PART 230—CERTIFICATION AND POSTMARKETING REPORTING FOR DESIGNATED MEDICAL GASES Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f, 356, 356a, 356b, 356c, 356e, 360b, 360cc, 360ddd, 360ddd-1, 371, 374, 379e, 379k-1, 381. Source: 89 FR 51777, June 18, 2024, unless otherwise noted. Subpart A—General Provisions § 230.1 Scope of this part. This part sets forth procedures and requirements for the submission to, and the review by, the Food and Drug Administration of certifications to market designated medical gases under sections 575 and 576 of the Federal Food, Drug, and Cosmetic Act, as well as amendments and supplements to those certifications. This part also sets forth the postmarketing safety reporting requirements for designated medical gases. § 230.2 Purpose. The purpose of this part is to establish an efficient process for the certification of designated medical gases and to establish an effective system for surveillance of such gases. § 230.3 Definitions. (a) The definitions and interpretations contained in sections 201 and 575 of the Federal Food, Drug, and Cosmetic Act apply to those terms when used in this part. (b) The following definitions of terms apply to this part: (1) Adverse event e.g., (2) Applicant (3) Certification request (4) FDA Agency (5) Individual case safety report (6) ICSR attachments (7) Life-threatening adverse event immediate i.e., (8) Minimum data set for an ICSR for an adverse event (9) Nonapplicant (10) Serious adverse event (i) An adverse event is considered “serious” if it results in any of the following outcomes: (A) Death; (B) A life-threatening adverse event; (C) Inpatient hospitalization or prolongation of existing hospitalization; (D) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; and/or (E) A congenital anomaly/birth defect. (ii) Other events that may be considered serious adverse events: Important medical events that may not result in one of the listed outcomes in this definition may be considered serious adverse events when, based upon appropriate medical judgment, they may jeopardize the patient or study subject and may require medical or surgical intervention to prevent one of the outcomes listed in this paragraph (b)(10). Examples include: Allergic bronchospasm requiring intensive treatment in an emergency department or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of product dependency or product abuse. Additional examples in animals include: Severe hypersensitivity reactions or respiratory distress. Subpart B—Certification of Designated Medical Gases § 230.50 General requirements for all submission types. (a) Who must submit a request for certification. (2) Any person that proposes to market a medical gas that is a new drug for human use must obtain approval under part 314 of this chapter, and any person that proposes to market a medical gas that is a new animal drug for animal use must obtain approval under part 514 of this chapter, unless— (i) The medical gas meets the definition of a designated medical gas; and (ii) The medical gas is proposed to be marketed alone or in combination (as medically appropriate) with another designated medical gas or other designated medical gases, for which a certification or certifications have been granted, for a use described under section 576(a)(3)(A)(i) of the Federal Food, Drug, and Cosmetic Act. (b) The applicant must include the following information in its certification request Applicant information. (2) Type of submission. (i) Original certification request. (ii) Amendment to a pending certification request. (iii) Resubmission. (iv) Supplement to a granted certification. (v) Other. (3) Description of medical gas. (4) Facility information. (5) Certification of adequate manufacture, processing, packaging, and holding of designated medical gas. (6) Additional information. (c) Where and how to submit a request for certification. § 230.65 Withdrawal by the applicant of a certification request before it is deemed granted. An applicant may at any time withdraw a certification request that is not yet deemed granted by notifying FDA in writing. A decision to withdraw the certification request is without prejudice to refiling. The Agency will retain the certification request and will provide a copy to the applicant on request under the fee schedule in § 20.45 of this chapter (FDA's public information regulations). § 230.70 Supplements and other changes to a granted certification. (a) The applicant must submit a supplement if any information in the certification request changes after the request has been deemed granted, including, but not limited to, the addition of a new facility manufacturing the designated medical gas, a change in contact information, or a change in the corporate name. (b) Each supplement must include a signed, completed request for certification form with the updated information in accordance with § 230.50. The updated information must be submitted no later than 30 calendar days after the date the change occurred. § 230.72 Change in ownership of a granted certification. An applicant may transfer ownership of its certification. At the time of transfer the new and former owners are required to submit information to FDA as follows: (a) The former owner must submit a letter or other document that states that all rights to the certification have been transferred to the new owner. (b) The new owner must submit a supplement under § 230.70 signed by the new owner describing any changes in the conditions in the granted certification and a letter or other document containing the date that the change in ownership is effective. § 230.80 Annual report. (a) The applicant must submit each year within 60 calendar days of the new calendar year an annual report containing the information described in paragraph (b) of this section. The applicant must submit a signed, completed annual report form either in an electronic format that FDA can process, review, and archive, or in hard copy by submitting two paper copies to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705. (b) The report must contain, for the prior calendar year, the following information in the order listed: (1) Summary. (2) Distribution data. (3) Administrative changes. (4) Current facilities. § 230.100 FDA review of submissions. (a) In reviewing a submission pursuant to § 230.50, FDA will consider information provided with the submission along with any other available, relevant information of which FDA becomes aware, including information obtained from State or Federal officials, FDA inspection reports, or any other source. (b) FDA will deny a submission if FDA finds that: (1) The medical gas that is the subject of the submission is not a designated medical gas; (2) The submission does not contain the required information or otherwise appears to lack sufficient information to determine that the medical gas is a designated medical gas; (3) The applicant's methods, facilities, and controls used for the manufacture, processing, and handling of the designated medical gas, as applicable, are not adequate to ensure its safety, identity, strength, quality, and purity; or (4) Denying the request is otherwise necessary to protect the public health. (c) Within 60 calendar days of filing of a submission, FDA may contact the applicant to request additional information regarding the submission if it determines that required information is not included in the submission, that FDA needs such information to determine whether the medical gas is a designated medical gas, or that FDA determines such information is necessary to protect the public health. Upon receipt of an amendment to a pending certification request, this 60-day review period will restart. If FDA is not able to contact the applicant to obtain and evaluate the information within the 60-day review period, FDA may find that the submission lacks sufficient information to permit a determination that the medical gas is a designated medical gas and deny the submission. If FDA is able to contact the applicant but is not provided with the additional information requested within the 60-day review period, FDA may find that the request lacks sufficient information to permit a determination that the medical gas is a designated medical gas and deny the submission. (d) Within 60 calendar days of filing of a submission, if FDA makes one of the findings described in paragraph (b) of this section, FDA will notify the applicant in writing that the submission is denied and provide the basis for FDA's determination. § 230.105 When a submission is deemed granted. Unless FDA makes one of the findings described in § 230.100(b) and notifies the applicant within 60 calendar days of filing that the submission is denied, the certification is deemed to be granted and the designated medical gas will be deemed to have in effect an approved application under section 505 or section 512 of the Federal Food, Drug, and Cosmetic Act, or both, as applicable, for the indications described in section 576(a)(3)(A)(i) of the Federal Food, Drug, and Cosmetic Act. FDA will notify the applicant in writing. § 230.150 Withdrawal or revocation of approval of an application. (a) Withdrawal. (i) The Secretary of Health and Human Services has suspended the approval of the application for a designated medical gas on a finding that there is an imminent hazard to the public health. FDA will promptly afford the applicant an expedited hearing following summary suspension on a finding of imminent hazard to health. (ii) FDA finds: (A) That clinical or other experience, tests, or other scientific data show that the designated medical gas is unsafe for use under the conditions of use upon the basis of which the application was approved; or (B) That new evidence of clinical experience not available to FDA until after the application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when the application was approved, evaluated together with the evidence available when the application was approved, reveal that the designated medical gas is not shown to be safe for use under the conditions of use upon the basis of which the application was approved; or (C) Upon the basis of new information before FDA with respect to the designated medical gas, evaluated together with the evidence available when the application was approved, that there is a lack of substantial evidence from adequate and well-controlled investigations as defined in § 314.126 of this chapter, that the designated medical gas will have the effect it is purported or represented to have under the conditions of use prescribed, recommended, or suggested in its labeling; or (D) That the application contains any untrue statement of a material fact. (2) FDA may notify the applicant, and afford an opportunity for a hearing on a proposal to withdraw approval of the application under the procedure in § 314.200 of this chapter, § 514.200 of this chapter, or both, as applicable, if the Agency finds: (i) That the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain required records or to make required reports applicable to designated medical gases, including under sections 505(k) and 512(l) of the Federal Food, Drug, and Cosmetic Act and this part, part 213 of this chapter, and § 314.81(b)(3) of this chapter, or that the applicant has refused to permit access to, or copying or verification of, its records. (ii) That on the basis of new information before FDA, evaluated together with the evidence available when the application was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the designated medical gas are inadequate to ensure and preserve its identity, strength, quality, and purity and were not made adequate within a reasonable time after receipt of written notice from the Agency. (iii) That on the basis of new information before FDA, evaluated together with the evidence available when the application was approved, the labeling of the designated medical gas, based on a fair evaluation of all material facts, is false or misleading in any particular, and the labeling was not corrected by the applicant within a reasonable time after receipt of written notice from the Agency. (iv) That the applicant has failed to comply with the notice requirements of section 510(j)(2) of the Federal Food, Drug, and Cosmetic Act. (3) FDA will withdraw approval of an application if the applicant requests its withdrawal because the designated medical gas subject to the application is no longer being marketed, provided none of the conditions listed in paragraphs (a)(1) and (2) of this section applies to the designated medical gas. FDA will consider a written request for a withdrawal under this paragraph (a)(3) to be a waiver of an opportunity for hearing otherwise provided for in this section. Withdrawal of approval of an application under this paragraph (a)(3) is without prejudice to refiling. (4) FDA may notify an applicant that it believes a potential problem associated with a designated medical gas is sufficiently serious that the designated medical gas should be removed from the market and may ask the applicant to waive the opportunity for hearing otherwise provided for under this section, to permit FDA to withdraw approval of the application for the product, and to remove voluntarily the product from the market. If the applicant agrees, the Agency will not make a finding under paragraph (a)(1) or (2) of this section, but will withdraw approval of the application in a notice published in the Federal Register (5) If FDA withdraws an approval, FDA will publish a notice in the Federal Register (b) Revocation. Subpart C—Postmarketing Quality and Safety Reporting § 230.205 Field alert reports. The applicant shall submit a field alert report containing all information described in paragraphs (a) and (b) of this section about distributed designated medical gases and articles to the FDA district office that is responsible for the facility involved as soon as possible but no later than 45 calendar days from the date the applicant, or its agent or contractor, obtained information suggesting that a reportable incident has occurred. If the information suggests that the reportable incident may require a rapid response to address a public health risk, the applicant must as soon as possible, but no later than 3 working days from obtaining the information, submit a field alert report. The information may be provided by telephone or other rapid communication means, with prompt written followup. The report and its mailing cover should be plainly marked: “Designated Medical Gas—Field Alert Report.” (a) Information concerning any incident that causes the designated medical gas or its labeling to be mistaken for, or applied to, another article. (b) Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed designated medical gas, or any failure of one or more distributed batches of the designated medical gas to meet established specifications. § 230.210 General reporting requirements for designated medical gas adverse events. (a) Review of safety information. (b) Safety reporting disclaimer. (2) An applicant or nonapplicant need not admit, and may deny, that the report or information submitted under § 230.220 or § 230.230 constitutes an admission that the designated medical gas caused or contributed to an adverse effect. § 230.220 Human designated medical gas ICSR requirements. (a) ICSR reporting General. (2) Copies of ICSRs obtained from FDA. (3) Followup information. (b) Reporting requirements Serious adverse events Reported to or otherwise received by the applicant or nonapplicant. (ii) Reported from the scientific literature. (iii) Exception to reporting requirements for serious adverse events. (2) Other adverse event reports to be submitted upon notification by FDA. (c) Completing and submitting ICSRs. (1) Electronic format for submissions. (ii) An applicant or nonapplicant may request, in writing, a temporary waiver of the requirements in paragraph (c)(1)(i) of this section. These waivers will be granted on a limited basis for good cause shown. (2) Submitting ICSRs Single submission of each ICSR. (ii) Separate ICSR for each patient. (iii) Coding terms. (iv) Minimum data set. (v) ICSR elements. (A) For adverse events, applicants and nonapplicants must actively seek any information needed to complete all applicable elements, consistent with their written procedures under paragraph (f) of this section. (B) Applicants and nonapplicants must document and maintain records of their efforts to obtain the missing information. (vi) Supporting documentation. (A) A copy of the autopsy report if the patient died, or a copy of the hospital discharge summary if the patient was hospitalized. The applicant or nonapplicant must submit each document as an ICSR attachment. The ICSR attachment must be submitted either with the initial ICSR or no later than 15 calendar days after obtaining the document. English translations of foreign language documents must be provided. (B) A copy of the published article as an ICSR attachment for each ICSR of an adverse event obtained from the published scientific and medical literature. Foreign language articles must be accompanied by an English translation of the abstract. When submitting more than one ICSR from the same published article, the applicant or nonapplicant must submit only one copy of the article with one of the ICSRs. For the remaining ICSRs not accompanied by a copy of the published article, the applicant or nonapplicant must include the cross-reference to the specific ICSR to which the article is attached. (d) Information reported on ICSRs. (1) Patient information, which includes: (i) Patient identification code; (ii) Patient age at the time of adverse event, or date of birth; (iii) Patient sex; and (iv) Patient weight. (2) Adverse event, which includes: (i) Outcome attributed to adverse event; (ii) Date of adverse event; (iii) Date of ICSR submission; (iv) Description of adverse event; (v) Adverse event term(s); (vi) Description of relevant tests conducted, including dates and laboratory data; and (vii) Other relevant patient history, including preexisting medical conditions. (3) Suspect designated medical gas(es), which includes: (i) Name; (ii) Dose, frequency, and route of administration used; (iii) Therapy dates; (iv) Diagnosis for use (indication); (v) Whether the adverse event abated after the use of the designated medical gas(es) stopped or the dose was reduced; (vi) Whether the adverse event reappeared after reintroduction of the designated medical gas(es); (vii) Lot number; (viii) National Drug Code (NDC) number; and (ix) Concomitant medical products and therapy dates. (4) Initial reporter information, which includes: (i) Name, address, email address, and telephone number; (ii) Whether the initial reporter is a healthcare professional; and (iii) Occupation, if a healthcare professional. (5) Applicant or nonapplicant information, which includes: (i) Applicant or nonapplicant name, address, email address, and telephone number; (ii) Report source, such as spontaneous, literature, or study; (iii) Date the report was received by applicant or nonapplicant; (iv) New drug application and/or new animal drug application number; (v) Whether the ICSR is an expedited report; (vi) Whether the ICSR is an initial report or followup report; and (vii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s). (e) Recordkeeping. (2) These records must include raw data, correspondence, and any other information relating to the evaluation and reporting of adverse event information that is received or otherwise obtained by the applicant or nonapplicant. (3) Upon written notice by FDA, the applicant or nonapplicant must submit any or all of these records to FDA within 5 calendar days after receipt of the notice. The applicant or nonapplicant must permit any authorized FDA employee, at reasonable times, to access, copy, and verify these established and maintained records described in this section. (f) Written procedures. (g) Patient privacy. § 230.230 Animal designated medical gas adverse event reporting requirements. (a) Report for adverse events. (1) Serious adverse events. (i) Reported to or otherwise received by the applicant or nonapplicant. each serious adverse event (ii) Reported from the scientific and medical literature. (iii) Exception to reporting requirements for serious adverse events. (2) Other adverse event reports to be submitted upon notification by FDA. (3) Copies of adverse event reports obtained from FDA. (b) Format for submissions Electronic submissions. e.g., (2) Waivers. (c) Records to be maintained. (2) These records must include raw data, correspondence, and any other information relating to the evaluation and reporting of adverse event information that is received or otherwise obtained by the applicant or nonapplicant. (3) Upon written notice by FDA, the applicant or nonapplicant must submit any or all of these records to FDA within 5 calendar days after receipt of the notice. The applicant or nonapplicant must permit any authorized FDA employee, at reasonable times, to access, copy, and verify these established and maintained records described in this section.