The latest on the big three: 1) draft cGMP Guidance; 2) the April 2006 proposed rule on Medical Gas Labeling and Medical Gas Containers and Closures; and 3) the recent FDA and NIOSH public health notification for oxygen regulator fires resulting from incorrect use of CGA 870 seals issued on April 24, 2006, and revised on June 19.

Although the long-awaited Good Manufacturing Practice (GMP) for Medical Gases Guidance, issued in draft form for comment in May 2003, has still not been issued in its final form at press time, there has been significant FDA activity impacting home respiratory care companies. When the cGMP regulations were published in 1978, the FDA acknowledged that medical gases did not fit the typical pharmaceutical mold in many respects. In the preamble to the final rule almost three decades ago, the agency announced that it intended to develop specific regulations for this segment of the drug industry. In the interim, the FDA published a medical gases guidance document in June 1981 that was then revised in December 1983.  

In February 1989, the guidance was updated again, primarily to provide the home respiratory industry with an acceptable means to comply with the cGMP for liquid oxygen filling and distribution operations. Although no new official medical gas guidance has been published since 1989, several papers titled “Fresh Air” were published in the 1990s.

In 2003, the FDA published a draft of its latest cGMP Guidance for Medical Gases. A significant difference between this draft guidance and previous guidance is that this draft offers agency “recommendations” as opposed to listing acceptable means to comply with certain sections of the cGMP. In the industry’s opinion, this language may confer greater authority to the agency “recommended” practice vs alternate compliant approaches that firms may use. This will require firms to defend their rationale for using an alternate method during an agency inspection. Another difference is the agency’s extensive use of paraphrasing of the cGMP regulations, which in the industry’s opinion blurs the differences between guidance and requirements. This is of special concern in those areas where medical gases do not fit the typical pharmaceutical mold. The agency has indicated in meetings (after industry submitted its comments) that they do not intend to modify the “recommendation” language or use of paraphrasing.

Two major issues still being worked on are expiration dating related to agency concerns about leakage, and validation of the long-standing industry practice of evacuating high-pressure cylinders to 25 inches of mercury as a means to remove residual gases prior to filling. The Compressed Gas Association (CGA) submitted a Citizens Petition to exempt medical gases from the requirement of expiration dating when the cGMP regulations were published in 1978. CGA then conducted a study in support of its petition in the early 1980s and submitted the data in 1994 showing that common medical gases do not degrade over time.

Although the agency has acknowledged that gases studied in steel cylinders did not degrade, they have recently raised a concern with cylinders leaking over time. They also raised concerns that the CGA studies did not include aluminum or composite cylinders commonly used in home care and did not identify the cylinder valve materials.

The draft guidance requires that medical gases bear an expiration date, that the date be based on stability studies conducted in the type of container with the type of valve that the gas is sold in, and that a copy of the studies be maintained by the filling firm. CGA and AAHomecare have had several discussions with FDA on this topic, and CGA has proposed a plan to conduct the testing in an attempt to satisfy the agency’s concerns. The agency has not yet approved the plan submitted in 2005.

Although evacuating cylinders to 25 inches of mercury has been a long-standing and even agency-accepted practice, the FDA indicated in the draft guidance that they expected each cylinder-filling firm to validate their process to assure all potential cylinder contaminants were removed. Industry experts commented that other prefill inspections were used to determine the presence of contaminants. Industry further commented that evacuation was never intended to remove all contaminants but was designed to remove a sufficient amount of residual product so that, when the cylinder was filled, the resulting percentage of the product in the cylinder would not be significantly different from the percentage of the supply gas used.  AAHomecare is conducting the vacuum evacuation validation of the 25-inch level for oxygen-filling operations. The agency has agreed that this study, when completed, will be permitted to be used by any operation filling oxygen cylinders provided the study confirms the long-standing practice.

Industry associations provided the FDA with general and detailed comments and recommendations to revise the draft. AAHomecare alone proposed more than 100 detailed changes. AAHomecare’s comments expressed concern with the agency recommendation regarding the Quality Control Unit, equipment and cylinder cleaning and maintenance recommendations, production and testing control recommendations, and the increase in record keeping associated with them.

FDA indicated to AAHomecare that “more than 95%” of comments are being accepted, but we are not sure how they have been accepted. The HME industry is also concerned with the comments that have not been accepted and curious as to the agency’s rationale for not accepting them. AAHomecare and other industry associations have requested the agency to republish a second draft of the guidance based on the changes; however, the agency has not committed to doing so, and has stated that they are not required to republish a second draft prior to issuing a final guidance. Stay posted on the status of the Medical Gases Guidance by checking the FDA Web site and the AAHomecare Web site at http: //www.aahomecare.org.

Medical Gas Proposed Rule
On April 10, 2006, the FDA published a notice of proposed rule making (NPRM) in the Federal Register. The NPRM included proposed changes to medical gas labeling regulations, proposed regulations to prohibit converting cylinders from industrial to medical gas service, requiring large cryogenic containers to have permanent connections, 360-degree wraparound labels, and color coding cylinders.

The HME industry supports adding oxygen to the list of gases that are exempt from certain prescription drug labeling requirements. However, there are concerns that the proposed rule also had the potential to require changing every oxygen label on every high-pressure cylinder (including aluminum cylinders with labels that may be under a protective coating) and every liquid oxygen home unit. The proposal would also eliminate the ability of first responders to administer oxygen without a doctor’s prescription. Industry has commented back to this proposed rule with recommendations to allow the current wording for oxygen to continue to be used, including continuing the provision for emergency use without a prescription.

Even though most home care companies use only medical gas containers, the NPRM proposal prohibiting the conversion of cylinders from industrial gas service to medical gas service has the potential to require home care companies to generate and maintain paperwork and systems to prove, throughout the life of a container, that it was never in industrial service. Industry commented that it is opposed to this proposal and that the focus of any proposed regulation should be to assure whenever a cylinder changes service that proper conversion systems and procedures be utilized.

Industry is supportive of the proposal to require “permanent” gas outlet connections on large cryogenic containers and commented to the agency that the proposal should extend to the liquid fill/withdrawal and vent connections as well. AAHomecare commented that the definition of large cryogenic containers should exclude small cryogenic gas containers designed for use by patients at their residence, even if those vessels are used in health care facilities. Industry is also generally supportive of the proposal to require 360-degree wraparound labels on large cryogenic containers to assist with product identification. Industry commented in opposition to some of the prescriptive requirements of the wraparound label proposals, such as a requirement for larger than standard letter height, the use of a “standard name,” and label placement “so that it cannot be easily worn.”

FDA and NIOSH Public Health Notification
On April 24, 2006, FDA and NIOSH issued a public health notification attributing oxygen regulator fires to the incorrect use of certain seals at the cylinder valve/regulator interface. All of the incidents occurred with cylinders and regulators associated with emergency medical use and not with cylinders used in a hospital or home setting. Unfortunately, the agency did not consult with the suppliers of medical gas cylinders prior to issuing the notice.

Although the FDA acknowledged that it was likely that there were other contributing factors causing the regulator fires, FDA indicated a major factor in both the ignition and severity of the fires was attributable to the type of sealing gaskets/washers used between the cylinder valve and the regulator. A revised notice, updated on June 19, 2006, appropriately emphasizes that the user should inspect any seal to assure that it is in good condition. To view the notification, go to the FDA’s Web site, www.fda.gov/cdrh/safety.html, for medical device public health notifications in reverse order of issue date. The FDA’s relevant Web site is www.fda.gov/cder/dmpq/gases.htm

John K. Willenbrock, RAC, is president of Gas Regs Inc, Jamestown, NC, a quality assurance/FDA regulatory affairs and compliance consulting firm. He can be reached at www.gasregs.com, or via e-mail: john.willenbrock@gasregs.com.