PART 4—REGULATION OF COMBINATION PRODUCTS Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360b-360f, 360h-360j, 360l, 360hh-360ss, 360aaa-360bbb, 360ddd, 360ddd-1, 371(a), 372-374, 379e, 381, 383, 394; 42 U.S.C. 216, 262, 263a, 264, 271. Source: 78 FR 4321, Jan. 22, 2013, unless otherwise noted. Subpart A—Current Good Manufacturing Practice Requirements for Combination Products § 4.1 What is the scope of this subpart? This subpart applies to combination products. It establishes which current good manufacturing practice requirements apply to these products. This subpart clarifies the application of current good manufacturing practice regulations to combination products, and provides a regulatory framework for designing and implementing the current good manufacturing practice operating system at facilities that manufacture co-packaged or single-entity combination products. § 4.2 How does FDA define key terms and phrases in this subpart? The terms listed in this section have the following meanings for purposes of this subpart: Biological product Combination product Constituent part Co-packaged combination product Current good manufacturing practice operating system Current good manufacturing practice requirements Device Drug Drug CGMP requirements HCT/Ps Manufacture Medical gas CGMP requirements QMSR Single-entity combination product Type of constituent part [89 FR 57165, June 2, 2024] § 4.3 What current good manufacturing practice requirements apply to my combination product? If you manufacture a combination product, the requirements listed in this section apply as follows: (a) The current good manufacturing practice requirements in parts 210 and 211 of this chapter apply to a combination product that includes a drug constituent part other than a medical gas; (b) The current good manufacturing practice requirements in part 820 of this chapter apply to a combination product that includes a device constituent part; (c) The current good manufacturing practice requirements among the requirements (including standards) for biological products in parts 600 through 680 of this chapter apply to a combination product that includes a biological product constituent part to which those requirements would apply if that constituent part were not part of a combination product; (d) The current good tissue practice requirements including donor eligibility requirements for HCT/Ps in part 1271 of this chapter apply to a combination product that includes an HCT/P; and (e) The current good manufacturing practice requirements in part 213 of this chapter apply to a combination product that includes a drug constituent part that is a medical gas. [78 FR 4321, Jan. 22, 2013, as amended at 89 FR 51766, June 18, 2024] § 4.4 How can I comply with these current good manufacturing practice requirements for a co-packaged or single-entity combination product? (a) Under this subpart, for single entity or co-packaged combination products, compliance with all applicable current good manufacturing practice requirements for the combination product shall be achieved through the design and implementation of a current good manufacturing practice operating system that is demonstrated to comply with: (1) The specifics of each set of current good manufacturing practice regulations listed under § 4.3 as they apply to each constituent part included in the combination product; or (2) Paragraph (b) of this section. (b) If you elect to establish a current good manufacturing practice operating system in accordance with paragraph (b) of this section, the following requirements apply: (1) If the combination product includes a device constituent part and a drug constituent part, and the current good manufacturing practice operating system has been shown to comply with the drug CGMP requirements or the medical gas CGMP requirements, as applicable, the following clauses of ISO 13485 (together with the definitions in Clause 3 of ISO 9000), which is incorporated by reference into the QMSR under § 820.7 of this chapter, and certain other provisions within the QMSR must also be shown to have been satisfied; upon demonstration that these requirements have been satisfied, no additional showing of compliance with respect to the QMSR need be made: (i) General requirements and management responsibility. (ii) Design and development. (iii) Purchasing. (iv) Analysis of data, improvement, and complaint handling. (v) Installation activities. (vi) Servicing activities. (2) If the combination product includes a device constituent part and a drug constituent part other than a medical gas, and the current good manufacturing practice operating system has been shown to comply with the QMSR requirements for devices, the following provisions of the drug CGMP requirements must also be shown to have been satisfied; upon demonstration that these requirements have been satisfied, no additional showing of compliance with respect to the drug CGMP requirements need be made: (i) Section 211.84 of this chapter. Testing and approval or rejection of components, drug product containers, and closures. (ii) Section 211.103 of this chapter. Calculation of yield. (iii) Section 211.132 of this chapter. Tamper-evident packaging requirements for over-the-counter (OTC) human drug products. (iv) Section 211.137 of this chapter. Expiration dating. (v) Section 211.165 of this chapter. Testing and release for distribution. (vi) Section 211.166 of this chapter. Stability testing. (vii) Section 211.167 of this chapter. Special testing requirements. (viii) Section 211.170 of this chapter. Reserve samples. (3) If the combination product includes a device constituent part and a drug constituent part that is a medical gas, and the current good manufacturing practice operating system has been shown to comply with the QMSR regulation, the following provisions of the medical gas CGMP requirements must also be shown to have been satisfied; upon demonstration that these requirements have been satisfied, no additional showing of compliance with respect to the medical gas CGMP requirements need be made: (i) Section 213.84 of this chapter. Testing and approval or rejection of components, containers, and closures. (ii) Section 213.94 of this chapter. Medical gas containers and closures. (iii) Section 213.122 of this chapter. Materials examination and usage criteria. (iv) Section 213.165 of this chapter. Testing and release for distribution. (v) Section 213.166 of this chapter. Stability testing and expiration dating for medical gases marketed under applications submitted under section 505 or section 512 of the Federal Food, Drug, and Cosmetic Act. (vi) Section 213.204 of this chapter. Returned medical gases. (vii) Section 213.208 of this chapter. Salvaging of medical gases. (4) In addition to being shown to comply with the other applicable manufacturing requirements listed under § 4.3, if the combination product includes a biological product constituent part, the current good manufacturing practice operating system must also be shown to implement and comply with all manufacturing requirements identified under § 4.3(c) that would apply to that biological product if that constituent part were not part of a combination product. (5) In addition to being shown to comply with the other applicable current good manufacturing practice requirements listed under § 4.3, if the combination product includes an HCT/P, the current good manufacturing practice operating system must also be shown to implement and comply with all current good tissue practice requirements identified under § 4.3(d) that would apply to that HCT/P if it were not part of a combination product. (c) During any period in which the manufacture of a constituent part to be included in a co-packaged or single entity combination product occurs at a separate facility from the other constituent part(s) to be included in that single-entity or co-packaged combination product, the current good manufacturing practice operating system for that constituent part at that facility must be demonstrated to comply with all current good manufacturing practice requirements applicable to that type of constituent part. (d) When two or more types of constituent parts to be included in a single-entity or co-packaged combination product have arrived at the same facility, or the manufacture of these constituent parts is proceeding at the same facility, application of a current good manufacturing process operating system that complies with paragraph (b) of this section may begin. (e) The requirements set forth in this subpart and in parts 210, 211, 213, 820, 600 through 680, and 1271 of this chapter listed in § 4.3, supplement, and do not supersede, each other unless the regulations explicitly provide otherwise. In the event of a conflict between regulations applicable under this subpart to combination products, including their constituent parts, the regulations most specifically applicable to the constituent part in question shall supersede the more general. (f) The material listed in this paragraph (f) is incorporated by reference into this section with the approval of the Director of the Federal Register under 5 U.S.C. 552(a) and 1 CFR part 51. All approved incorporation by reference (IBR) material is available for inspection at the Food and Drug Administration (FDA) and at the National Archives and Records Administration (NARA). Contact FDA at Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852; 240-402-7500; https://www.regulations.gov/document/FDA-2013-S-0610-0003. www.archives.gov/federal-register/cfr/ibr-locations [email protected] https://www.iso.org/obp/ui#iso:std:iso:9000:ed-4:v1:en. [email protected], https://www.iso.org/store.html. (1) ISO 9000:2015(E), (“ISO 9000”), Quality Management systems—Fundamentals and vocabulary, Terms and definitions, (2) ISO 13485:2016(E), (“ISO 13485”), Medical devices—Quality management systems—Requirements for regulatory purposes, [78 FR 4321, Jan. 22, 2013, as amended at 89 FR 7522, Feb. 2, 2024; 89 FR 51766, June 18, 2024] Subpart B—Postmarketing Safety Reporting for Combination Products Source: 81 FR 92624, Dec. 20, 2016, unless otherwise noted. § 4.100 What is the scope of this subpart? (a) This subpart identifies postmarketing safety reporting requirements for combination product applicants and constituent part applicants. (b) This subpart does not apply to investigational combination products, combination products that have not received marketing authorization, or to persons other than combination product applicants and constituent part applicants. (c) This subpart supplements and does not supersede other provisions of this chapter, including the provisions in parts 314, 600, 606, 803, and 806 of this chapter, unless a regulation explicitly provides otherwise. § 4.101 How does the FDA define key terms and phrases in this subpart? Abbreviated new drug application (ANDA) Agency or we Applicant Application Biological product Biological product deviation report (BPDR) Biologics license application (BLA) Combination product Combination product applicant Constituent part Constituent part applicant Correction or removal report De novo classification request de novo Device Device application de novo Drug Field alert report Fifteen-day report . Five-day report Humanitarian device exemption (HDE) Malfunction report New drug application (NDA) Premarket approval application (PMA) Premarket notification submission Product Development Protocol (PDP) § 4.102 What reports must you submit to FDA for your combination product or constituent part? (a) In general. (b) Reporting requirements applicable to both combination product applicants and constituent part applicants. (1) If your combination product or device constituent part received marketing authorization under a device application, you must comply with the requirements for postmarketing safety reporting described in parts 803 and 806 of this chapter with respect to your product. (2) If your combination product or drug constituent part received marketing authorization under an NDA or ANDA, you must comply with the requirements for postmarketing safety reporting described in part 314 of this chapter with respect to your product. (3) If your combination product or biological product constituent part received marketing authorization under a BLA, you must comply with the requirements for postmarketing safety reporting described in parts 600 and 606 of this chapter with respect to your product. (c) Reporting requirements applicable only to combination product applicants. (1) If your combination product contains a device constituent part, you must submit: (i) Five-day reports; (ii) Malfunction reports; and (iii) Correction or removal reports, and maintain records as described in § 806.20 of this chapter for corrections and removals not required to be reported. (2) If your combination product contains a drug constituent part, you must submit: (i) Field alert reports; and (ii) Fifteen-day reports as described in § 314.80 of this chapter, which must be submitted within 30 calendar days instead of 15 calendar days if your combination product received marketing authorization under a device application. (3) If your combination product contains a biological product constituent part, you must submit: (i) Biological product deviation reports; and (ii) Fifteen-day reports as described in § 600.80 of this chapter, which must be submitted within 30 calendar days instead of 15 calendar days if your combination product received marketing authorization under a device application. (d) Other reporting requirements for combination product applicants. (2) If you are the combination product applicant for a combination product that received marketing authorization under a device application, in addition to the reports required under paragraphs (b) and (c) of this section, you must submit reports regarding postmarketing safety events if notified by the Agency in writing that the Agency requires additional information. We will specify what safety information is needed and will require such information if we determine that protection of the public health requires additional or clarifying safety information for the combination product. In any request under this section, we will state the reason or purpose for the safety information request, specify the due date for submitting the information, and clearly identify the reported event(s) related to our request. § 4.103 What information must you share with other constituent part applicants for the combination product? (a) When you receive information regarding an event that involves a death or serious injury as described in § 803.3 of this chapter, or an adverse experience as described in § 314.80(a) of this chapter or § 600.80(a) of this chapter, associated with the use of the combination product, you must provide the information to the other constituent part applicant(s) for the combination product no later than 5 calendar days of your receipt of the information. (b) With regard to information you must provide to the other constituent part applicant(s) for the combination product, you must maintain records that include: (1) A copy of the information you provided, (2) The date the information was received by you, (3) The date the information was provided to the other constituent part applicant(s), and (4) The name and address of the other constituent part applicant(s) to whom you provided the information. § 4.104 How and where must you submit postmarketing safety reports for your combination product or constituent part? (a) If you are a constituent part applicant, you must submit postmarketing safety reports in accordance with the regulations identified in § 4.102(b) that are applicable to your product based on its application type. (b) If you are a combination product applicant, you must submit postmarketing safety reports required under § 4.102 in the manner specified in the regulation applicable to the type of report, with the following exceptions: (1) You must submit the postmarketing safety reports identified in § 4.102(c)(1)(i) and (ii) in accordance with § 314.80(g) of this chapter if your combination product received marketing authorization under an NDA or ANDA or in accordance with § 600.80(h) of this chapter if your combination product received marketing authorization under a BLA. (2) You must submit the postmarketing safety reports identified in § 4.102(c)(2)(ii) and (c)(3)(ii) in accordance with § 803.12(a) of this chapter if your combination product received marketing authorization under a device application. § 4.105 What are the postmarketing safety reporting recordkeeping requirements for your combination product or constituent part? (a) If you are a constituent part applicant: (1) You must maintain records in accordance with the recordkeeping requirements in the applicable regulation(s) described in § 4.102(b). (2) You must maintain records required under § 4.103(b) for the longest time period required for records under the postmarketing safety reporting regulations applicable to your product under § 4.102(b). (b) If you are a combination product applicant, you must maintain records in accordance with the longest time period required for records under the regulations applicable to your product under § 4.102.