[Federal Register: April 10, 2006 (Volume 71, Number 68)]
[Proposed Rules]
[Page 18039-18053]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr10ap06-17]
[[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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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:
Duane.Sylvia@FDA.HHS.GOV.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
A. Need for Revised Regulations
1. Incidents Involving Portable Cryogenic Containers
2. Incidents Involving High-Pressure Medical Gas Cylinders
B. Current Regulatory Requirements and Recommendations for Medical
Gas Containers and Closures
II. Description of Proposed Requirements
A. Revisions to Labeling Exemptions
B. Revised Requirements for Medical Gas Containers and Closures
1. Prohibition on Conversion of Cryogenic Containers and High-
Pressure Cylinders From Industrial to Medical Use
2. Requirements for Secure Gas Use Outlet Connections on Portable
Cryogenic Medical Gas Containers
3. Requirement for 360[deg] Wraparound Label for Portable Cryogenic
Medical Gas Containers
4. Requirement to Color High-Pressure Medical Gas Cylinders
III. Legal Authority
IV. Analysis of Impacts
A. Benefits
B. Costs
1. Brazing or Locking of Gas Use Outlet Connections on Portable
Cryogenic Medical Gas Containers
2. 360[deg] Wraparound Label for Portable Cryogenic Medical Gas
Containers
3. Painting of High-Pressure Medical Gas Cylinders
4. Prohibition of Container Use for Both Industrial and Medical
Purposes
5. Records Maintenance
6. Total Costs
C. Comparison of Costs and Benefits
D. Regulatory Flexibility Analysis
1. Need for and Objectives of the Rule
2. Description and Estimate of Small Entities
3. Reporting, Recordkeeping, and Compliance Requirements
4. Other Federal Rules
5. Alternate Policies
V. Paperwork Reduction Act of 1995
VI. Environmental Impact
VII. Effective Date
VIII. Federalism
IX. Request for Comments
I. Background
A. Need for Revised Regulations
FDA is proposing to add requirements to its CGMP regulations to
address repeated incidents of medical gasmixups (e.g., the
inappropriate administration of an industrial gas to a patient intended
to receive a medical gas) and medical gas contamination that have
resulted in serious patient injuries and even deaths. As explained in
this document, FDA believes that the number of such incidents will be
reduced by implementation of the medical gas label, color, design, and
dedication requirements proposed in section II.B of this document.
Between 1996 and April 2004, FDA received several reports of
medical gas mixups that resulted in at least 8 patient deaths and 16
serious patient injuries. Because nursing homes and hospitals are not
required to report adverse events associated with medical gas mixups to
FDA, it is likely that the actual number of these events exceeds the
number reported. The reports FDA has received involve two major types
of containers in which medical gases are currently stored, portable
cryogenic containers and high-pressure medical gas cylinders.
1. Incidents Involving Portable Cryogenic Containers
Portable cryogenic containers are used to store gases in liquid
form at extremely low temperatures and pressures. These containers are
made of stainless steel and are double-walled and vacuum-insulated to
minimize the evaporation and venting of their contents. FDA is aware of
at least 7 deaths and 12 serious injuries that occurred between 1996
and April 2004
[[Page 18040]]
in connection with mixups of gases stored in portable cryogenic
containers. Each of these incidents involved the improper connection of
a portable cryogenic container holding an industrial gas to a health
care facility's oxygen supply system.
Portable cryogenic gas containers have gas-specific use outlet
connections that are used to connect the containers to supply systems.
Oxygen supply systems are compatible only with gas use outlet
connections designed for portable cryogenic containers holding oxygen.
In each of the incidents of which FDA is aware, described in more
detail in the following paragraphs, the person making the faulty
connection to the health care facility's oxygen supply system: (1) Did
not check the label on the portable cryogenic container that was
inappropriately connected or was not otherwise able to verify the
container's contents and (2) was able to readily remove the oxygen-
specific gas use outlet connection from an empty medical oxygen
container and use it to inappropriately connect the industrial gas
container to the supply system.
On December 7, 2000, four patients in a Bellbrook, Ohio, nursing
home died and six were injured after being administered industrial
nitrogen instead of oxygen. The nursing home had received a shipment of
four portable cryogenic medical gas containers. Each was labeled
medical oxygen, but one of the containers also bore an industrial
nitrogen label that partially obscured the medical oxygen label and was
filled with industrial nitrogen instead. When asked to select a new
oxygen container, a nursing home employee mistakenly selected the
nitrogen container. The employee was initially unable to connect the
container to the oxygen supply system because the container's nitrogen-
specific gas use outlet connection was incompatible with the connector
on the oxygen supply system. However, the employee ultimately made the
fatal connection by removing an oxygen-specific gas use outlet
connection from an empty portable cryogenic medical oxygen container
and by substituting it for the nitrogen-specific connection on the
industrial nitrogen container.
On April 22, 1998, a portable cryogenic container of industrial
nitrogen was improperly connected to the oxygen supply system for the
operating rooms, labor and delivery rooms, and emergency room in an
Idaho hospital. The connection was enabled when the supplier's truck
driver used a wrench to disconnect the container's existing nitrogen
gas use outlet connection, which was incompatible with the hospital's
oxygen supply system, and replaced it with a compatible oxygen gas use
outlet connection. Two patients died after receiving nitrogen through
this misconnection.
On October 14, 1997, a hospital in Nebraska received a shipment of
medical oxygen in portable cryogenic containers. The shipment included
one portable cryogenic container of industrial argon. The hospital was
running low on oxygen and sent a maintenance employee to connect an
oxygen container to the oxygen supply system. Although it was properly
labeled, the employee selected the argon container without examining
its label. When he was unable to connect the container to the oxygen
supply system, the employee removed an oxygen gas use outlet connection
from an empty portable cryogenic medical gas container, installed it in
place of the argon gas use outlet connection on the industrial argon
container, and connected the argon container to the oxygen supply
system. Argon was administered to a patient undergoing minor surgery
who died as a result of this mixup.
On December 2, 1996, nine patients in a children's home in New York
experienced adverse reactions after inhaling carbon dioxide in a
medical gas mixup. Two of the patients were injured critically and four
patients experienced varying stages of respiratory distress following
this mixup. The mixup resulted when an employee of the home mistakenly
attached a carbon dioxide container to the home's oxygen supply
system.After noting that the gas use outlet connection on the carbon
dioxide container was not compatible with the connector on the oxygen
supply system, the employee removed a gas use outlet connection from an
empty medical oxygen container, installed it on the carbon dioxide
container, and attached the carbon dioxide container to the home's
oxygen supply system.
In addition to the deaths and serious injuries described earlier in
this preamble, FDA is aware of other serious cases of medical gas
mixups involving portable cryogenic containers. For example, on
December 19, 2000, a mixup occurred in a hospital in Arizona. A
ventilator alarm sounded during a surgical procedure, and the
anesthesiologist quickly removed the ventilator after noticing that the
patient's oxygen saturation level was decreasing. An investigation
revealed that a portable cryogenic container of industrial nitrogen had
been mistakenly connected to the hospital's oxygen supply system. To
make the connection, the nitrogen tank's original gas use outlet
connection was removed and replaced with an oxygen-specific gas use
outlet connection. Although the anesthesiologist's quick response
avoided patient injury in this instance, the mixup was caused by events
that have resulted in death and serious injury in other cases, such as
the ones previously discussed.
FDA anticipates that mixups like those described earlier in this
document will be largely averted if: (1) Users can more readily
identify portable cryogenic containers that contain medical gases and
(2) the gas use outlet connections on these containers cannot be
readily removed by persons other than the manufacturers responsible for
filling them. As detailed in section II.B of this document, FDA is
proposing requirements to achieve these effects. As further discussed
in section I.B of this document, the proposed requirements are intended
to supplement existing CGMP requirements and related agency guidance
and industry recommendations regarding the safe use of medical gases.
Existing agency requirements and guidance already address appropriate
education and training for persons responsible for connecting portable
cryogenic containers to medical gas systems (e.g., training such
persons to check the containers' labels and to understand that the
containers' gas-specific use outlet connections are safeguards against
mixups and that they are not to be removed.)\1\
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\1\ See 21 CFR 211.25(a). The agency's draft guidance for
industry on ``Current Good Manufacturing Practice for Medical
Gases'' (66 FR 24005, May 6, 2003) and its ``Guidance for Hospitals,
Nursing Homes, and Other Health Care Facilities--FDA Public Health
Advisory'' (66 FR 18257, April 6, 2001), both discussed in section
I.B. of this document, contain specific recommendations for, among
other things, the appropriate education and training of health care
facilities' and medical gas manufacturers' employees who are
involved in handling medical gases and their containers. These
guidances are available on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cdrh/safety/medical-gas-misconnect.html.
Additional information on
this subject may be accessed on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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.
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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).
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\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).
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\15\ Estimate provided to FDA by a major consulting firm for
medical gas companies.
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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