapsulating,
    (8) Coating,
    (9) Sterilizing,
    (10) Filling sterile or aerosol drugs into dispensing containers,
and
    (11) With respect to a medical gas, fabricating the gas by chemical
reaction, physical separation, compression of atmospheric air,
purification (e.g., re-processing an industrial gas into a medical
gas), by combining two or more distinct medical gases, or by other
process.
* * * * *
0
9. In Sec.  201.10, revise paragraph (d)(2) to read as follows:

Sec.  201.10  Drugs; statement of ingredients.

* * * * *
    (d) * * *
    (2) A statement of the percentage of an ingredient in a drug shall,
if the term percent is used without qualification, mean percent weight-
in-weight, if the ingredient and the drug are both solids, or if the
ingredient is a liquid and the drug is a solid; percent weight in
volume at 68 [deg]F. (20 [deg]C.), if the ingredient is a solid and the
drug is a liquid; percent volume in volume at 68 [deg]F. (20 [deg]C.),
if both the ingredient and the drug are liquids, except that alcohol
shall be stated in terms of percent volume of absolute alcohol at 60
[deg]F. (15.56 [deg]C.); and percent volume in volume if the ingredient
is a designated medical gas (as defined in Sec.  201.161(c)(1)).
* * * * *
0
10. In Sec.  201.51, revise paragraphs (a) and (b) to read as follows:

Sec.  201.51  Declaration of net quantity of contents.

    (a) The label of a prescription or insulin-containing drug in
package form shall bear a declaration of the net quantity of contents.
This shall be expressed in the terms of weight, measure, numerical
count, or a combination of numerical count and weight or measure. The
statement of quantity of drugs in tablet, capsule, ampule, or other
unit dosage form shall be expressed in terms of numerical count; the
statement of quantity for drugs in other dosage forms shall be in terms
of weight if the drug is solid, semi-solid, or viscous, in terms of
fluid measure if the drug is liquid, or in terms of volume measure if
the drug is a designated medical gas (as defined in Sec.
201.161(c)(1)) or a medically appropriate combination of designated
medical gases in a gaseous state. When the drug quantity statement is
in terms of the numerical count of the drug units, it shall be
augmented to give the weight or measure of the drug units or the
quantity of each active ingredient in each drug unit or, when quantity
does not accurately reflect drug potency, a statement of the drug
potency.
    (b) Statements of weight of the contents shall in the case of
prescription drugs be expressed in terms of avoirdupois pound, ounce,
and grain or of kilogram, gram, and subdivisions thereof. A statement
of liquid measure of the contents shall in the case of prescription
drugs other than designated medical gases and medically appropriate
combinations thereof be expressed in terms of the U.S. gallon of 231
cubic inches and quart, pint, fluid-ounce, and fluid-dram subdivisions
thereof, or of the liter and milliliter, or cubic centimeter, and shall
express the volume at 68 [deg]F. (20 [deg]C.). A statement of the
liquid measure of the contents in the case of insulin-containing drugs
shall be expressed in terms of the liter and milliliter, or cubic
centimeter, and shall express the volume at 68 [deg]F. (20 [deg]C.). A
statement of the measure of the contents shall in the case of
designated medical gases (as defined in Sec.  201.161(c)(1)) and
medically appropriate combinations thereof be expressed as follows:
    (1) If in a gaseous state in a high pressure container, it shall be
expressed in liters or cubic feet based on the filled pressure at 70
[deg]F.;
    (2) If in a liquefied compressed gas state in a high pressure
container, it shall be expressed in gaseous liters or by an appropriate
net weight statement;
    (3) If in a liquefied state in a portable cryogenic container, it
shall be expressed in gaseous liters, liquid liters (if identified as a
liquid measure), gallons, or by an appropriate net weight statement at
the time of fill;
    (4) If in a bulk or transport container (as defined in Sec.
201.161(c)(3)), labeling for net quantity of contents is not required;
* * * * *
0
11. In Sec.  201.105 revise the introductory text paragraph to read as
follows:

Sec.  201.105   Veterinary drugs.

    A drug subject to the requirements of section 503(f)(1) of the act
shall be exempt from section 502(f)(1) of the act if it is a designated
medical gas (as defined in Sec.  201.161(c)(1)) or a medically
appropriate combination of designated medical gases and is in
compliance with Sec.  201.161, or if all the following conditions are
met:
* * * * *
0
12. Revise Sec.  201.161 to read as follows:

Sec.  201.161   Medical gases.

    (a) The requirements of sections 503(b)(4) and 502(f) of the
Federal Food, Drug, and Cosmetic Act are deemed to have been met for a
designated medical gas or a medically appropriate combination of
designated medical gases if the labeling on its final use container
bears the following:
    (1) In the case of oxygen:
    (i) A warning statement providing that uninterrupted use of high
concentrations of oxygen over a long duration, without monitoring its
effect on oxygen content of arterial blood, may be harmful; that oxygen
should not be used on patients who have stopped breathing unless used
in conjunction with resuscitative equipment; and, in the case of oxygen
that may be provided without a prescription for use in the event of
depressurization or other environmental oxygen deficiency, or for
oxygen deficiency or for use in emergency resuscitation when
administered by properly trained personnel, a warning statement
providing that oxygen may be used for emergency use only when
administered by properly trained personnel for oxygen deficiency and
resuscitation, and that for all other medical applications a
prescription is required.
    (ii) A clear and prominent warning containing the statements ``No
Smoking'' and ``No Vaping'' and a graphic symbol conveying that
smoking, vaping, and open flames near oxygen are dangerous.
    (2) In the case of a designated medical gas other than oxygen, and
in the case of medically appropriate combinations of any designated
medical gases:
    (i) A warning statement providing that the administration of the
gas or gas combination (as applicable) may be hazardous or
contraindicated; and that the gas or gas combination (as applicable)
should be used only by or under the supervision of a licensed
practitioner who is experienced in the use and administration of the
gas or gas combination (as applicable) and is familiar with the
indications, effects, dosages, methods, and frequency and duration of
administration, and with the hazards, contraindications, and side
effects and the precautions to be taken.
    (ii) The symbol ``Rx only.''

    (3) Appropriate directions and warnings concerning storage and
handling.
    (b) A designated medical gas or medically appropriate combination
of designated medical gases in a bulk or transport container must be
identified with the name of the product contained therein and
accompanied by documentation identifying the product as meeting
applicable compendial standards.
    (c) For purposes of this section:
    (1) A ``designated medical gas'' means a drug that:
    (i) Is manufactured or stored in a liquefied, nonliquefied, or
cryogenic state;
    (ii) Is administered as a gas; and
    (iii) Meets the definition in section 575(1) of the Federal Food,
Drug, and Cosmetic Act.
    (2) A ``final use container'' means a container that is for direct
use or access by a patient or healthcare provider to administer a
designated medical gas or medically appropriate combination of
designated medical gases. The term ``final use container'' does not
include bulk or transport containers and does not include containers
that are described in Sec.  868.5655 of this chapter.
    (3) A ``bulk or transport container'' means a container used to
transport or store designated medical gases or medically appropriate
combinations of designated medical gases and that is not used directly
to administer such gases to a patient.
0
13. In Sec.  201.328, revise paragraph (a)(1) introductory text and add
paragraph (d) to read as follows.

Sec.  201.328   Labeling of medical gas containers.

    (a) * * *
    (1) Each portable cryogenic medical gas container must be
conspicuously marked with a 360[deg] wraparound label identifying its
contents. Such label must meet the requirements of Sec.  213.94(e)(3)
of this chapter and the following additional requirements.
* * * * *
    (d) Notwithstanding Sec.  201.1, a container filled with a
designated medical gas (as defined in Sec.  201.161(c)(1)) or medically
appropriate combination of designated medical gases may bear a
statement identifying the name of the owner of the container or the
address to which the container should be returned after use. Such
statement may appear on a separate sticker or decal. If the owner of
the medical gas container is not the manufacturer, packer, or
distributor of the designated medical gas or medically appropriate
combination of designated medical gases, that shall be clearly stated
on the container. The addition of such statement shall not cause the
owner of the cylinder to be a ``relabeler'' for purposes of
registration and listing under part 207 of this chapter.

PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING,
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

0
14. The authority citation for part 210 is revised to read as follows:

    Authority:  21 U.S.C. 321, 351, 352, 355, 360b, 360ddd, 360ddd-
1, 371, 374; 42 U.S.C. 216, 262, 263a, 264.

0
15. In Sec.  210.1, revise paragraphs (a) and (b) to read as follows:

Sec.  210.1   Status of current good manufacturing practice
regulations.

    (a) The regulations set forth in this part and in parts 211, 213,
225, and 226 of this chapter contain the minimum current good
manufacturing practice for methods to be used in, and the facilities or
controls to be used for, the manufacture, processing, packing, or
holding of a drug to assure that such drug meets the requirements of
the act as to safety, and has the identity and strength and meets the
quality and purity characteristics that it purports or is represented
to possess.
    (b) The failure to comply with any regulation set forth in this
part and in parts 211, 213, 225, and 226 of this chapter in the
manufacture, processing, packing, or holding of a drug shall render
such drug to be adulterated under section 501(a)(2)(B) of the act and
such drug, as well as the person who is responsible for the failure to
comply, shall be subject to regulatory action.
* * * * *
0
16. In Sec.  210.2, revise paragraphs (a) and (b) to read as follows:

Sec.  210.2   Applicability of current good manufacturing practice
regulations.

    (a) The regulations in this part and in parts 211, 213, 225, and
226 of this chapter as they may pertain to a drug; in parts 600 through
680 of this chapter as they may pertain to a biological product for
human use; and in part 1271 of this chapter as they are applicable to a
human cell, tissue, or cellular or tissue-based product (HCT/P) that is
a drug (subject to review under an application submitted under section
505 of the act or under a biological product license application under
section 351 of the Public Health Service Act); shall be considered to
supplement, not supersede, each other, unless the regulations
explicitly provide otherwise. In the event of a conflict between
applicable regulations in this part and in other parts of this chapter,
the regulation specifically applicable to the drug product in question
shall supersede the more general.
    (b) If a person engages in only some operations subject to the
regulations in this part and in parts 211, 213, 225, 226, 600 through
680, and 1271 of this chapter, and not in others, that person need only
comply with those regulations applicable to the operations in which the
person is engaged.
* * * * *

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS

0
17. The authority citation for part 211 is revised to read as follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 360ddd, 360ddd-1,
371, 374; 42 U.S.C. 216, 262, 263a, 264.

0
18. In Sec.  211.1, revise paragraph (a) to read as follows:

Sec.  211.1   Scope.

    (a) The regulations in this part contain the minimum current good
manufacturing practice for preparation of drug products (excluding
positron emission tomography drugs and medical gases as defined in
Sec.  213.3(b)(12) of this chapter) for administration to humans or
animals.
* * * * *

Sec.  211.94   [Amended]

0
19. In Sec.  211.94, remove paragraph (e).
0
20. In Sec.  211.125 revise paragraph (c) to read as follows:

Sec.  211.125   Labeling issuance.

* * * * *
    (c) Procedures shall be used to reconcile the quantities of
labeling issued, used, and returned, and shall require evaluation of
discrepancies found between the quantity of drug product finished and
the quantity of labeling issued when such discrepancies are outside
narrow preset limits based on historical operating data. Such
discrepancies shall be investigated in accordance with Sec.  211.192.
Labeling reconciliation is waived for cut or roll labeling if a 100-
percent examination for correct labeling is performed in accordance
with Sec.  211.122(g)(2).
* * * * *
0
21. In Sec.  211.132, revise paragraph (c)(1) introductory text to read
as follows:

Sec.  211.132   Tamper-evident packaging requirements for over-the-
counter (OTC) human drug products.

* * * * *
    (c) * * *
    (1) In order to alert consumers to the specific tamper-evident
feature(s) used, each retail package of an OTC drug product covered by
this section (except ammonia inhalant in crushable glass ampules or
aerosol products that depend upon the power of a liquefied or
compressed gas to expel the contents from the container) is required to
bear a statement that:
* * * * *
0
22. In Sec.  211.170, revise paragraph (b) introductory text to read as
follows:

Sec.  211.170   Reserve samples.

* * * * *
    (b) An appropriately identified reserve sample that is
representative of each lot or batch of drug product shall be retained
and stored under conditions consistent with product labeling. The
reserve sample shall be stored in the same immediate container-closure
system in which the drug product is marketed or in one that has
essentially the same characteristics. The reserve sample consists of at
least twice the quantity necessary to perform all the required tests,
except those for sterility and pyrogens. Except for those for drug
products described in paragraph (b)(2) of this section, reserve samples
from representative sample lots or batches selected by acceptable
statistical procedures shall be examined visually at least once a year
for evidence of deterioration unless visual examination would affect
the integrity of the reserve sample. Any evidence of reserve sample
deterioration shall be investigated in accordance with Sec.  211.192.
The results of the examination shall be recorded and maintained with
other stability data on the drug product. The retention time is as
follows:
* * * * *
0
23. Revise Sec.  211.196 to read as follows:

Sec.  211.196   Distribution records.

    Distribution records shall contain the name and strength of the
product and description of the dosage form, name and address of the
consignee, date and quantity shipped, and lot or control number of the
drug product.
0
24. Add part 213 to subchapter C to read as follows:

PART 213--CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICAL GASES

Subpart A--General Provisions
Sec.
213.1 Scope.
213.3 Definitions.
Subpart B--Organization and Personnel
213.22 Responsibilities of quality unit.
213.25 Personnel qualifications and responsibilities.
213.34 Consultants.
Subpart C--Buildings and Facilities
213.42 Design and construction features.
Subpart D--Equipment
213.63 Equipment design, size, and location.
213.65 Equipment construction.
213.67 Equipment maintenance and cleaning.
213.68 Automatic, mechanical, and electronic equipment.
Subpart E--Control of Incoming Designated Medical Gas, Components, and
Medical Gas Containers and Closures
213.80 General requirements.
213.82 Receipt and storage of incoming designated medical gases.
213.84 Testing and approval or rejection of components, containers,
and closures.
213.89 Rejected components, incoming designated medical gases, and
medical gas containers and closures.
213.94 Medical gas containers and closures.
Subpart F--Production and Process Controls
213.100 Written procedures; deviations.
213.101 Charge-in of components and incoming designated medical
gases.
213.110 Sampling and testing of in-process materials.
Subpart G--Packaging and Labeling Control
213.122 Materials examination and usage criteria.
213.125 Labeling issuance.
213.130 Packaging and labeling operations.
Subpart H--Holding and Distribution
213.150 Warehousing and distribution procedures.
Subpart I--Laboratory Controls
213.160 General requirements.
213.165 Testing and release for distribution.
213.166 Stability testing and expiration dating for medical gases
marketed under applications submitted under section 505 or section
512 of the Federal Food, Drug, and Cosmetic Act.
Subpart J--Records
213.180 General requirements.
213.182 Equipment cleaning and use log.
213.184 Records for components, medical gas containers and closures,
and labeling.
213.186 Master production and control records.
213.189 Batch production and control records.
213.192 Production record review.
213.194 Laboratory records.
213.196 Distribution records.
213.198 Complaint files.
Subpart K--Returned and Salvaged Medical Gases
213.204 Returned medical gases.
213.208 Salvaging of medical gases.

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360b, 360ddd,
360ddd-1, 371, 374.

Subpart A--General Provisions

Sec.  213.1  Scope.

    The regulations in this part contain the minimum current good
manufacturing practice for preparation of medical gases for
administration to humans or animals.

Sec.  213.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of
the Federal Food, Drug, and Cosmetic Act shall be applicable to such
terms when used in this part.
    (b) The following definitions of terms apply to this part:
    (1) Acceptance criteria means the product specifications and
acceptance/rejection criteria, such as acceptable quality level and
unacceptable quality level, with an associated sampling plan, that are
necessary for making a decision to accept or reject a lot or batch (or
any other convenient subgroups of manufactured units).
    (2) Batch means a specific quantity of a medical gas or other
material that is intended to have uniform character and quality, within
specified limits, and is produced according to a single manufacturing
order during the same cycle of manufacture.
    (3) Commingling or commingled refers to the act of combining one
lot of designated medical gas or component with another lot or lots of
the same designated medical gas or component.
    (4) Component means any ingredient intended for use in the
manufacture of a medical gas, including those that may not appear in
such gas. It does not include an incoming designated medical gas.
    (5) Designated medical gas means a drug that is manufactured or
stored in a liquefied, nonliquefied, or cryogenic state; is
administered as a gas; and is defined in section 575(1) of the Federal
Food, Drug, and Cosmetic Act.
    (6) FDA means the Food and Drug Administration.
    (7) In-process material means any material fabricated, compounded,
blended, or derived by chemical reaction that is produced for, and used
in, the preparation of the medical gas.

    (8) Incoming designated medical gas means a designated medical gas
received from one source that is commingled with the same gas from
another source, used in a medically appropriate combination of
designated medical gases or in the production of another medical gas,
or further distributed.
    (9) Lot means a batch, or a specific identified portion of a batch,
having uniform character and quality within specified limits; or, in
the case of a medical gas produced by continuous process, it is a
specific identified amount produced in a unit of time or quantity in a
manner that assures its having uniform character and quality within
specified limits.
    (10) Lot number, control number, or batch number means any
distinctive combination of letters, numbers, or symbols, or any
combination of them, from which the complete history of the
manufacture, processing, packing, holding, and distribution of a batch
or lot of medical gas, or other material can be determined.
    (11) Manufacture, processing, packing, or holding of medical gases
includes packaging and labeling operations, testing, and quality
control.
    (12) Medical gas has the meaning given the term in section 575(2)
of the Federal Food, Drug, and Cosmetic Act.
    (13) Original manufacturer means the person or entity that
initially produces a designated medical gas by chemical reaction,
physical separation, compression of atmospheric air, purification
(e.g., re-processing an industrial gas into a medical gas), or other
means.
    (14) Quality unit means any person or persons designated with the
authority and responsibility for overall quality management and other
responsibilities as defined in Sec.  213.22.
    (15) Strength means:
    (i) The concentration of the medical gas (for example, weight/
weight, weight/volume, or unit dose/volume basis), and/or
    (ii) The potency, that is, the therapeutic activity of the medical
gas as indicated by appropriate laboratory tests or by adequately
developed and controlled clinical data (expressed, for example, in
terms of units by reference to a standard).

Subpart B--Organization and Personnel

Sec.  213.22   Responsibilities of quality unit.

    (a) There shall be a quality unit that shall have the
responsibility and authority to approve or reject all components,
medical gas containers and closures, in-process materials, packaging
material, labeling, and medical gases, and the authority to review
production records to assure that no errors have occurred or, if errors
have occurred, that they have been fully investigated. The quality unit
shall be responsible for approving or rejecting medical gases
manufactured, processed, packed, or held under contract by another
company.
    (b) Adequate laboratory facilities for the testing and approval (or
rejection) of components, medical gas containers and closures,
packaging materials, in-process materials, and medical gases shall be
available to the quality unit.
    (c) The quality unit shall have the responsibility for approving or
rejecting all procedures or specifications impacting on the identity,
strength, quality, and purity of the medical gas.
    (d) The responsibilities and procedures applicable to the quality
unit shall be in writing; such written procedures shall be followed.
    (e) Quality unit personnel may perform other functions provided
appropriate written controls are in place to ensure any other functions
are performed separately from quality unit responsibilities and such
other functions do not interfere with the quality unit's
responsibilities or subordinate the quality unit's responsibilities to
any other unit.

Sec.  213.25   Personnel qualifications and responsibilities.

    (a) Each person engaged in the manufacture, processing, packing, or
holding of a medical gas shall have education, training, and
experience, or any combination thereof, to enable that person to
perform the assigned functions. Training shall be in the particular
operations that the employee performs and in current good manufacturing
practice (including the current good manufacturing practice regulations
in this chapter and written procedures required by these regulations)
as they relate to the employee's functions. Training in current good
manufacturing practice shall be conducted by qualified individuals on a
continuing basis and with sufficient frequency to assure that employees
remain familiar with current good manufacturing practice requirements
applicable to them. Written documentation shall be maintained
demonstrating the completion of employee training, and shall include
the date of the training, the type of the training, and the results of
any completion criteria, such as test results.
    (b) There shall be an adequate number of qualified personnel to
perform the manufacture, processing, packing, or holding of each
medical gas.
    (c) Only authorized personnel shall enter those areas of the
buildings and facilities designated as limited-access areas.

Sec.  213.34   Consultants.

    Consultants advising on the manufacture, processing, packing, or
holding of medical gases shall have sufficient education, training, and
experience, or any combination thereof, to advise on the subject for
which they are retained. Records shall be maintained stating the name,
address, and qualifications of any consultants and the type of service
they provide.

Subpart C--Buildings and Facilities

Sec.  213.42   Design and construction features.

    (a)(1) Any buildings and facilities used in the manufacture,
processing, packing, or holding of a medical gas shall be of adequate
design, including having adequate space, for the orderly placement of
equipment and materials to prevent mix-ups between:
    (i) Components;
    (ii) Incoming designated medical gases;
    (iii) Medical gas containers and closures;
    (iv) Labeling;
    (v) In-process materials; or
    (vi) Medical gases.
    (2) Such buildings and facilities shall also allow for adequate
cleaning, maintenance, and proper operations.
    (b)(1) Operations shall be performed within specifically defined
areas of adequate size. There shall be separate or defined areas or
such other control systems for the firm's operations as are necessary
to prevent contamination or mix-ups during the course of the following
procedures:
    (i) Receipt, identification, storage, and withholding from use of
components, incoming designated medical gases, medical gas containers
and closures, and labeling, pending the appropriate sampling, testing,
or examination by the quality unit before release for manufacturing or
packaging;
    (ii) Holding rejected components, incoming designated medical
gases, medical gas containers and closures, and labeling before
disposition;
    (iii) Storage of released components, incoming designated medical
gases, medical gas containers and closures, and labeling;
    (iv) Storage of in-process materials;
    (v) Manufacturing and processing operations;

    (vi) Packaging and labeling operations;
    (vii) Quarantine storage before release of medical gases;
    (viii) Storage of medical gases after release; and
    (ix) Control and laboratory operations.
    (2) The flow of components, incoming designated medical gases,
medical gas containers and closures, labeling, in-process materials,
and medical gases through the buildings and facilities shall be
designed to prevent contamination and mix-ups.
    (c) Any building or facility used in the manufacture, processing,
packing, or holding of a medical gas shall be maintained in a clean
condition so as to assure the safety, identity, strength, quality, and
purity of the medical gas. Written procedures applicable to the
maintenance and cleaning of buildings and facilities shall be
established and followed.

Subpart D--Equipment

Sec.  213.63   Equipment design, size, and location.

    Equipment used in the manufacture, processing, packing, or holding
of a medical gas shall be of appropriate design and adequate size, and
be suitably located to facilitate operations for its intended use and
any necessary cleaning and maintenance.

Sec.  213.65   Equipment construction.

    (a) Equipment shall be constructed so that surfaces that contact
components, in-process materials, or medical gases shall not be
reactive, additive, or absorptive so as to alter the safety, identity,
strength, quality, or purity of the medical gas beyond the official or
other established requirements.
    (b) Any substances required for operation, such as lubricants or
coolants, shall not come into contact with components, containers,
closures, in-process materials, or medical gases so as to alter the
safety, identity, strength, quality, or purity of the medical gas
beyond the official or other established requirements.

Sec.  213.67   Equipment maintenance and cleaning.

    (a) Written procedures shall be established, maintained, and
followed for adequate cleaning and maintenance of equipment used in the
manufacture, processing, packing, or holding of medical gases. These
procedures shall include, but are not necessarily limited to, the
following:
    (1) Assignment of responsibility for cleaning and maintaining
equipment;
    (2) Maintenance and cleaning schedules, including, where
appropriate, sanitizing schedules;
    (3) A description in sufficient detail of the methods, equipment,
and materials used in cleaning and maintenance operations, and the
methods of disassembling and reassembling equipment as necessary to
assure proper cleaning and maintenance;
    (4) Removal or obliteration of previous batch identification;
    (5) Protection of clean equipment from contamination prior to use;
and
    (6) Inspection of equipment for cleanliness immediately before use.
    (b) The procedures described in paragraph (a) of this section shall
not alter the safety, identity, strength, quality, or purity of the
medical gas beyond the established requirements.
    (c) Records shall be kept of cleaning, maintenance, and inspection
as specified in Sec.  213.180.

Sec.  213.68   Automatic, mechanical, and electronic equipment.

    (a) Automatic, mechanical, and electronic equipment used in the
manufacture of medical gases shall be routinely calibrated, inspected,
and checked according to a written program designed to ensure proper
performance. Written procedures and records of calibration,
inspections, and checks shall be maintained.
    (b) Computerized systems that record, store, or use data shall be
appropriately validated.
    (c) A backup file of data entered into the computer system shall be
maintained except where certain data, such as calculations performed in
connection with laboratory analysis, are eliminated by computerization
or other automated processes.
    (d) Appropriate change control shall be used whenever modifications
are made to computer systems to assure that any changes do not
adversely affect data integrity or product quality. Records of such
modifications shall be maintained.

Subpart E--Control of Incoming Designated Medical Gas, Components,
and Medical Gas Containers and Closures

Sec.  213.80   General requirements.

    (a) There shall be written procedures describing in sufficient
detail the receipt, identification, storage, handling, sampling,
testing, and approval or rejection of components, incoming designated
medical gases, and medical gas containers and closures; such written
procedures shall be followed.
    (b) Components, incoming designated medical gases, and medical gas
containers and closures shall at all times be handled and stored in a
manner to prevent contamination and mix-ups.
    (c) Lots of incoming designated medical gases or components,
whether used directly as supply or commingled with an existing supply,
shall be assigned a unique identification number.

Sec.  213.82   Receipt and storage of incoming designated medical
gases.

    (a)(1) Upon receipt of an incoming designated medical gas, the firm
shall verify and record that a signed certificate of analysis from the
supplier accompanies each different designated medical gas in a
shipment. The certificate of analysis shall include the following:
    (i) Supplier's name;
    (ii) Name of the incoming designated medical gas;
    (iii) Lot number or other unique identification number;
    (iv) Actual analytical result obtained for strength, as well as the
results of other tests performed;
    (v) Identification of the test method(s) used for analysis;
    (vi) New drug application and/or new animal drug application number
of the incoming designated medical gas; and
    (vii) Supplier representative's signature and the date of
signature.
    (2) If the incoming designated medical gas is obtained from a
supplier other than the original manufacturer, the shipment shall also
include complete information from the original manufacturer's
certificate of analysis. The firm shall establish and maintain a
program to ensure the reliability of the supplier's capabilities
through appropriate assessment and testing procedures.
    (b) An identity test shall be performed upon receipt of the
incoming designated medical gas.

Sec.  213.84   Testing and approval or rejection of components,
containers, and closures.

    (a) Components, containers, and closures (including valves) shall
be examined for conformance with appropriate written procedures and
specifications, and approved or rejected, prior to the manufacturing or
filling process. In lieu of such examination by the firm, a statement
of verification that the component, container, or closure meets
specifications may be accepted from the supplier, provided that the
firm establishes and maintains a program to ensure the reliability of
the supplier's capabilities through appropriate assessment and testing
provisions. Any rejected items shall be handled in accordance with
Sec.  213.89.

    (b) Firms shall take appropriate actions to protect against
container and closure leaks, which shall include performing leak tests
on containers and closures at the time of fill and after fill but prior
to release.
    (c) Each component shall be sampled, tested, and approved or
rejected as appropriate prior to use. This requirement can be met by
performing testing for conformance with written specifications or by an
identity test on the component accompanied by an acceptable certificate
of analysis from the supplier, provided that the firm establishes and
maintains a program to ensure the reliability of the supplier's
capabilities through appropriate assessment and testing procedures.

Sec.  213.89   Rejected components, incoming designated medical gases,
and medical gas containers and closures.

    Rejected components, incoming designated medical gases, and medical
gas containers and closures shall be identified and controlled under a
quarantine system designed to prevent their use in manufacturing or
processing operations for which they are unsuitable and shall be
documented and assessed.

Sec.  213.94   Medical gas containers and closures.

    (a) Medical gas containers and closures shall not be reactive,
additive, or absorptive so as to alter the safety, identity, strength,
quality, or purity of the gas beyond the official or established
requirements.
    (b) Container closure systems shall provide adequate protection
against foreseeable external factors in storage and use that can cause
deterioration or contamination of the medical gas.
    (c) Medical gas containers and closures shall be clean to assure
that they are suitable for their intended use.
    (d) Standards or specifications, methods of testing, and, where
indicated, methods of cleaning shall be written and followed for
medical gas containers and closures.
    (e) Medical gas containers and closures must meet the following
requirements--
    (1) Gas-specific use outlet connections. Portable cryogenic medical
gas containers that are not manufactured with permanent gas use outlet
connections (e.g., those that have been silver-brazed) must have gas-
specific use outlet connections that are attached to the valve body so
that they cannot be readily removed or replaced (without making the
valve inoperable and preventing the containers' use) except by the
manufacturer. For the purposes of this paragraph, the term
``manufacturer'' includes any individual or firm that fills high-
pressure medical gas cylinders or cryogenic medical gas containers. For
the purposes of this section, a ``portable cryogenic medical gas
container'' is one that is capable of being transported and is intended
to be attached to a medical gas supply system within a hospital,
healthcare entity, nursing home, other facility, or home healthcare
setting, or is a base unit used to fill small cryogenic gas containers
for use by individual patients. The term does not include cryogenic
containers that are not designed to be connected to a medical gas
supply system, e.g., tank trucks, trailers, rail cars, or small
cryogenic gas containers for use by individual patients (including
portable liquid oxygen units as defined at Sec.  868.5655 of this
chapter).
    (2) Gauges for certain medical gas containers. Portable cryogenic
medical gas containers as described in paragraph (e)(1) of this section
and small cryogenic gas containers for use by individual patients
(including portable liquid oxygen units as defined at Sec.  868.5655 of
this chapter) must have a working gauge sufficient to indicate whether
the container contains an adequate supply of medical gas for continued
use.
    (3) Label and coloring requirements. The labeling specified at
Sec.  201.328(a) of this chapter must be affixed to the container in a
manner that does not interfere with other labeling. Each such label as
well as materials used for coloring medical gas containers must be
reasonably resistant to fading, durable when exposed to atmospheric
conditions, and not readily soluble in water.

Subpart F--Production and Process Controls

Sec.  213.100   Written procedures; deviations.

    (a) There shall be written procedures for production and process
controls designed to assure that medical gases have the identity,
strength, quality, and purity they purport or are represented to
possess. Such procedures shall include all requirements in this
subpart. These written procedures, including any changes, shall be
drafted, reviewed, and approved by the appropriate organizational units
and reviewed and approved by the quality unit.
    (b) Written production and process control procedures shall be
followed in the execution of the various production and process control
functions and shall be documented at the time of performance. Any
deviation from the written procedures shall be recorded and justified.

Sec.  213.101   Charge-in of components and incoming designated medical
gases.

    Written production and control procedures shall include the
following, which are designed to assure that the medical gases produced
have the identity, strength, quality, and purity they purport or are
represented to possess:
    (a) Except when a monograph or formulary specifies a range, the
batch shall be formulated with the intent to provide 100 percent of the
labeled or established amount of each medical gas. When a monograph or
formulary specifies a range for the contents of a medical gas, the
batch shall be formulated with the intent to provide an amount of the
medical gas within such specified range.
    (b) Components and incoming designated medical gases added to in-
process supply or final product containers shall be weighed or measured
as appropriate. In-process and final product containers shall identify
the name of the component or designated medical gas or the name and
percentage of each component or designated medical gas if they contain
multiple components or designated medical gases, and the unique lot
number assigned.

Sec.  213.110   Sampling and testing of in-process materials.

    (a) In-process materials shall be tested for identity, strength,
quality, and purity as appropriate, and approved or rejected by the
quality unit during the production process.
    (b) To assure batch uniformity and integrity of drug products,
written procedures shall be established and followed that describe the
in-process controls, and tests, or examinations to be conducted on
appropriate samples of in-process materials of each batch. Such control
procedures shall be established to monitor the output and to validate
the performance of those manufacturing processes.
    (c) Rejected in-process materials shall be identified and
controlled under a quarantine system designed to prevent their use in
manufacturing or processing operations for which they are unsuitable.

Subpart G--Packaging and Labeling Control

Sec.  213.122   Materials examination and usage criteria.

    (a) There shall be written procedures describing in sufficient
detail the receipt, identification, storage, handling, sampling,
examination, and/or testing of labeling and packaging materials; such

written procedures shall be followed. Labeling and packaging materials
shall be representatively sampled, and examined or tested upon receipt
and before use in packaging or labeling of a medical gas.
    (b) Any labeling or packaging materials meeting appropriate written
specifications may be approved and released for use. Any labeling or
packaging materials that do not meet such specifications shall be
rejected to prevent their use in operations for which they are
unsuitable.
    (c) Records shall be maintained for each shipment received of each
different labeling and packaging material indicating receipt,
examination, and whether accepted or rejected.
    (d) Labels and other labeling materials for each different medical
gas, strength, or quantity of contents, shall be stored with suitable
identification to avoid mix-ups. Access to the label storage area shall
be limited to authorized personnel.
    (e) Labels, labeling, and other packaging materials that are
obsolete, outdated, or that do not meet applicable requirements shall
be destroyed.
    (f) Packaging and labeling operations shall include one of the
following special control procedures:
    (1) Dedication of labeling and packaging lines to each different
strength of each different medical gas;
    (2) Use of appropriate electronic or electromechanical equipment to
conduct a 100-percent examination for correct labeling during or after
completion of finishing operations; or
    (3) Use of visual inspection to conduct a 100-percent examination
for correct labeling during or after completion of labeling operations
for hand-applied labeling. Such examination shall be performed by one
person and independently verified by a second person.
    (g) Printing devices on, or associated with, manufacturing lines
used to imprint labeling upon the unit label or case shall be monitored
to assure that all imprinting conforms to the print specified in the
batch production record.
    (h) Labels may be reused if they are legible, properly affixed to
the container, and otherwise meet all applicable requirements.

Sec.  213.125   Labeling issuance.

    (a) Labeling and packaging operations must be controlled to prevent
labeling and product mix-ups. Procedures shall be written and followed
describing in sufficient detail the control procedures employed for the
issuance of labeling.
    (b) Procedures shall be used to reconcile the quantities of
labeling issued, used, and returned, and shall require evaluation of
discrepancies found between the quantity of medical gas and the
quantity of labeling issued when such discrepancies are outside narrow
preset limits based on historical operating data. Such discrepancies
shall be investigated in accordance with Sec.  213.192. Labeling
reconciliation is waived for cut or roll labeling if a 100-percent
examination for correct labeling is performed in accordance with Sec.
213.122(f)(2). Labeling reconciliation is also waived for 360[deg]
wraparound labels on portable cryogenic medical gas containers.
    (c) All excess lot number stickers or decals bearing lot or control
numbers shall be discarded.
    (d) Bulk or transport containers (as defined in Sec.  201.161(c)(3)
of this chapter) are exempt from this section.

Sec.  213.130   Packaging and labeling operations.

    There shall be written procedures designed to assure that correct
labels, labeling, and packaging materials are used for medical gases;
such written procedures shall be followed. These procedures shall
incorporate the following features:
    (a) Prevention of mix-ups by physical or spatial separation from
operations on other products.
    (b) Identification and handling of filled containers of medical gas
that are set aside and held in unlabeled condition for future labeling
operations to preclude mislabeling of individual containers, lots, or
portions of lots. Identification need not be applied to each individual
container but shall be sufficient to determine name, strength, quantity
of contents, and lot or control number of each container.
    (c) Identification of the medical gas with a lot or control number
that permits determination of the history of the manufacture and
control of the batch. The lot or control number of the medical gas may
be identified by use of a separate identification sticker or decal.
    (d) Examination of packaging and labeling materials for suitability
and correctness before packaging operations, and documentation of such
examination in the batch production record. Product labels, including
360[deg] wraparound labels, can be reused provided they meet all
applicable labeling requirements, all information on the label is
legible, and the label is in good condition.
    (e) Inspection of the packaging and labeling facilities immediately
before use to assure that all medical gases have been removed from
previous operations. Inspection shall also be made to assure that
packaging and labeling materials not suitable for subsequent operations
have been removed. Results of inspection shall be documented in the
batch production records.
    (f) Bulk or transport containers (as defined in Sec.  201.161(c)(3)
of this chapter) are exempt from this section provided they are
identified with the name of the product contained therein and
accompanied by documentation identifying the product as meeting
applicable compendial standards.

Subpart H--Holding and Distribution

Sec.  213.150   Warehousing and distribution procedures.

    (a) Written procedures shall be established, and followed,
describing the distribution of medical gases and including a system by
which the distribution of each lot can be readily determined to
facilitate its recall if necessary.
    (b) Written procedures shall be established, and followed,
describing the warehousing of medical gases, including quarantine of
such gases before release by the quality unit.

Subpart I--Laboratory Controls

Sec.  213.160   General requirements.

    (a) The establishment of any specifications, standards, sampling
plans, test procedures, or other laboratory control mechanisms required
by this subpart, including any change in such specifications,
standards, sampling plans, test procedures, or other laboratory control
mechanisms, shall be drafted by the appropriate organizational unit and
reviewed and approved by the quality unit. The requirements in this
subpart shall be followed and shall be documented at the time of
performance. Any deviation from the written specifications, standards,
sampling plans, test procedures, or other laboratory control mechanisms
shall be recorded and justified.
    (b) Laboratory controls shall include the establishment of
scientifically sound and appropriate specifications, standards,
sampling plans, and test procedures designed to assure that components,
medical gas containers and closures, in-process materials, labeling,
and medical gases conform to appropriate standards of identity,
strength, quality, and purity. Laboratory controls shall include:
    (1) Determination of conformity to applicable written
specifications for the acceptance of each lot within each shipment of
components, medical gas containers and closures, and labeling used in
the manufacture, processing,

packing, or holding of a medical gas. The specifications shall include
a description of the sampling and testing procedures used. Samples
shall be representative and adequately identified. Such procedures
shall also require appropriate retesting of any component, container,
or closure that is subject to deterioration.
    (2) Determination of conformance to written specifications and a
description of sampling and testing procedures for in-process
materials. Such samples shall be representative and properly
identified.
    (3) Determination of conformance to written descriptions of
sampling procedures and appropriate specifications for medical gases.
Such samples shall be representative and properly identified.
    (4) The calibration or verification of calibration for instruments,
apparatus, gauges, and recording devices at suitable intervals in
accordance with an established written program containing specific
directions, schedules, limits for accuracy and precision, and
provisions for remedial action in the event accuracy and/or precision
limits are not met. Instruments, apparatus, gauges, and recording
devices not meeting established specifications shall not be used.

Sec.  213.165   Testing and release for distribution.

    (a) For each batch of medical gas, there shall be appropriate
laboratory determination of satisfactory conformance to final
specifications for the medical gas, including the identity and
strength, prior to release.
    (b) Any sampling and testing plans shall be described in written
procedures that shall include the method of sampling, the number of
units per batch to be tested, and acceptance criteria. Such written
procedures shall be followed.
    (c) The accuracy, sensitivity, specificity, and reproducibility of
test methods employed by the firm shall be established and documented.
Such validation and documentation may be accomplished in accordance
with Sec.  213.194(a)(2). The suitability of all testing methods shall
be verified under actual conditions of use.
    (d) Medical gases failing to meet established standards or
specifications and any other relevant quality criteria shall be
rejected.
    (e) This section does not apply to the filling of a designated
medical gas or medically appropriate combination of designated medical
gases via liquid to liquid into a container at a delivery site.

Sec.  213.166   Stability testing and expiration dating for medical
gases marketed under applications submitted under section 505 or
section 512 of the Federal Food, Drug, and Cosmetic Act.

    (a) For medical gases marketed under applications submitted under
section 505 or section 512 of the Federal Food, Drug, and Cosmetic Act,
any stability testing performed and any expiration date established
shall be in accordance with paragraph (b) of this section, subject to
the conditions established in their approved applications, if any.
    (b) To assure that the medical gas described in paragraph (a) of
this section meets applicable standards of identity, strength, quality,
and purity at the time of use:
    (1) The stability testing program shall be designed to assess the
stability characteristics of the medical gas and its container closure
system. The results of stability testing shall be used in determining
appropriate storage conditions and any expiration date included on the
label. The stability program shall include the appropriate sample size,
test intervals, container closure systems, and storage conditions for
samples retained for testing.
    (2) Any expiration dates included on the label shall appear in
accordance with the requirements of Sec.  201.17 of this chapter.
    (3) Stability shall be evaluated periodically to ensure that the
medical gas continues to meet the standards for identity, strength,
quality, and purity stated on the labeling to support the expiration
date.

Subpart J--Records

Sec.  213.180   General requirements.

    (a) Record availability. All records required under this part, or
copies of such records, shall be readily available for authorized
inspection during the retention period at the establishment where the
activities described in such records occurred and are subject to
copying as part of such inspection. Records that can be immediately
retrieved from another location by computer or other electronic means
shall be considered as meeting the requirements of this paragraph.
    (b) Record requirements. All records must be legible, stored to
prevent deterioration or loss, and original or accurate reproductions
of the original records.
    (c) Record retention period. Except where otherwise provided, all
records required to be maintained in compliance with this part must be
maintained for a period of at least 3 years after the distribution of
the batch of medical gas.
    (d) Maintenance of written records. Written records required by
this part shall be maintained so that data therein 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 shall be
established and followed for such evaluations and shall include
provisions for:
    (1) A review of a representative number of batches, whether
approved or rejected, and, where applicable, records associated with
the batch; and
    (2) A review of complaints, recalls, returned or salvaged medical
gases, and investigations conducted under Sec.  213.192 for each gas.
    (e) Written procedure requirements. A firm shall establish and
follow written procedures to assure that responsible officials of the
firm are notified in writing of any recalls, reports of inspectional
observations by FDA, regulatory actions related to good manufacturing
practices brought by FDA, or investigations resulting from adverse
event complaints.

Sec.  213.182   Equipment cleaning and use log.

    A written record of major equipment cleaning, maintenance (except
routine maintenance such as lubrication and adjustments), and use shall
be included in individual equipment logs that show the date, time,
product, and lot number of each batch processed. If equipment is
dedicated to manufacture of one product, then individual equipment logs
are not required, provided that lots or batches of such product follow
in numerical order and are manufactured in numerical sequence. In cases
where dedicated equipment is employed, the records of cleaning,
maintenance, and use shall be part of the batch record. The persons
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 the cleaning and maintenance
done by the automated equipment) shall date and sign or initial the log
indicating that the work was performed. Entries in the log shall be in
chronological order.

Sec.  213.184   Records for components, medical gas containers and
closures, and labeling.

    These records shall include the following:
    (a) The results of any test or examination performed (including
those performed as required by Sec.  213.84 or Sec.  213.122) and the
conclusions derived therefrom.

    (b) 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.
    (c) The disposition of rejected components, medical gas containers
and closures, and labeling.

Sec.  213.186   Master production and control records.

    (a) To assure uniformity from batch to batch, master production and
control records for each medical gas shall be prepared, dated, and
signed. The preparation of master production and control records shall
be described in a written procedure and such written procedure shall be
followed.
    (b) Master production and control records shall include:
    (1) The name and strength of the product;
    (2) A complete list of components and any incoming designated
medical gases used in manufacturing designated by names or codes
sufficiently specific to indicate any special quality characteristic;
    (3) A description of the medical gas containers and closures, and
packaging materials and labels; and
    (4) Complete manufacturing and control instructions, sampling and
testing procedures, specifications, special notations, and precautions
to be followed.

Sec.  213.189   Batch production and control records.

    (a) Batch production and control records shall be prepared for each
batch of medical gas produced.
    (b) These records shall include documentation that each significant
step in the manufacture, processing, packing, or holding of the medical
gas produced was accomplished, including:
    (1) Dates and times of each significant step, including in-process
and laboratory tests as applicable;
    (2) A description of the container for the medical gas, including
the number and size of the containers filled as applicable;
    (3) Specific identification of each component and its source or in-
process material used as applicable;
    (4) Measures of components used in the course of processing as
applicable;
    (5) Testing results, including any in-process test results and
finished product test results;
    (6) Dated signature or initials of the persons performing and
directly supervising or checking each significant event in the
operation;
    (7) Inspection of the packaging and labeling area before and after
use;
    (8) Complete labeling control records, including specimens or
copies of all labeling used and label application and reconciliation
records as appropriate;
    (9) Any investigation made according to Sec.  213.192.

Sec.  213.192   Production record review.

    (a) Manufacturing production and control records, including those
for packaging and labeling, shall be reviewed and approved by the
quality unit to determine compliance with all established, approved
written procedures before a batch is released or distributed. The
quality unit must review production records to determine whether errors
or unexplained discrepancies have occurred prior to batch release. If
errors or unexplained discrepancies have occurred, or a batch or any
component of the batch fails to meet any of its specifications, the
firm must thoroughly investigate and take appropriate corrective
actions. A written record of the investigation shall be made and shall
include the conclusions and followup.
    (b) For production and control records of filling at a delivery
site, quality unit review as described in paragraph (a) of this section
shall be within one business day after fill.

Sec.  213.194   Laboratory records.

    (a) Laboratory records related to the manufacture of a medical gas
must include complete data derived from all tests necessary to assure
compliance with established specifications and standards, including
examinations and assays, as follows:
    (1) 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.
    (2) The method used in the testing of the sample, the result of the
test, how the results compare with established standards of identity,
strength, quality, and purity for the component, container, closure,
in-process materials (as applicable), and medical gas tested, a record
of any calculations performed in connection with each test and any
calculated results, and the unit of measurement of the result for each
test. It is not necessary to provide the actual calculation where the
result is evident through use of simple addition and subtraction.
    (3) 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.
    (4) The initials or signature of the person performing the test and
the initials or signature of a second person showing that the original
records have been reviewed for accuracy, completeness, and compliance
with established standards.
    (b) Complete records shall be maintained of any modification of an
established method employed in testing. Such records shall 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.
    (c) Complete records shall be maintained of any testing and
standardization of laboratory reference standards, reagents, and
standard solutions.
    (d) Complete records shall be maintained of the periodic
calibration or verification of calibration of laboratory instruments,
apparatus, gauges, and recording devices required by Sec.
213.160(b)(4).
    (e) Complete records shall be maintained of all stability testing
performed in accordance with Sec.  213.166.

Sec.  213.196   Distribution records.

    Distribution records shall contain the name of the product, lot or
batch number, name and address of the consignee, and date and quantity
shipped. For medical air and medically appropriate combinations of
designated medical gases, the distribution record shall include the
percentage of each gas.

Sec.  213.198   Complaint files.

    (a) Written procedures shall be established and followed for the
receipt and handling of all written or oral complaints concerning a
medical gas. These procedures must include quality unit review of any
complaint involving the possible failure of a medical gas to meet any
of its specifications and an investigation to determine the cause of
the failure. Such procedures shall include provisions for determining
the need for an investigation in accordance with Sec.  213.192 as well
as determining whether the complaint represents an event that is
required to be reported to FDA under part 230 of this chapter.
    (b) A written record of each complaint regarding a medical gas must
be maintained. The record must include the name of the 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 must also include the findings of any investigation and
followup. Where an investigation is not conducted, the written record
shall include the reason that an investigation

was found not to be necessary and the name of the responsible person
making such a determination.
    (c) Complaint files shall be maintained in a manner such that they
are readily available for inspection by the firm or by FDA during an
inspection. Complaint files shall be maintained for at least 1 year
after the date the complaint was received or for at least 3 years after
distribution of the medical gas, whichever is longer.

Subpart K--Returned and Salvaged Medical Gases

Sec.  213.204   Returned medical gases.

    Returned medical gases shall be identified as such and held. If the
conditions under which such 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,
casts doubt on the safety, identity, strength, quality, or purity of
the gas, the returned gas shall be destroyed unless examination,
testing, or other investigations prove the gas meets appropriate
standards of safety, identity, strength, quality, or purity. Records of
returned medical gases shall be maintained and shall include the name,
lot number (or control number or batch number), reason for the return,
quantity returned, date of disposition, and ultimate disposition of the
returned gas. If the reason for a medical gas being returned implicates
associated batches, an appropriate investigation shall be conducted in
accordance with the requirements of Sec.  213.192. Procedures for the
holding, testing, and use of returned medical gases shall be in writing
and shall be followed. This section is not applicable to the routine
refilling of cryogenic medical gas containers in the normal course of
business, unless the cryogenic medical gas container was returned due
to a quality issue.

Sec.  213.208   Salvaging of medical gases.

    Medical gases in containers that have been subjected to improper
storage conditions may be salvaged unless their containers have been
subjected to adverse conditions that impact the identity, strength,
quality, and purity of the product or integrity of the container
closure. Whenever there is a question whether medical gases have been
subjected to such conditions, salvaging operations may be conducted
only if there is evidence from laboratory tests that such gases meet
all applicable standards of identity, strength, quality, and purity,
and the integrity of the container closure system is not compromised.
Procedures for the holding, testing, and use of salvaged medical gases
shall be in writing and shall be followed.
0
25. Add part 230 to subchapter C to read as follows:

PART 230--CERTIFICATION AND POSTMARKETING REPORTING FOR DESIGNATED
MEDICAL GASES

Sec.
Subpart A--General Provisions
230.1 Scope of this part.
230.2 Purpose.
230.3 Definitions.
Subpart B--Certification of Designated Medical Gases
230.50 General requirements for all submission types.
230.65 Withdrawal by the applicant of a certification request before
it is deemed granted.
230.70 Supplements and other changes to a granted certification.
230.72 Change in ownership of a granted certification.
230.80 Annual report.
230.100 FDA review of submissions.
230.105 When a submission is deemed granted.
230.150 Withdrawal or revocation of approval of an application.
Subpart C--Postmarketing Quality and Safety Reporting
230.205 Field alert reports.
230.210 General reporting requirements for designated medical gas
adverse events.
230.220 Human designated medical gas ICSR requirements.
230.230 Animal designated medical gas adverse event reporting
requirements.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f,
356, 356a, 356b, 356c, 356e, 360b, 360cc, 360ddd, 360ddd-1, 371,
374, 379e, 379k-1, 381.

Subpart A--General Provisions

Sec.  230.1   Scope of this part.

    (a) This part sets forth procedures and requirements for the
submission to, and the review by, the Food and Drug Administration of
certifications to market designated medical gases under sections 575
and 576 of the Federal Food, Drug, and Cosmetic Act, as well as
amendments and supplements to those certifications. This part also sets
forth the postmarketing safety reporting requirements for designated
medical gases.
    (b) References in this part to regulations in the Code of Federal
Regulations are to chapter I of title 21, unless otherwise noted.

Sec.  230.2   Purpose.

    The purpose of this part is to establish an efficient process for
the certification of designated medical gases and to establish an
effective system for surveillance of such gases.

Sec.  230.3   Definitions.

    (a) The definitions and interpretations contained in sections 201
and 575 of the Federal Food, Drug, and Cosmetic Act apply to those
terms when used in this part of this chapter.
    (b) The following definitions of terms apply to this part:
    (1) Adverse event means 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. An
adverse event can occur in the course of the use of a designated
medical gas; from overdose of a designated medical gas, whether
accidental or intentional; from abuse of a designated medical gas; from
discontinuation of the designated medical gas (e.g., physiological
withdrawal); and it includes any failure of expected pharmacological
action.
    (2) Applicant means any person or entity who submits a
certification request for a designated medical gas under this part,
including a supplement, and any person or entity who owns a granted
certification for a designated medical gas under this part.
    (3) Certification request means a submission under section 576 of
the Federal Food, Drug, and Cosmetic Act requesting certification of a
medical gas as a designated medical gas.
    (4) FDA or Agency means the Food and Drug Administration.
    (5) Individual case safety report (ICSR) means a description of an
adverse event related to an individual patient or subject.
    (6) ICSR attachments means documents related to the adverse event
described in an ICSR, such as medical records, hospital discharge
summaries, or other documentation.
    (7) Life-threatening adverse event means 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, i.e., it does not
include an adverse event that, had it occurred in a more severe form,
might have caused death.
    (8) Minimum data set for an ICSR for an adverse event means the
minimum four elements required for reporting an ICSR of an adverse
event: An identifiable patient, an identifiable reporter, a suspect
designated medical gas, and an adverse event.
    (9) Nonapplicant means any person other than the applicant whose
name appears on the label of a designated

medical gas container as a manufacturer, packer, or distributor.
    (10) Serious adverse event means:
    (i) An adverse event is considered ``serious'' if it results in any
of the following outcomes:
    (A) Death;
    (B) A life-threatening adverse event;
    (C) Inpatient hospitalization or prolongation of existing
hospitalization;
    (D) A persistent or significant incapacity or substantial
disruption of the ability to conduct normal life functions; and/or
    (E) A congenital anomaly/birth defect.
    (ii) Other events that may be considered serious adverse events:
Important medical events that may not result in one of the listed
outcomes in this definition 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 in this definition.
Examples include: Allergic bronchospasm requiring intensive treatment
in an emergency department 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.

Subpart B--Certification of Designated Medical Gases

Sec.  230.50   General requirements for all submission types.

    (a) Who must submit a request for certification.
    (1) The certification process described in this subpart applies to
designated medical gases for the indications described in section
576(a)(3)(A)(i) of the Federal Food, Drug, and Cosmetic Act. Any person
who seeks to initially introduce or deliver for introduction a
designated medical gas into interstate commerce shall file a request
for certification. The certification process is the same for all
designated medical gases, regardless of whether it is intended for
human use, animal use, or both. The applicant must identify its
intention to market its designated medical gas for human use, animal
use, or both.
    (2) Any person that proposes to market a medical gas that is a new
drug for human use must obtain approval under part 314 of this chapter,
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 of this
chapter, unless--
    (i) The medical gas meets the definition of a designated medical
gas; and
    (ii) The medical gas is proposed to be marketed:
    (A) Alone, or
    (B) In combination (as medically appropriate) with another
designated medical gas or other designated medical gases; and
    (C) For which a certification or certifications have been granted,
for a use described under section 576(a)(3)(A)(i) of the Federal Food,
Drug, and Cosmetic Act.
    (b) The applicant must include the following information in its
certification request:
    (1) Applicant information. The applicant must identify 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 is
required 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.
    (2) Type of submission. The applicant must indicate the type of
submission as one of the following:
    (i) Original Certification Request--An initial request submitted by
an applicant for certification of a medical gas as a designated medical
gas.
    (ii) Amendment to a Pending Certification Request--Any submission
related to a pending submission that revises existing information or
provides additional information, including responses to Information
Request Letters.
    (iii) Resubmission--Any submission that has been revised and
submitted again following a previous denial. If an applicant chooses to
resubmit its submission, it must provide a written response to the
deficiencies identified in FDA's denial letter, along with other
information required for certification requests.
    (iv) Supplement to a granted certification--Any submission that
contains a change to a granted certification.
    (v) Other--Any submission that does not fit in one of the other
categories.
    (3) Description of medical gas. A separate certification request is
required to be submitted for each designated medical gas for which
certification is sought. Each designated medical gas certification
request must include the name of the medical gas and a certification
statement from the applicant that the designated medical gas meets the
appropriate compendial standard.
    (4) Facility information. Each certification request must include
the name and address of the facility or facilities where the designated
medical gas will be initially produced. For each facility, include a
brief description of the manufacturing or processing activities
performed, the FDA Establishment Identifier (FEI), if one exists, and
the Unique Facility Identifier in accordance with the requirements of
part 207 of this chapter and section 510 of the Federal Food, Drug, and
Cosmetic Act. For amendments and supplements, only changes to the list
of facilities are required to be included.
    (5) Certification of adequate manufacture, processing, packaging,
and holding of designated medical gas. The applicant must certify that
the applicant's methods, facilities, and controls used for the
manufacture, processing, packing, and holding of the designated medical
gas, as applicable, are adequate to ensure its safety, identity,
strength, quality, and purity.
    (6) Additional information. The applicant must provide any other
information which FDA deems appropriate to determine whether the
medical gas is a designated medical gas. The applicant may also provide
other information that the applicant believes will assist FDA in
evaluating the request.
    (c) Where and how to submit a request for certification. The
applicant must submit a signed, completed request for certification
form either in an electronic format that FDA can process, review, and
archive, or in hard copy by submitting two paper copies to the Central
Document Room, Center for Drug Evaluation and Research, Food and Drug
Administration, 5901-B Ammendale Road, Beltsville, MD 20705.

Sec.  230.65   Withdrawal by the applicant of a certification request
before it is deemed granted.

    An applicant may at any time withdraw a certification request that
is not yet deemed granted by notifying FDA in writing. A decision to
withdraw the certification request is without prejudice to refiling.
The Agency will retain the certification request and will provide a
copy to the applicant on request under the fee schedule in Sec.  20.45
of this chapter (FDA's public information regulations).

Sec.  230.70   Supplements and other changes to a granted
certification.

    (a) The applicant must submit a supplement if any information in
the certification request changes 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.
    (b) Each supplement must include a signed, completed request for
certification form with the updated information in accordance with
Sec.  230.50. The updated information must be submitted no later than
30 calendar days after the date the change occurred.

Sec.  230.72   Change in ownership of a granted certification.

    An applicant may transfer ownership of its certification. At the
time of transfer the new and former owners are required to submit
information to FDA as follows:
    (a) The former owner must submit a letter or other document that
states that all rights to the certification have been transferred to
the new owner.
    (b) The new owner must 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 containing the
date that the change in ownership is effective.

Sec.  230.80   Annual report.

    (a) The applicant must submit each year within 60 calendar days of
the anniversary of the date the certification was deemed granted, an
annual report containing the information described in paragraph (b) of
this section. The applicant must 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
the Central Document Room, Center for Drug Evaluation and Research,
Food and Drug Administration, 5901-B Ammendale Road, Beltsville, MD
20705.
    (b) The report must contain, for the prior 12 months, the following
information in the order listed:
    (1) Summary. A brief summary of significant new information that
might affect the safety, effectiveness, or labeling of the designated
medical gas, including any actions the applicant has taken or intends
to take as a result of this new information.
    (2) Distribution data. Information about the quantity of the
designated medical gas distributed by the applicant. The information
must include the National Drug Code (NDC) numbers and the quantities
distributed for domestic use and the quantities distributed for foreign
use. Disclosure of financial or pricing data is not required.
    (3) Administrative changes. Any changes to the applicant's name or
contact information.
    (4) Current facilities. A list of current facilities, and a list of
facilities that are no longer in use.

Sec.  230.100   FDA review of submissions.

    (a) In reviewing a submission pursuant to Sec.  230.50, FDA will
consider information provided with the submission along with any other
available, relevant information of which FDA becomes aware, including
information obtained from State or Federal officials, FDA inspection
reports, or any other source.
    (b) FDA will deny a submission if FDA finds that:
    (1) The medical gas that is the subject of the submission is not a
designated medical gas;
    (2) 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;
    (3) 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
    (4) Denying the request is otherwise necessary to protect the
public health.
    (c) Within 60 calendar days of filing of a submission, FDA may
contact the applicant to request additional information regarding the
submission if it determines that required information is not included
in the submission, 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. Upon
receipt of an amendment to a pending certification request, this 60-day
review period will restart. If FDA is not able to contact the applicant
to obtain and evaluate the information within the 60-day review period,
FDA may find that the submission lacks sufficient information to permit
a determination that the medical gas is a designated medical gas and
deny the submission. If FDA is able to contact the applicant but is not
provided with the additional information requested within the 60-day
review period, FDA may find that the request lacks sufficient
information to permit a determination that the medical gas is a
designated medical gas and deny the submission.
    (d) Within 60 calendar days of filing of a submission, if FDA makes
one of the findings described in Sec.  230.100(b), FDA will notify the
applicant in writing that the submission is denied and provide the
basis for FDA's determination.

Sec.  230.105   When a submission is deemed granted.

    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, the 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 section 512 of the Federal Food, Drug,
and Cosmetic Act, or both, as applicable, for the indications described
in section 576(a)(3)(A)(i) of the Federal Food, Drug, and Cosmetic Act.
FDA will notify the applicant in writing.

Sec.  230.150   Withdrawal or revocation of approval of an application.

    (a) Withdrawal.
    (1) FDA 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. Sec.  314.200, 514.200, or both, as applicable, if
any of the following apply:
    (i) The Secretary of Health and Human Services has suspended the
approval of the application for a designated medical gas on a finding
that there is an imminent hazard to the public health. FDA will
promptly afford the applicant an expedited hearing following summary
suspension on a finding of imminent hazard to health.
    (ii) FDA finds:
    (A) That 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;
or
    (B) That 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; or
    (C) 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 Sec.  314.126 of this chapter, 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
    (D) That the application contains any untrue statement of a
material fact.
    (2) FDA 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. Sec.  314.200, 514.200, or both, as applicable, if
the Agency finds:
    (i) That 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 Federal Food, Drug, and Cosmetic Act and this part and part 213 of
this chapter, or that the applicant has refused to permit access to, or
copying or verification of, its records.
    (ii) That 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.
    (iii) That 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.
    (iv) That the applicant has failed to comply with the notice
requirements of section 510(j)(2) of the Federal Food, Drug, and
Cosmetic Act.
    (3) FDA will withdraw approval of an application 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 paragraphs (a)(1) and (2) of this section applies
to the designated medical gas. FDA will consider a written request for
a withdrawal under this clause to be a waiver of an opportunity for
hearing otherwise provided for in this section. Withdrawal of approval
of an application under this clause is without prejudice to refiling.
    (4) FDA may 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 for under this section, to permit FDA to withdraw
approval of the application for the product, and to remove voluntarily
the product from the market. If the applicant agrees, the Agency will
not make a finding under paragraph (a) of this section, but will
withdraw approval of the application in a notice published in the
Federal Register that contains a brief summary of the Agency's and the
applicant's views of the reasons for withdrawal.
    (5) If FDA withdraws an approval, FDA will publish a notice in the
Federal Register announcing the withdrawal of approval.
    (b) Revocation. FDA may revoke the grant of a certification if FDA
determines, after providing the applicant with notice and opportunity
for an informal hearing in accordance with part 16 of this chapter,
that the request for certification contains any material omission or
falsification.

Subpart C--Postmarketing Quality and Safety Reporting

Sec.  230.205   Field alert reports.

    The applicant shall submit all information described in paragraphs
(a) and (b) of this section about distributed designated medical gases
and articles to the FDA district office that is responsible for the
facility involved within 3 working days of receipt by the applicant.
The information may be provided by telephone or other rapid
communication means, with prompt written followup. The report and its
mailing cover should be plainly marked: ``Designated Medical Gas--Field
Alert Report.''
    (a) Information concerning any incident that causes the designated
medical gas or its labeling to be mistaken for, or applied to, another
article.
    (b) Information concerning any bacteriological contamination, or
any significant chemical, physical, or other change or deterioration in
the distributed designated medical gas, or any failure of one or more
distributed batches of the designated medical gas to meet established
specifications.

Sec.  230.210   General reporting requirements for designated medical
gas adverse events.

    (a) Review of safety information. Each applicant and nonapplicant
must promptly review all safety information that the applicant or
nonapplicant receives or otherwise obtains from any source, foreign or
domestic, such as information derived from commercial marketing
experience, reports in the published scientific and medical literature,
unpublished scientific papers, and reports from regulatory authorities.
    (b) Safety reporting disclaimer. (1) A report or information
submitted by an applicant or nonapplicant (and any release by FDA of
that report or information) under Sec.  230.220 or 230.230 does not