[Federal Register Volume 71, Number 68 (Monday, April 10, 2006)]
[Proposed Rules]
[Pages 18039-18053]
From the Federal Register Online via the Government Publishing 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: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://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 http://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 http://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: 
[email protected].

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 http://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 http://www.fda.gov/cdrh/safety/medical-gas-misconnect.html. Additional information on 
this subject may be accessed on the Internet at http://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, the only 
cryogenic medical gas containers such firms would fill would be small 
cryogenic containers for use at home by individual patients. These 
containers would be exempt from proposed Sec.  211.94(e)(3).
    The cost of materials and labor for the silver brazing process is 
expected to range from $50 to $150 per cryogenic container.\13\ This 
range reflects estimated costs for companies that are capable of 
performing brazing operations in-house, as well as for those that would 
need to contract this work to an outside company. An informal industry 
estimate of current compliance with silver brazing is between 90 
percent and 100 percent for larger distributors.\14\ Very few small 
firms, which may have lower compliance rates, are expected to operate 
portable cryogenic container facilities that would be subject to this 
proposed rule. FDA conservatively estimates, therefore, that about 90 
percent of all portable cryogenic medical gas containers (approximately 
276,000 containers [306,250 x .9 = 275,625]) currently comply with 
proposed Sec.  211.94(e)(3). The compliance cost of silver brazing all 
other cryogenic containers that would be subject to this provision is 
estimated to range from approximately $1,531,000 (30,625 x $50) to 
approximately $4,594,000 (30,625 x $150).
---------------------------------------------------------------------------

    \13\ Lower estimate made by medical gas manufacturer during a 
site visit by FDA on June 28, 2001. Upper estimate projected by FDA.
    \14\ Estimate provided to FDA by a major consulting firm for 
medical gas companies.
---------------------------------------------------------------------------

    An alternative to silver brazing that would also comply with the 
proposed requirement would be locking gas use outlet connections on 
portable cryogenic medical gas containers to the valve bodies on such 
containers using any of several locking valves or devices. These 
locking valves or devices are priced at about $10 to $15 each. FDA 
estimates that, at most, another $2 to $3 would be required in labor 
costs to attach each locking valve or device. Accordingly, FDA 
estimates that the total cost of complying with proposed Sec.  
211.94(e)(3) through the use of locking valves or devices would range 
from $12 to $18 per cryogenic container. Again assuming a current 
compliance rate with the proposed provision of 90 percent (275,625 
containers), the total cost of this option for industry would be 
expected to be no more than approximately $551,000 ([306,250-275,625] x 
$18).
    Because locking valves or devices are less costly than silver 
brazing and have become more widely used by industry, FDA expects that 
firms that do not currently comply with proposed Sec.  211.94(e)(3) 
will choose to use these devices to achieve compliance with the 
proposed requirement. Accordingly, the cost estimate for the proposed 
rule includes the locking device option and excludes the silver brazing 
option.
2. 360[deg] Wraparound Label for Portable Cryogenic Medical Gas 
Containers
    Proposed Sec.  211.94(e)(4)(i) would require that portable 
cryogenic containers used to hold medical gases be identified with a 
360[deg] wraparound label specifying their contents. FDA received a 
cost estimate of the wraparound label from only one manufacturer. 
Although the manufacturer reported this cost at about $1 per label, the 
size of the shipment ordered may affect the average price for all 
manufacturers. Taking this into account, as well as the lack of 
estimates from other manufacturers that could result in a higher 
estimate, FDA assumes that the average cost is $1.50 per label for this 
analysis. FDA estimates that an additional labor cost of about $3 would 
be required to attach each label to a portable cryogenic container. As 
noted previously in this document, FDA estimates that approximately 
306,000 cryogenic containers would be subject to this proposed rule 
when finalized. The current compliance rate for proposed Sec.  
211.94(e)(4)(i) is not known with certainty but is conservatively 
estimated at 90 percent (approximately 276,000 containers).\15\ Based 
on this estimate, total industry compliance costs for proposed Sec.  
211.94(e)(4)(i) would amount to approximately $135,000 ([306,000 - 
276,000] x $4.50).
---------------------------------------------------------------------------

    \15\ Estimate provided to FDA by a major consulting firm for 
medical gas companies.
---------------------------------------------------------------------------

3. Painting of High-Pressure Medical Gas Cylinders
    Proposed Sec.  211.94(e)(4)(ii) would require that high-pressure 
cylinders holding medical gases identified in proposed Sec.  
211.94(e)(5) be painted in the standard colors also identified in Sec.  
211.94(e)(5). As discussed previously

[[Page 18048]]

in this document, the coloring standards identified in proposed Sec.  
211.94(e)(5) have been widely used throughout the industry for many 
years. Consequently, the current compliance rate with this proposed 
provision is expected to be extremely high, and only a very small 
percentage of customer-owned cylinders are expected to be out of 
compliance. Although the current compliance rate cannot be predicted 
with certainty, FDA believes that it is at least 99 percent.\16\ The 
compliance costs for proposed Sec.  211.94(e)(4)(ii) have been 
calculated based on an estimated compliance rate of 99.5 percent.
---------------------------------------------------------------------------

    \16\ Based on experience of The Center for Drug Evaluation and 
Research personnel involved in medical gas issues.
---------------------------------------------------------------------------

    FDA does not have a complete set of data upon which to confidently 
estimate the number of high-pressure cylinders used for medical gases. 
Data from several industrial gas producers that also supply medical 
gases show that the number of cylinders per establishment varies 
greatly, even among this subset of medical gas suppliers.\17\ Using 
this data, FDA estimates that the average industrial gas establishment 
has about 3,000 high-pressure cylinders for use with medical gases. 
There are 3,400 establishments that are known to supply medical gases. 
The total number of high-pressure medical gas cylinders that would be 
subject to proposed Sec.  211.94(e)(4)(ii) is therefore estimated at 
about 10.3 million (3,000 x 3,400). This estimate likely exceeds the 
actual number of high-pressure cylinders that would be affected by this 
proposed rule because certain firms that supply medical gases in these 
cylinders are not expected to operate establishments as large as those 
of industrial gas manufacturers and, consequently, are not expected to 
have as many high-pressure medical gas cylinders. As noted earlier in 
this document, FDA estimates that 99.5 percent of the high-pressure 
medical gas cylinders that would be subject to this proposed rule are 
currently in compliance with the proposed coloring requirements 
(approximately 10,249,000 cylinders [10,300,000 x .995]). Thus, even if 
each affected establishment handled the estimated average of 3,000 
high-pressure medical gas cylinders, only approximately 51,000 such 
cylinders (10,300,000-10,249,000) would need to be colored to come into 
compliance with proposed Sec.  211.94(e)(5). Painting costs for these 
cylinders are estimated to range from $5 to $10 each, including both 
labor and materials. The total cost of this provision is therefore 
estimated at between $255,000 (51,000 x 5) and $510,000 (51,000 x 10).
---------------------------------------------------------------------------

    \17\ Based on phone contacts between FDA personnel and medical 
gas suppliers in June 2002.
---------------------------------------------------------------------------

4. Prohibition of Container Use for Both Industrial and Medical 
Purposes
    Proposed Sec.  211.94(e)(1) and (e)(2) would prohibit high-pressure 
cylinders and portable cryogenic containers from being used to store 
medical gases if they were previously used to hold liquid or compressed 
industrial gases and were not converted to medical use by the effective 
date of the final rule. FDA has anecdotal information that the practice 
of converting these containers back and forth from industrial to 
medical use is very rare, although it does occur. To the extent that 
such conversion occurs, FDA expects this provision to cause a small 
percentage of firms to purchase additional high-pressure cylinders or 
portable cryogenic containers to maintain their current supplies of 
these products for both medical and industrial uses. The agency does 
not have enough data or information to predict the number of additional 
containers that the average firm would purchase. The number should be 
very low, however, and the majority of firms should not be affected by 
this provision. Additionally, some off-setting savings would be 
expected if proposed Sec.  211.94(e)(1) and (e)(2) are implemented 
because certain costs associated with converting high-pressure 
cylinders or portable cryogenic containers from industrial to medical 
use would be eliminated, including the costs of cleaning, purging, 
relabeling, and changing the gas use outlet connections on containers 
being converted. FDA invites public comment and data on the prevalence 
and public health risk of container conversion across the medical gas 
industry and estimated costs of compliance with proposed Sec.  
211.94(e)(1).
5. Records Maintenance
    As mentioned previously in this document, proposed Sec.  
211.94(e)(3) would require that gas use outlet connections on portable 
cryogenic medical gas containers be permanently attached to the valve 
body or otherwise attached so that they cannot be readily removed, 
except by the manufacturer. As explained earlier in this document, FDA 
is aware of at least two methods by which industry could comply with 
this proposed requirement: (1) Silver brazing the gas use outlet 
connection to the valve body so that the outlet connection is 
permanently attached, or (2) using a locking valve or device to secure 
the gas use outlet connection to the valve body. Locking valves and 
devices would be considered part of a medical gas' container closure.
    Under existing Sec.  211.184, manufacturers are required to 
maintain certain records for medical gas container closures because 
they are considered part of the finished drug product. Specifically, 
under Sec.  211.184(a), the following information must be maintained:
     Records regarding the identity and quantity of each 
shipment of container closures;
     The name of the supplier;
     The supplier's lot number or numbers, if known;
     The receiving code; and
     The date of receipt.
    Under Sec.  211.184(b), records of the results of any test or 
examination conducted on a container closure under Sec.  211.182(a) 
must be maintained. Under Sec.  211.184(c), an individual inventory 
record must be maintained for each container closure. Under Sec.  
211.184(e), records of the disposition of any rejected container 
closure must be maintained.
    In light of the requirements described in this subsection of the 
rule, proposed Sec.  211.94(e)(3) could result in a slight increase in 
the medical gas industry's record maintenance activities if, after this 
provision is finalized, industry chooses to use locking valves or 
devices on portable cryogenic medical gas containers that do not 
already comply with the proposed provision. As noted earlier in this 
document, such valves or devices would be considered part of the 
medical gas' container closure. FDA would not, however, expect the 
costs of establishing and keeping the records required by Sec.  211.184 
for locking valves or devices to be substantial. Additionally, FDA 
anticipates that, in the vast majority of cases, records for locking 
valves or devices would not be required to be updated after the valves 
or devices have been inspected upon their receipt by medical gas 
manufacturers, or would only very rarely be required to be updated, 
under Sec.  211.184.
    To account for the records maintenance costs potentially associated 
with proposed Sec.  211.94(e)(3), including the possibility that some 
small percentage of maintenance records for locking valves or devices 
could require periodic updating, FDA estimates that manufacturers would 
be required to expend approximately 2 minutes (mins.) on record 
maintenance activities per locking device per year. This estimate 
includes time that would be associated with the initial inspection of 
the locking valve or device by the manufacturer. As previously 
discussed

[[Page 18049]]

in section IV.B.1 of this document, FDA estimates that 306,250 portable 
cryogenic medical gas containers are currently in use and that about 90 
percent of these (approximately 275,625 containers) already comply with 
proposed Sec.  211.94(e)(3). FDA expects that, with respect to the 
remaining estimated 30,625 containers, industry would opt to comply 
with proposed Sec.  211.94(e)(3), when finalized, through the use of 
locking valves or devices, which are less costly than silver brazing. 
As explained earlier in this document, records maintenance costs would 
be associated with these valves and devices and, thus, would be costs 
of compliance associated with proposed Sec.  211.94(e)(3). At an 
industrial manager's wage rate of approximately $53 per hour (including 
a 35 percent increase for benefits), FDA estimates that this proposed 
provision would result in a records maintenance compliance cost of 
approximately $54,000 per year for the entire industry (30,625 x 2 
mins. x [$53/60 mins.]).
6. Total Costs
    Individual cost elements of this proposed rule as well as total 
costs are shown in table 1 of this document.

                      Table 1.--Proposed Rule Costs
------------------------------------------------------------------------
     Cost Component           One-Time Cost         Annualized Cost\1\
------------------------------------------------------------------------
Brazing/locking of gas   $551,000                 $78,000
 use outlet connections
 for portable cryogenic
 medical gas containers
------------------------------------------------------------------------
360[deg] Wraparound      $138,000                 $20,000
 labels for portable
 cryogenic medical gas
 containers
------------------------------------------------------------------------
Painting high-pressure   $255,000 to $510,000     $36,000 to $73,000
 medical gas cylinders
 the standard industry
 color
------------------------------------------------------------------------
Records maintenance      N/A                      $54,000
------------------------------------------------------------------------
Total costs              $944,000 to $1,199,000   $188,000 to $225,000
------------------------------------------------------------------------
\1\Over 10 years at 7 percent discount rate.

C. Comparison of Costs and Benefits

    The estimated benefits of this proposed rule compare favorably to 
the estimated costs. The medical gas accident data noted earlier in 
this analysis show that these accidents have been claiming more than 
one life and two additional injuries per year. On average, the benefit 
of avoiding one statistical death per year is estimated at about $7 
million. The one-time costs of this proposed rule are expected to total 
from about $950,000 to $1.2 million. These costs (not including the 
records maintenance costs), when annualized over a 10-year period at 7 
percent, are estimated to range from about $134,000 to $171,000 per 
year. With the addition of annual records maintenance costs of 
approximately $54,000, the total annualized cost is estimated to be 
between $188,000 and $225,000. Average one-time establishment and firm 
costs would be expected to range from about $300 to $400 and $900 to 
$1,200, respectively. Even at an effectiveness rate of only about 10 
percent (or one death avoided every 10 years), the benefits of the 
proposed rule would still compare favorably with its costs.

D. Regulatory Flexibility Analysis

    The following analysis, along with other sections of this preamble, 
constitutes the regulatory flexibility analysis as required under the 
Regulatory Flexibility Act.
1. Need for and Objectives of the Rule
    The agency is proposing this rule to help prevent deaths and 
injuries from the improper use of medical gases. The rule is intended 
to dramatically lower the incidence of the types of potentially fatal 
medical gas mixups that have occurred in the past.
2. Description and Estimate of Small Entities
    This proposed rule would affect manufacturers and distributors of 
medical gases. The Small Business Administration (SBA) sets size limits 
for small businesses according to the North American Industrial 
Classification System (NAICS) business categories. Medical gas 
suppliers fall into the following categories:
     Small industrial gas manufacturers (NAICS code 325120) are 
those with less than 1,000 employees,
     Small home health care service companies (NAICS code 
621610) are those with less than $11.5 million in revenue,
     Small chemical and allied product wholesalers (NAICS code 
422690) are those with less than 100 employees, and
     Small home health equipment rental companies are those 
with less than $6 million in revenue.
    It can be difficult to assign a company to a single or primary 
NAICS code because of the similarities between NAICS categories and 
because companies often have product sales or service sales in more 
than one category. For example, home health care service firms and home 
health equipment rental firms are very similar and often have sales 
that fall into both categories. For purposes of this rulemaking, they 
have been assigned to one category, a combined home health care service 
and equipment rental companies category, with a small business limit of 
$11.5 million. This limit reflects the higher of the two applicable 
limits under the NAICS for home health care service firms and home 
health equipment rental firms, respectively.
    The 3,400 establishments on FDA's list of medical gas suppliers are 
operated by about 1,020 individual companies. A sample of the 
establishments run by these companies was taken to generate data to 
estimate the economic impacts on small businesses that would be imposed 
by this proposed rule. This sampling of the firms and their 
corresponding establishments shows the following: (1) Approximately 80 
percent of the firms (about 800) and 32 percent of the establishments 
(about 1,100) would be in the home health care service and equipment 
rental industry, (2) approximately 13 percent of the firms (about 130) 
and 67 percent of the establishments (about 2,300) would be in the 
industrial gas industry, and (3) approximately 6 percent of the firms 
(about 70) and 2 percent of the establishments (about 70) would be in

[[Page 18050]]

the chemical and allied products wholesale industry. Because of the 
small sample size, the true size of these categories may vary. In 
particular, the last category, which would include welding supply 
companies, may be substantially larger than the 6 percent of firms 
reported. A separate counting of welding firms in the database shows 
that they may represent over 15 percent of all registered medical gas 
firms.
    The 1997 Economic Census (the Census) (the last census for which 
detailed data are available) reports 118 industrial gas manufacturers 
with 643 establishments. About 10 of these manufacturers are reported 
to have more than 1,000 employees. Therefore, FDA estimates that about 
108 industrial gas manufacturers are small businesses according to the 
SBA criteria. For the chemical and allied products wholesale industry, 
the 1997 data show that the average establishment has less than 15 
employees. The data also show that none of these companies has more 
than 100 employees. FDA assumes, therefore, that all the companies in 
this category are small businesses according to the SBA criteria. The 
Census data show that only about 4 percent of the combined home health 
care equipment rental companies and home health care service companies 
would exceed the NAICS revenue criteria for small business inclusion. 
Therefore, FDA estimates that about 768 firms (800 firms x 96 percent) 
in this category are small businesses. In total, FDA estimates that 
about 950 of the 1,020 companies in the medical gas supply industry are 
small businesses according to the SBA criteria. If welding supply 
companies in fact do represent a significantly higher percentage of all 
firms than shown by our sample, FDA would expect that more than 950 of 
the 1,020 medical gas distributors would be small businesses. In either 
case, over 93 percent of the firms providing medical gases would be 
considered small businesses according to the SBA criteria.
3. Reporting, Recordkeeping, and Compliance Requirements
    The size of the compliance burden, as described previously in this 
document, would probably be smaller on a per establishment basis for 
those firms that are not categorized as industrial gas manufacturers or 
welding supply companies. Home health care service and equipment rental 
companies do not fill or distribute portable cryogenic medical gas 
containers to hospitals or nursing homes. To the agency's knowledge, 
the only cryogenic medical gas containers these firms would fill would 
be small cryogenic containers for use at home by individual patients. 
As discussed earlier in this document, these containers would not be 
subject to the requirements proposed for portable cryogenic medical gas 
containers in this rule. These proposed requirements comprise the 
majority of the estimated total compliance cost burden. While most 
industrial gas manufacturers were classified as small according to the 
SBA criteria, it is believed that all, or almost all, of these 
manufacturers would provide cryogenic gas filling services and would 
therefore incur a larger share of the compliance burden.
    The one-time compliance costs for all firms were previously 
reported to range, on average, from about $900 to $1,200 per firm. 
Average firm costs for small businesses would be expected to be 
slightly less than this average. However, even at the level described 
here, one-time compliance costs would represent the following: (1) Less 
than 0.01 percent of revenues for the average small industrial gas 
manufacturer, (2) about 0.03 percent of revenues for the average small 
chemical and allied product wholesaler, and (3) about 0.1 percent of 
revenues for the average small home health care service and equipment 
rental company. It is not likely that these amounts would create a 
significant impact on these small businesses. However, because we 
estimated average impacts across fewer than 1,000 small businesses, we 
cannot state with confidence that a substantial number of affected 
firms would not have impacts significantly higher than the average 
costs estimated. We request public comment and data on the industry 
sectors and impacts as discussed in this analysis.
4. Other Federal Rules
    FDA is not aware of any other Federal rules that overlap, 
duplicate, or conflict with the proposed rule.
5. Alternative Policies
    Alternative policies were considered during the development of this 
proposed rule. One alternative would have been to require that all 
high-pressure medical gas cylinders and portable cryogenic medical gas 
containers be physically separated on delivery trucks according to the 
specific medical gas each contained. The purpose of this requirement 
would have been to further reduce the risk of accidental mixups between 
containers containing different industrial and medical gases. This 
alternative would, however, be expected to greatly reduce delivery 
truck capacity and productivity. To promote efficiency, medical gas 
cylinders and containers are currently loaded onto delivery trucks in 
the order they are received from customers along the trucks' delivery 
routes, without regard to the type of gas being loaded. Further, 
requiring the physical separation of gas containers on delivery trucks 
would necessitate additional container handling by personnel during the 
delivery process, thereby potentially increasing the risk of human 
handling errors, such as errors in medical gas identification. FDA 
believes that, on the whole, this alternative would impose greater 
annual compliance costs without significantly reducing the risk of 
accidents beyond those reductions provided by the provisions of the 
proposed rule. Therefore, it was not included in this proposal.
    Another option would have been to delete the general warning 
statement that is currently required to appear on the labeling of 
certain medical gases under Sec.  201.161(a)(1)\18\ and require instead 
that each such gas be labeled with a gas-specific statement of 
warnings. However, the agency could not identify any accidents or other 
problems that could be directly traced to a misunderstanding of the 
general warning statement currently in effect. Additionally, the 
current warning statement has the advantage of being familiar and well-
established. Allowing manufacturers to create differing warning 
statements specific to each medical gas could cause identical gases 
from different manufacturers to have different warnings and result in 
unnecessary confusion for medical gas users. For both of these reasons, 
this option was not included in the proposed rule.
---------------------------------------------------------------------------

    \18\ This warning statement reads: ``Warning--Administration of 
(name of gas) may be hazardous or contraindicated. For use only by 
or under the supervision of a licensed practitioner who is 
experienced in the use and administration of (name of gas) and is 
familiar with the indications, effects, dosages, methods, and 
frequency and duration of administration, and with the hazards, 
contraindications, and side effects and the precautions to be 
taken.''
---------------------------------------------------------------------------

    A third option would have been to require that the shoulders of 
portable cryogenic medical gas containers be painted the appropriate 
standard color designated in proposed Sec.  211.94(e)(5). This 
alternative was not adopted because the proposed alternative of 
requiring a 360[deg] wraparound label was deemed appropriate to ensure 
the easy identification of medical gases stored in portable cryogenic 
containers. Further, as discussed earlier in this document, these 
containers are currently rarely painted. Rather, most of industry has 
been identifying medical gases stored in these containers using 
360[deg] wraparound

[[Page 18051]]

labels instead. Accordingly, compliance costs would be expected to be 
relatively greater if FDA pursued the alternative of requiring that 
portable cryogenic medical gas containers be colored.
    The final alternative would have been to exempt small businesses 
from this proposed rule. However, this option would present greater 
risks to the public health and nullify most of the rule's expected 
effects. As noted previously in this document, using the SBA criteria 
for identifying small businesses in the relevant industry categories, 
FDA estimates that about 950 of the 1,020 firms that would be subject 
to this rule, or about 93 percent, would be considered small 
businesses. Accordingly, if small businesses were exempted from the 
rule, it would be too limited in scope to effectively reduce the risk 
of medical gas mixups. Moreover, FDA believes that the expected costs 
of compliance with the proposed rule, discussed earlier in this 
document, are low and not sufficient to warrant a small business 
exemption. Therefore, no such exemption was adopted as part of the 
proposed rule.

V. Paperwork Reduction Act of 1995

    This proposed rule contains collection of information requirements 
that are subject to review by OMB under the Paperwork Reduction Act of 
1995 (the PRA) (44 U.S.C. 3501-3520). Collections of information 
include any request or requirement that persons obtain, maintain, 
retain, or report information to the agency, or disclose information to 
a third party or to the public (44 U.S.C. 3502(3) and 5 CFR 1320.3(c)). 
The information collection requirements included in this proposed rule 
are described in this section of the preamble with an estimate of the 
annual reporting burden. Included in the estimate is the time for 
reviewing instructions, gathering and maintaining the data needed, and 
completing and reviewing each collection of information.
    FDA invites comments on the following topics: (1) Whether the 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden created by 
the collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Medical Gas Containers and Closures; Current Good 
Manufacturing Practice Requirements.
    Description: FDA is proposing requirements for medical gases to 
help prevent deaths and serious injuries that can result from the 
improper use of such products. The proposed rule would revise FDA's 
CGMP regulations and other regulations to include new requirements for 
the label, color, dedication, and design of medical gas containers and 
closures. Among other proposed requirements, Sec.  211.94(e)(4)(i) 
would require that portable cryogenic containers used to hold medical 
gases be conspicuously marked with a 360[deg] wraparound label. 
Additionally, proposed Sec.  211.94(e)(3) would require that portable 
cryogenic medical gas containers that are not manufactured with 
permanent gas use outlet connections be equipped with connections that 
are secured to the container using a locking device or other method 
that ensures that the connection cannot be readily removed or replaced 
except by the manufacturer.
    Description of Respondents: Persons and businesses, including small 
businesses and manufacturers.
    Burden Estimates: The total annual reporting and recordkeeping 
burden is estimated to be 4,070 hours. Table 2 of this document 
provides estimates of the annual reporting burden under the proposed 
rule. Table 3 of this document provides estimates of the annual 
recordkeeping burden.
    Proposed Sec.  211.94(e)(4)(i) would require that each portable 
cryogenic container used to hold medical gases be marked with a 
360[deg] wraparound label identifying the container's contents. FDA's 
database of establishments that manufacture medical gases includes 
about 3,400 such establishments. As discussed in section IV.B.1 of this 
document, we estimate that there are approximately 306,000 portable 
cryogenic containers in distribution that would be subject to the 
proposed 360[deg] wraparound label requirement. FDA estimates that 
approximately 90 percent of these containers have already been marked 
with such a label. Thus, on average, each manufacturer would need to 
put labels on approximately nine containers ([306,000 / 3,400] - [.9 x 
(306,000 / 3,400]). FDA estimates that approximately 6 minutes would be 
required to attach a label to each container. Thus, the total burden 
hours associated with proposed Sec.  211.94(e)(4)(i) would be 
approximately 3,060 hours (3,400 x 9 x .10 hours).
    Under proposed Sec.  211.94(e)(3), medical gas manufacturers that 
use portable cryogenic medical gas containers that are not manufactured 
with permanent gas use outlet connections would be required to use a 
locking device or other method to ensure that the gas use outlet 
connection on the container cannot be readily removed or replaced 
except by the manufacturer. As noted earlier in this document, the 
locking device or other method used would be considered part of the 
container closure, and manufacturers would be required to maintain 
records in accordance with Sec.  211.184 for such articles. This would 
result in a slight increase in the recordkeeping burden under Sec.  
211.184 for medical gas manufacturers.
    The burdens for maintaining records under Sec.  211.184 have 
previously been estimated by FDA, and this collection of information 
was approved by OMB until August 31, 2005, under OMB control number 
0910-0139. FDA is not re-estimating approved burdens in this 
rulemaking. Only the additional recordkeeping burdens on medical gas 
manufacturers under Sec.  211.184 that are associated with proposed 
Sec.  211.94(e)(3) are estimated in table 3 of this document.
    As discussed in section IV.B.1 of this document, FDA estimates that 
90 percent of the roughly 306,000 portable cryogenic medical gas 
containers that would be subject to proposed Sec.  211.94(e)(3) (.9 x 
306,000 = 275,400) already comply with this proposed provision. The 
agency therefore expects that approximately 30,600 portable cryogenic 
containers (306,000-275,400) would need to be brought into compliance 
with the provision when it is finalized. As explained earlier in this 
document, with respect to these 30,600 containers, FDA expects that 
manufacturers will elect to use locking devices or other articles that 
would be considered drug product container closures to achieve 
compliance with proposed Sec.  211.94(e)(3). Accordingly, these 30,600 
portable cryogenic medical gas containers would be subject to 
additional records maintenance requirements under Sec.  211.184. As 
discussed previously in this document, FDA estimates additional time of 
approximately 2 minutes (2 mins. / 60 mins. per hour = .033 hours) per 
container per year will be needed to maintain records under Sec.  
211.184 for portable cryogenic medical gas containers as a result of 
proposed Sec.  211.94(e)(3). Therefore, the total additional 
recordkeeping burden resulting from proposed Sec.  211.94(e)(3) would 
be approximately 1,010 hours

[[Page 18052]]

(30,600 containers x .033 hours) per year.
    FDA estimates the burden for the collection of information as 
follows:

                                                       Table 2.--Estimated Annual Reporting Burden
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                          No. of         Annual Frequency  of      Total Annual         Hours per
                  21 CFR Section                       Respondents             Response             Responses           Response          Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
211.94(e) (4)(i)(labeling--third party disclosure)              3,400                        9             30,600                 .10              3,060
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                               .................  .......................  .................  ..................              3,060
--------------------------------------------------------------------------------------------------------------------------------------------------------


                                                   Table 3.--Estimated Annual Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                          No. of         Annual Frequency of       Total Annual
                  21 CFR Section                      Recordkeepers         Recordkeeping            Records        Hours Per  Record     Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
211.184                                                         3,400                        9             30,600                .033              1,010
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                               .................  .......................  .................  ..................              1,010
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\Capital, operating, and/or maintenance costs associated with this proposed rulemaking are estimated in section IV of this document.

    In compliance with section 3507(d) of the Paperwork Reduction Act 
of 1995 (44 U.S.C. 3507(d)), the agency has submitted the information 
collection provisions of this proposed rule to OMB for review. 
Interested persons are requested to send comments regarding this 
information collection to the Office of Information and Regulatory 
Affairs, OMB.
    The Office of Management and Budget (OMB) is still experiencing 
significant delays in the regular mail, including first class and 
express mail, and messenger deliveries are not being accepted. To 
ensure that comments on the proposed information collection 
requirements are received, OMB recommends that written comments be 
faxed to the Office of Information and Regulatory Affairs, OMB, Attn: 
Fumie Yokota, Desk Officer for FDA, FAX: 202-395-6974.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Effective Date

    FDA proposes that any final rule based on this proposal become 
effective 60 days after publication in the Federal Register. Because 
the proposed requirements have largely already been adopted as standard 
industry practice, the agency believes that it would be reasonable to 
implement the final rule as rapidly as possible.

VIII. Federalism

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

IX Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit written comments regarding information collection to OMB (see 
ADDRESSES). Submit a single copy of electronic comments or two paper 
copies of any mailed comments, except that individuals may submit one 
paper copy. Comments are to be identified with the docket number found 
in brackets in the heading of this document. Received comments may be 
seen in the Division of Dockets Management between 9 a.m. and 4 p.m., 
Monday through Friday.

List of Subjects

21 CFR 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR 211

    Drugs, Labeling, Laboratories, Packaging and containers, 
Prescription drugs, Reporting and recordkeeping requirements, 
Warehouses.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and 
authority delegated to the Commissioner of Food and Drugs, FDA proposes 
to amend 21 CFR parts 201 and 211 as follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
    2. Section 201.161 is amended by revising the section heading and 
the introductory text of paragraph (a) to read as follows:


Sec.  201.161  Medical gases.

    (a) Medical air, oxygen, nitrogen, carbon dioxide, 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, 
where applicable, the requirements of Sec.  211.94(e)(4) of this 
chapter are met and the labeling bears, in addition to any other 
information required by the Federal Food, Drug, and Cosmetic Act, the 
following:
* * * * *

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED 
PHARMACEUTICALS

    3. The authority citation for 21 CFR part 211 continues to read as 
follows:

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

[[Page 18053]]

    4. Section 211.94 is amended by adding paragraph (e) to read as 
follows:


Sec.  211.94  Drug product containers and closures.

* * * * *
    (e) Medical gas containers and closures must meet the following 
requirements:
    (1) Except as provided in paragraph (e)(2) of this section, 
cryogenic containers or high-pressure cylinders used at any time to 
hold a liquid or compressed industrial gas may not be subsequently used 
to hold any type of liquid or compressed medical gas.
    (2) The prohibition in paragraph (e)(1) of this section does not 
apply to any cryogenic container or high-pressure cylinder that was 
once used to hold a liquid or compressed industrial gas if the 
container or cylinder:
    (i) Was converted to use for holding a liquid or compressed medical 
gas in accordance with standard industry practice before [effective 
date of final regulation]; and
    (ii) Is used solely to hold a liquid or compressed medical gas on 
and after [effective date of final regulation] and is in compliance 
with all other applicable requirements.
    (3) Portable cryogenic medical gas containers that are not 
manufactured with permanent gas use outlet connections (e.g., those 
that have been silver-brazed) must have gas-specific use outlet 
connections that are attached to the valve body so that they cannot be 
readily removed or replaced (without making the valve inoperable and 
preventing the containers' use) except by the manufacturer. For the 
purposes of this paragraph, the term ``manufacturer'' includes any 
individual or firm that fills high-pressure medical gas cylinders or 
cryogenic medical gas containers by any of the following methods: 
Liquid to liquid, liquid to gas, or gas to gas. For the purposes of 
paragraphs (e)(3) and (e)(4) of this section, a ``portable cryogenic 
medical gas container'' is one that is capable of being transported and 
is intended to be attached to a medical gas supply system within a 
hospital, health care entity, nursing home, other facility, or home 
health care setting. The term does not include small cryogenic gas 
containers for use by individual patients or portable liquid oxygen 
units when distributed empty, as defined at Sec.  868.5655 of this 
chapter.
    (4) Label and color requirements. (i) Each portable cryogenic 
medical gas container must be conspicuously marked with a 360[deg] 
wraparound label identifying its contents.
    (A) The label must identify the medical gas held in the container 
by the gas' standard name, as designated in paragraph (e)(5) of this 
section.
    (B) The standard name must be printed on the label in one of the 
following ways:
    (1) Using lettering that appears in the standard color designated 
for the gas in paragraph (e)(5) of this section and that is printed 
against a white background, or
    (2) Using lettering that appears in white against a background that 
is painted in the standard color for the gas as designated in paragraph 
(e)(5) of this section.
    (C) The lettering for the name of the gas on the label must be at 
least 2 3/4 inches high.
    (D) The name of the gas must be printed continuously around the 
label and be capable of being read around the entire container.
    (E) The label must be on the sidewall of the container, as close to 
the top of the container as possible but below the top weld seam.
    (F) The label must be affixed to the container so that it cannot be 
easily detached or worn, and in a manner that does not interfere with 
other labeling.
    (G) If the shoulder portion of a portable cryogenic medical gas 
container is colored, the color used must be that designated in 
paragraph (e)(5) of this section for the gas held within the container.
    (ii) High-pressure medical gas cylinders must be identified with 
FDA-designated standard colors according to the following:
    (A) Non-aluminum high-pressure medical gas cylinders must be 
colored in whole in the standard color designated in paragraph (e)(5) 
of this section for the gas contained in the cylinder.
    (B) Aluminum high-pressure medical gas cylinders must be colored on 
the shoulder portion of the cylinder in the standard color designated 
in paragraph (e)(5) of this section for the gas contained in the 
cylinder.
    (C) The materials used for coloring must be reasonably resistant to 
fading, durable when exposed to atmospheric conditions, and not readily 
soluble in water after they have been applied and properly dried or 
cured.
    (D) High-pressure medical gas cylinders containing a blend or 
combination of medical gases must be colored with the standard colors 
of each component gas, as designated in paragraph (e)(5) of this 
section. Each such color must be visible when viewed from the top of 
the cylinder and must appear in rough proportion to the fraction of the 
gas it represents in the combination or mixture.
    (5) The standard names and colors required to identify medical 
gases under paragraph (e)(4) of this section are:

------------------------------------------------------------------------
             Standard Name                       Standard Color
------------------------------------------------------------------------
Medical Air                             Yellow
------------------------------------------------------------------------
Medical Carbon Dioxide                  Gray
------------------------------------------------------------------------
Medical Helium                          Brown
------------------------------------------------------------------------
Medical Nitrogen                        Black
------------------------------------------------------------------------
Medical Nitrous Oxide                   Blue
------------------------------------------------------------------------
Medical Oxygen                          Green
------------------------------------------------------------------------
Mixture or Blend of Medical Gases       Standard colors for each
                                         component
------------------------------------------------------------------------

    5. Section 211.125 is amended by adding a sentence to the end of 
paragraph (c) to read as follows:


Sec.  211.125  Labeling issuance.

* * * * *
    (c) * * * Labeling reconciliation is also waived for 360[deg] 
wraparound labels on portable cryogenic medical gas containers.

    Dated: November 21, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-3370 Filed 4-7-06; 8:45 am]
BILLING CODE 4160-01-S