**Guidance for Industry**

**Current Good Manufacturing**

**Practice for Medical Gases**

###### ***DRAFT GUIDANCE***

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document must be submitted
within 120 days of publication in the *Federal Register* of the notice
announcing the availability of the draft guidance. Submit comments to
Docket Management Branch (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm.1061, Rockville, MD 20852. All comments must be
identified with the docket number listed in the notice of availability
that publishes in the *Federal Register*.

For questions regarding this draft document contact Duane Sylvia (301)
594-0095, sylviad@cder.fda.gov.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**May 2003**

**Compliance**

**Guidance for Industry**

**Current Good Manufacturing**

**Practice for Medical Gases**

*Additional copies are available from:*

#### *Office of Training and Communications*

*Division of Communications Management*

*Drug Information Branch, HFD-210*

*Center for Drug Evaluation and Research*

*Food and Drug Administration*

*5600 Fishers Lane, Rockville, MD 20857*

*(Phone 301-827-4573)*

*Internet: http://www.fda.gov/cder/guidance/index.htm*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**May 2003**

**Compliance**

##### **TABLE OF CONTENTS**

# [I. INTRODUCTION [1](#i.-introduction)]{.smallcaps} {#i.-introduction-1 .TOC-1}

# II. STATUTORY AND REGULATORY REQUIREMENTS [2](#ii.-statutory-and-regulatory-requirements) {#ii.-statutory-and-regulatory-requirements-2 .TOC-1}

# III. ORGANIZATION AND PERSONNEL [3](#iii.-organization-and-personnel) {#iii.-organization-and-personnel-3 .TOC-1}

## A. Responsibilities of the Quality Control Unit [3](#a.-responsibilities-of-the-quality-control-unit) {#a.-responsibilities-of-the-quality-control-unit-3 .TOC-2}

## B. Personnel Qualifications [3](#b.-personnel-qualifications) {#b.-personnel-qualifications-3 .TOC-2}

## C. Consultants [5](#c.-consultants) {#c.-consultants-5 .TOC-2}

# Iv. BUILDINGS AND FACILITIES [5](#iv.-buildings-and-facilities) {#iv.-buildings-and-facilities-5 .TOC-1}

## A. Design and Construction [5](#a.-design-and-construction) {#a.-design-and-construction-5 .TOC-2}

## B. Security [6](#b.-security) {#b.-security-6 .TOC-2}

# V. EQUIPMENT [6](#v.-equipment) {#v.-equipment-6 .TOC-1}

## A. Equipment Cleaning and Maintenance [6](#a.-equipment-cleaning-and-maintenance) {#a.-equipment-cleaning-and-maintenance-6 .TOC-2}

## B. Equipment Calibration [7](#b.-equipment-calibration) {#b.-equipment-calibration-7 .TOC-2}

## C. Computerized Systems [8](#c.-computerized-systems) {#c.-computerized-systems-8 .TOC-2}

# VI. COMPONENTS, CONTAINErS, AND CLOSURES [8](#vi.-components-containers-and-closures) {#vi.-components-containers-and-closures-8 .TOC-1}

## A. General Recommendations [8](#a.-general-recommendations) {#a.-general-recommendations-8 .TOC-2}

### 1. Prefill Inspections for Cylinders [9](#prefill-inspections-for-cylinders) {#prefill-inspections-for-cylinders-9 .TOC-3}

### 2. Prefill Inspections for Cryogenic Home Containers [11](#prefill-inspections-for-cryogenic-home-containers) {#prefill-inspections-for-cryogenic-home-containers-11 .TOC-3}

### 3. Dedication of Large Cryogenic Containers to Medical Use Only [11](#dedication-of-large-cryogenic-containers-to-medical-use-only) {#dedication-of-large-cryogenic-containers-to-medical-use-only-11 .TOC-3}

### 4. Prefill Inspections of Large Cryogenic Containers [11](#prefill-inspections-of-large-cryogenic-containers) {#prefill-inspections-of-large-cryogenic-containers-11 .TOC-3}

### 5. Prefill Inspections for Permanently Mounted Cryogenic Containers [12](#prefill-inspections-for-permanently-mounted-cryogenic-containers) {#prefill-inspections-for-permanently-mounted-cryogenic-containers-12 .TOC-3}

## B. Retesting of Containers [12](#b.-retesting-of-containers) {#b.-retesting-of-containers-12 .TOC-2}

# VII. PRODUCTION AND PROCESS CONTROLS [12](#vii.-production-and-process-controls) {#vii.-production-and-process-controls-12 .TOC-1}

## A. Written Procedures [12](#a.-written-procedures) {#a.-written-procedures-12 .TOC-2}

## B. Charge-in of Components [13](#b.-charge-in-of-components) {#b.-charge-in-of-components-13 .TOC-2}

### 1. Temperature/Pressure Readings (Boyle\'s Law) [14](#temperaturepressure-readings-boyles-law) {#temperaturepressure-readings-boyles-law-14 .TOC-3}

### 2. Valve Assembly Leak Testing [14](#valve-assembly-leak-testing) {#valve-assembly-leak-testing-14 .TOC-3}

### 3. Heat of Compression [15](#heat-of-compression) {#heat-of-compression-15 .TOC-3}

## C. Calculation of Yield [15](#c.-calculation-of-yield) {#c.-calculation-of-yield-15 .TOC-2}

# VIII. PACKAGING AND LABELING CONTROLS [15](#viii.-packaging-and-labeling-controls) {#viii.-packaging-and-labeling-controls-15 .TOC-1}

## A. Materials Examination and Usage [15](#a.-materials-examination-and-usage) {#a.-materials-examination-and-usage-15 .TOC-2}

## B. Labeling Control [16](#b.-labeling-control) {#b.-labeling-control-16 .TOC-2}

## C. Packaging and Labeling Operations [17](#c.-packaging-and-labeling-operations) {#c.-packaging-and-labeling-operations-17 .TOC-2}

## D. Drug Product Inspection [18](#d.-drug-product-inspection) {#d.-drug-product-inspection-18 .TOC-2}

## E. Expiration Dating [18](#e.-expiration-dating) {#e.-expiration-dating-18 .TOC-2}

# IX. HOLDING AND DISTRIBUTION [19](#ix.-holding-and-distribution) {#ix.-holding-and-distribution-19 .TOC-1}

## A. Warehousing Procedures [19](#a.-warehousing-procedures) {#a.-warehousing-procedures-19 .TOC-2}

## B. Distribution Procedures and Recalls [19](#b.-distribution-procedures-and-recalls) {#b.-distribution-procedures-and-recalls-19 .TOC-2}

# X. LABORATORY CONTROLS [20](#x.-laboratory-controls) {#x.-laboratory-controls-20 .TOC-1}

## A. General Controls [20](#a.-general-controls) {#a.-general-controls-20 .TOC-2}

### 1. Sampling Plan [21](#sampling-plan) {#sampling-plan-21 .TOC-3}

### 2. USP Oxygen Monograph [21](#usp-oxygen-monograph) {#usp-oxygen-monograph-21 .TOC-3}

### 3. Calibration of Instruments [22](#calibration-of-instruments) {#calibration-of-instruments-22 .TOC-3}

## B. Testing and Release for Distribution [22](#b.-testing-and-release-for-distribution) {#b.-testing-and-release-for-distribution-22 .TOC-2}

### 1. Liquid-to-Liquid Filling; Oxygen Only [23](#liquid-to-liquid-filling-oxygen-only) {#liquid-to-liquid-filling-oxygen-only-23 .TOC-3}

### 2. Liquid-To-Gas; Filling Large Cryogenic Containers [25](#liquid-to-gas-filling-large-cryogenic-containers) {#liquid-to-gas-filling-large-cryogenic-containers-25 .TOC-3}

### 3. Liquefied (gas on top of liquid) Compressed Gas [25](#liquefied-gas-on-top-of-liquid-compressed-gas) {#liquefied-gas-on-top-of-liquid-compressed-gas-25 .TOC-3}

### 4. Gas Mixtures [25](#gas-mixtures) {#gas-mixtures-25 .TOC-3}

### 5. Liquid Nitrogen [25](#liquid-nitrogen) {#liquid-nitrogen-25 .TOC-3}

## C. Alternate Testing Methods [26](#c.-alternate-testing-methods) {#c.-alternate-testing-methods-26 .TOC-2}

## D. Stability Testing [26](#d.-stability-testing) {#d.-stability-testing-26 .TOC-2}

## E. Reserve Samples [27](#e.-reserve-samples) {#e.-reserve-samples-27 .TOC-2}

# XI. RECORDS AND REPORTS [27](#xi.-records-and-reports) {#xi.-records-and-reports-27 .TOC-1}

## A. Record Retention [27](#a.-record-retention) {#a.-record-retention-27 .TOC-2}

## B. Equipment Cleaning and Use Log [28](#b.-equipment-cleaning-and-use-log) {#b.-equipment-cleaning-and-use-log-28 .TOC-2}

## C. Component, Drug Product Container, Closure, and Labeling Records [28](#c.-component-drug-product-container-closure-and-labeling-records) {#c.-component-drug-product-container-closure-and-labeling-records-28 .TOC-2}

## D. Master Production and Control Records [29](#d.-master-production-and-control-records) {#d.-master-production-and-control-records-29 .TOC-2}

## E. Batch Production and Control Records [29](#e.-batch-production-and-control-records) {#e.-batch-production-and-control-records-29 .TOC-2}

## F. Production Record Review [30](#f.-production-record-review) {#f.-production-record-review-30 .TOC-2}

## G. Laboratory Records [31](#g.-laboratory-records) {#g.-laboratory-records-31 .TOC-2}

## H. Liquid Supply (Certificate of Analysis (COA)) [32](#h.-liquid-supply-certificate-of-analysis-coa) {#h.-liquid-supply-certificate-of-analysis-coa-32 .TOC-2}

## I. Distribution Records [33](#i.-distribution-records) {#i.-distribution-records-33 .TOC-2}

## J. Complaint Files [33](#j.-complaint-files) {#j.-complaint-files-33 .TOC-2}

## K. Reporting Deaths and Injuries [34](#k.-reporting-deaths-and-injuries) {#k.-reporting-deaths-and-injuries-34 .TOC-2}

# XII. RETURNED AND SALVAGED DRUG PRODUCTS [35](#xii.-returned-and-salvaged-drug-products) {#xii.-returned-and-salvaged-drug-products-35 .TOC-1}

## A. Returned Drug Products [35](#a.-returned-drug-products) {#a.-returned-drug-products-35 .TOC-2}

## B. Drug Product Salvaging [35](#b.-drug-product-salvaging) {#b.-drug-product-salvaging-35 .TOC-2}

# XIII. AIR SEPARATION PLANTS OR UNITS (ASU) [35](#xiii.-air-separation-plants-or-units-asu) {#xiii.-air-separation-plants-or-units-asu-35 .TOC-1}

# XIV. STORAGE TANK INSTALLATIONS AT HEALTH CARE FACILITIES [36](#xiv.-storage-tank-installations-at-health-care-facilities) {#xiv.-storage-tank-installations-at-health-care-facilities-36 .TOC-1}

# XV. Medical Gas Mix-Ups [37](#xv.-medical-gas-mix-ups) {#xv.-medical-gas-mix-ups-37 .TOC-1}

# XVI. CARBON DIOXIDE AND Helium Manufacturers AND WHOLESALE DISTRIBUTORS [38](#xvi.-carbon-dioxide-and-helium-manufacturers-and-wholesale-distributors) {#xvi.-carbon-dioxide-and-helium-manufacturers-and-wholesale-distributors-38 .TOC-1}

# XVII. EMERGENCY MEDICAL SERVICE (EMS) [39](#xvii.-emergency-medical-service-ems) {#xvii.-emergency-medical-service-ems-39 .TOC-1}

# XVIII. GAS-TO-GAS ADAPTERS [39](#xviii.-gas-to-gas-adapters) {#xviii.-gas-to-gas-adapters-39 .TOC-1}

# XVIX. ALTERNATIVE APPROACHES [39](#xvix.-alternative-approaches) {#xvix.-alternative-approaches-39 .TOC-1}

# Attachment: MedicaL Gas Mix-Ups [40](#attachment-medical-gas-mix-ups) {#attachment-medical-gas-mix-ups-40 .TOC-1}

# GLOSSARY [43](#glossary) {#glossary-43 .TOC-1}

**Guidance for Industry**[^1]

**Current Good Manufacturing Practice for Medical Gases**

#  {#section .TOC-1}

# I. INTRODUCTION

This guidance is intended to provide recommendations on how to comply
with the current good manufacturing practice (CGMP) regulations as they
apply to manufacturing, filling, transfilling, cascading, transferring,
and distributing compressed and cryogenic medical gases. The
recommendations should help manufacturers, fillers, and distributors[^2]
comply with CGMP requirements to ensure the identity, strength, quality,
and purity of medical gases. This guidance also provides recommendations
to medical gas manufacturers on how to comply with certain aspects of
the PDMA final rule (i.e., 21 CFR part 205). This guidance is not
intended to be an all-inclusive listing of all relevant CGMP; instead,
it covers certain sections of the CGMP regulations followed by a
discussion of recommendations that the Agency considers acceptable means
of meeting the requirements.

Three previous documents were published on current good manufacturing
practice for medical gases. FDA\'s first guideline on compressed medical
gases was issued in June of 1981 and revised in 1983. In February of
1989, FDA issued another revision of the guideline to address the
evolving home care area, including the delivery of oxygen to patients at
home. This guidance builds on the previous guidelines. It provides
details on the filling of high-pressure cylinders and cryogenic
containers and includes new information on CGMP policy for large
cryogenic containers, as well as discussion of CGMP relating to storage
tank installation, carbon dioxide and helium manufacturing, and
emergency medical services. Once finalized, this version of the guidance
will supersede those earlier guidelines.

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency\'s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# II. STATUTORY AND REGULATORY REQUIREMENTS

Medical gases (e.g., oxygen, carbon dioxide, helium, nitrogen, nitrous
oxide, medical air, and combinations of these) are drugs within the
meaning of section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act
(the Act) (21 U.S.C. 321(g)(1)) and pursuant to section 503(b)(1)(A) of
the Act (21 U.S.C. 353(b)(1)(A) are required to be dispensed by
prescription.

Medical gases are considered adulterated under section 501(a)(2)(B) of
the Act (21 U.S.C. 351(a)(2)(B)) if the methods used in, or the
facilities or controls used during their manufacture, processing,
packing, or holding do not conform to, or are not operated or
administered in conformity with CGMP. The CGMP regulations are intended
to ensure that a drug meets the safety requirements of the Act and has
the identity and strength and meets the quality and purity
characteristics that it purports or is represented to possess. Medical
gases are finished drug products and are subject to the CGMP regulations
at 21 CFR parts 210 and 211. Manufacturers of medical gases must follow
the requirements in the CGMP regulations to comply with section
501(a)(2)(B). For example, each time a medical gas is filled into
another container, finished product testing must be performed in
accordance with § 211.165(a).

Medical gases that are not produced and handled in accordance with CGMP
regulations can cause serious injury or death to the patients who use
them. A number of injuries and deaths have resulted from mix-ups of
medical gases associated with CGMP violations including:

-   Mislabeling (in some cases the container had two or more labels)

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-   Inadequate training, including training of medical gas filling
    personnel as well as delivery personnel

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-   Inadequate finished product testing

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-   Inadequate quality control unit

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-   Failure to qualify equipment prior to use (e.g., stainless steel
    hoses, large cryogenic containers)

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-   Inadequate written procedures for manufacturing, processing, testing

The Attachment, Medical Gas Mix-Ups, describes in detail some of the
adverse events that the Agency has investigated, including mix-ups that
have resulted in serious injury or death.

FDA can take several courses of action when a CGMP violation is found:
(1) issue a warning letter; (2) seize gas-related products (including
storage tanks, high-pressure cylinders, vehicles containing permanently
mounted large cryogenic containers, tankers, and/or cryogenic home
containers on the company\'s premises and trucks); (3) seek an
injunction; and/or (4) initiate prosecution. FDA may also recommend
disapproval of certain government contracts with the manufacturer. FDA
can also notify the Centers for Medicare & Medicaid Services (formerly
the Health Care Financing Administration) of the violation. This may
affect Medicare reimbursement for that company\'s products. FDA has
issued numerous warning letters and on many occasions has successfully
pursued seizure actions, injunctions, prosecutions, civil contempt
actions, and inspectional warrants to enforce the CGMP regulations as
they apply to medical gases.

# III. ORGANIZATION AND PERSONNEL

## A. Responsibilities of the Quality Control Unit

Medical gases are subject to the requirements in 21 CFR § 211.22 -
Responsibilities of quality control unit (QCU).

Manufacturers must have a QCU with the responsibility and authority to
approve or reject all product containers, closures, in-process
materials, labeling, and drug products, the authority to review
production records to ensure that no errors have occurred, or if errors
have occurred, that they have been fully investigated. The QCU is
responsible for approving or rejecting drug products manufactured,
processed, packed, or held under contract by another company
(§ 211.22(a)).

The QCU must have the responsibility for approving or rejecting all
procedures or specifications affecting the identity, strength, quality,
and purity of the drug product (§ 211.22(c)).

The responsibilities and procedures applicable to the QCU must be in
writing and must be followed (§ 211.22(d)).

We recommend that the QCU perform more than a testing function, be
independent of the production process, and have both quality assurance
and quality control responsibilities. Ideally, the QCU would participate
in and have final responsibility for all functions that could affect
product quality. The corporate QCU would be responsible for reviewing
and approving all written procedures, even those written by each
individual location's organizational units.

We recommend that all individuals who are part of the QCU be identified
in the manufacturer\'s operating procedures. In a well-structured and
well-defined corporate structure, the QCU would be included as a
separate unit. A small medical gas manufacturer can designate a single
individual as the QCU.

We recommend that QCU individuals receive adequate CGMP training on a
continuing basis, including quality assurance training.

## B. Personnel Qualifications

Medical gases are subject to the requirements in § 211.25 - Personnel
qualifications.

Each person engaged in the manufacturing, filling, processing, packing,
or holding of a medical gas must have the education, training, and
experience, or a combination thereof, to enable that person to perform
the assigned functions. Training must be in the particular operations
that the employee performs and in current good manufacturing practice
regulations as they relate to the employee's functions. Training in the
CGMP regulations must be conducted by qualified individuals on a
continuing basis and with sufficient frequency to ensure that employees
remain familiar with CGMP requirements applicable to them (§ 211.25(a)).

FDA recommends that CGMP training not be conducted in one massive
training session. Rather, it should be presented in smaller more
manageable sessions held throughout the year, or at a minimum be held
once a year. We recommend that the specific type of training received or
covered, the time, and the attendance at each session be documented, and
records of the training be maintained.

Regulations at § 211.25(c) require an adequate number of qualified
personnel be available to perform and supervise the manufacturing,
processing, or holding of medical gases.

Useful training information and training materials are available as
shown below.

-   The following FDA Internet sites:

http://www.fda.gov/cder/dmpq/gases.htm

[www.fda.gov/cder/dmpq/cgmpregs.htm](http://www.fda.gov/cder/dmpq/cgmpregs.htm)

> www.fda.gov/oc/industry

-   Title 21 of the Code of Federal Regulations, Parts 210 and 211,
    available at:
    [www.access.gpo.gov/nara](http://www.access.gpo.gov/nara)

-   Qualified suppliers who offer CGMP training

-   A qualified medical gas consultant or consulting firm

-   Industry or professional associations

The Agency recommends that each manufacturer establish and follow
written training procedures for all truck drivers specific to their
function, including CGMP training. Truck drivers responsible for
delivery of medical gases should be trained to examine the drug label
and distinguish between medical gases and industrial gases, prior to
unloading a container.

We recommend that all manufacturers who allow their drivers to connect
large cryogenic containers to customer gas supply systems train their
drivers in the specifics of those supply systems. We recommend cargo
tanker drivers who fill medical gases into storage tanks also be
trained.

We recommend that an individual responsible for performing an odor test
not have an ailment (e.g., a cold or allergies) that would adversely
affect his or her sense of smell. Likewise, employees responsible for
performing the inspection for the standardized colors should be able to
distinguish colors.

## C. Consultants

Medical gases are subject to the requirements in § 211.34 - Consultants.

Consultants advising on the manufacturing, processing, packing, or
holding of medical gases must have sufficient education, training, and
experience, or any combination thereof, to advise on the subject for
which they are retained. A company must maintain records stating the
name, address, and qualifications of any consultants and the type of
services they provide (§ 211.34).

We recommend that consultants hired to provide assistance in achieving
CGMP compliance have sufficient medical gas education, training, and/or
experience.

# Iv. BUILDINGS AND FACILITIES

## A. Design and Construction

Medical gases are subject to the requirements in § 211.42 - Design and
construction features.

Any building or buildings used in the manufacture, processing, packing,
or holding of a medical gas must be of a suitable size, construction,
and location to facilitate cleaning, maintenance, and proper operations
(§ 211.42(a)).

Buildings must have adequate space for the orderly placement of
equipment and materials to prevent mix-ups and to prevent contamination
(§ 211.42(b)).

Operations must be performed within specifically defined areas of
adequate size. There must be separate or defined areas or other such
control systems for the manufacturer's operations as are necessary to
prevent contamination or mix-ups (§ 211.42(c)).

The Agency recommends that buildings be maintained in good physical
condition, kept clean, and have a sufficient number of areas for
organized sequential operations, such as a well-defined filling area and
a well-defined quarantine area. The Agency also recommends the creation
of quarantine areas to separate incoming medical gases, high-pressure
cylinders, cryogenic containers, manufacturing equipment, rejected
containers and closures, and the finished product. No matter how large
your operation, we recommend you avoid storing industrial gases and
medical gases in close proximity to each other.

We also recommend that delivery vehicles have well-defined, separate
areas for medical gases and industrial gases to prevent mix-ups from
occurring. For example, medical and industrial gases could be separated
physically in the delivery truck, or a manufacturer could use a unique
identifier to distinguish medical gases from industrial gases. The
Agency recommends the use of 360-degree wrap-around label to identify
medical gases in large cryogenic containers. If a manufacturer applies a
360-degree wrap-around label to its large cryogenic containers, this
could serve as the control system for preventing mix-ups, as long as a
manufacturer has established adequate driver training, adequate written
procedures, and proper stock inventory systems.

## B. Security

Medical gas manufacturers are wholesale distributors who are subject to
the requirements of § 205.50 - Minimum requirements for the storage and
handling of prescription drugs and for the establishment and maintenance
of prescription drug distribution records.

All facilities used for medical gas distribution must be secure from
unauthorized entry

(§ 205.50(b)(1)).

Entry into areas where medical gases are held must be limited to
authorized personnel

(§ 205.50(b)(1)(iii)). We recommend areas where nitrous oxide is held be
especially secure.

The security requirements of § 205.50(b) apply to all facilities used
for medical gas distribution. FDA interprets this regulation to include
all facilities where loaded medical gas delivery trucks are parked prior
to making deliveries, including at an employee\'s home when a loaded
medical gas delivery truck is driven there and parked overnight for
early morning runs.

A manufacturer could use an alarm system to secure the building and keep
loading docks secure, rather than open and easily accessible.

# V. EQUIPMENT

##  A. Equipment Cleaning and Maintenance

Medical gases are subject to the requirements in § 211.67 - Equipment
cleaning and maintenance.

Equipment must be cleaned, maintained, and sanitized at appropriate
intervals to prevent malfunctions or contamination that would alter the
safety, identity, strength, quality, or purity of the medical gas beyond
the official or other established requirements (§ 211.67(a)).

Written procedures must be established and followed (§ 211.67(b), (4),
(5), & (6)), including maintenance and cleaning schedules, removal or
obliteration of previous batch identification, protection of clean
equipment from contamination prior to use, and inspection of equipment
for cleanliness immediately prior to use.

We recommend that equipment used in the manufacture of medical gas
(e.g., manifolds, pigtails, valve assemblies, hoses, and gauges) be
cleaned at initial use and if exposed to a contaminant. We recommend
that hoses used to fill cryogenic containers have protective end caps to
prevent contamination from insects, dirt, debris, and other materials.
We also recommend that high-pressure cylinders exposed to the elements
be provided with protective caps or some other protective device,
applied to the valve opening to prevent contamination. See related
clarifications in § 211.80(b).

We recommend that storage tanks (especially those installed at a health
care facility, nursing home, or hospital), tractor trailers, rail cars,
high-pressure cylinders, and cryogenic containers prior to the
introduction of a medical gas be cleaned in the following circumstances:
when they previously contained industrial gases; when they are first
received, whether new or used; and when they are or could be,
contaminated.

##  B. Equipment Calibration

Medical gases are subject to the requirements in § 211.68 - Automatic,
mechanical, and electronic equipment.

Automatic, mechanical, or electronic equipment or other types of
equipment, including computers, or related systems can be used in the
manufacture, processing, packing, and holding of a drug product. If such
equipment is used, it must be routinely calibrated, inspected, or
checked according to a written program designed to ensure proper
performance (§ 211.68(a)). Written records of those calibration checks
and inspections must be maintained (§ 211.68(a)).

The Agency recommends that medical gas manufacturers use either the
equipment manufacturer recommended calibration schedule or a schedule
based on their own historical data. A company can reference the
equipment manufacturer instruction manual in its written procedures if
the manual is available for use at the manufacturing site.

We recommend that vacuum gauges undergo two calibrations. The first
calibration, performed daily, would ensure that the needle on the gauge
returns to zero. This check can be performed with no vacuum present, and
recorded on either a batch production record or a separate log. The
second calibration would ensure that vacuum gauges are calibrated based
on standards established by the National Institute of Standards and
Technology (NIST) on an annual basis at a minimum. Low pressure gauges
and flow meters used in filling cryogenic home containers would not
require calibration.

We recomment that thermometers be calibrated in accordance with
manufacturer recommendations, and that the calibrations be documented in
a separate log.

We also recommend that medical gas companies ensure that check valves
used in a supply system to prevent the back flow of a foreign product or
contaminant into the lines create a proper seal and cannot be
compromised. This recommendation applies to check valves placed at
various points in a supply line to protect the pump, manifold, or other
equipment from over-pressurization or an undesirable back flow. Check
valves do not need to be qualified if they are intended to act only as
an added safety feature and do not prevent the cross contamination of
gases or do not affect product identity, strength, purity, or quality.

## C. Computerized Systems

Medical gases are subject to the requirements in § 211.68 - Automatic,
mechanical, and electronic equipment.

Appropriate controls must be exercised over computer or related systems
to ensure that changes in master production and control records or other
records are instituted only by authorized personnel (§ 211.68(b)).
 Input to and output from the computer or related system of records or
data must be checked for accuracy (§ 211.68(b)). The degree and
frequency of input/output verification must be based on the complexity
and reliability of the computer or related system

(§ 211.68(b)).

The Agency recommends that computerized systems, including hardware and
software, used in the manufacturing, processing, and holding of medical
gases be validated. The depth and scope of the validation depends on the
diversity, complexity, and significance of the computerized application.
Commercially available software that has been qualified does not need
the same level of testing as software that has been specifically
developed for a company.

The Agency recommends that computerized systems have sufficient controls
to prevent unauthorized access or changes to data and to preclude
omissions in data. The Agency also recommends that records be kept of
any changes made to data, including who made the change, when the change
was made, and the previous entry.

We recommend that any change to computerized systems be made according
to specified procedures and would be formally authorized, documented,
and tested. We recommend that records of all changes, including
modifications and enhancements made to hardware, software, and any other
critical component of the system be kept as long as the manufacturer is
still using that system.

# VI. COMPONENTS, CONTAINErS, AND CLOSURES

## A. General Recommendations

Medical gases are subject to the requirements in §§ 211.80 - 211.94:
Control of components and drug product containers and closures.

Manufacturers must have written procedures describing in sufficient
detail the receipt, identification, storage, handling, sampling,
testing, and approval or rejection of components and medical gas
containers and closures (§ 211.80(a)). Containers and closures must at
all times be handled and stored in a manner to prevent contamination (§
211.80(b)).

Each medical gas container and closure, upon receipt and before
acceptance, must be examined visually for appropriate labeling as to
contents, container damage, and contamination

(§ 211.82(a)). Containers and closures must be stored under quarantine
until they have been tested or examined, as appropriate (§ 211.82(b)).

Medical gas containers and closures must be withheld from use until the
lot has been sampled, tested, or examined, as appropriate, and released
for use by the quality control unit (QCU)

(§ 211.84(a)). The containers must be opened, sampled, and resealed in a
manner designed to prevent contamination (§ 211.84(c)(2)). Each medical
gas container and closure that is liable to contamination with filth,
insect infestation, or other extraneous adulterant must be examined
against established specifications for such contamination (§
211.84(d)(5)).

Rejected containers and closures must be identified and controlled under
a quarantine system designed to prevent their use in manufacturing or
processing operations for which they are unsuitable (§ 211.89).

Medical gas containers and closures must not be reactive, additive, or
absorptive so as to alter the safety, identity, strength, quality, or
purity of the drug beyond the official or established requirements (§
211.94(a)). Container closure systems must provide adequate protection
against foreseeable external factors in storage and use that can cause
deterioration or contamination of the drug product (§ 211.94(b)).
Containers and closures must be clean (§ 211.94(c)).

Medical gas containers and closures are used repeatedly and therefore
play a critical role in ensuring that the drug product provided to the
patient has the appropriate identity, strength, quality, and purity.
Containers and closures used for medical gases are integral parts of the
drug delivery system. We recommend they undergo strict inspections and
examinations prior to the introduction of the drug product. In addition,
we advise medical gas manfacturers to determine valve assembly
compatibility prior to installation on a high-pressure cylinder and
during the lifetime of the valve*.*

To avoid the possibility of contamination, we recommend that all
high-pressure cylinders and cryogenic containers used for medical gases
be dedicated to medical use only.

### 1. Prefill Inspections for Cylinders

We recommend that the following prefill inspections be performed on each
medical gas cylinder prior to the start of the filling operation.
Cylinders failing any of these procedures would be quarantined to
prevent their use in any subsequent filling operation. We recommend that
medical gas manufacturers document all prefill inspections on a batch
production record.

**Hydrostatic testing date inspection:** Hydrostatic tests offer
assurance of the integrity of a cylinder. Ultrasonic inspection of steel
high-pressure cylinders can be performed instead of internal visual and
hydrostatic testing. We recommend that manufacturers consult U.S.
Department of Transportation (DOT) requirements pertaining to
hydrostatic testing of certain cylinders as appropriate (see, e.g., 49
CFR 180.209).

**External examination:** We recommend that each cylinder be examined
externally for dents, arc burns, dings, oil, grease, and other signs of
damage, including fire or thermal damage, that can cause a cylinder to
be unacceptable or unsafe for use. Any cylinder found to have any of
these conditions would be removed from service and placed in an
appropriate quarantine area until their suitability has been determined
by the QCU.

**Venting or blowing down:** If any gas is present in a cylinder,
venting or blowing down a cylinder can be performed until atmospheric
pressure occurs. We recommend that cylinders containing liquid be
inverted and drained.

**Odor test:** The odor test is a very important prefill test for
detecting the presence of any foreign gas or odor. Do not perform this
test on carbon dioxide, nitrous oxide, toxic, or corrosive gases. If a
cylinder is empty (contains no pressure), a medical gas can be
introduced into the cylinder at a predetermined pressure, and an odor
test can be performed on the resulting gas. Use only medical gases, as
an industrial gas could contain industrial contaminants.

***Do not confuse this odor test with the finished product odor test
conducted under § 211.165(a) and required by the USP.***

**Hammer or dead ring test**: One way to determine if a cylinder has
internal corrosion is by performing a hammer or dead ring test. This
test consists of lightly tapping the cylinder sidewall with a
hammer-like instrument. A cylinder in good condition will make a clear
bell-like ring, while a dull ring indicates possible internal corrosion.
All cylinders that produce a dull ring would be quarantined until their
suitability has been determined. This procedure cannot be performed on
aluminum or fiber wrapped cylinders because the test would not indicate
internal corrosion. A hammer test works best on empty unpressurized
cylinders with a 10-year test date (stamped into the cylinder shoulder
area). It is not necessary to test cylinders with a 5-year test date.

**Valve assembly examination:** The Agency recommends that the valve
assembly be appropriate for the medical gas being dispensed and be
examined for debris, oil, or grease. The inspection would examine
whether any of the threads on the valve or on top of the valve stem are
damaged; whether the handwheel or valve stem is bent; and whether there
are indications of damage, corrosion inside the valve, or excessive heat
or fire damage.

**Color code examination:** The following colors are used by the medical
gas industry in the United States to aid in identifying a medical gas.
We recommend manufacturers use them.

-   Carbon Dioxide - gray;

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-   Helium - brown;

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-   Medical Air - yellow;

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-   Nitrogen - black;

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-   Nitrous Oxide - blue;

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-   Oxygen - green; and

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-   Blends of medical gases use a combination of the corresponding color
    for each component gas. For example, oxygen and carbon dioxide would
    be green and gray.

Color coding alone cannot be relied on for identification of the medical
gas; use color coding in addition to examining the product label on the
cylinder.

**Label inspection**: We recommend that the label on the cylinder be
inspected and that obsolete labels or labels containing outdated lot
numbers be removed. A label on an empty cylinder does not need to be
removed if it is in good condition and is identical to the label that
will be used for the filled cylinder. We suggest that you ensure that
cylinders bear only one manufacturer or filler's label and that you not
apply new labels on top of an old label.

**Residual gas removal:** We recommend that residual gases be removed
from medical gas cylinders by means of a vacuum pump prior to filling a
medical gas.

All the above inspections can be documented on a batch production
record.

### 2. Prefill Inspections for Cryogenic Home Containers 

The FDA recommends that the following prefill inspections be performed
on all cryogenic home containers (patient-specific containers):

-   An external inspection for any signs of damage, oil, or grease that
    would cause the container to be unacceptable for use

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-   An inspection of the inlet and outlet connection for any signs of
    damage, oil, or grease

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-   An inspection of the volume or quantity of contents gauge to ensure
    that it is operating properly

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-   An inspection of the drug label to ensure correctness.

All the above inspections can be documented on a batch production
record.

### 3. Dedication of Large Cryogenic Containers to Medical Use Only

To avoid the possibility of industrial contaminants, we recommend that
large cryogenic containers used to contain medical gases be dedicated to
medical service only.

### 4. Prefill Inspections of Large Cryogenic Containers 

We recommend the following prefill inspections be performed on large
cryogenic containers:

-   An external examination for any signs of damage, oil, or grease that
    could cause the container to be unacceptable for use

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-   An inspection of the inlet and outlet connections for any signs of
    damage, oil, or grease and to ensure that they are the correct
    fittings for the corresponding medical gas. Permanently attach all
    connections or fittings to the container.

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-   An inspection of the label for correctness.

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-   An examination for a 360-degree wrap-around label applied on the
    sidewall of the cylinder, as close to the top portion of the
    container as possible, but below the top weld seam. These labels are
    designed to repeat the drug product name (e.g., Medical Oxygen) in
    the appropriate color around the entire container. See the "Color
    Code Examination" discussed above under section *1. Prefill
    Inspections for Cylinders;* and in the Glossary under "Wrap-around"
    Label.

We recommend all the above inspections be documented on a batch
production record.

###  5. Prefill Inspections for Permanently Mounted Cryogenic Containers

We recommend that the following prefill inspections be performed on
permanently mounted cryogenic containers:

-   An external examination for any signs of damage, oil, or grease

-   An inspection of the inlet and outlet connections for any signs of
    damage, oil, or grease

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-   An inspection of the product label

## B. Retesting of Containers

Containers and closures must be retested or reexamined, as appropriate,
for identity, strength, quality, and purity and approved or rejected by
the QCU in accordance with § 211.84 as necessary (e.g., after storage
for long periods or after exposure to air, heat or other conditions that
might adversely affect the medical gas container or closure) (§ 211.87).

# 

# VII. PRODUCTION AND PROCESS CONTROLS

## A. Written Procedures

Manufacturers must have written procedures for production and process
controls designed to ensure that medical gases have the identity,
strength, quality, and purity they purport or are represented to
possess. These written procedures, including any changes, must be
drafted, reviewed, and approved by the appropriate organizational units
and reviewed and approved by the QCU (§ 211.100(a)).

Written production and process control procedures must be followed in
the execution of the various production and process control functions
and must be documented at the time of performance (§ 211.100(b)).

To guarantee batch uniformity and integrity of medical gases, written
procedures must 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
must be established to monitor the output and to validate the
performance of those manufacturing processes that may be responsible for
causing variability in the drug product (§ 211.110(a)).

The Agency recommends that the corporate QCU not allow the local QCU to
establish and implement written procedures that have not been reviewed
and approved by the corporate QCU.

Written procedures provide a basis for the uniform performance of a
function and a step-by-step description of how to perform a specific
task, function, or operation, regardless of its size or complexity. We
recommend the procedures be readily available to all employees and be
read, understood, and followed by them.

We recommend that a manufacturer or individual, especially a
manufacturer filling multiple gases, have data on file demonstrating the
amount of vacuum evacuation required to remove all contaminants from
high-pressure cylinders. We also recommend that the manufacturer have
data demonstrating that each different gas it fills would be removed by
the established vacuum evacuation limit.

We recommend that portable racks, such as those added to the main header
or manifold via pigtails, be evaluated to ensure that the cylinders
being filled on the portable rack are being properly vacuum evacuated
and are being filled to the correct pressure, as indicated by the net
content statement on the label.

We recommend that automated filling systems (that is, systems that fill
from large cryogenic containers into high pressure cylinders) be
validated to provide assurance that the filling is done to the correct
pressure.

## B. Charge-in of Components

Written production and control procedures must include the following,
which are designed to ensure that the medical gases produced have the
identity, strength, quality, and purity they purport or are represented
to possess (§ 211.101):

-   The batch must be formulated with the intent to provide not less
    than 100 percent of the labeled or established amount of active
    ingredient (§ 211.101(a)).

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-   Components for medical gas manufacturing must be weighed, measured,
    or subdivided as appropriate (§ 211.101(b)).

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-   Each component must be added to the batch by one person and verified
    by a second person (§ 211.101(d)).

The Agency recommends that all high-pressure cylinders and cryogenic
containers be filled according to the net content statement indicated on
the label in accordance with section 502(b)(2) of the act. This includes
blends or mixtures of medical gases (i.e., multiple gases). The net
content statement can be the same as the fill pressure or the service
pressure. Refer to § 201.51, Declaration of net quantity of contents,
for further information.

### 1. Temperature/Pressure Readings (Boyle\'s Law) 

A medical gas in a high-pressure cylinder increases in pressure as the
temperature of the gas rises. Overfilled cylinders could reach
dangerously high pressures if exposed to elevated temperatures, even if
the pressure at room temperature is safe. This temperature rise can be
properly compensated for during filling, so that the cylinder contents
do not exceed the net content statement on the label. A
temperature/pressure chart or other temperature/pressure calculation
algorithms can be used to adjust the filling pressure so that the proper
contents are achieved (this is usually stated as the pressure at 70^o^F
with appropriate tolerances). We recommend that temperatures measured on
the wall of a cylinder during filling operations not exceed 130^o^F.
Before the filling is complete, the temperature and pressure reading
would be recorded on the batch production record.

To ensure that high-pressure cylinders have the correct contents as
indicated on the label, the manufacturer can attach a thermometer to one
cylinder per manifold-filling sequence and adjust the temperature and
pressure readings according to a temperature pressure chart. We
recommend that, when filling cylinders one at a time (also known as the
cascade method), each cylinder have a thermometer attached to it.

If a \"+\" symbol follows the hydrostatic testing date, the cylinder can
be overfilled by 10 percent unless the valve is equipped with a fusible,
metal-backed safety. It is critical not to overfill aluminum cylinders.

### 2. Valve Assembly Leak Testing

The Agency recommends that a valve assembly leak test be performed
during the cylinder filling operation. Each valve assembly would be
tested for valve packing leaks, safety plug leaks, and other valve leaks
using an appropriate leak detection solution. The test would be
performed while the cylinder is under pressure with the cylinder valve
open. The leak detection solution would be sprayed on and around the
entire valve assembly. A leak would be indicated when bubbles appear in
the solution. We recommend the solution be oxygen compatible and not
contain any hydrocarbons. Solutions containing soap are not recommended
because they can corrode the valve stem and can leave a residue.

After the filling of high-pressure cylinders, and after all valves have
been closed, we recommend a second valve assembly leak test be performed
to detect any valve outlet leaks. If any leaks are detected, the
cylinder would be removed from service and quarantined until repaired.

The two valve assembly leak tests provide assurance that the cylinder
contents do not leak out during storage or shipment, resulting in a
partially filled or empty cylinder that would not contain sufficient
contents for a patient.

### 3. Heat of Compression

During the filling of high-pressure cylinders, we recommend a
heat-of-compression check be performed by lightly touching the exterior
of each and every cylinder. A warm cylinder indicates that the cylinder
is filling properly; a cool or cold cylinder indicates that the cylinder
may not be filling properly. Such a situation would be investigated.

## C. Calculation of Yield

Actual yields and percentages of theoretical yield must be determined at
the conclusion of each appropriate phase of manufacturing, processing,
packing, or holding of medical gases. Such calculations must be
performed by one person and independently verified by a second person

(§ 211.103).

FDA recognizes that accurate inventory records and reconciliation of use
are difficult to maintain for liquefied gases. Normal losses of gas
occur through vaporization, the filling process, and venting and could
reach 10 percent or more. The FDA does not expect the reconciliation to
be 100 percent accurate. A manufacturer\'s procedures for reconciling
the use of medical gases can include allowances for normal storage and
operating losses. The procedures would include provisions for further
investigation when unexplained discrepancies occur, such as losses
beyond established normal levels.

# VIII. PACKAGING AND LABELING CONTROLS

## A. Materials Examination and Usage

Medical gases are subject to the requirements in § 211.122 - Materials
examination and usage criteria.

There must be written procedures describing in sufficient detail the
receipt, identification, storage, handling, sampling, and examination of
labeling and packaging materials, and these written procedures must be
followed. Labeling and packaging materials must be representatively
sampled, and examined or tested upon receipt and before use in packaging
or labeling of a medical gas (§ 211.122(a)).

Records must be maintained for each shipment received of each different
labeling indicating receipt, examination, and whether accepted or
rejected (§ 211.122(c)).

Labels for each different medical gas must be stored separately with
suitable identification. Access to the storage area must be limited to
authorized personnel (§ 211.122(d)).

Obsolete and outdated labels must be destroyed (§ 211.122(e)).

If cut labeling is used, labeling operations must include one of the
following special control procedures (§ 211.122(g)):

-   Dedication of labeling lines to each different strength of each
    different medical gas

> (§ 211.122(g)(1))

-   Use of appropriate electronic or electromechanical equipment to
    conduct a 100 percent examination for correct labeling during or
    after completion of finishing operations

-   Use of visual inspection to conduct a 100 percent examination for
    correct labeling during or after completion of finishing operations
    for hand-applied labeling. Such examination must be performed by one
    person and independently verified by a second person (§
    211.122(g)(3))

Upon receipt from the printer, labels would be counted to verify the
quantity received and would be examined to ensure correctness when
compared against the master label.

We recommend that labels be locked in a secure area with access limited
to authorized personnel. Different medical gas labels would be stored
separately. We recommend that industrial labels be stored in a separate
area.

It is industry practice to apply labels by hand, therefore, we recommend
a second person verify the correctness of the label and document the
verification. In light of recent deaths and injuries, this examination
is critical to ensure that the correct label has been applied to a
container of medical gas.

## B. Labeling Control

Medical gases are subject to the requirements in § 211.125 - Labeling
issuance.

Strict control must be exercised over labeling issued for use in medical
gas labeling operations

(§ 211.125(a)).

Labeling materials issued for a batch must be carefully examined for
identity and conformity to the labeling specified in the master or batch
production records (§ 211.125(b)).

Procedures must be used to reconcile the quantities of labeling issued,
used, and returned, and must require evaluation of discrepancies found
between the quantity of drug product finished and the quantity of
labeling issued if the discrepancies are outside narrow preset limits
based on historical operating data (§ 211.125(c)). However, this
paragraph does not apply to the 360-degree wrap-around label that is
applied to large cryogenic containers.

The Agency recommends that all labels be issued by authorized personnel
only. Before release of issued labels to an employee, we recommend a
representative label be checked against the master label to ensure
correctness.

## C. Packaging and Labeling Operations

Medical gases are subject to the requirements in § 211.130 - Packaging
and labeling operations.

There must be written procedures designed to ensure that correct labels
and labeling are used for medical gases; such written procedures must be
followed. These procedures must incorporate the following features (§
211.130):

-   Prevention of mix-ups and cross contamination by physical or spatial
    separation from operations on other medical gases (§ 211.130(a))

-   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 (§ 211.130(c))

-   Examination of labeling materials for suitability and correctness
    before packaging operations, and documentation of such examination
    in the batch production record (§ 211.130(d))

We recommend manufacturers consider each batch of medical gas a separate
entity with unique filling procedures to help ensure that the batch is
uniform and consistent. Assigning a single lot number to an entire
day\'s production is not appropriate. Each manifold filling sequence;
each uninterrupted filling sequence; and each filled cryogenic
container, storage tank, and trailer would be considered a new lot and
be assigned a unique lot number.

In addition, we recommend each large cryogenic container containing
liquid oxygen for delivery to patients at home, whether portable or
permanently mounted in a van or a truck, be considered a lot and be
assigned a unique lot number. Cryogenic home containers filled at a
patient\'s home do not need a lot number. However, we recommend that
cryogenic home containers filled on site or by a third party in advance
for future delivery be given a lot number.

For safety reasons, we recommend each medical gas container bear only
one drug label containing the appropriate information. Do not place a
current label on top of an obsolete label.

In accordance with 502(b)(2) of the Act, all medical gas cylinders and
cryogenic containers must bear a label with an accurate statement of the
net contents. We recommend that the net contents appear on the body
label or shoulder label and not on (1) a removable tag, (2) a
certificate of analysis, or (3) a small separate sticker.

If a medical gas company sells medical oxygen to emergency medical
services for emergency use, the label would contain the statement:

> For emergency use only when administered by properly trained personnel
> for oxygen deficiency and resuscitation. For all other medical
> applications, Rx Only.[^3]

FDA would not prohibit the sale of medical oxygen with this labeling to
emergency medical services (see Glossary for definition of an EMS)
without a prescription.

We recommend the labeling for large permanently mounted containers,
trailers, and rail cars bear a statement consisting of "Name of the
Medical Gas, Refrigerated Liquid USP or NF," such as \"Oxygen
Refrigerated Liquid USP.\"

The Agency recommends the use of a 360-degree wrap-around label to
identify medical gases in large cryogenic containers.

## D. Drug Product Inspection

Medical gases are subject to the requirements in § 211.134 -- Drug
product inspection.

Labeled products must be examined during finishing operations to provide
assurance that containers in the lot have the correct label (§
211.134(a)).

A representative sample of units must be collected at the completion of
finishing operations and must be visually examined for correct labeling
(§ 211.134(b)).

Results of these examinations must be recorded in the batch production
or control records

(§ 211.134(c)).

Only one medical gas label would appear on a cylinder or container, and
the manufacturer of the medical gas would apply the label in accordance
with section 502(b) of the act.

## E. Expiration Dating

Medical gases are subject to the requirements in § 211.137 - Expiration
dating.

To ensure that a medical gas meets applicable standards of identity,
strength, quality, and purity at the time of use, each container must
bear an expiration date determined by appropriate stability testing
described in § 211.166 (§ 211.137(a)).

Expiration dates must be related to any storage conditions stated on the
label, as determined by stability studies described in § 211.166 (§
211.137(b)).

Expiration dates must appear on the labeling in accordance with the
requirements of § 201.17

(§ 211.137(d)).

New drug products for investigational use are exempt from the
requirements of this section, provided that they meet appropriate
standards or specifications as demonstrated by stability studies during
their use in clinical investigations (§ 211.137(g)).

The Agency recommends that high-pressure cylinders stored for long
periods of time, such as those provided to patients as a backup to their
oxygen concentrator, be monitored to ensure they contain the correct net
contents (i.e., pressure). We recommend that companies, especially home
care companies and durable medical equipment suppliers, establish and
follow a written plan to periodically verify the pressure (i.e., net
content) of each high-pressure cylinder stored at a patient\'s home and
that the results be documented.

# IX. HOLDING AND DISTRIBUTION

## A. Warehousing Procedures

Medical gases are subject to the requirements in § 211.142 - Warehousing
procedures.

Manufacturers must develop and follow written procedures describing the
warehousing of medical gases. Procedures must include (§ 211.142):

-   Quarantine of medical gases before release by the QCU (§ 211.142(a))

-   Storage of medical gases under appropriate conditions (§ 211.142(b))

The Agency recommends that separate areas be designated for the
following: (1) empty containers, (2) full containers, (3) in-process
containers, (4) different types of medical gases, (5) rejected
containers and closures, (6) medical gases that have been released, and
(7) medical gases that have not been released. We also recommend that
industrial gases, containers, and equipment be stored separately from
medical gases, containers, and equipment.

We recommend medical gas containers be stored under protective covering
and not be subject to temperature extremes. Based on this
recommendation, storage areas would be clean, dry, well ventilated, and
free of combustible materials. Also all valve assemblies, hoses, and
other relevant equipment would be protected from contamination such as
insect infestation.

## B. Distribution Procedures and Recalls

Medical gases are subject to the requirements in § 211.150 -
Distribution procedures.

Manufacturers must establish and follow written procedures describing
the distribution of medical gases (§ 211.150). They must include a
system by which the distribution of each lot of the drug product can be
readily determined to facilitate its recall if necessary (§ 211.150(b)).

We recommend that manufacturers have procedures to explain who would
evaluate distribution information if a recall were necessary, how a
recall would be initiated, who would be informed about the recall, and
what would be done with the recalled product.

The Agency recommends that delivery vehicles have well-defined, separate
areas for medical gases and industrial gases to prevent mix-ups from
occurring. For example, medical and industrial gases can be separated
physically in the delivery truck, or a manufacturer can use a unique
identifier to distinguish medical gases from industrial gases. As
mentioned above, the Agency recommends the use of a 360-degree
wrap-around label to identify medical gases in large cryogenic
containers. If a manufacturer applies a 360-degree wrap-around label to
its large cryogenic containers, and the manufacturer has established
adequate driver training, written procedures, and proper stock inventory
systems, physical separation on a delivery vehicle is not critical.

We recommend that handheld computer devices or computers used during
distribution operations be validated to ensure proper performance.

# X. LABORATORY CONTROLS

## A. General Controls

Medical gases are subject to the requirements in § 211.160 - Laboratory
control general requirements.

The establishment of any specifications, standards, sampling plans, test
procedures, or other laboratory control mechanisms required by Subpart I
of 21 CFR Part 211, including any change in such specifications,
standards, sampling plans, test procedures, or other laboratory control
mechanisms, must be drafted by the appropriate organizational unit and
reviewed and approved by the QCU. The requirements in Subpart I of 21
CFR Part 211 must be followed and must be documented at the time of
performance (§ 211.160(a)).

The Agency recommends that a manufacturer follow the specifications for
the specific medical gas as described in the respective monograph of the
current U.S. Pharmacoepia/National Formulary (USP/NF), or a manufacturer
can establish its own specifications capable of producing equivalent or
better-than-USP results.

Medical gases approved under a new drug application (NDA) or covered by
an investigational new drug application (IND) would comply with the
specifications established in the application.

Although a primary objective of the USP is to ensure the identity,
strength, quality, and purity of a product, it is impossible to include
in each monograph a test for every impurity, contaminant, or adulterant
that might be present, including microbial contamination. Contaminants
can arise from a change in the source of material or from a change in
processing, or contaminants can be introduced from extraneous sources.
We recommend that a manufacturer use tests suitable for detecting such
occurrences in addition to the tests provided in the individual
monograph (refer to the USP General Notices, Foreign Substances and
Impurities).

In the past, deaths and injuries have resulted from adulterated products
that contained contaminants or impurities that were not detected. In one
example, a carbon dioxide (CO~2~) manufacturer in Tennessee failed to
include an analysis for hydrogen cyanide in its finished product
testing. As a result, the manufacturer released several large liquid
batches of medical CO~2~ that were contaminated with this deadly toxin.
The source of this problem was the lack of an agreement between the
supplier and the CO~2~ manufacturer requiring notification of any change
in the manufacturing process. Fortunately, the problem was discovered
before any injury occurred. Our investigation found the supplier of the
raw material had changed the manufacturing process, which resulted in
elevated hydrogen cyanide levels. Because testing for hydrogen cyanide
was not performed, an adulterated drug product was released.

### 1. Sampling Plan

We recommend that a sampling plan describe the following:

-   How many cylinders or cryogenic containers will be tested

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-   When the testing will occur

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-   What acceptance criteria will be used for selecting samples

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-   What action will be taken if test results are outside established
    specifications

### 2. USP Oxygen Monograph

Medical gas manufacturers can establish their own testing specifications
that meet or exceed the requirements of the USP or can use the USP
specifications.

[USP Testing Specifications]{.underline} - Specifications recommend that
the potency of oxygen not be less than 99.0 percent by volume. Oxygen
produced by the air liquefaction process is exempt from tests for carbon
dioxide and carbon monoxide. However, if there is no documentation that
the oxygen is produced by the air liquefaction process, we recommend
that two additional impurity tests for carbon dioxide and for carbon
monoxide be performed.

***Note: The official method is explained below. The Agency recommends
that you check periodically with the USP to determine if the official
method has changed or has been modified.***

The ORSAT testing method uses a calibrated 100-ml buret, copper wire,
and an ammonium chloride - ammonium hydroxide solution mixed together
and equilibrated by agitation with the copper wire. Prior to the
introduction of a sample from a pumped cylinder, a series of analyses
(minimum of 3 runs) using a calibration standard would be performed to
properly age the test solution and to eliminate any air bubbles that may
have become trapped in the apparatus. The Agency recommends that a
manufacturer not proceed with testing a filled or pumped cylinder until
these analyses are completed. A 100-ml sample of the unknown gas would
be drawn into the buret, agitated, and measured. An identification test,
using a carbon dioxide detector tube, would be performed at the same
time.

Note: The ammonium chloride - ammonium hydroxide solution used in this
method would be expected to bear an expiration date supported by
appropriate stability studies.

The USP Oxygen Monograph requires a finished drug product odor test to
be performed on each container undergoing testing.

The Agency recommends that USP tests not be performed on an industrial
gas in an attempt to convert it to a medical gas.

The accuracy of the USP procedure is [+]{.underline}0.1 percent.

### 

### 3. Calibration of Instruments

Laboratory controls must include the calibration of 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 (§ 211.160(b)(4)).

Oxygen analyzers and other instruments can be calibrated at intervals
specified in the instructions from the equipment manufacturer. The FDA
recommends that gas manufacturers not use other medical or industrial
gases as the basis for calibrating their instruments.

We recommend that standards be certified to ensure the proper level of
precision and accuracy as reported on the certificate of analysis (COA).

We also recommend that each COA for a medical gas calibration standard
be specific for that cylinder and provide the following information:

-   Name and address of the calibration standard supplier

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-   Name of the product

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-   Lot number or unique identification number specific for each
    cylinder

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-   Analytical methodology used to assay the calibration standard

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-   Actual analytical results (for example, 99.9 percent nitrogen)

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-   The responsible person's signature and the date signed

## B. Testing and Release for Distribution

Medical gases are subject to the requirements in § 211.165 - Testing and
release for distribution.

For each batch of medical gas, there must be appropriate laboratory
determination of satisfactory conformance to final specifications, prior
to release (§ 211.165(a)).

The Agency recommends that each manufacturer determine the specific
testing to be performed on any incoming medical gas and on medical gases
delivered to a consignee, customer, or patient. We recommend that
testing methods conform to official specifications (i.e., the USP
testing methodology or a validated test procedure capable of producing
equivalent or better-than-USP test method performance).

If batch results do not conform to specifications, retesting is not
recommended unless a thorough investigation is performed in accordance
with established written procedures.[^4]

For high-pressure cylinders filled on a multiple outlet manifold, the
Agency recommends that one or more cylinders from each manifold filling
sequence be assayed for identity, strength, and odor. For high-pressure
cylinders filled individually, one cylinder per uninterrupted filling
sequence can be tested for identity, strength, and odor.

### 1. Liquid-to-Liquid Filling; Oxygen Only

This section pertains to the filling of liquid medical oxygen into
cryogenic home containers, either at a patient\'s home (curbside), or on
site. Due to the unique nature of this operation, the Agency recognizes
that testing for conformance to final specifications prior to release is
impractical. Therefore, FDA recommends using the following procedures.

#### a. Testing of the incoming liquid oxygen 

In lieu of testing, the home care company (HCC) can (1) witness the
testing for identity and strength of the large cryogenic container(s)
performed by the supplier for each container received, (2) document that
the testing has been witnessed, and (3) obtain a valid COA for each
container. The employee responsible for witnessing the testing would
have been trained on the analytical methodology used by their supplier.
Training would be documented by the employee's company.

If the testing is not witnessed and the HCC chooses to rely on a valid
COA, the Agency recommends that the HCC perform a specific identity
test. The HCC would also periodically verify the reliability of the
supplier\'s analysis. This can be done by (1) visiting the supplier to
verify that the supplier is following appropriate written testing
procedures, (2) observing the supplier's analytical testing, including
calibration of the analyzer, and (3) documenting that steps 1 and 2 have
been taken. Alternatively, to periodically verify the reliability of the
supplier's analysis, the HCC can submit to a third party a sample from a
recent delivery to be analyzed for conformance with the USP requirements
or established specifications.

If an HCC does not follow the above methods or chooses to test the large
cryogenic containers, the Agency recommends that full testing on the
incoming medical oxygen (each large cryogenic container) be performed.

#### b. Testing of an oxygen storage tank used to fill large vehicle-mounted cryogenic containers

If a new shipment of oxygen is combined in a storage tank with a
previously received, tested, and approved lot, we recommend that the
manufacturer test the combined product and approve it before use. If the
storage tank is located on the company's premises and is used to fill
vehicle-mounted containers or cryogenic home containers, the Agency
recommends an identity and strength test be performed by sampling from
the storage tank after each oxygen delivery and prior to the filling of
any cryogenic containers.

After the storage tank has been tested, the company can forego testing a
large cryogenic container filled from the storage tank if:

-   No other storage tank is located on the premises

-   The container is dedicated to the delivery of medical oxygen for
    home care use only

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-   The container has not been completely emptied (i.e., gaseous
    pressure below 15 pounds per square inch in gauge) and has not been
    out of service

-   A valid COA is received with each delivery and is maintained on file

#### c. Testing of cryogenic home containers

It is important to exercise control over the home container during the
filling operation. We recommend that appropriate methods be developed to
control situations where external contamination may occur, such as
failing to cap or cover the ends of a filling hose to prevent dirt,
debris, or insect infestation.

Testing of a cryogenic home container is less of a concern if:

-   Liquid oxygen is the only liquid being filled on the premises

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-   The incoming liquid oxygen is tested according to one of the methods
    outlined above under Testing of Incoming Liquid Oxygen or Testing of
    an Oxygen Storage Tank

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-   The container is filled by the company that owns it

If any other medical gas is filled on site or if the incoming liquid
oxygen is not tested by one of the testing methods discussed above, we
recommend all filled cryogenic home containers be tested for conformance
with USP or established specifications.

If cryogenic home containers are filled by another individual or another
company prior to release to the patient, we recommend that the
manufacturer distributing the containers inspect each container to
ensure that a correct label including a lot number has been applied.

### 2. Liquid-To-Gas; Filling Large Cryogenic Containers

This section pertains to medical gas companies, such as welding supply
companies, who fill multiple gases, both industrial and medical. In this
situation, the potential for mix-ups is greatest. The Agency recommends
that the incoming product be tested for full USP or established
specifications immediately after each lot is received. This can be done
either by taking a sample directly from the storage tank or by testing
one cylinder from the first medical filling sequence.

Each filled large cryogenic container would be tested prior to release.
Cryogenic containers usually contain a residual product and a
commingling of new and old product would result in a new batch or lot.
This new batch or lot would be analyzed and assigned a new batch or lot
number. A valid COA would be provided with each cryogenic container.

### Liquefied (gas on top of liquid) Compressed Gas

The pressure in a closed container containing carbon dioxide or nitrous
oxide increases as the temperature rises. A cylinder filled at a safe
pressure at normal temperatures can reach a dangerously high pressure at
high ambient temperatures. Therefore, the Agency recommends that nitrous
oxide and carbon dioxide be filled individually as liquids on a scale
where the pressure does not indicate the amount filled. Instead, we
recommend these cylinders be filled individually, and the weight not
exceed 68 percent of the weight of water the cylinder will hold at
60^o^F (15.6 C).

The Agency recommends that one of the cylinders filled during an
uninterrupted filling sequence be tested for conformance with
specifications prior to release. For both carbon dioxide and nitrous
oxide, a specific carbon dioxide identification test would be conducted
concurrently with the assay in accordance with USP monograph.

### Gas Mixtures

If a product is a mixture of two gases, the Agency recommends that each
cylinder of the blended product be tested for the identity and strength
of one of the gases, usually the active ingredient. In addition, an
identity test for the other gas would be performed on one cylinder from
the manifold filling sequence. For product mixtures containing three
gases, each cylinder of the blended product would be tested for the
identity and strength of two of the gases, and one cylinder from each
manifold filling sequence would be tested for the identity of the third
gas.

### 5. Liquid Nitrogen 

An assay of the finished product using the official gas chromatographic
method would not be necessary for a manufacturer who receives shipments
of medical nitrogen. However, we recommend a manufacturer meet all of
the following conditions:

-   A valid COA is received with each delivery and the product is
    designated Nitrogen NF

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-   The filling system has dedicated lines, and these supply lines are
    traceable from the storage tank to the filling manifold. If there is
    a possibility that another gas, either industrial or medical, could
    be introduced and could contaminate the product, we recommend that
    USP testing and a test for the absence of the contaminating gas be
    performed.

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-   Testing for the lack of oxygen (less than or equal to 1.0 percent)
    is performed with an oxygen analyzer that has been validated against
    the USP methodology

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-   Initially and at appropriate intervals, testing for complete
    specifications is recommended. Once the reliability of the supplier
    is established, a manufacturer can rely upon the supplier's
    certificate of analysis. Auditing the supplier's testing and
    manufacturing is an additional measure that would be used to
    determine that the product complies with the USP. This testing can
    be performed by the manufacturer, by a third party, or by a
    contract-testing laboratory.

To ensure that they receive medical nitrogen, we recommend that
manufacturers use suppliers registered with FDA.

In light of several reported injuries due to patient exposure to toxic
compounds contained in a supply of contaminated *industrial* nitrogen
used to power surgical or dental equipment, the FDA strongly recommends
the use of *medical* nitrogen by hospitals and dentist offices, even
when the nitrogen is used for industrial purposes in those settings.[^5]

## C. Alternate Testing Methods

The accuracy, sensitivity, specificity, and reproducibility of test
methods employed by the manufacturer must be established and documented.
We recommend that such validation and documentation be accomplished in
accordance with § 211.194(a)(2).

We recommend that any alternative testing method (e.g.,
spectrophotometer, handheld analyzers) used to analyze a medical gas be
compared against the official testing methodology.

We also recommend that each medical gas manufacturer maintain a copy of
the entire validation study, including the actual data generated for
each analyzer by model number that demonstrates USP equivalence and any
changes made to the analytical methodology, such as a different column
length or a different carrier gas. Validation of alternate methods can
be performed in accordance with USP Validation of Compendia Methods.

## 

## D. Stability Testing

Medical gases are subject to the requirements in § 211.166 -- Stability
Testing.

There must be a written testing program designed to assess the stability
characteristics of medical gases. The results of such stability testing
must be used in determining appropriate storage conditions and
expiration dates. The written program must be followed and must include
( 211.166(a)):

-   Reliable, meaningful, and specific test methods (§ 211.166(a)(3))

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-   Testing of the medical gas in the same container-closure system as
    that in which the medical gas is marketed (§ 211.166(a)(4))

An adequate number of batches of each medical gas must be tested to
determine an appropriate expiration date, and a record of such data must
be maintained ( 211.166(b)).

The Agency recommends that the testing program take into account the
compatibility of the valve assembly, the acceptability of the valve
packing and the valve seal used, the type of cylinder, and any other
factor that can have an effect on the stability of the medical gas. Each
medical gas would be tested for stability in the exact container closure
system that it is marketed in, such as steel high-pressure cylinders,
aluminum high-pressure cylinders, and cryogenic containers.

## E. Reserve Samples

Reserve samples of compressed medical gases do not need to be retained
(§ 211.170).

# XI. RECORDS AND REPORTS

Medical gases are subject to the requirements on records and reports in
§§ 211.180 - 198.

## A. Record Retention

Any production, control, or distribution record that is required to be
maintained in compliance with this part and is specifically associated
with a batch of medical gas must be retained for at least 1 year after
the expiration date of the batch (§ 211. 180(a)).

All records required under this part, or copies of such records, must be
readily available for authorized inspection during the retention period
at the establishment where the activities described in such records
occurred (§ 211.180(c)). The records or copies thereof are subject to
photocopying or other means of reproduction as part of such an
inspection (§ 211.180(c)). Records that can be immediately retrieved
from another location by computer or other electronic means will be
considered as meeting the requirements of this paragraph (§ 211.
180(c)).

Records required under this part may be retained either as original
records or as true copies such as photocopies or other accurate
reproductions of the original records (§ 211.180(d)).

Records can be kept on paper or electronically. Electronic records must
comply with the requirements of 21 CFR part 11.

Medical gas manufacturers are required to maintain a number of documents
and records including:

-   Equipment cleaning and use logs (§ 211.182)

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-   Computer and process validation data (§ 211.68)

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-   Analyzer validation studies and data (§ 211.194)

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-   Label reconciliation logs (§ 211.184)

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-   Master production records (§ 211.186)

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-   Batch production records (§ 211.188)

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-   Analytical equipment calibration logs (§ 211.194(d))

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-   Testing records (§ 211.194)

-   Stability studies (§ 211.194(e))

-   Complaint files (§ 211.198)

The Agency recommends that medical gas manufacturers also maintain
training records and certificates of analysis.

## B. Equipment Cleaning and Use Log

Medical gases are subject to the requirements in § 211.182 -- Equipment
cleaning and use log.

A written record of major equipment cleaning, maintenance (except
routine maintenance such as lubrication and adjustments), and use must
be included in individual equipment logs that show the date, time,
product, and lot number of each batch processed (§ 211.182). In cases
where dedicated equipment is employed, the records of cleaning,
maintenance, and use must be part of the batch record (§ 211.182). The
persons performing and double-checking the cleaning and maintenance must
date and sign or initial the log indicating that the work was performed

(§ 211.182).

Equipment cleaning and use logs can be maintained for trailers, rail
cars, and storage tanks, especially those installed at a health care
facility or a hospital.

## C. Component, Drug Product Container, Closure, and Labeling Records

Medical gases are subject to the requirements in § 211.184 - Component,
drug product container, closure, and labeling records.

These records must include the following (§ 211.184):

-   The identity and quantity of each shipment of each lot of medical
    labeling

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-   The results of any test or examination performed (including those
    performed as required by § 211.82(a), 211.84(d), or § 211.122(a))
    and the conclusions derived therefrom

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-   Documentation of the examination and review of labels and labeling
    for conformity with established specifications in accordance with §§
    211.122(c) and 211.130(c)

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-   The disposition of rejected medical gas containers, closures, and
    labeling

## D. Master Production and Control Records

Medical gases are subject to the requirements in § 211.186 -- Master
Production and Control Records.

To ensure uniformity from batch to batch, master production and control
records for each medical gas, including each batch size thereof, must be
prepared, dated, and signed (full signature, handwritten) by one person
and independently checked, dated, and signed by a second person (§
211.186(a)). The preparation of master production and control records
must be described in a written procedure, and the written procedures
must be followed (§ 211.186(a)).

Master production and control records must include (§ 211.186(b)):

-   A description of the medical gas containers and closures, and
    packaging materials, including a specimen or copy of each label and
    all other labeling signed and dated by the person or persons
    responsible for approval of such labeling (§ 211.186(b)(8))

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-   Complete manufacturing and control instructions, sampling, and
    testing procedures, specifications, special notations, and
    precautions to be followed (§ 211.186(b)(9))

The Agency recommends that a manual containing all of the above be on
site and available to personnel to ensure that individuals are able to
perform their assigned functions

## E. Batch Production and Control Records

Medical gases are subject to the requirements in § 211.188 -- Batch
Production and Control Records.

Batch production and control records must be prepared for each batch of
medical gas produced and must include complete information relating to
the production and control of each batch. These record must include (§
211.188):

-   An accurate reproduction of the appropriate master production or
    control record, checked for accuracy, dated, and signed (§
    211.188(a))

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-   Documentation that each significant step in the manufacture,
    processing, packing, or holding of the batch was accomplished,
    including (§ 211.188(b)):

> \--Dates (§ 211.188(b)(1))
>
> \--Inspection of the packaging and labeling area before and after use
> (§ 211.188(b)(6)
>
> \--Complete labeling control records (§ 211.188(b)(8))
>
> \--Description of medical gas containers and closures (§
> 211.188(b)(9))
>
> \--Any sampling performed (§ 211.188(b)(10))
>
> \--Identification of the persons performing and directly supervising
> or checking each significant step in the operations (§ 211.188(b)(11))
>
> \--Any investigation made according to § 211.192 (§ 211.188(b)(12))
>
> \--Results of examinations made in accordance with § 211.134 (§
> 211.188(b)(13))

The Agency recommends that the records include documentation of the
following:

-   Prefill inspections

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-   Number and size of the cylinders or cryogenic containers filled

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-   Filling inspections

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-   Post-fill inspections

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-   Lot number assigned

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-   Final temperature and pressure results

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-   Initials of the filler and/or analyst

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-   Signature of the individual who checked the entries for accuracy and
    completeness

Historically, the industry has used pumper's logs or filler's logs as
batch production records. This is appropriate as long as the logs
contain all of the relevant information. A batch production record acts
as a snapshot of the actual production at the time of its performance.
One batch production record would document the filling of high-pressure
cylinders and a separate record would document the filling of cryogenic
containers.

Based on the requirements of § 211.188, batch production records would
include an item-by-item entry. A manufacturer would not use a single
entry to indicate that all of the significant steps have been performed,
nor a check mark or other symbol when an actual value should be
recorded, such as temperature and pressure readings, purity, and
identity results.

## 

## F. Production Record Review

Medical gases are subject to the requirements in § 211.192 -- Production
record review.

All medical gas production and control records, including those for
packaging and labeling, must be reviewed and approved by the QCU to
determine compliance with all established, approved written procedures
before a batch is released or distributed (§ 211.192). Any unexplained
discrepancy or the failure of a batch to meet any of its specifications
must be thoroughly investigated (§ 211.192). A written record of the
investigation must be made and must include conclusions and follow-up (§
211.192).

Any test result that is outside of the established limits would be
considered an unexplained discrepancy or the failure of a batch to meet
its specifications.

The Agency recommends that the release of a drug product from an air
separation plant or unit (ASU) not be performed by a third-party
consignee (usually known as a transporter or a trucking company). That
is, the third-party consignee receiving the product would not sign as
the ASU's QCU to release the product.

For ASUs where filling occurs at night, the ASU\'s QCU would be
responsible for the release of the product, prior to distribution. For
swap agreements, the manufacturer having its trailers filled would be
responsible for and would have its own QCU review and approve the
cleaning of any trailers that have contained industrial product, prior
to filling with a medical gas.

## G. Laboratory Records

Medical gases are subject to the requirements in § 211.194 -- Laboratory
records.

Laboratory records must include complete data derived from all tests
necessary to ensure compliance with established specifications and
standards, including examinations and assays, as follows (§ 211.194(a)):

-   A description of the sample received for testing with identification
    of source (that is, location from where the sample was obtained),
    quantity, lot number or other distinctive code, date sample was
    taken, and date sample was received for testing (§ 211.194(a)(1))

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-   A statement of each method used in the testing of the sample. The
    statement must indicate the location of the data that establish that
    the methods used in the testing of the sample meet proper standards
    of accuracy and reliability as applied to the product tested (§
    211.194(a)(2))

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-   A complete record of all data secured in the course of each test,
    including all graphs, charts, and spectra from laboratory
    instrumentation, properly identified to show the specific medical
    gas and lot tested (§ 211.194(a)(4))

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-   A record of all calculations performed in connection with the test,
    including units of measure, conversion factors, and equivalency
    factors (§ 211.194(a)(5))

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-   The initials or signature of the person who performs each test and
    the date(s) the tests were performed (§ 211.194(a)(7))

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-   The initials or signature of a second person showing that the
    original records have been reviewed for accuracy, completeness, and
    compliance with established standards (§ 211.194(a)(8))

Complete records must be maintained of any modification of an
established method employed in testing (§ 211.194(d)). Such records must
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 (§ 211.194(b)).

Complete records must be maintained of any testing and standardization
of laboratory reference standards, reagents, and standard solutions (§
211.194(c)).

Complete records must be maintained of the periodic calibration of
laboratory instruments, apparatus, gauges, and recording devices
required by § 211.160(b)(4) (§ 211.194(d)).

Complete records must be maintained of all stability testing performed
in accordance with

§ 211.166 (§ 211.194(e)).

The Agency recommends that when using a handheld oxygen analyzer to
perform an identity test, the actual value obtained be recorded, and the
manufacturer establish written procedures describing an acceptable range
that meets the accuracy of the analyzer.

## 

The suitability of all testing methods must be verified under actual
conditions of use

( 211.194(a)(2)).

When testing is done by a gas chromatographic method specified in a USP
monograph (such as the assay method for Nitrogen NF), the Agency
recommends the chromatographic system used be adjusted to meet all
system suitability requirements listed in the monograph. We recommend
that after tests are run to verify that the requirements have been met,
the results be documented. For monograph methods that lack specific
system suitability requirements, the section on system suitability in
USP \"Chromatography\" can be used as a guide.

When an alternative testing methodology is employed, we recommend that
the methodology be validated against an official test method and the
method be carried out under substantially the same conditions that
prevailed during the validation study. If the testing environment is
substantially different, some additional on-site \"spot check\" tests of
the method, perhaps with a small number of standard gases, would help
show that its performance has not been affected by local conditions. For
example, paramagnetic oxygen analyzers can give inaccurate readings when
used at high altitudes unless special adjustments are made. We recommend
such an on-site spot check also be made if the analyzer is installed as
part of a control or alarm system. The results of these tests would be
fully documented. Certain changes made to instrumentation may be
substantive enough that they would be considered a change in the method
itself; these changes would require additional documentation of accuracy
and reliability (see § 211.194(b), above) or a new validation study.

## H. Liquid Supply (Certificate of Analysis (COA))

The medical gas industry routinely relies on COAs to reduce the amount
of finished product testing performed. For example, if a COA lists all
of the impurities tested for by a supplier, then it would be unnecessary
for a manufacturer to perform a test for the listed impurities on the
finished drug product. If no COA is received, the Agency recommends that
the finished drug product testing include all impurities listed in the
USP monograph or established specifications for each medical gas.

In addition, the COA for medical oxygen usually contains the *air
liquefaction statement* as required by the USP, and as a result, it
would be unnecessary for a manufacturer to test for carbon dioxide and
carbon monoxide impurities. If a manufacturer does not maintain the air
liquefaction statement for its medical oxygen, the Agency recommends
that the manufacturer perform testing for carbon dioxide and carbon
monoxide impurities.

We also recommend that a COA contain the following information and would
accompany all incoming deliveries of liquid medical gas:

-   Supplier's name and complete address

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-   Name of the product (e.g., oxygen USP, carbon dioxide USP, nitrogen
    NF, nitrous oxide USP, helium USP, or medical air USP)

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-   An air liquefaction statement, where appropriate

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-   Lot number or other unique identification number

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-   Actual analytical results for full USP monograph testing, (e.g.,
    99.5 percent oxygen)

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-   Test method used to perform the analysis. If an analyzer is used,
    the specific model number is indicated.

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-   Supplier\'s signature and the date

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-   Signature of the employee witnessing any testing at a supplier, if
    applicable

If a company relies on a COA to reduce the amount of testing required by
the USP, we recommend the company establish the reliability of the
supplier's analysis at appropriate intervals. This can be accomplished
by the manufacturer, by a third party, or by a contract-testing
laboratory.

## I. Distribution Records

Medical gases are subject to the requirements in § 211.196 --
Distribution records.

Distribution records must contain the name and strength of the product
and description of the dosage form, name and address of the consignee,
and date and quantity shipped (§ 211.196).

A manufacturer must establish and follow written procedures that include
a system whereby the distribution of each lot of a medical gas can be
determined if a recall becomes necessary, as required in § 211.150. For
compressed medical gases, distribution records are not required to
contain lot or control numbers.

## J. Complaint Files

Medical gases are subject to the requirements in § 211.198 -- Complaint
files.

Written procedures describing the handling of all written and oral
complaints regarding a medical gas must be established and followed (§
211.198(a)). Such procedures must include provisions for review by the
QCU, of any complaint involving the possible failure of a medical gas to
meet any of its specifications and, for such a medical gas, a
determination as to the need for an investigation in accordance with §
211.192 (§ 211.198(a)). Such procedures must include provisions for
review to determine whether the complaint represents a serious and
unexpected adverse drug experience, which is required to be reported to
the Food and Drug Administration in accordance with § 301.305 (§
211.198(a)).

A written record of each complaint must be maintained in a file
designated for medical gas complaints (§ 211.198(b)). The file regarding
such medical gas complaints must be maintained at the establishment
where the medical gas involved was manufactured, processed, or packed,
or the file may be maintained at another facility if the written records
in the file are readily available for inspection at that other facility
(§ 211.198(b)).

The Agency recommends that complaint records include, where known:

-   Name of the drug product

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-   Name and address of complainant

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-   Name (and, where appropriate, title) and telephone number of the
    person submitting the complaint

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-   Nature of the complaint

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-   Date the complaint is received

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-   Action initially taken, including dates and identity of person
    taking the action

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-   Follow-up action taken

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-   Response provided to the originator of complaint, including the date
    the response was sent

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-   Final outcome regarding the issues raised by the complaint

Where an investigation under § 211.192 is conducted, the written record
must include the findings of the investigation and follow-up
(211.198(b)(2)). The record or copy of the record of the investigation
must be maintained at the establishment where the investigation occurred
in accordance with § 211.180(c) (§ 211.198(b)(2)).

## K. Reporting Deaths and Injuries

The following is intended to clarify current adverse event reporting
requirements.

In accordance with § 310.305, manufacturers of prescription medical
gases must establish and maintain records and must make reports to FDA
of all serious, unexpected adverse drug experiences, such as deaths or
life-threatening adverse events, associated with the use of their
medical gases. More information can be obtained on FDA\'s web site, at
http://www.fda.gov/medwatch/report/mfg.htm.

According to § 310.305(b) Definitions -- an adverse drug experience is
any adverse event associated with the use of a drug in humans, whether
or not considered drug related. This would include problems with valves,
such as valve seat combustion resulting in a release of chlorine gas,
contamination from cleaning solutions, and mix-ups that result in an
adverse event to a patient.

We also encourage hospitals, nursing homes, and other health care
facilities dispensing medical gases to report serious adverse events and
product problems associated with the use of those gases. They can report
adverse events directly to the medical gas manufacturer. Or, they can
report to **MedWatch**, the FDA's voluntary reporting program, in one of
the following four ways:

-   Online at <http://www.accessdata.fda.gov/scripts/medwatch/>

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-   By telephone at 1-800-FDA-1088

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-   By FAX at 1-800-FDA-0178

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-   By mail to:

> **MedWatch**
>
> Food and Drug Administration (HF-2)
>
> 5600 Fishers Lane
>
> Rockville, MD 20857-9787

# XII. RETURNED AND SALVAGED DRUG PRODUCTS

## A. Returned Drug Products

Medical gases are subject to the requirements in § 211.204 -- Returned
drug products.

Returned medical gases must be identified as such and held (§ 211.204).
If the conditions under which returned medical gases have been held,
stored, or shipped before or during their return, or if the condition of
the drug product, as a result of storage or shipping, casts doubt on the
safety, identity, strength, quality or purity of the medical gas, the
returned medical gas must be destroyed unless examination, testing, or
other investigations prove the medical gas meets appropriate standards
of safety, identity, strength, quality, or purity (§ 211.204).

## B. Drug Product Salvaging

Medical gases are subject to the requirements in § 211.208 -- Drug
product salvaging.

Medical gases that have been subjected to improper storage conditions
must not be salvaged and returned to the marketplace (§ 211.208).

# XIII. AIR SEPARATION PLANTS OR UNITS (ASU)

ASUs separate atmospheric air into the constituent gases of oxygen,
nitrogen, and argon by using a purification process of cleaning,
compressing, and cooling. ASUs are generally highly computerized and
have very few employees in attendance during operations, which usually
take place 24 hours a day, 7 days a week. ASUs are drug manufacturers
and as such must comply with all relevant CGMP regulations.

The Agency recommends that an ASU that receives deliveries of a drug
product into its storage tanks from outside sources perform finished
product testing on the incoming supply, prior to accepting the delivery.
Appropriate COAs would be maintained.

The Agency plans to develop and publish a separate guidance on the
validation of the manufacturing process and computerized systems at
ASUs.

# XIV. STORAGE TANK INSTALLATIONS AT HEALTH CARE FACILITIES

This section pertains to the installation of a storage tank that will
contain a medical gas, usually oxygen, at a hospital, nursing home, or
long-term health care facility. During the installation of a storage
tank and associated equipment (i.e., equipment used for the delivery of
medical gases --- usually oxygen --- to hospitals, nursing homes,
clinics, and long-term health care facilities), following CGMP would be
very important for manufacturers or individuals installing the storage
tank. CGMP would also be important any time the system is exposed to a
possible contaminant or impurity, such as installation of a new valve or
piping. The company would determine the stage of the installation where
problems or contamination may occur and ensure compliance. CGMP would be
applicable to activities involving all equipment that is part of the
medical gas storage and delivery mechanism, including the storage tank
that holds the drug product, all related equipment such as piping and
valves, and all other equipment up to the wall leading into the
facility.

For storage tank filling, we recommend a focus on the following aspects
of CGMP:

-   Establish a QCU and written procedures

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-   Perform training for service technicians in their job functions and
    in CGMP

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-   Qualify all equipment for medical use, including delivery vehicles
    and storage tanks

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-   Audit contracted cleaning firms

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-   Develop and follow detailed written procedures

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-   Calibrate testing equipment

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-   Test finished products prior to introduction of the drug product
    into the supply system

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-   Use USP equivalent testing methodology

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-   Log equipment cleaning and use, especially for storage tanks

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-   Maintain batch production records

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-   Provide COAs to the receiving facility with each delivery

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-   Maintain documentation

If a third party is contracted to install a health care facility storage
tank and associated equipment, the supplier of the medical gas would
determine whether the system has been installed in accordance with CGMP.
This determination would be made prior to introducing the medical gas
into the supply system and would be fully documented. The supply firm
would consider itself responsible for the actions of the third party
installer.

# XV. Medical Gas Mix-Ups

FDA has investigated a number of deaths and injuries resulting from
medical gas mix-ups. In all of these incidents, the injuries and deaths
could have been prevented if the manufacturer had followed the CGMP and
industry standards.[^6] Specific CGMP deviations noted repeatedly
included:

-   § 211.100(a & b): Failure to establish and follow adequate written
    procedures

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-   § 211.25(a): Failure to provide adequate CGMP training to all
    persons involved with the handling and delivery of a medical gas

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-   § 211.42(c): Inadequate storage areas on delivery vehicles for the
    storing of medical gases and industrial gases

In particular, over the past several years, FDA has received reports
from separate hospitals, nursing homes, and clinics involving 7 deaths
and 15 injuries to patients who were thought to be receiving medical
oxygen when in fact they were receiving a toxic industrial gas, (e.g.,
nitrogen). The Agency recommends the following steps to help prevent
similar deaths or injuries from occurring:

-   Ensure that all employees involved in the manufacturing, processing,
    packaging, or holding of medical gases have the education, training,
    and experience, or any combination thereof, to enable them to
    perform their assigned functions.

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-   Ensure that employees understand that they are handling a drug. Make
    sure they learn how to examine the label on each container before
    delivering the container or connecting the container to a supply
    system. Make sure employees know what to do if a label does not
    match the invoice or the connections do not fit (e.g., possibly not
    accept the product and/or notify their supervisor immediately).

-   Be aware that most fittings or connectors are permanently attached
    on all large cryogenic containers used to deliver medical gases.

-   Never remove fittings and connectors. If an employee is unable to
    connect a container to a supply system, he or she would contact the
    supplier immediately. This is especially true for oxygen.

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-   Ensure that written procedures are developed and followed. Train
    employees regularly on how to perform the procedures.

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-   Ensure that separate storage areas for medical and industrial gases
    are identified and used on each delivery vehicle.

-   Make sure that all large cryogenic containers are dedicated to
    medical use and are not used for industrial gases.

-   Ensure that all cryogenic containers have clear labeling, such as a
    360-degree wrap-around label on the sidewalls. The wrap-around label
    would be placed as close to the top portion of the container as
    possible, but below the top weld seam, and would contain and repeat
    the product name (e.g., *Medical Oxygen Medical Oxygen Medical
    Oxygen)* and be the appropriate color (e.g., green for oxygen).

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-   Make sure only one drug label is applied to a container. Never apply
    a label on top of another label.

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-   Provide each consignee (e.g., hospital, nursing home, and clinic)
    with a copy of FDA's Public Health Advisory, *Guidance to Hospitals,
    Nursing Homes, and Other Health Care Facilities*.

# XVI. CARBON DIOXIDE AND Helium Manufacturers AND WHOLESALE DISTRIBUTORS

Manufacturers of medical carbon dioxide and medical helium also are
subject to CGMP requirements. The Agency recommends that manufacturers
perform process and computer systems validation and have a written
agreement with the raw material manufacturer to be notified of any
changes in the manufacturing process or the quality of the raw material.
We also recommend that manufacturers perform an initial *fingerprinting*
or characterization of the incoming raw material for any contaminants or
impurities that could affect the quality, strength, purity, or identity
of the finished drug product.

Carbon dioxide and helium manufacturers, as well as shippers, wholesale
distributors, jobbers, and transporters that fill these medical gases
into or out of rail cars, storage tanks, trailers, and containers are
required to comply with CGMP, including the following:

-   Process validation and computer systems validation (§ 211.68)

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-   Establishment of a QCU and written procedures (§ 211.22)

-   In-process testing (§ 211.110)

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-   Lot numbering (§ 211.80(d))

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-   Written operating procedures (§§ 211.80(a) and 211.100)

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-   Calibration of analytical equipment (§ 211.160(b)(4))

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-   Testing of the finished product via USP or equivalent testing
    methodology (§ 211.165)

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-   Batch production records (§ 211.188)

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-   Maintaining documentation (§ 211.180)

The Agency also recommends that carbon dioxide and helium manufacturers,
as well as shippers, wholesale distributor jobbers, and transporters
that fill these medical gases into or out of rail cars, storage tanks,
trailers, and containers, do the following:

-   Conduct training, including for CGMP

-   Test residual gas in tankers, trailers, and rail cars prior to
    filling

The Agency recommends that all tankers or trailers used for the delivery
of carbon dioxide be dedicated to medical use only.

# XVII. EMERGENCY MEDICAL SERVICE (EMS)

An EMS can follow this guidance to comply with CGMP when filling small
high-pressure cylinders. Given the limited nature of the operation, an
EMS would emphasize:

-   CGMP training

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-   Operating procedures

-   Procedures for accurate labeling

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-   Receiving oxygen from reliable sources

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-   Performing pre-fill inspections

-   Traceability, so that a recall can be performed if necessary

# XVIII. GAS-TO-GAS ADAPTERS

For safety reasons, ***avoid the use of*** gas-to-gas adapters of any
kind to circumvent the specific medical gas valves and connections
associated with a specific medical gas. The Agency recommends that
companies only use adapters that reduce or expand the connection size
for a specific medical gas while still maintaining the proper connection
system. This practice would be described in written procedures.

Adapters can be used when filling mixtures or blends. However,
documented written procedures detailing a system of checks will help
prevent mix-ups or contamination. We recommend that adapters be under
strict control and be kept under limited access.

# XVIX. ALTERNATIVE APPROACHES

As noted, this guidance represents FDA's current thinking on CGMP for
medical gases. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. An alternative
approach can be used if that approach satisfies the applicable statutes
and regulations. In the event you have ideas, questions, or concerns
regarding an alternative approach, we encourage you to contact the
Director of the Division of Manufacturing and Product Quality in the
Office of Compliance of the Center for Drug Evaluation and Research at
FDA.

# Attachment: MedicaL Gas Mix-Ups

The purpose of this section is to highlight the serious consequences of
failing to follow CGMP in the production and delivery of medical gases.

On December 7, 2000, a nursing home in Bellbrook, Ohio, reported the
death of two patients and the injury of eight patients following a
mix-up in the nursing home\'s oxygen supply system. The nursing home had
received a shipment from their supplier of four cryogenic containers
supposedly containing medical oxygen. Included in the delivery, however,
was a cryogenic container of industrial nitrogen that bore two different
labels. The nursing home was running low on oxygen and sent a
maintenance employee to connect a new oxygen container to the oxygen
supply system. The employee selected the nitrogen container and
discovered, correctly, that he was unable to connect the container to
the oxygen system. The employee removed a fitting from an empty oxygen
container and installed it on the nitrogen container. He then connected
the deadly product to the oxygen system. Several days later, two more
patients died from exposure to industrial nitrogen, bringing the death
toll from this one incident to four.

On December 6, 2000, an industrial nitrogen container was connected to
the oxygen supply system at a Medical Center in Springerville, Arizona.
The nitrogen container was properly labeled and had the correct nitrogen
fitting. The supplier removed the nitrogen fitting and replaced it with
an oxygen fitting. A female who had been undergoing a hysterectomy was
coming off anesthesia when a ventilator alarm sounded. The
anesthesiologist immediately removed the ventilator and started her on
an ambu bag. The patient demonstrated no ill effects.

On July 12, 1999, a patient in a California hospital was undergoing
dialysis treatment. Since he required a continuous supply of oxygen he
was connected to the wall oxygen source during the procedure. Upon
completion of dialysis, the oxygen connection was removed from the wall
source and reattached to a portable cylinder. The cannula was attached
to the patient's existing tracheostomy and the patient was transported
to the Intensive Care Unit (ICU). When the patient arrived at the ICU,
he was in ventricular fibrillation, became apneic and sustained a
cardiac arrest. The patient died. An investigation found that the
patient had been attached to a cylinder of carbon dioxide, not oxygen.
This cylinder had a green top, was labeled for CO2 and had the specific
CO2 valve.

On April 22, 1998, a hospital in Idaho discovered that a large cryogenic
container of industrial nitrogen had been connected to their oxygen
system supplying the operating rooms, labor and delivery rooms, and the
emergency room. When the supplier's truck driver was unable to connect
the incompatible nitrogen container fitting to the oxygen supply system,
he used a wrench to disconnect the nitrogen fitting and replaced it with
an oxygen fitting. Two patients died as a result of this medical gas
mix-up.

In October 1997, a hospital in Nebraska received a shipment of large
cryogenic containers which were supposed to contain medical oxygen. The
shipment included one cryogenic container of industrial argon that was
labeled as argon. The hospital was running low on oxygen and sent a
maintenance employee to connect a new oxygen container to the oxygen
supply system. Without examining the label, the employee selected the
argon container, and, discovering he was unable to connect the container
to the oxygen supply system, he removed a fitting from an empty oxygen
container, installed it on the argon container, and connected the deadly
product to the oxygen supply system. Argon was administered to a patient
undergoing minor surgery. The patient died.

On December 2, 1996, a children's home located in New York reported
adverse reactions experienced by nine patients due to the inhalation of
carbon dioxide. An employee of the home, asked to attach a large
cryogenic container of medical oxygen, unknowingly selected a carbon
dioxide container from their inventory. He noted that the fitting on the
carbon dioxide container was not compatible with the connector on the
oxygen supply system. He removed an oxygen fitting from an empty
container, installed it on the carbon dioxide container, and attached it
to the oxygen supply system. Two patients were injured critically, four
patients experienced varying stages of respiratory distress, and three
patients recovered with no lasting side effects.

In March of 1996, 11 deaths were associated with contaminated oxygen
delivered to a hospital during installation of a new storage tank. A
500-gallon cryogenic container was temporarily connected to the
hospital\'s oxygen supply system with a 50-foot hose. An analysis of the
50-foot hose tested positive for the presence of trichloroethylene
(TCE), a standard cleaning chemical that is very toxic to humans.

In December of 1993, a home care company (HCC) that filled liquid oxygen
containers authorized an inadequately trained employee to obtain from
their supplier a container (GP-45) of medical oxygen. The supplier\'s
employees did not accompany the HCC employee to the loading dock to pick
up the medical oxygen. The home care company\'s employee who failed to
examine the label selected a container of argon instead of a container
of medical oxygen. The employee loaded the container into the van and
went to three patients\' homes to fill their containers. When he
attempted to fill the cryogenic containers containing oxygen, the
discharge line was not compatible with the container fittings. The
employee removed a fitting from an empty oxygen container and attached
it to the container containing argon, and was able to fill the patients'
containers with argon. The next day, the employee became aware of the
argon mix-up and retrieved all three containers before the patients used
the gas.

In July of 1986, a large welding supply company filled four gray-colored
oxygen cylinders with carbon dioxide (CO~2~). The cylinders were
subsequently sent to a hospital and administered to two patients
undergoing surgery. One patient\'s death was attributed to CO~2~
exposure; the other patient was seriously injured. The cylinders had the
proper medical oxygen label and the correct oxygen valve. Some hospitals
paint their cylinders a certain color to designate a specific unit or
room located within the hospital. In this case, the gray-colored
cylinders denoted cylinders to be delivered to the surgery rooms only.

In May of 1983, a large welding supply company delivered and connected
to a hospital a large cryogenic container thought to contain medical
oxygen. The gas was administered to a premature infant, a 46-year-old
male, and a 27-year-old female in three separate areas of the hospital.
All three patients died. Analysis of the container found that it
contained argon instead of oxygen, and the container bore two labels,
one label read \"Liquid O\" while a second label on the opposite side of
the container read \"Argon\"; the fill line of the container had an
argon fitting; and the discharge line had an oxygen fitting.

# GLOSSARY

The following terms and definitions are provided to assist the reader in
using this guidance document.

**Cascading:** This operation pertains to gas-to-gas filling of
high-pressure cylinders only, and consists of a supply cylinder unit
(usually called a *bank*) containing a group of *H* or *K*-sized
cylinders, a receiving cylinder unit, a filling manifold, and a vacuum
evacuation pump. The first supply cylinder's valve is opened and the gas
flows into the smaller cylinder(s) to be filled until equilibrium or the
correct net contents is reached. If the smaller cylinder is not full and
requires additional pressure or contents, the second supply cylinder's
valve is opened and the gas is allowed to flow into the smaller
cylinder. This process is repeated to the third, and fourth, etc.,
supply cylinder until the desired pressure or contents is reached in the
smaller cylinder(s). Individual cylinders in the bank are replaced
sequentially as their respective pressures or contents are diminished to
levels that are ineffective for the transfilling operation.

**Certificate of analysis (COA):** A single document provided with each
shipment of incoming liquid medical gas that undergoes further
processing (filling, transfilling). A COA contains all of the required
information that would allow the receiving manufacturer to determine if
the medical gas is acceptable. A COA can also reduce the amount of
finished product testing a manufacturer performs by allowing the
manufacturer to rely on the contaminants or impurities testing performed
by the supplier and documented on the COA. Otherwise, a manufacturer
would test each finished drug product for all contaminants and
impurities required by the USP or the manufacturer's established
specifications. See above for details.

**Cryogenic containers:** Containers used to hold a low-temperature,
low-pressure liquid product that are similar in design to an insulated
thermos bottle with a vacuum between the inner and outer container. They
may be portable or permanently mounted in a vehicle, and are commonly
known as VGLs (vertical gas liquids), GPs (gas packs), or PLCs (portable
liquid containers), or HL119s, MDX 60s, 80s, and 190s. This does not
include tankers, trailers, or rail cars.

**Cryogenic home containers:** Containers designed to hold liquid oxygen
at a patient\'s home under low pressure and very low temperature.

**Distributor:** An individual or a manufacturer that receives liquid
and/or compressed gas in labeled high-pressure cylinders or cryogenic
containers and does not manipulate or apply a label to the product. The
product is then delivered to a patient or consignee.

**Emergency medical services (EMSs):** EMSs include fire departments,
ambulance companies, and rescue squads that are usually
government-affiliated emergency services. EMSs transfill medical oxygen
for their own use (no other gases are filled on site other than
compressed breathing air) and administer medical oxygen to patients
and/or victims in emergency situations.

**Handheld oxygen analyzers:** Oxygen analyzers that operate on the fuel
cell, electrochemical cell, galvanic cell, or polarographic principle.
When properly calibrated, these analyzers provide a specific oxygen
identification test result only. They do not have the required USP
accuracy for determining potency. We recommend they be validated.

**Home care company/home respiratory care company (HCC):** Manufacturers
that sell durable medical equipment and usually supply liquid oxygen to
patients at their home. They may also fill high-pressure cylinders by
means of cascading as a back up for their oxygen concentrators.

**Oxygen for environmental use:** Oxygen that meets USP specifications
and is used to support life artificially in environments that are
normally deficient. This includes, but is not limited to, space and
space simulation capsules, deep submersibles, and scuba systems. This
definition excludes oxygen used in chambers or devices. This product is
not to be used for inhalation or the medical therapeutic treatment of
humans or animals.

**Oxygen for industrial use:** Oxygen not intended for inhalation or
therapeutic treatment of humans or animals. Because of the many
contaminants and impurities associated with industrial oxygen,
industrial oxygen is not appropriate for breathing purposes.

**Oxygen for aircraft use (Aviators Breathing Oxygen (ABO)):** Oxygen in
fixed or portable oxygen containers or systems intended for commercial
or private aircraft use. ABO meets USP specifications for oxygen and has
special moisture and/or other limiting characteristics. We recommend
against the use of ABO for recreational inhalation or medical
therapeutic treatment of humans or animals.

**Process validation:** Documented evidence that provides a high degree
of assurance that a specific process will consistently produce a product
meeting its predetermined specifications and quality attributes (see the
FDA guidance, *General Principles of Process Validation*).

**Storage tank or stand tank:** A large cryogenic stationary holding
tank with a capacity of several thousand to several million
gallons/liters of a liquid product.

**Uninterrupted filling sequence:** A single, continuous filling
sequence with no breaks or shutdowns occurring during the filling
operation. This procedure uses the same personnel, equipment, and lot of
component. It does not apply to the filling of high-pressure cylinders
on a multiple outlet manifold or rack. The filling of nitrous oxide and
carbon dioxide is covered by this definition.

**United States Pharmacopeia /National Formulary (USP/NF):** A reference
containing a select list of articles in the form of monographs. Included
in each monograph are the standards for determining the identity,
strength, quality, and purity of the articles. Except for medical gases
approved under a new drug application or an investigational new drug
application, manufacturers can use the specifications for single medical
gases described under the individual medical gas monograph. Medical gas
mixtures are not listed in the USP.

**Wrap-around label:** A 360-degree label that encircles and is applied
to the top of large cryogenic containers. We recommend the lettering on
the label be at least 2¾ inches high and contain the name of the medical
gas. The Agency recommends that the medical gas name be repeated so that
the name can be visible when viewed from all angles. We also recommend
one of the following: (1) the name of the medical gas (text) in the
standard color for that medical gas with a white background or (2) the
background in the standard color for that medical gas with the name of
the medical gas (text) in white (See Color Code examination).

[^1]: This guidance has been prepared by the Division of Manufacturing
    and Product Quality in the Office of Compliance of the Center for
    Drug Evaluation and Research (CDER) at the Food and Drug
    Administration.

[^2]: For the purposes of this document, the term *manufacturer*
    includes fillers, transfillers, cascaders, distributers, and
    transferers of medical gases.

[^3]: See September 19, 1996, citizen petition response in docket
    87P-0167.

[^4]: A draft guidance, on *Investigating Out-of-Specification Test
    Results for Pharmaceutical Production* was issued on September 30,
    1998.

[^5]: Compressed Gas Association, Inc., Saftey Alert (SA-6) Use of
    Nitrogen NF for Surgical Air Tools.

[^6]: See CGA standards.