In a new final rule, FDA carves out a regulatory niche for medical gases
Life Sciences
| By AMANDA CONTI, ALEXANDER GAFFNEY, MS, RACRACHEL COE, MSC
Industry has been lobbying FDA and Congress to regulate medical gases different from other types of drug products since the 1970s. Nearly fifty years later, a final rule has made concessions industry has long been calling for, but retains reporting and safety provisions the agency deems important.
Major milestones in medical gas regulation
- Medical gases such as oxygen and medical air are widely used in a variety of healthcare and home/community settings. While the use of medical gases raises few safety concerns when they are used as intended, there have been instances where mix-ups involving medical gases have resulted in serious patient injuries. In 2001, the FDA issued a guidance to “alert hospitals, nursing homes, and other health care facilities to the hazards of medical gas mix-ups.” Overall, the FDA stated that these cases of patient injury and death resulted from several, preventable lapses in safety procedure related either to improper labeling, or to poorly trained personnel not checking the labels of cryogenic vessels and connecting the wrong vessels to patient oxygen supply systems, despite connection incompatibilities.
- Still, three years later, the FDA reported that it had received several reports of medical gas mix-ups resulting in at least 8 patient deaths and 16 serious patient injuries between 1996 and April 2004. During this time, the agency had issued several guidances on medical gases; however, the recommendations in those documents were not binding. To address this problem, the FDA eventually issued a proposed rule in April 2006, seeking to codify many of its previously issued recommendations. Broadly, the rule sought to require the use of certain safeguards in the production, storage, and use of medical gases. For example, the proposal prohibited repurposing high-pressure cylinders or cryogenic containers that previously held industrial gases for medical use unless properly converted for sole medical use. It also proposed several packaging changes to safeguard against misidentification. However, the proposed rule sat in limbo for years without ever being finalized.
- Six years later with the reauthorization of several FDA-industry user fee programs in 2012, Congress took the opportunity to set a series of policy changes into motion. Medical gases were one of several topics during the deliberations that led up to the passage of the final legislative package, which was known as the Food and Drug Administration Safety and Innovation Act (or FDASIA). The Medical Gas Safety Act, introduced by Rep. LEONARD LANCE (R-NJ), intended to address some of the long-standing issues raised by the medical gas industry. The proposal included several major reforms, such as the establishment of a certification and approval process for designated medical gases (those with a long-standing, well-established medical use). The act also proposed a separate, risk-based inspection regime specific to medical gas manufacturers, and a new user fee program for the review of non-designated medical gases. It also directed the FDA to establish regulations for medical gases on five topics: 1) appropriate current good manufacturing practice requirements, 2) separate labeling requirements, 3) separate wholesale distribution requirements, 4) a streamlined electronic process for registration and listing of medical gases, and 5) separate and proportionate product tracking and anti-counterfeiting rules for medical gases.
- Some provisions – including the user fees — were dropped from the final bill, but a few medical gas policy reforms were included in FDASIA. One of these major changes was the addition of an entirely new section on medical gases to the Food, Drug, and Cosmetic (FD&C) Act, including a new definition of medical gases as drugs that are “manufactured or stored in a liquefied, nonliquefied, or cryogenic state” and are administered as a gas. FDASIA also addressed a challenge cited by then-CDER Director JANET WOODCOCK when she testified before Congress in March 2012 on medical gases. During a House Energy and Commerce (E&C) Health Subcommittee meeting, Woodcock explained that certain medical gases have been used for so long in medicine that they actually predate the establishment of the FDA’s review practice and thus, were technically being used without any sort of FDA approval. However, the agency felt (per Woodcock) that a designation process, rather than a “whole, new regulatory regime” would offer a suitable process to bring the use of “traditional medical gases for traditional uses” under the umbrella of FDA-regulated products. Additionally, Woodcock stated that the FDA could leverage existing approval pathways to review applications for new uses of traditional medical gases or for new types of medical gases.
- Lawmakers obliged and amended the FD&C Act to include “designated medical gases” as a subset of medical gases with well-established uses. Following a streamlined certification process, these products would then be “deemed to have in effect” an approved new drug application and would be subject to all applicable postapproval requirements, though they would not be eligible for any sort of marketing exclusivity period. Per FDASIA, designated medical gases are oxygen, nitrogen, nitrous oxide, carbon dioxide, helium, medical air, and carbon monoxide – as long as they “meet the standards set forth in an official compendium.” In a guidance later issued by the FDA explaining its implementation of the certification process for designated medical gases, the agency clarified that the official compendia it recognizes are: the official United States Pharmacopoeia (USP), the official Homeopathic Pharmacopeia of the United States (HPUS), the official National Formulary (NF), or any supplement to any of them.
- Lawmakers ultimately directed the FDA to “determine whether any changes to federal drug regulations are necessary for medical gases” after “obtaining input from medical gas manufacturers and other interested members of the public,” taking a middle ground between FDA and industry stances on regulation. Following this process, FDASIA directed the FDA to submit a report to Congress summarizing its findings. It also charged the agency with issuing final regulations revising Federal drug regulations for medical gases within 48 months after the Act was enacted, if it was determined that changes to Federal drug regulations with respect to medical gases were necessary.
- In July 2015, the FDA presented its findings that: “After extensive deliberation, FDA has determined that although some regulation changes are necessary to implement the medical gas labeling provisions contained in FDASIA, the current regulatory framework is adequate and sufficiently flexible to appropriately regulate medical gases. FDA can continue to work within this framework to appropriately regulate these products.” The report asserted that “There is […] no compelling need to undertake the sweeping regulatory makeover requested by the medical gas industry,” but that the agency “may in the future determine that rulemaking is necessary to address specific issues affecting medical gases.” In particular, the report stated that FDA agreed with stakeholders that medical gas warning label changes may be necessary, though it disagreed “with stakeholder comments that designated medical gases should be entirely exempt from the periodic postapproval reporting requirements generally applicable to all approved drugs.” As a result, the report noted that FDA would continue to consider the “appropriate frequency and content of such reporting for designated medical gases […] as FDA and the medical gas industry gain practical experience with the regulation of medical gases as NDA products.”
Stakeholders largely disagreed with the FDA on adapting the existing drug framework
- One of the major points of contention between industry and FDA was the application of existing drug regulations to medical gases. Though FDASIA created a streamlined process for long-time manufacturers of medical gases to circumvent the conventional new drug application submission and approval process, it didn’t exclude medical gas manufacturers from other regulatory requirements. According to the FDA’s 2006 proposed rule (which predated FDASIA), the agency felt that medical gas manufacturers needed to comply with applicable regulations that other sponsors with approved drug products had to adhere to. This included the current good manufacturing practice (CGMP) requirements outlined in 21 CFR 210 and 211 as well as labeling requirements. Even after FDASIA became law, the agency stood its ground regarding CGMP requirements. After all, reasoned the FDA, FDASIA’s streamlined approval process enabled medical gas manufacturers to secure the equivalent of an approved new drug application.
- It reiterated this position in November 2016 when it finalized the 2006 proposed rule. The final rule asserted that the FDA possessed the authority to “create and modify CGMP and labeling regulations to ensure that drugs meet the requirements of the FD&C Act as to safety and have the identity and strength, and meet the quality and purity characteristics,” and that “Medical gas containers, closures, and labeling 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. Medical gas mix-ups have caused deaths and serious injuries. These incidents have occurred despite current regulations and guidance addressing the safe handling of medical gases. FDA is therefore invoking the authority granted by sections 701(a), 501(a)(2)(B), 502(f), and 576(a) of the FD&C Act to issue CGMP and labeling regulations designed to facilitate the safe use of medical gases and to ensure that medical gases are labeled with adequate warnings and instructions for use.”
- However, in between the passage of FDASIA in 2012 and the finalization of FDA’s rule on medical gases in 2016, industry had continued to advocate against FDA’s handling of medical gases as drug products. Leading the charge, the Compressed Gas Association (CGA) and the Gases and Welding Distributors Association (GAWDA) submitted a nearly 50-page Citizen Petition to the FDA in September 2015. The petition harshly criticized the FDA’s regulation of medical gases, its lack of knowledge regarding medical gas manufacturing, and unwillingness to address industry’s concerns.
- According to the petition, CGA had “attempted to work with FDA to formulate appropriate regulations and standards for medical gases” for almost 40 years. It also cited FDA staff impressions when they had toured a medical gas manufacturing facility several months prior to the submission of the petition. Per the letter, agency staff were “surprised at how different the medical gas manufacturing process was than a traditional drug manufacturer” and engaged in a lengthy discussion with industry representatives, who explained how “many current FDA regulations are impossible, impractical or generally a bad fit for the medical gas manufacturing process.”
- Nevertheless, CGA and GAWDA stated their conclusion that “changes to FDA’s current regulations are necessary because, to date, FDA has proven that guidances, training of inspectors and interaction with industry stakeholders is not a viable pathway to appropriate regulation of medical gases.” The petition went on to request that both organizations be proactively informed on any agency efforts to develop guidance or to reform federal regulations, given “FDA’s track record of difficulties in developing appropriate guidance and training documents that address the unique manufacturing process for medical gases.”
- While FDA’s 2016 final rule stood strong on various CGMP requirements, it did take some of industry’s feedback into account. The final rule walked back a number of the originally proposed changes based on industry feedback that the impact of these changes was “disproportionate to and beyond the scope of any public health risk associated with medical gases” and that “FDA significantly underestimated the costs to industry imposed by the rule as proposed.” As a result, the FDA explained that “following reanalysis of expected costs and benefits,” it “declined to adopt certain provisions in the proposed rule and has revised other proposed provisions to more efficiently achieve public health objectives.” The agency also stated that many of the requirements in the final rule had been modified to achieve consistency with “what [FDA] understand[s] to be industry practices.”
- However, the medical gas industry still had a bone to pick with FDA. Within the 2017 omnibus funding bill, lawmakers made a more definitive request to the FDA to issue final regulations on medical gases. In contrast to the roomy 48 months allotted by FDASIA for the FDA to consider regulatory changes, this time, lawmakers gave the FDA just two months (by July 2017) to get the job done.
- In reality, it took five years before the FDA issued a proposed rule to reform the regulation of medical gases. The May 2022 proposed rule directly responded to many of industry’s grievances by admitting that “Some existing regulations are not well-tailored to addressing designated medical gases and other medical gases” and that “FDA is undertaking this rulemaking to address these differences, and to decrease regulatory burden where appropriate.”
- The proposed rule outlined numerous changes, including the creation of two, entirely new sections under 21 CFR Chapter 1 Subchapter C (213 and 230) specific to medical gases. The newly proposed Part 213 would establish CGMP regulations that are specifically tailored to “reflect differences in how medical gases are manufactured, packaged, labeled, stored, and distributed.” Additionally, the new Part 230 would detail the requirements for filing a certification request for a designated medical gas for human use, animal use, or both.
- It also described FDA’s plan to amend seven other sections of existing regulations. In line with the changes noted above, the FDA proposed conforming edits to 21 CFR Part 210 and Part 211 (CGMP requirements for drug products) to remove some of the previous language on medical gases now addressed in the new Part 213. Likewise, the FDA suggested “carving out designated medical gases from certain provisions” in Part 314 (marketing authorization for new drug products) and Part 514 (marketing authorization for new animal drug products) since the process for submitting certification requests would now be covered for both product types in the new Part 230. Other changes included amending 21 CFR Part 4 to clarify that postmarketing safety reporting requirements for combination products apply to medical gases when approved as part of a combination product. Next, 21 CFR Part 16 would be amended to enable the revocation of a grant of certification if it was determined that the request contained any material omission or falsification. Finally, a handful of changes to 21 CFR 201 (medical gas labeling requirements) were described in the proposed rule. [Read AgencyIQ’s analysis of the proposed rule here]
What’s new?
- Last week, the FDA announced the final version of its 2022 proposed rule. Per the Federal Register notice, FDA has now completed the task it was assigned by Congress seven years ago in the 2017 Consolidated Appropriations Act to amend medical gas regulations. For industry, however, these changes are far more than five years overdue. In the joint comment letter submitted by CGA and GAWDA on the 2022 proposed rule, the groups wrote, “We thank FDA for providing the May 23, 2022, proposals for separate regulations, following through on the FDA’s commitment to issue medical gas regulations that was made in the Preamble to the 1978 21 CFR Parts 210 and 211 final rulemaking and as stipulated in Section 756 of FY 2017 Consolidated Appropriations Act (Public Law 115-31) [emphasis added].”
- Their joint comment letter also suggests industry was involved in drafting the proposed rule. The dynamic between the three groups appears to have taken a positive turn following the submission of industry’s 2015 Citizen Petition to the FDA. To this point, the joint comment letter states that “CGA and GAWDA have enjoyed a long-standing working relationship with the FDA,”—a vastly different characterization than what was described in the 2015 petition.
- Per the Federal Register notice, the FDA received fewer than 25 comments on the proposed rule. Overall, the comments addressed: “General considerations, including general support, definitions, timing of the rule, and the effective date; Labeling requirements, including labeling statements and the applicability of labeling provisions to different types of containers; CGMP requirements, including buildings and facilities, equipment, control of incoming products, packaging and labeling control, holding and distribution, laboratory controls, records, and returned medical gases; Certification requirements, including annual reporting, withdrawal, and the applicability of current requirements in part 314 (21 CFR part 314); and Postmarketing quality and safety reporting requirements, including submitting FARs, reporting of individual case safety reports (ICSRs) related to human use, and reporting of adverse events related to animal use.”
- The final rule includes a breakdown of the feedback FDA received from stakeholders along with the agency’s response to the points raised. While some of the comments were incorporated into the final rule, others were rejected. By reading through the agency’s response to comments, especially those that were rejected, it’s possible to identify the factors FDA uses to draw a line between medical gases and other product types.
FDA responded to the feedback it got
- First up, the final rule calls out the factors that make medical gas manufacturers unique from other types of drug manufacturers. Now, regulations state that the term “medical gas manufacturer” specifically refers to “the person fabricating the gas by chemical reaction, physical separation, compression of atmospheric air, purification (e.g., reprocessing an industrial gas into a medical gas), by combining two or more distinct medical gases, or by other process.” While one comment suggested this definition be revised to exclude processing agents such as nitrogen used in bottle purging and product overlay, the FDA declined this request, stating that “We agree that gases used in the production of drugs that are not medical gases are not subject to Part 213 [CGMP requirements]. Such gases may be subject to part 211 if the drug product is subject to those regulations depending on the use of the gas, but that is outside the scope of this rulemaking.”
- A topic that was frequently addressed in comments was the difference between a medical gas being administered as a drug product versus being used as a device. For example, several comments on the FDA’s proposed changes to 21 CFR Part 4 inquired about situations where a medical gas might be administered by healthcare providers in liquid form (e.g., cryogenic nitrogen for dermatological use). However, the FDA makes it clear in its responses that the rule applied to the use of medical gases that are drugs; the use of a medical gas as a tool to perform a procedure would fall under the definition of a medical device and would be subject to a different set of regulations.
- A similar question came up related to labeling requirements. The proposed rule referred to a portable cryogenic medical gas container as 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, or is a base unit used to fill small cryogenic gas containers for use by individual patients.” However, one comment pointed out that a portable cryogenic medical gas container, as defined in the proposed rule, could be interpreted to include devices maintained at a patient’s home that are filled with oxygen. The FDA agreed and cleared up this definition in the final rule by specifically excluding this scenario. In its response, the agency observed that the “distinction between containers that are devices, and those that are not, is important, and FDA believes that the definition as revised makes clear which containers are devices subject to applicable device requirements, and which are portable cryogenic medical gas containers subject to applicable drug requirements.”
- The FDA also emphasized the importance of the context of use for a medical gas in labeling. One comment recommended that the definition of “final use container” in CFR Part 201 be revised to mean a container that is labeled for direct use, rather than a container that is for direct use. It also noted that FDA’s proposed definition of “bulk or transport container” includes cylinders that are connected to a medical gas supply system, such as a hospital’s oxygen system, although cylinder banks may contain individual labeled cylinders. The agency disagreed with this comment: “First, specifying that a container is a final use container if it is “labeled” for direct use would be circular, and a firm could avoid being regulated as a final use container simply by not labeling its containers accordingly. Second, FDA believes that the purpose of the container should determine the appropriate labeling. If the container is intended to be used as a final use container, it must be labeled in compliance with § 201.161(a), and if a container is intended to be used as a bulk or transport container, it must be labeled in compliance with § 201.161(b).”
- The FDA modified its previous request that firms receiving designated medical gases verify and record a signed certificate of analysis (COA) from the supplier for each designated medical gas contained in a shipment. One comment requested that firms be allowed to “to conduct full compendial testing on the commingled product as an alternative to verifying that a COA accompanies the shipment.” The FDA obliged. The final rule states that “Upon receipt of each shipment of each incoming designated medical gas, the firm shall either perform full compendial testing on the gas and record the results, or verify and record that a signed COA from the supplier accompanies each different designated medical gas in a shipment.”
- The FDA also tightened up its requirements for investigating complaints on leaking and empty containers. These changes appear to be based on the FDA’s own initiative rather in response to any particular comments. Per the final rule, the FDA “continue[s] to believe that leaking and empty container complaints is a serious concern, in light of the numerous instances of leaking and empty containers described in the proposed rule. […] In several instances, firms did not appropriately evaluate the complaints in that the investigation conducted was inadequate, even when similar complaints were received, lacking steps such as evaluating the durability and suitability of containers and closures to identify a root cause. Therefore, we are adding to the complaint files provision at Part 213.198(a) a requirement that all complaints involving leaking containers or closures be reviewed, evaluated, and investigated (emphasis added) in accordance with Part 213.192.”
- Annual reporting requirements: The proposed rule stated that applicants who successfully obtained a certification for a designated medical gas would need to submit an annual report each year within 60 calendar days of the anniversary of the date the certification was granted. However, per the suggestion of stakeholders, the FDA has adjusted this requirement in the final rule. To align with reporting requirements per the Coronavirus Aid, Relief, and Economic Security Act (CARES Act), the final version now requires that annual reports be submitted within 60 calendar days of the new calendar year.
- Adverse event reporting: The final rule has also been adjusted to “describe more clearly the requirement that applicants and nonapplicants must submit ICSRs for serious adverse events reported to or otherwise received by the applicant or nonapplicant,” an action that FDA chose to take on its own initiative. For context, the final rule states that this revision “is intended to help ensure that reports of serious adverse events otherwise received (or obtained) by the applicant or nonapplicant are submitted to the Agency. Accordingly, this requirement includes, for example, serious adverse event reports received at the request of the applicant or nonapplicant (such as reports received as part of a patient support program), in addition to unsolicited communications such as reports initiated by a patient, consumer, or healthcare professional.”
- The FDA has also newly included a requirement for ICSRs and their attachments to be submitted in an electronic format that FDA can process, review, and archive. While this was the intention of the proposed rule too, the FDA has now explicitly included this language in the new Part 230 regulations instead of just referencing them. The final rule states that “FDA intends to issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files)” as well as a guidance on temporary waivers for the electronic reporting requirements.
- Designated medical gases will not be subject to periodic safety reporting requirements. In the proposed rule, the FDA requested input from stakeholders on whether it should impose periodic safety reporting requirements for designated medical gases. While the final rule states that arguments were made both in support and in opposition of such a requirement, the FDA has ultimately decided not to impose a periodic safety reporting requirement—at least not “in this rulemaking.” As “medical gases have historically been manufactured, labeled, and distributed in a manner different than most other drugs,” the FDA reasons that “the likelihood of identifying new safety issues for medical gases is low, and that ICSRs are an adequate and efficient means of identifying any new safety issues for these products.”
To contact the author of this item, please email Rachel Coe ( rcoe@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).