(Answer 7) The FDA does not agree that medical xenon should be included in the list of gases for which conditional labeling exemptions under Section 201.161(a) are available. Xenon is not a designated medical gas and is not otherwise approved for use as general anesthesia. Some xenon gas radioisotopes have been approved as diagnostic agents, but these products have approved prescription drug labeling. Therefore, it would be inappropriate to include xenon gas in the list of gases in paragraph 201.161(a). Proposed § 213.82 regulates the receipt and storage of incoming medical gases. The proposed requirements deviate from the current requirements of § 211.82 to better reflect the use of medical gases entering subsequent production. Proposed paragraph (a) requires that upon receipt of a designated medical gas, a company should verify and document that the shipment contains a Certificate of Analysis (COA) signed by the supplier and that the Certificate of Authenticity contains: Proposed section 213.89 is similar to the requirements of § 211.89 in that rejected components, containers and closures should be identified and controlled as part of a quarantine system, intended to prevent their use in manufacture or processing. Transactions for which they are not suitable, but proposed section 213.89 would also apply to incoming designated medical gases. Start printing page 31315 Such a quarantine system does not necessarily have to include physical quarantine, as other methods may be sufficient to ensure that inappropriate products are not used. The FDA is proposing to add a requirement that released components, incoming medical gases, and medical gas containers and closures be documented and evaluated. This proposed additional requirement would help identify any trends that warrant further investigation. The final regime also revises the conditional labelling exemption for medical gases to add oxygen and nitrogen to the list of medical gases covered by the exemption and to remove cyclopropane and ethylene from the list.
The definitive regime further revises this Regulation by adding new warnings to be included in the oxygen labelling and by extending the scope of the Regulation to medically appropriate medicinal gas mixtures. Comments support the proposed amendments to the list of exempt gases. However, many commentators have expressed concerns about how these proposed changes would affect the labelling of oxygen and medical air. These concerns are described in comments 3 and 4, followed by the FDA`s response. If multiple gases are produced in the same plant, it is important that personnel can easily determine which gas is produced in each area of the plant. These requirements also help staff distinguish between the product received, in progress and the finished product. The FDA assumes that companies can meet this requirement with physical barriers, signage, or both, although companies may use other appropriate means. Proposed paragraph 213.42(b) would also require that the flow of components, incoming medical gases, means of containment, closures, labels, in-process materials and medical gases be designed to avoid contamination and confusion. (Comment 1) Many commentators argue that the FDA`s proposal does not reflect the risk-based principles articulated in the past in the context of the recent CGMP policy. These comments indicate that risk-based principles focus regulation on critical areas that are likely to have the greatest impact on public health.
These comments therefore indicate that the impact of the FDA`s proposed rule is disproportionate to a public health risk associated with medical gases and goes beyond what is inconsistent with the agency`s risk-based approach to CGMP. Comments also argue that the incidents listed in the preamble to the proposed regime did not support the number of requirements proposed and that only one requirement in the proposed rule – the requirement for secure connections on portable containers – would have prevented all but one of the deaths mentioned in the preamble. Proposed paragraph (b) requires laboratory controls to include the establishment of scientifically valid and appropriate specifications, standards, sampling plans and test methods to ensure that components, medical gas containers, closures, in-process materials, markings and medical gases meet appropriate standards of identity, strength, of quality and purity and include the following four elements: Section 576 of the FD&C Act describes the certification process for designated medical gases (as defined in Section 575 of the FD&C Act) and the implications of certification, the applicability of FDA prescription requirements, and certain labeling requirements. In accordance with section 576(a)(3)(A)(i), a certified designated medical gas is subject to all applicable post-approval requirements. Pursuant to Section 505(k) of the FD&C Act, FDA has the authority to establish certain postmarket safety reporting requirements for human drugs so that FDA may determine or facilitate a decision as to whether there are or may be grounds for invoking Section 505(e) of the FD&C Act. that relates to the revocation or suspension of the approval of an NDA or an Abbreviated New Drug Application (ANDA). Section 512(L) of the FD&C Act authorizes FDA to establish postmarket safety reporting requirements for new veterinary drugs so that FDA can determine or facilitate whether there are grounds to revoke approval of an application under Section 512(e) or 512(m)(4) of the FD&C Act. We also propose requirements for the reporting of adverse events related to the use of designated medicinal gases in humans and animals.
For designated medical gases certified for human consumption that are considered an approved application under Section 505 of the FD&C Act (21 U.S.C. 355), we propose that applicants and non-applicants be required to report serious adverse events within 15 calendar days of the date the applicant or non-applicant meets certain reporting criteria and obtains certain minimum data. The FDA is making additional amendments to section 201.161 to address the concerns raised by the comments. First, in response to a comment questioning Section 201.161(b)`s exclusion of gas mixtures from the scope of Section 201.161(a)`s conditional labeling exemptions for certain medical gases printed on page 81688 printed on the home page, FDA is removing this exclusion. Second, paragraph (a) of section 201.161 now contains new requirements for oxygen-specific precautionary statements in response to comments that oxygen labelling should include a different warning than other medical gases listed in section 201.161.