§ 4.4 - How can I comply with these current good manufacturing practice requirements for a co-packaged or single-entity combination product?

§ 4.4 How can I comply with these current good manufacturing practice requirements for a co-packaged or single-entity combination product?

Cross Reference

Link to an amendment published at 89 FR 7522, Feb. 2, 2024.

Cross Reference

Link to an amendment published at 89 FR 51766, June 18, 2024.

(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 requirementsCGMPs, the following clauses provisions 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 the QS regulation 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 QS regulation need be made:

(i) General requirements and management responsibility. Clause 4.1, Clause 5 and its subclauses, Clause 6.1 of ISO 13485, and § 820.10 of this chapter;

(ii) Design and development. Clause 7.3 and its subclauses of ISO 13485. The organization shall document one or more processes for risk management in product realization. Records of risk management activities shall be maintained;

(iii) Purchasing. Clause 7.4. and its subclauses of ISO 13485;

(iv) Analysis of data, improvement, and complaint handling. Clause 8.2.2 and § 820.35(a) of this chapter, Clause 8.4, and Clause 8.5. and its subclauses of ISO 13485;

(v) Installation activities. Clause 7.5.3 of ISO 13485; and

(vi) Servicing activities. Clause 7.5.4 of ISO 13485 and § 820.35(b) of this chapter.

Section 820.20 of this chapter. Management responsibility.

(ii) Section 820.30 of this chapter. Design controls.

(iii) Section 820.50 of this chapter. Purchasing controls.

(iv) Section 820.100 of this chapter. Corrective and preventive action.

(v) Section 820.170 of this chapter. Installation.

(vi) Section 820.200 of this chapter. Servicing.

(2) 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 QMSR requirements for devicesQS regulation, the following provisions of the drug CGMP requirements CGMPs 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 CGMPs 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) 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.

(4) 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, 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. For information on the availability of this material at NARA, visit www.archives.gov/federal-register/cfr/ibr-locations or email [e-mail]. In addition, the terms and definitions given in ISO 9000:2015 are available for viewing, without cost, at https://www.iso.org/obp/ui#iso:std:iso:9000:ed-4:v1:en. This material is available from the International Organization for Standardization (ISO), BIBC II, Chemin de Blandonnet 8, CP 401, 1214 Vernier, Geneva, Switzerland; [phone]; [e-mail], https://www.iso.org/store.html.

(1) ISO 9000:2015(E), (“ISO 9000”), Quality Management systems—Fundamentals and vocabulary, Clause 3—Terms and definitions, Fourth edition, September 15, 2015.

(2) ISO 13485:2016(E), (“ISO 13485”), Medical devices—Quality management systems—Requirements for regulatory purposes, Third edition, March 1, 2016.

[78 FR 4321, Jan. 22, 2013, as amended at 89 FR 7522, Feb. 2, 2024]