On April 10th of this year, the Food and Drug Administration issued a set of proposals on regulations intended to augment the good manufacturing practices that currently cover portable cryogenic medical gas containers and high-pressure medical gas cylinders. As is the FDA's practice, comments on the proposal are being solicited for 90 days.
The need for the added rules is long overdue, as they deal directly with problems that have led to severe injury and death for patients who were to receive medical oxygen, yet were subjected accidentally to gases such as industrial nitrogen, argon and CO 2 . The accidents were not all a matter of installing the wrong bottle. There were occasions where persons replacing a gas bottle had difficulty matching the fitting on a new bottle to the line, so their solution was to swap fittings from an old cylinder. In other cases, the fault was not in installing the wrong bottle, but rather supplying medical grade gases in a cylinder previously used for industrial gas and improperly cleaned, leaving behind traces of harmful substances.
Already on the books
The FDA regards medical gas containers as integral parts of the drug product, ensuring that the drug product provided to a patient has the appropriate identity, strength, quality and purity. All medical gases (oxygen, United 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), including those produced by an air liquefaction process 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).
FDA regulations under Sec. 211 that currently address the safety of medical gas containers and closures are extensive, and address container quality, inspection of containers and contents, labeling and requirements for personnel handling medical gas manufacture. The rules also make recommendations for container fill and storage space, to prevent mix-ups with industrial containers. The FDA rules do not cover configuration of outlet connections on containers; however, the agency acknowledges within the proposal that manufacturers "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." The agency then notes that such connections "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."
An overview of the proposals
To reduce the number of incidents caused by mix-ups and contamination of medical gases, the FDA proposes, first, changes in the labeling of medical gas containers. Section 201.100 (21 CFR 201.100) of the Federal Food, Drug, and Cosmetic Act lists conditions that, if all are met, exempt prescription drug products from the act's requirement that their labeling bear extensive directions for use. Several medical gases have the same exemption. The regulations state that carbon dioxide, cyclopropane, ethylene, helium, and nitrous oxide gases intended for drug use are exempted from the extensive labeling requirements provided that their labels have the following:
- The complete information already required by the regulations.
- A specific set of warnings that say the gases are to be used by experienced and licensed practitioners only.
- Specific directions concerning the individual gas's conditions of storage.
- And, warnings against the dangers that are inherent in the gas's handling.
The agency suggests additional compliance with the labeling warnings is unnecessary for medical air, oxygen and nitrogen if the all past and proposed warning and direction requirements are met. In addition, the FDA proposes to remove cyclo-propane and ethylene from Sec. 201.161(a), since these flammable gases are no longer used in medical procedures.
Proposed regulation Sec. 211.94(e)(4)(i) would require each portable cryogenic medical gas container to be conspicuously marked with a wraparound label that identifies its contents. Containers subject to this requirement would not include small cryogenic units for use by individual patients in their homes, or portable liquid oxygen units intended to be distributed empty. Additionally, the labels would have to be printed with an FDA-designated standard name for the medical gas contained in the cylinder, and the lettering for the standard name would have to appear in either an FDA-designated standard color against a white background, or in white against an FDA-designated color background. The color coding is one of the keys to the proposed changes in the regulations.
Besides improving labels for cylinders, Sec. 211.94(e)(5) would require non-aluminum, high-pressure medical gas cylinders to be colored completely in the designated standard color for the gas contained in the cylinder. Those cylinders would be required to be colored only on the shoulder portions, because the bodies of aluminum high-pressure medical gas are coated with a thermal indicator that changes color when the cylinders have been exposed to fire.
Standard names and colors are listed in Table 1. All the standard names are to include the word "medical'' to distinguish containers labeled with these names from those holding industrial gases.
The proposed regulations [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 attached to the valve body in such a way that they cannot be readily removed or replaced except by the medical gas manufacturer. Included would be all cryogenic medical gas containers that are both capable of being transported and intended to be attached to a medical gas supply system within specific medical facilities or home health care settings, except small cryogenic containers for use by individual patients in their homes and portable liquid oxygen units that are intended to be distributed empty. This proposed requirement would not apply to high-pressure medical gas. The Compressed Gas Association's safety bulletin SB-26 already advises, in part, that outlet connections on cryogenic medical gas containers be affixed using either silver brazing or another method that prevents their removal. Moreover, this bulletin advises that outlet connections on cryogenic industrial gas containers be used with a device that deters the connections' removal, and provides indication that removal was attempted.
Finally, the 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. The 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. 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.
The FDA estimated that its proposed rule changes would result in an annualized cost to small businesses equivalent to 0.1 percent of their revenues or less. The agency believes that the changes are unlikely to have a significant economic impact on a substantial number of small entities; however, the FDA admits 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. Still, the agency expresses confidence that even a small cost "will be justified by the lives saved and injuries prevented."
The FDA notes in several sections expenses associated with the changes would be further lessened because several of the proposals already are used as procedures at many medical gas manufacturer and distributor facilities. For example, Mike Miller at Mittler Supply, Inc., a supplier of industrial, specialty and medical gases in Michigan, Indiana and Illinois, comments that his company has been welding connectors onto medical cylinders for years, as well as using color codes and other techniques to keep medical containers separate from other product.
To examine the proposed rule in detail, go to http://www.fda.gov and type "2005N-0437" in the Search box in the upper left corner of the page. Comments on the proposal will be accepted until July 10, 2006.
|Table 1 - Standard names and identifying container colors for medical gases|
|Standard Name||Standard Color|
|Medical Carbon Dioxide||Gray|
|Medical Nitrous Oxide||Blue|
|Mixture or blend of medical gases||Standard colors for each component|
Photo courtesy of Mittler Supply Inc. (www.mittler.com)