Medical Gas Containers and Closures; Current Good Manufacturing Practice Requirements, 18039-18053 [06-3370]

Agencies

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

[Federal Register Volume 71, Number 68 (Monday, April 10, 2006)]
[Proposed Rules]
[Pages 18039-18053]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 06-3370]



[[Page 18039]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 211

[Docket No. 2005N-0437]


Medical Gas Containers and Closures; Current Good Manufacturing 
Practice Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its current good manufacturing practice (CGMP) regulations to include 
new requirements for the label, color, dedication, and design of 
medical gas containers and closures. These requirements are intended to 
do the following: Make the contents of medical gas containers more 
readily identifiable, reduce the likelihood that containers of 
industrial or other gases would be inappropriately connected to medical 
oxygen supply systems, and reduce the risk of contamination of medical 
gases. FDA is also proposing to include medical air, oxygen, and 
nitrogen among, and exclude cyclopropane and ethylene from, those gases 
intended for drug use that are exempt from certain labeling 
requirements.

DATES: Submit written or electronic comments by July 10, 2006. Submit 
written comments on the information collection requirements by May 10, 
2006. See section VII of this document for the proposed effective date 
of a final rule based on this document.

ADDRESSES: You may submit comments, identified by Docket No. 2005N-
0437, by any of the following methods:
    Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
    Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to https://www.fda.gov/ohrms/dockets/
default.htm, including any personal information provided. For 
additional information on submitting comments, see the ``Request for 
Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Duane Sylvia, Center for Drug 
Evaluation and Research (HFD-326), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-9040, e-mail: 
Duane.Sylvia@FDA.HHS.GOV.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. Need for Revised Regulations
    1. Incidents Involving Portable Cryogenic Containers
    2. Incidents Involving High-Pressure Medical Gas Cylinders
    B. Current Regulatory Requirements and Recommendations for Medical 
Gas Containers and Closures
II. Description of Proposed Requirements
    A. Revisions to Labeling Exemptions
    B. Revised Requirements for Medical Gas Containers and Closures
    1. Prohibition on Conversion of Cryogenic Containers and High-
Pressure Cylinders From Industrial to Medical Use
    2. Requirements for Secure Gas Use Outlet Connections on Portable 
Cryogenic Medical Gas Containers
    3. Requirement for 360[deg] Wraparound Label for Portable Cryogenic 
Medical Gas Containers
    4. Requirement to Color High-Pressure Medical Gas Cylinders
III. Legal Authority
IV. Analysis of Impacts
    A. Benefits
    B. Costs
    1. Brazing or Locking of Gas Use Outlet Connections on Portable 
Cryogenic Medical Gas Containers
    2. 360[deg] Wraparound Label for Portable Cryogenic Medical Gas 
Containers
    3. Painting of High-Pressure Medical Gas Cylinders
    4. Prohibition of Container Use for Both Industrial and Medical 
Purposes
    5. Records Maintenance
    6. Total Costs
    C. Comparison of Costs and Benefits
    D. Regulatory Flexibility Analysis
    1. Need for and Objectives of the Rule
    2. Description and Estimate of Small Entities
    3. Reporting, Recordkeeping, and Compliance Requirements
    4. Other Federal Rules
    5. Alternate Policies
V. Paperwork Reduction Act of 1995
VI. Environmental Impact
VII. Effective Date
VIII. Federalism
IX. Request for Comments

I. Background

A. Need for Revised Regulations

    FDA is proposing to add requirements to its CGMP regulations to 
address repeated incidents of medical gasmixups (e.g., the 
inappropriate administration of an industrial gas to a patient intended 
to receive a medical gas) and medical gas contamination that have 
resulted in serious patient injuries and even deaths. As explained in 
this document, FDA believes that the number of such incidents will be 
reduced by implementation of the medical gas label, color, design, and 
dedication requirements proposed in section II.B of this document.
    Between 1996 and April 2004, FDA received several reports of 
medical gas mixups that resulted in at least 8 patient deaths and 16 
serious patient injuries. Because nursing homes and hospitals are not 
required to report adverse events associated with medical gas mixups to 
FDA, it is likely that the actual number of these events exceeds the 
number reported. The reports FDA has received involve two major types 
of containers in which medical gases are currently stored, portable 
cryogenic containers and high-pressure medical gas cylinders.
1. Incidents Involving Portable Cryogenic Containers
    Portable cryogenic containers are used to store gases in liquid 
form at extremely low temperatures and pressures. These containers are 
made of stainless steel and are double-walled and vacuum-insulated to 
minimize the evaporation and venting of their contents. FDA is aware of 
at least 7 deaths and 12 serious injuries that occurred between 1996 
and April 2004

[[Page 18040]]

in connection with mixups of gases stored in portable cryogenic 
containers. Each of these incidents involved the improper connection of 
a portable cryogenic container holding an industrial gas to a health 
care facility's oxygen supply system.
    Portable cryogenic gas containers have gas-specific use outlet 
connections that are used to connect the containers to supply systems. 
Oxygen supply systems are compatible only with gas use outlet 
connections designed for portable cryogenic containers holding oxygen. 
In each of the incidents of which FDA is aware, described in more 
detail in the following paragraphs, the person making the faulty 
connection to the health care facility's oxygen supply system: (1) Did 
not check the label on the portable cryogenic container that was 
inappropriately connected or was not otherwise able to verify the 
container's contents and (2) was able to readily remove the oxygen-
specific gas use outlet connection from an empty medical oxygen 
container and use it to inappropriately connect the industrial gas 
container to the supply system.
    On December 7, 2000, four patients in a Bellbrook, Ohio, nursing 
home died and six were injured after being administered industrial 
nitrogen instead of oxygen. The nursing home had received a shipment of 
four portable cryogenic medical gas containers. Each was labeled 
medical oxygen, but one of the containers also bore an industrial 
nitrogen label that partially obscured the medical oxygen label and was 
filled with industrial nitrogen instead. When asked to select a new 
oxygen container, a nursing home employee mistakenly selected the 
nitrogen container. The employee was initially unable to connect the 
container to the oxygen supply system because the container's nitrogen-
specific gas use outlet connection was incompatible with the connector 
on the oxygen supply system. However, the employee ultimately made the 
fatal connection by removing an oxygen-specific gas use outlet 
connection from an empty portable cryogenic medical oxygen container 
and by substituting it for the nitrogen-specific connection on the 
industrial nitrogen container.
    On April 22, 1998, a portable cryogenic container of industrial 
nitrogen was improperly connected to the oxygen supply system for the 
operating rooms, labor and delivery rooms, and emergency room in an 
Idaho hospital. The connection was enabled when the supplier's truck 
driver used a wrench to disconnect the container's existing nitrogen 
gas use outlet connection, which was incompatible with the hospital's 
oxygen supply system, and replaced it with a compatible oxygen gas use 
outlet connection. Two patients died after receiving nitrogen through 
this misconnection.
    On October 14, 1997, a hospital in Nebraska received a shipment of 
medical oxygen in portable cryogenic containers. The shipment included 
one portable cryogenic container of industrial argon. The hospital was 
running low on oxygen and sent a maintenance employee to connect an 
oxygen container to the oxygen supply system. Although it was properly 
labeled, the employee selected the argon container without examining 
its label. When he was unable to connect the container to the oxygen 
supply system, the employee removed an oxygen gas use outlet connection 
from an empty portable cryogenic medical gas container, installed it in 
place of the argon gas use outlet connection on the industrial argon 
container, and connected the argon container to the oxygen supply 
system. Argon was administered to a patient undergoing minor surgery 
who died as a result of this mixup.
    On December 2, 1996, nine patients in a children's home in New York 
experienced adverse reactions after inhaling carbon dioxide in a 
medical gas mixup. Two of the patients were injured critically and four 
patients experienced varying stages of respiratory distress following 
this mixup. The mixup resulted when an employee of the home mistakenly 
attached a carbon dioxide container to the home's oxygen supply 
system.After noting that the gas use outlet connection on the carbon 
dioxide container was not compatible with the connector on the oxygen 
supply system, the employee removed a gas use outlet connection from an 
empty medical oxygen container, installed it on the carbon dioxide 
container, and attached the carbon dioxide container to the home's 
oxygen supply system.
    In addition to the deaths and serious injuries described earlier in 
this preamble, FDA is aware of other serious cases of medical gas 
mixups involving portable cryogenic containers. For example, on 
December 19, 2000, a mixup occurred in a hospital in Arizona. A 
ventilator alarm sounded during a surgical procedure, and the 
anesthesiologist quickly removed the ventilator after noticing that the 
patient's oxygen saturation level was decreasing. An investigation 
revealed that a portable cryogenic container of industrial nitrogen had 
been mistakenly connected to the hospital's oxygen supply system. To 
make the connection, the nitrogen tank's original gas use outlet 
connection was removed and replaced with an oxygen-specific gas use 
outlet connection. Although the anesthesiologist's quick response 
avoided patient injury in this instance, the mixup was caused by events 
that have resulted in death and serious injury in other cases, such as 
the ones previously discussed.
    FDA anticipates that mixups like those described earlier in this 
document will be largely averted if: (1) Users can more readily 
identify portable cryogenic containers that contain medical gases and 
(2) the gas use outlet connections on these containers cannot be 
readily removed by persons other than the manufacturers responsible for 
filling them. As detailed in section II.B of this document, FDA is 
proposing requirements to achieve these effects. As further discussed 
in section I.B of this document, the proposed requirements are intended 
to supplement existing CGMP requirements and related agency guidance 
and industry recommendations regarding the safe use of medical gases. 
Existing agency requirements and guidance already address appropriate 
education and training for persons responsible for connecting portable 
cryogenic containers to medical gas systems (e.g., training such 
persons to check the containers' labels and to understand that the 
containers' gas-specific use outlet connections are safeguards against 
mixups and that they are not to be removed.)\1\
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    \1\ See 21 CFR 211.25(a). The agency's draft guidance for 
industry on ``Current Good Manufacturing Practice for Medical 
Gases'' (66 FR 24005, May 6, 2003) and its ``Guidance for Hospitals, 
Nursing Homes, and Other Health Care Facilities--FDA Public Health 
Advisory'' (66 FR 18257, April 6, 2001), both discussed in section 
I.B. of this document, contain specific recommendations for, among 
other things, the appropriate education and training of health care 
facilities' and medical gas manufacturers' employees who are 
involved in handling medical gases and their containers. These 
guidances are available on the Internet at https://www.fda.gov/cder/
guidance/index.htm.
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2. Incidents Involving High-Pressure Medical Gas Cylinders
    High-pressure medical gas containers are used to store gases at 
relatively high pressures and ambient temperatures. These containers 
are tubular in design and are constructed of steel or aluminum. Between 
1996 and April 2004, FDA received several reports of serious injury 
attributable to high-pressure medical gas cylinders that were 
contaminated with residue of industrial cleaning solvents, most likely 
as a result of improper cleaning during the cylinders' conversion from 
industrial to

[[Page 18041]]

medical use. There have also been incidents in which industrial gases 
in high-pressure cylinders have been mistakenly identified for medical 
use and their contents inappropriately administered to patients, 
resulting in injury and death. Examples of incidents involving high-
pressure medical gas cylinders are described in the following 
paragraphs.
    On July 12, 1999, a hospital in California reported the death of a 
patient after carbon dioxide was mistakenly administered instead of 
oxygen. Although it had an appropriate carbon dioxide gas use outlet 
connection and label, the shoulder of the high-pressure cylinder 
containing the carbon dioxide was improperly color-marked in green. 
According to voluntary color standards adopted by the Compressed Gas 
Association (CGA) and largely followed by industry, green is the 
standard color used to indicate a high-pressure medical oxygen 
cylinder.
    On March 20, 1998, a surgery center in South Dakota reported that a 
strong chlorine-like odor emanated from a patient's high-pressure 
medical oxygen cylinder during surgery.An analysis of the cylinder 
revealed that it contained traces of freon. It is likely that the root 
cause of the contamination was inadequate cleaning during the 
cylinder's conversion from industrial to medical use. In this case, the 
patient experienced burning eyes and respiratory problems.
    On March 27, 1996, a surgical center in Florida detected a 
chlorine/bleach-like odor emanating from its oxygen supply system, 
which was comprised of several high-pressure medical gas cylinders. An 
analysis of the high-pressure cylinders revealed contaminating traces 
of benzene and xylene that were likely attributable to improper 
cleaning of the cylinders during their conversion from industrial to 
medical use. Several patients experienced minor respiratory problems as 
a result of the contamination.
    FDA anticipates that incidents like those described in this 
subsection can be avoided if, as proposed in this document, all high-
pressure medical gas cylinders are painted in the standard colors for 
identifying gases adopted by the CGA and if, as also proposed, high-
pressure cylinders used to hold industrial gases are not converted to 
medical use. As discussed in section II.B of this document, FDA does 
not intend to prohibit the continued medical use of high-pressure gas 
cylinders that have been appropriately converted from industrial to 
medical use before the date that the requirements proposed in section 
II.B are finalized and take effect, as long as such cylinders remain 
dedicated solely to medical use on and after that date.

B. Current Regulatory Requirements and Recommendations for Medical Gas 
Containers and Closures

    As detailed in this subsection, medical gas containers and closures 
are currently addressed by many regulations, guidances, voluntary 
standards, and recommendations that promote the safe and effective use 
of medical gases. The proposals in section II.B of this document are 
intended to supplement, rather than supercede, existing regulations and 
guidance by adding requirements, based largely on current industry 
practices, to minimize the incidence of adverse events like those 
previously described.
    All medical gases,\2\ including those produced by the air 
liquefaction process\3\ or processed, purified, or refined from a raw 
material, are prescription drugs under sections 201(g)(1)and 503(b)(1) 
of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
321(g)(1) and 353(b)(1)). As such, medical gases are subject to 
regulation under, among others, section 501(a)(2)(B) of the act (21 
U.S.C. 351(a)(2)(B)) and parts 210 and 211 (21 CFR parts 210 and 211).
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    \2\ Medical gases include: oxygen, Unites States Pharmacopeia 
(USP), nitrogen, National Formulary, nitric oxide, nitrous oxide 
USP, carbon dioxide USP, helium USP, medical air USP, and any 
mixture of these gases or other gas products approved under a new 
drug application (NDA).
    \3\ This process involves extracting atmospheric air and 
separating it into constituent gases (i.e., nitrogen, oxygen, and 
argon).
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    Medical gas containers and closures, such as portable cryogenic 
containers and high-pressure cylinders, are integral parts of the drug 
product. These containers and closures play a critical role in ensuring 
that the drug product provided to a patient has the appropriate 
identity, strength, quality, and purity. Under parts 210 and 211, 
medical gas manufacturers and distributors must comply with specific 
CGMP requirements applicable to medical gas containers and closures. 
Medical gas manufacturers include any individual or firm that fills 
high-pressure medical gas cylinders or cryogenic medical gas containers 
by any of the following methods: Liquid to liquid, liquid to gas, or 
gas to gas. This term includes any third-party company (not the 
original manufacturer or end user) that acquires liquid medical gas and 
delivers or fills it into a storage tank. In industry vernacular, a 
manufacturer is more commonly referred to as a filler, a repackager, or 
a transfiller. Medical gas distributors include any individual or firm 
that receives and holds, but does not manipulate, compressed or liquid 
medical gas in labeled high-pressure cylinders or cryogenic containers.
    FDA CGMP regulations that currently address the safety of medical 
gas containers and closures are extensive and include the following:
     Section 211.80(a), which requires manufacturers of medical 
gases to establish and follow written procedures for the testing and 
approval or rejection of containers and closures;
     Section 211.82(a), which requires that medical gas 
containers and closures be inspected visually for appropriate labeling 
content, container damage or broken seals, and contamination;
     Section 211.84(a), which requires that medical gas 
containers and closures be withheld from use until they are examined 
and released by the quality control unit;
     Section 211.84(d)(3), which requires that medical gas 
containers and closures be tested for conformance with all written 
procedures; and
     Section 211.94(b), which requires that medical gas 
container and closure systems provide adequate protection against 
foreseeable external factors in storage and use that can cause 
deterioration or contamination of a stored drug product.
    Additionally, under Sec.  211.100(a) and (b), manufacturers of 
medical gases must establish and follow written procedures for 
production and process control to ensure that medical gases meet 
applicable specifications for identity, strength, quality, and purity. 
Also, medical gases are subject to the labeling requirements in 
Sec. Sec.  211.122 through 211.137 to ensure that they are correctly 
labeled with respect to their identity and bear appropriate lot numbers 
and expiration dating. Further, under Sec.  211.42(b), buildings used 
by manufacturers and distributors of medical gases must have adequate 
space for the orderly placement of medical gas containers to prevent 
mixups or contamination. Under Sec.  211.42(c), operations must be 
performed within specifically defined areas of adequate size to avoid 
mixups or contamination of gases during manufacturing, packaging, and 
labeling operations, as well as during the storage of medical gases 
after release.
    As mandated by Sec.  211.25, individuals involved in the 
manufacture, processing, packing, or holding of medical gases must have 
the appropriate combination of education, training, and experience to 
perform their job functions. Further, before release for

[[Page 18042]]

distribution, finished product testing must be conducted on medical 
gases in accordance with Sec.  211.165 to ensure that they conform to 
final specifications. Medical gas manufacturers are also subject to 
several recordkeeping and reporting requirements in Sec. Sec.  211.180 
through Sec.  211.198. As earlier noted, the requirements in this 
subsection will be supplemented by the additional safety measures FDA 
is proposing for codification in section II.B of this document.
    FDA can take several courses of action in response to identified 
CGMP violations, including the following:
     Issuing a written warning or notice;
     Seizing affected products, including storage tanks, high-
pressure medical gas cylinders, portable cryogenic medical gas 
containers, cryogenic medical gas containers for home use\4\ on the 
company's premises, cryogenic medical gas containers mounted to trucks 
and vehicles, as well as tankers;
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    \4\ Containers designed to hold liquid oxygen at a patient's 
home under low pressure and at a very low temperature.
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     Seeking an injunction against the manufacturer and/or 
distributor; and
     Initiating prosecution.
    FDA has issued numerous warning letters and initiated numerous 
seizure actions, injunctions, prosecutions and civil contempt actions 
to enforce the CGMP regulations as they apply to medical gases and will 
continue to take such actions where appropriate.
    To supplement existing regulations, FDA has issued guidances and 
other recommendations for the safe use of medical gases. As further 
discussed in section II.B of this document, several of the provisions 
FDA is currently proposing would codify as requirements current 
recommendations to ensure that they are adopted. In the Federal 
Register of May 6, 2003 (68 FR 24005), FDA announced the availability 
of a draft guidance for industry entitled ``Current Good Manufacturing 
Practice for Medical Gases'' (May 6, 2003, draft guidance). This draft 
guidance provides recommendations for CGMP compliance in the 
manufacture of compressed and cryogenic medical gases. When finalized, 
it is expected to help manufacturers and distributors comply with CGMP 
requirements to ensure the identity, strength, quality, and purity of 
medical gases. Among other things, the draft guidance includes 
recommendations that are intended to prevent medical gas mixups and are 
proposed for codification in section II.B of this document (e.g., using 
standard colors to identify medical gas cylinders and 360[deg] 
wraparound labels to identify medical gases in portable cryogenic 
containers). When these proposals are finalized, the guidance will be 
amended to reflect their codification.
    The May 6, 2003, draft guidance referenced in the previous 
paragraph follows FDA's February 1989 ``Compressed Medical Gases 
Guideline,'' which addresses the use of medical gases in the home care 
setting, including the delivery of oxygen to patients at home, as well 
as FDA's ``Guidance for Hospitals, Nursing Homes, and Other Health Care 
Facilities--FDA Public Health Advisory'' (66 FR 18257, April 6, 2001). 
This public health advisory describes incidents of medical gas mixups 
and provides recommendations for avoiding these types of incidents, 
including training facility employees to check the labels of medical 
gases and to avoid removing the gas-specific fittings (i.e., gas use 
outlet connections) on portable cryogenic medical gas containers. In 
July 2001, FDA issued a public health advisory that also discusses 
medical gas mixups and actions recommended to avoid them.\5\ This 
advisory reiterates the importance of checking labels and not changing 
the fittings or connectors on cryogenic medical gas containers.
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    \5\ See ``FDA Public Health Advisory: Potential for Injury from 
Medical Gas Misconnections of Cryogenic Vessels'' (July 20, 2001). 
This advisory may be accessed on the Internet at https://www.fda.gov/
cdrh/safety/medical-gas-misconnect.html. Additional information on 
this subject may be accessed on the Internet at https://www.fda.gov/
cder/consumerinfo/medgas.htm.
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    In addition to agency efforts, the medical gas industry and other 
bodies have taken steps to help prevent medical gas mixups and ensure 
the safe use of medical gases. For example, since 1973, the CGA has 
issued a color-marking pamphlet recommending that certain standard 
colors be used to identify the contents of medical gas containers. The 
current (fourth) edition of this standard, entitled ``CGA C-9--2004 
Standard Color Marking of Compressed Gas Containers Intended for 
Medical Use,'' was issued on March 10, 2004. Most medical gas 
manufacturers presently use the colors recommended in the CGA standard 
to mark high-pressure medical gas cylinders so that their contents can 
be readily identified. Although the stainless steel composition of 
portable cryogenic containers renders paint more difficult to apply and 
maintain, manufacturers that fill these containers have also sought to 
ease the identification of gases held within them by other methods. As 
further discussed in sections II.B and IV.B of this document, in recent 
years, a large majority of these manufacturers have used 360[deg] 
wraparound labels to identify the contents of portable cryogenic 
containers used for medical gases. The CGA recommended the use of these 
labels in a safety bulletin issued in 2001.\6\
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    \6\ See CGA Safety Bulletin SB-26, 2d edition (November 26, 
2001).
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    Manufacturers have also voluntarily designed the gas use outlet 
connections on portable cryogenic medical gas containers using varying 
thread dimensions so that these outlet connections are specific to a 
particular type of gas and compatible only with connectors to supply 
systems used to deliver the particular gas. For these reasons, gas-
specific use outlet connections on portable cryogenic medical gas 
containers provide a barrier against the misuse of these gases, 
provided they are not removed and replaced with, or substituted for, 
outlet connections specific to a different type of gas. To help ensure 
that gas use outlet connections on portable cryogenic medical gas 
containers will not be removed, the CGA has issued a safety bulletin 
that recommends that these connections be silver brazed or attached by 
another method to the valve body in a manner that prevents removal or 
that would render the connection or valve body outlet unusable if 
removal were attempted or accomplished.\7\
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    \7\ See id.
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    Furthering the safety initiatives discussed in the previous 
paragraphs, the Joint Commission on Accreditation of Healthcare 
Organizations (JCAHO) has encouraged industry's adherence to 
recommendations provided in FDA's March 2001 ``Guidance for Hospitals, 
Nursing Homes, and Other Health Care Facilities--FDA Public Health 
Advisory'' regarding the training of health care employees who handle 
medical gas containers and the proper storage and handling of these 
containers.\8\ As previously explained, this guidance recommends, among 
other things, that employees who handle medical gases be trained to 
carefully check container labels and to avoid changing the gas use 
outlet connections on cryogenic medical gas containers. In 2002 the 
JCAHO also added to its Comprehensive Accreditation Manual for 
Hospitals a description of a hospital medical gas management and 
training program that emphasized several of the safety measures 
recommended in FDA's March 2001 guidance. The JCAHO cited this program 
as an example of how its accreditation standard for utilities

[[Page 18043]]

management (EC.1.7), which addresses in part the reduction of 
nosocomial (or hospital-related) illnesses and injuries, may be 
implemented.
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    \8\ See JCAHO Sentinel Event Alert, issue 21 (July 2001).
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    Additionally, the National Fire Protection Association (NFPA) 
recently revised its Standard for Health Care Facilities to include 
various measures to prevent medical gas mixups.\9\ Many State and local 
governments require health care facilities to comply with NFPA 
standards. Certain measures adopted by the NFPA, such as wraparound 
labeling for cryogenic liquid cylinders and the use of gas-specific use 
outlet connections on such cylinders that are difficult to remove, are 
similar to requirements that FDA is proposing in section II.B of this 
document. When followed, existing regulations, guidances, and standards 
have helped to enhance the safe use of medical gases. However, as 
previously noted, despite these requirements and recommendations, 
instances of death and serious injury attributable to medical gas 
mixups and contamination have continued to occur. The requirements 
proposed in section II.B of this document will supplement existing 
requirements and increase the adoption of certain presently voluntary 
recommendations that help enhance medical gas safety.
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    \9\ See NFPA 99; Standard for Health Care Facilities (2005 
edition).
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II. Description of Proposed Requirements

A. Revisions to Labeling Exemptions

    Section 201.100 (21 CFR 201.100) lists various conditions, which if 
all are met, exempt prescription drug products from the act's 
requirement that their labeling bear adequate directions for use. Among 
others, these conditions include the following:
     The label of the drug bears its recommended or usual 
dosage (Sec.  201.100(b)(2)),
     For a drug not intended for oral use, the label bears the 
drug's route of administration (Sec.  201.100(b)(3)),
     Labeling on or within the drug's packaging bears adequate 
information for its use and any relevant hazards, contraindications, 
side effects, and precautions under which licensed practitioners can 
use the drug safely and for the purposes for which it is intended 
(Sec.  201.100(c)(1)).
    Current Sec.  201.161(a) (21 CFR 201.161(a)) states that carbon 
dioxide, cyclopropane, ethylene, helium, and nitrous oxide gases 
intended for drug use are exempted from the requirements of Sec.  
201.100(b)(2), (b)(3), and (c)(1), provided that their labeling bears, 
in addition to any other information required by the act: (1) The 
specific warning set forth in Sec.  201.161(a)(1) regarding use of 
these gases by experienced and licensed practitioners only, (2) any 
needed directions concerning the gases' conditions of storage, and (3) 
warnings against dangers inherent in their handling. FDA is proposing 
that medical air, oxygen, and nitrogen be added to Sec.  201.161(a)'s 
list of exempted gases. These drugs were, for various reasons, excluded 
when Sec.  201.161(a) was originally issued in 1970. However, based on 
its years of regulatory experience with medical air, oxygen, and 
nitrogen, FDA believes that compliance with the requirements of Sec.  
201.100(b)(2), (b)(3), and (c)(1) is unnecessary for these gases if the 
warning and direction requirements in Sec.  201.161(a), as well as the 
labeling and coloring requirements proposed in Sec.  211.94(e)(4) and 
described in the following paragraphs, are met. In addition, FDA 
proposes to delete cyclopropane and ethylene from Sec.  201.161(a). 
These gases are no longer used in medical procedures because they are 
flammable and pose a risk of explosion or fire.

B. Revised Requirements for Medical Gas Containers and Closures

    The proposed rule would add a new paragraph (e) under Sec.  211.94 
to provide requirements for medical gas containers and closures. The 
following proposed requirements would enhance the safe use of medical 
gases by: (1) Diminishing the likelihood that cryogenic containers or 
high-pressure cylinders used to store medical gases will be tainted 
with industrial contaminants, (2) decreasing the likelihood of medical 
gas mixups attributable to the removal and replacement of gas-specific 
use outlet connections on portable cryogenic containers, and (3) 
increasing the likelihood that the contents of high-pressure cylinders 
and portable cryogenic containers will be easily and accurately 
identified by persons selecting medical gases for administration to 
patients. The elements of proposed Sec.  211.94(e) are explained in the 
following paragraphs.
1. Prohibition on Conversion of Cryogenic Containers and High-Pressure 
Cylinders From Industrial to Medical Use
    Proposed Sec.  211.94(e)(1) would prohibit cryogenic containers and 
high-pressure cylinders that are used to hold industrial gases from 
being converted to medical use after the final rule becomes effective. 
The proposed rule would not prohibit the continued medical use of 
cryogenic containers or high-pressure cylinders previously used to hold 
industrial gases if such containers have been appropriately converted 
to medical use (according to standard industry practice) by the time 
the final rule takes effect and are used solely for medical purposes 
thereafter. See proposed Sec.  211.94(e)(2). When finalized, proposed 
Sec.  211.94(e) would supersede and codify an existing recommendation 
in FDA's draft guidance for industry on ``Current Good Manufacturing 
Practice for Medical Gases,'' (68 FR 24005) which recommends, among 
other things, that high-pressure cylinders and cryogenic containers 
used for medical gases be dedicated to medical use only.
    FDA believes that proposed Sec.  211.94(e)(1) is necessary to 
minimize the risk of contamination of medical gases by industrial 
contaminants (e.g., chlorine, hydrocarbons, arsenic compounds, 
industrial cleaning solvents, or foreign gas residue) and to ensure the 
safety, quality, and purity of medical gases. After the effective date 
of the final rule, by prohibiting the conversion of high-pressure 
cylinders or portable cryogenic containers from industrial to medical 
use, proposed Sec.  211.94(e)(1) would eliminate any potential 
uncertainty that might otherwise exist as to whether such a container, 
if converted to medical use, would have been properly cleaned and 
purged of industrial gas and contaminants.
2. Requirements for Secure Gas Use Outlet Connections on Portable 
Cryogenic Medical Gas Containers
    Proposed Sec.  211.94(e)(3) would require portable cryogenic 
medical gas containers that are not manufactured with permanent gas use 
outlet connections to have gas-specific use outlet connections that are 
attached to the valve body in such a way that they cannot be readily 
removed or replaced except by the medical gas manufacturer. This 
proposed requirement would not apply to high-pressure medical gas 
cylinders because FDA is not aware of any incidents of gas use outlet 
connection replacement or removal involving such cylinders or of a 
likelihood of such incidents.
    Proposed Sec.  211.94(e)(3) is designed to prevent the types of 
incidents (described in section I.B of this document) that have 
occurred when gas-specific use outlet connections on portable cryogenic 
containers have been removed and replaced with other outlet connections 
that permit containers of inappropriate gases to be connected to oxygen 
supply systems. It has been possible for gas use outlet connections

[[Page 18044]]

to be readily removed in cases where the connection is attached by a 
pipe thread outlet and tape. The proposed rule would require that gas 
use outlet connections on portable cryogenic medical gas containers be 
permanently attached to the valve body (e.g., by silver brazing) or 
otherwise attached to the valve body using a locking mechanism or other 
appropriate device that precludes the easy removal of the connections 
by parties other than the manufacturer. As earlier noted in section I.B 
of this document, the CGA has recommended in part that gas use outlet 
connections be permanently attached to cryogenic medical gas containers 
by silver brazing or another method that would prevent the connections' 
removal. Moreover, as discussed in section IV.B of this document, FDA 
estimates that approximately 90 percent of the containers that would be 
subject to this requirement already comply with its terms. Thus, this 
proposed requirement is consistent with current industry 
recommendations and practice.
    For the purposes of proposed Sec.  211.94(e)(3) and (e)(4) 
(discussed in the following paragraphs), portable cryogenic medical gas 
containers include all cryogenic medical gas containers that are both 
capable of being transported and intended to be attached to a medical 
gas supply system within a hospital, health care entity, nursing home, 
other facility, or home health care setting, except small cryogenic 
containers for use by individual patients in their homes and portable 
liquid oxygen units that are intended to be distributed empty (i.e., 
unfilled), as described by Sec.  868.5655 (21 CFR 868.5655). The agency 
is primarily concerned with situations in which medical gas mixups have 
most often occurred (i.e., where a portable cryogenic container holding 
a gas other than oxygen is delivered, and an employee of the gas 
manufacturer or the receiving facility misidentifies the container and 
is able (by substituting a gas-specific use outlet connection removed 
from an oxygen container) to connect the inappropriate container to an 
oxygen supply system for medical use). Proposed Sec.  211.94(e)(3) and 
(e)(4) would not apply to cryogenic containers that are too large 
(e.g., a tank truck or trailer) to be connected to a medical gas supply 
system.
    The proposed rule does not apply to containers of industrial gases 
because these products are not drugs, and thus would not require 
manufacturers of such gases to outfit portable cryogenic containers 
intended for industrial use with gas use outlet connections that are 
difficult to remove. However, as previously discussed, mixups may 
result if the gas use outlet connection on a portable cryogenic 
container holding a particular industrial gas is removed and replaced 
with a use outlet connection that is specific to a different gas and 
compatible with a medical gas supply system. Therefore, FDA strongly 
encourages medical gas manufacturers that handle portable cryogenic 
containers holding industrial gases, as well as portable cryogenic 
containers holding medical gases, to make the gas use outlet 
connections difficult to remove on both their industrial and medical 
containers. FDA believes that most manufacturers already comply with 
this recommendation. As noted in the previous paragraphs, the CGA's 
safety bulletin SB-26 advises, in part, that outlet connections on 
cryogenic medical gas containers be affixed using silver brazing or 
another method that prevents their removal. Among other things, this 
bulletin also advises that outlet connections on cryogenic industrial 
gas containers be used with a device that deters the connections' 
removal and provides indication in the case that removal is 
attempted.\10\
---------------------------------------------------------------------------

    \10\ See CGA Safety Bulletin SB-26, 2d edition (November 26, 
2001).
---------------------------------------------------------------------------

    The agency also notes that the delivery, after receipt in 
interstate commerce, of industrial gas to a medical account in a 
cryogenic container that is mislabeled as medical gas would be a 
prohibited act under section 301 of the act (21 U.S.C. 331). Section 
201(g)(1)(B) of the act defines drugs as all ``articles intended for 
use in the diagnosis, cure, mitigation, treatment, or prevention of 
disease in man.'' In the circumstances described in this paragraph, the 
industrial gas delivered to a medical account (such as a hospital or 
nursing home) and labeled as medical gas would be intended for such a 
medical use and thus would be a drug. Moreover, because the industrial 
gas would be unsuitable and improperly labeled for medical use, it 
would be adulterated and misbranded under sections 501 and 502 of the 
act (21 U.S.C. 352), respectively. Accordingly, its delivery and sale 
to a medical facility would violate section 301 of the act. In 
addition, the responsible individuals from the gas manufacturer and/or 
distributor could be held liable under the act for the illegal 
delivery. (See section 303 of the act (21 U.S.C. 333).)
3. Requirement for 360[deg] Wraparound Label for Portable Cryogenic 
Medical Gas Containers
    Proposed Sec.  211.94(e)(4)(i) would require each portable 
cryogenic medical gas container to be conspicuously marked with a 
360[deg] wraparound label identifying its contents. (As explained in 
section II.B.2 of this document, portable cryogenic medical gas 
containers subject to this requirement would not include small 
cryogenic containers for use by individual patients in their homes or 
portable liquid oxygen units intended to be distributed empty, as 
described in Sec.  868.5655.) This proposed label requirement is 
intended to make the contents of these containers more readily known to 
persons responsible for handling and connecting them to medical gas 
supply systems in hospitals or other health care facilities and thereby 
reduce the likelihood of medical gas mixups. Unlike high-pressure 
medical gas cylinders, which, as earlier noted, manufacturers usually 
voluntarily paint in standard colors to identify their contents, 
portable cryogenic medical gas containers are rarely colored. 
Therefore, it is difficult for users to distinguish these containers 
from portable cryogenic containers holding industrial gases without 
reading the containers' labels.
    As discussed in section I.B of this document, because of their 
stainless steel construction, it is difficult to apply and maintain 
paint on portable cryogenic containers. As also noted in section I.B, 
in recent years most manufacturers have voluntarily identified medical 
gases stored in these containers using 360[deg] wraparound labels. 
These labels are currently readily available from several large label 
manufacturing firms with the specific colors and wording that we are 
proposing to require. To ensure that all manufacturers use this method 
to correctly identify medical gas containers, FDA is proposing to 
require that portable cryogenic medical gas containers be identified 
using a 360[deg] wraparound label.
    Proposed Sec.  211.94(e)(4)(i)(A) would require that each 360[deg] 
wraparound label bear an FDA-designated standard name for the contained 
medical gas. Proposed Sec.  211.94(e)(4)(i)(B) would require that the 
lettering for the standard name appear in either an FDA-designated 
standard color against a white background, or in white against an FDA-
designated color background. Proposed standard names and colors, which 
are based on those already widely used by industry, are listed in 
proposed Sec.  211.94(e)(5). All the standard names

[[Page 18045]]

proposed in this provision include the word ``medical'' to distinguish 
containers labeled with these names from those holding industrial 
gases.
    Additionally, because portable cryogenic medical gas containers 
tend to be fairly large, the agency is proposing in Sec.  
211.94(e)(4)(i) (C) that the lettering for the names of medical gases 
held in these containers be at least 2 3/4 inches high so they can be 
easily seen. This proposal is based on discussions with industry, which 
revealed that 2 3/4-inch lettering is the standard size already 
commonly used by the medical gas industry. FDA is further proposing in 
Sec.  211.94(e)(4)(i)(D) that the names of the gases be printed 
continuously on the wraparound label and be capable of being read 
around the entire container. FDA believes that this proposal, too, 
reflects existing widespread industry practice. Additionally, proposed 
Sec.  211.94(e)(4)(i)(E) would require that the label be located on the 
sidewall near the top of the container but below the top weld seam. FDA 
understands that placing the label in this location increases its 
durability and is already common practice. Proposed Sec.  
211.94(e)(4)(i)(F) would require that the label be affixed to the 
container in a manner that ensures that it cannot be easily detached or 
worn, and that it does not interfere with other labeling.
    Although FDA is not proposing to require that portable cryogenic 
medical gas containers be colored, the agency is aware that, on rare 
occasions, manufacturers may voluntarily color the shoulders of these 
containers. To avoid confusion in these cases, manufacturers would be 
required by proposed Sec.  211.94(e)(4)(i)(G) to use the standard 
colors designated in proposed Sec.  211.94(e)(5) to identify the gases 
stored in the containers. If manufacturers choose to color portable 
cryogenic medical gas containers, the requirement to use the colors 
designated in proposed Sec.  211.94(e)(5) would be in addition to, and 
not instead of, the requirement to use the 360[deg] wraparound label in 
proposed Sec.  211.94(e)(4)(i).
    Current Sec.  211.125(c) requires manufacturers to follow 
procedures to reconcile the quantities of labeling issued, used, and 
returned, and to evaluate discrepancies found between the quantity of 
drug product finished and the quantity of labeling issued when such 
discrepancies are outside narrow, preset limits based on historical 
operating data. In light of the unique nature of the 360[deg] 
wraparound labels FDA is proposing for portable cryogenic medical gas 
containers, the agency has determined that compliance with the 
reconciliation requirements of Sec.  211.125(c) is not practical for 
these labels. Compliance would be impractical because the labels are 
not discrete but, rather, are supplied on a large reel or spool as a 
continuous string of repeated medical gas names that can be cut into an 
unfixed number of labels of varying sizes.
4. Requirement to Color High-Pressure Medical Gas Cylinders
    Proposed Sec.  211.94(e)(4)(ii) would require that high-pressure 
medical gas cylinders be identified with a standard color as provided 
in proposed Sec.  211.94(e)(5). Nonaluminum high-pressure medical gas 
cylinders would be required to be colored in whole in the applicable 
standard color. Aluminum high-pressure medical gas cylinders would be 
required to be colored only on the shoulder portion of the cylinder 
because the bodies of these cylinders are coated with a thermal 
indicator that turns a different color when the cylinders have been 
exposed to fire.
    The agency recognizes that hospitals, nursing homes, and other 
firms or individuals may occasionally purchase high-pressure medical 
gas cylinders from manufacturers for their own private use. Under 
proposed Sec.  211.94(e)(4)(ii), manufacturers would be required to 
color these cylinders in the applicable standard color designated in 
Sec.  211.94 (e)(5) prior to their sale for private use. FDA 
understands that private owners may wish to distinguish high-pressure 
medical gas cylinders they own from those owned by manufacturers and 
that, in the past, private owners have sometimes distinguished their 
cylinders by painting them a different color than those owned by 
manufacturers. To avoid confusion with cylinders painted in the 
standard colors proposed in Sec.  211.94(e)(5), the agency encourages 
private owners who wish to distinguish their high-pressure medical gas 
cylinders to mark those cylinders using a possession sticker or to 
stencil their name vertically on the body of the cylinders.
    The proposed container coloring requirements described in the 
preceding paragraphs are consistent with present industry practice and 
should not represent a significant burden for most medical gas 
manufacturers. Currently, the vast majority of high-pressure medical 
gas cylinders are voluntarily colored in accordance with the standard 
colors in proposed Sec.  211.94(e)(5). As discussed in section I.A.2 of 
this document, at least one death is known to have resulted from an 
inappropriately colored high-pressure medical gas cylinder. The agency 
emphasizes that employees responsible for handling medical gases are 
required to have the training and education necessary to identify a 
medical gas by reading the container label. However, as past events 
have demonstrated, individuals responsible for handling medical gases 
do not always read the labels on these gases carefully. The agency 
believes that coloring high-pressure medical gas cylinders in standard 
colors provides an important additional safeguard against the improper 
use of these cylinders and can be accomplished with minimal burden on 
industry.
    As noted earlier in this document, proposed Sec.  211.94(e)(5) 
specifies the colors that would be required to be used on the exterior 
surfaces of high-pressure medical gas cylinders under proposed Sec.  
211.94(e)(4)(ii). The colors proposed in Sec.  211.94(e)(5) are the 
same as those currently recommended by the CGA and voluntarily used by 
most of the U.S. medical gas industry to identify medical gases. Under 
proposed Sec.  211.94(e)(4)(ii)(D), high-pressure cylinders holding a 
mixture or blend of medical gases would be required to be colored with 
the standard colors representing each component. All colors would be 
required to be visible when viewed from the top of the cylinder. The 
portion of the cylinder painted in each color must correspond roughly 
to the proportion of each gas in the mixture. For example, a mixture of 
oxygen (95 percent) and carbon dioxide (5 percent) must be represented 
by a cylinder (or cylinder shoulder, if the cylinder is aluminum) that 
is predominantly green with a gray band or shoulder.
    To ensure that the colors painted on high-pressure medical gas 
cylinders will endure, under proposed Sec.  211.94(e)(4)(ii)(C), the 
materials used for coloring would be required to be reasonably 
resistant to fading and durable when exposed to atmospheric conditions. 
This provision would further require that the materials not be readily 
soluble in water after they have been applied and properly dried or 
cured. The agency declines to specify an exact shade of color or a 
color specification that must be used under proposed Sec.  
211.94(e)(5). However, to avoid confusion, the color shade selected 
should be such that its hue and intensity, when viewed in normal indoor 
light, cannot be mistaken for another color by persons having normal 
color perception.

III. Legal Authority

    As discussed in section I.B of this document, all medical gases are 
prescription drugs under sections 201(g)(1) and 503(b)(1) of the act, 
and

[[Page 18046]]

are subject to regulation under section 501(a)(2)(B) of the act and 
parts 210 and 211. Under sections 701(a) (21 U.S.C. 371(a)) and 
501(a)(2)(B) of the act, FDA has the authority to create and modify 
CGMP regulations to ensure that drugs are safe and have the identity, 
strength, quality, and purity they are purported or represented to 
possess. Medical gas containers and closures are integral parts of 
medical gas drug products and play a critical role in ensuring that 
these products are safe and have the appropriate identity, strength, 
quality, and purity. As discussed in section I.B of this document, 
incidents involving misuse and contamination of medical gases have 
caused death and serious injury to patients. As also previously 
discussed, these incidents have occurred despite current regulations 
and guidances addressing the safe handling of medical gases.
    FDA is therefore invoking the authority granted by sections 701(a) 
and 501(a)(2)(B) of the act to propose CGMP regulations that are 
designed to prevent the misuse and contamination of medical gases. The 
specific requirements in these proposed regulations would be an 
integral part of the manufacturing, processing, packing, and holding of 
medical gases and help to ensure the safety of these products. These 
requirements constitute current good manufacturing practice under 
section 501(a)(2)(B) of the act. In addition to this CGMP statutory 
authority, the labeling requirements in the proposed regulations (i.e., 
the use of wraparound labels and standard colors and names) are also 
authorized under section 502 of the act.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4)). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is not an economically significant regulatory action 
as defined by the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because, as explained in the following sections of 
this document, FDA estimates that the proposed rule would result in an 
annualized cost to small businesses equivalent to 0.1 percent of their 
revenues or less, the agency believes that the rule is unlikely to have 
a significant economic impact on a substantial number of small 
entities. However, since we cannot exclude the possibility of a 
significant economic impact because of the large number of small 
businesses that could be affected and the limited amount of data on 
which the estimate in the previous sentence is based, a regulatory 
flexibility analysis is included.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $115 million, using the most current (2003) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    FDA is proposing to amend Sec.  211.94 to require the use of 
certain safeguards in the production, storage, and use of medical 
gases. These changes to the CGMP regulations would include new 
requirements for the label, color, dedication, and design of medical 
gas containers and closures. Specifically, the amended regulations 
would require the following: (1) Gas use outlet connections on portable 
cryogenic medical gas containers be permanently attached or otherwise 
locked to the valve body so they cannot be readily removed except by 
the manufacturer, (2) a 360[deg] wraparound label clearly identifying 
the container's contents be affixed near the top of portable cryogenic 
medical gas containers, and (3) high-pressure medical gas cylinders be 
painted an FDA-designated standard color. Additionally, the proposal 
would prohibit the medical use of high-pressure cylinders or cryogenic 
containers that have previously been used to hold industrial gases if 
such containers have not been appropriately converted to medical use by 
the final rule's effective date and are not solely dedicated to medical 
use on and after this date.

A. Benefits

    This proposal is expected to reduce the risk of accidents involving 
the improper handling of medical gases and therefore the number of 
accidental injuries and deaths from these accidents.
    As discussed in section I.A of this document, FDA has received 
reports from nursing homes and hospitals of accidents involving the 
improper handling of portable cryogenic containers and high-pressure 
medical gas cylinders that resulted in 8 deaths and 16 injuries between 
1996 and April 2004. Because there is no requirement that nursing homes 
and hospitals report such incidents to us, we assume that these figures 
underestimate the number of deaths and injuries over this time period. 
On average, this equates to approximately one death and two injuries 
per year. As noted earlier in this document, these deaths and injuries 
have been associated with portable cryogenic containers and high-
pressure cylinders that were misidentified or contaminated, or whose 
gas-specific use outlet connections were inappropriately removed and 
replaced. FDA believes that this proposal, when finalized, will 
drastically reduce, if not completely eliminate, the foregoing errors 
and the human deaths and injuries that might otherwise occur. We 
estimate that this proposed rule could eliminate, on average, one death 
per year.
    There are different methodologies for valuing the avoidance of 
mortalities because of regulatory action. One approach is based on 
society's willingness-to-pay to avoid incremental risks of a 
statistical death. A widely cited study calculates this value based on 
occupational wage premiums necessary to accept increased work-place 
fatality risks.\11\ This study implies a societal value of about $5 
million per statistical death avoided. A more recent study by Viscusi 
that compares worldwide estimates of the value of a statistical life 
(VSL) concludes that a more appropriate VSL estimate for the United 
States is about $7 million.\12\ Because we estimate that this proposed 
rule could prevent, on average, one death per year, we estimate the 
benefit of the rule in the first year alone at about $7 million. The 
avoidance of the increased medical costs, lost productivity, and 
investigation or

[[Page 18047]]

litigation costs associated with up to two additional medical gas-
related injuries per year, although positive, would not be expected to 
add substantially to this total. Because of the small number of medical 
gas-related incidents that occur on average each year, there is some 
uncertainty surrounding the benefit of this proposed rule in any 
individual year.
---------------------------------------------------------------------------

    \11\ See Viscusi, W.K., Fatal Tradeoffs, Public and Private 
Responsibilities for Risk, Oxford University Press, 1992.
    \12\ See Viscusi, W.K., and J.E. Aldy, ``The Value of a 
Statistical Life: A Critical Review of Market Estimates Throughout 
the World,'' The Journal of Risk and Uncertainty, volume 27, no. 1, 
p. 63, 2003.
---------------------------------------------------------------------------

B. Costs

    Depending on their current level of compliance, medical gas 
manufacturers would be expected to incur compliance costs for the 
following:
     Silver brazing or locking gas use outlet connections on 
portable cryogenic medical gas containers,
     Purchasing and attaching 360[deg] wraparound labels on 
portable cryogenic medical gas containers,
     Painting high-pressure medical gas cylinders in the 
appropriate FDA-designated color(s), and
     Forgoing the use of portable cryogenic containers and 
high-pressure cylinders for both industrial and medical use. 
Additionally, manufacturers may be expected to incur a very slight 
increase in record maintenance costs for container closures subject to 
this proposed rule.
    The agency used the best available data from industry contacts and 
FDA personnel to generate cost estimates for this proposal, and we are 
inviting public comment and additional data on the methods used to make 
these estimates.
1. Brazing or Locking of Gas Use Outlet Connections on Portable 
Cryogenic Medical Gas Containers
    Under proposed Sec.  211.94(e)(3), portable cryogenic containers 
that hold medical gases would be required to have gas use outlet 
connections that are either permanently attached to the valve body or 
attached to the valve body in a manner that does not permit them to be 
readily removed except by the manufacturer. There are at least two 
methods of compliance: (1) Silver brazing the gas use outlet connection 
to permanently attach it to the valve body or (2) using any of several 
locking devices to lock the outlet connection to the valve body. 
Currently manufactured cryogenic containers incorporate brazed gas use 
outlet connections or locking devices, but some older containers that 
are still in use may not.
    Although FDA does not presently have a broader sample of company 
data to draw upon, data from several of the large industrial gas 
producers show that they have, on average, about 4,375 portable 
cryogenic medical gas containers each. Further, contacts at these firms 
suggested that industrial gas producers (seven in total) supply about 
10 percent of all portable cryogenic containers in medical use. Based 
on this information, FDA estimates that approximately 306,000 portable 
cryogenic medical gas containers would be subject to this proposed rule 
(4,375 x 7 x 10 = 306,250). FDA anticipates that cryogenic medical gas 
containers used by home care firms would not be subject to the proposed 
brazing or locking requirement. To the agency's knowledge, t