On June 4, 2020, the U.S. Food and Drug Administration (FDA) updated the Compliance Program Guidance Manual (CPGM) to include a program for “Inspections of CDER-led or CDRH-led Combination Products.” FDA’s CPGM provides instructions to FDA personnel, including FDA investigators, for conducting activities to evaluate compliance. The new compliance program (7356.000) “focuses on inspections of combination product manufacturers of CDER or CDRH-led single-entity and co-packaged finished combination products that include both drug and device or biological product and device constituent parts,” and aims to clarify and explain the application of cGMP requirements to combination products laid out in January 2017 final guidance, including application of the “streamlined approach” to cGMP compliance set forth in the final guidance.

The new compliance program also states that it “should be used for pre-approval, post-approval, surveillance, for cause, and other risk-based inspections, and notes that use of third-party audit programs such as MDSAP may “impact implementation of this compliance program.” FDA encourages combination product manufacturers to contact their lead center with any questions.

Compliance with cGMP for combination products 

The CPGM says that cGMP compliance for combination product manufacturing may be demonstrated either through compliance with all cGMP regulations applicable to each of the constituent parts, or through a “streamlined approach.” The “streamlined approach” to cGMP compliance requires compliance with: 

-either the drug cGMPs (21 CFR Parts 210 and 211), or the device Quality System (QS) regulation (21 CFR Part 820) (“base cGMPs”); and, 

-specified provisions (“called-out provisions”) from the other of these two sets of cGMP requirements. 

Because most combination product manufacturers have adopted a streamlined approach to demonstrating cGMP compliance, the CPGM focuses on providing instructions to FDA personnel on assessing compliance with the streamlined approach to cGMP compliance. The CPGM notes that it does not cover inspections for combination products for which CBER is the lead center and does not apply to facilities that make either only one type of the constituent part of a combination product or facilities that manufacture only components of constituent parts. 

Notable provisions 

The CPGM recognizes that a single combination product can be manufactured across multiple facilities. Accordingly, the compliance program directs FDA personnel to “[r]equest information about the facilities involved in the manufacturing for the combination product and about the scope of cGMP responsibilities of the facility to be inspected.” FDA personnel should adjust their inspectional approach based on this information. For example, “if another site is responsible for design controls for the combination product, (e.g., a specification developer contracting with the combination product manufacturer with documented responsibility for design), it may be more efficient or necessary to perform an additional inspection at that other site.” 

The compliance program provides additional specific considerations for FDA investigators carrying out different types of inspections, including preapproval, postapproval, surveillance, for-cause and risk-based inspections. For example, the CPGM provides that for PAIs, “the ORA program aligned with the lead center will be the lead on the inspection.” This means that for PAIs of CDER-led NDA products, “OPQO will be the lead on the inspection.” But the CPGM also notes that “for pre-licensing inspections for CDER-led BLAs, CDER will be the lead for the inspection.” Investigators are encouraged to request pre-inspectional meetings through the lead center to align instructions or approach. 

Given the complexities involved in conducting inspections of combination product manufacturers and that fact that FDA has “signaled some flexibility in the cGMP approach for combination products,” the CPGM encourages investigators “to request pre-inspectional meetings through the lead center and ORA supervisory staff to discuss inspectional coverage, center instructions, or the approach described in this compliance program.”   

Drug cGMP-based streamlined approach 

The CPGM explains that drug cGMPs and the following called-out provisions from the device QS regulation in accordance with 21 CFR 4.4(b)(1) include:

-Management responsibility, 21 CFR 820.20 

-Design controls (if applicable), 21 CFR 820.30 

-Purchasing controls, 21 CFR 820.50 

-CAPA, 21 CFR 820.100 

-Installation and servicing (if applicable), 21 CFR 820.170 and 21 CFR 820.200   

Device QS regulation-based streamlined approach 

The device QS regulation and the following called-out provisions from the drug cGMPs in accordance with 21 CFR 4.4(b)(2) (a) include: 

-Testing and approval or rejection of components, drug product containers, and closures, 21 CFR 211.84 

-Calculation of yield, 21 CFR 211.103. 

-Tamper-evident packaging requirements for OTC human drug products, 21 CFR 211.132 

-Expiration dating, 21 CFR 211.137 

-Testing and release for distribution, 21 CFR 211.165 

-Stability testing, 21 CFR 211.166 

-Special testing requirements, 21 CFR 211.167 

-Reserve samples, 21 CFR 211.170   

If you have any questions about this compliance program guidance manual, FDA inspections of combination product manufacturing facilities, or compliance with current good manufacturing practice standards generally, please contact any of the authors of this alert, or the Hogan Lovells attorney with whom you generally work.   

Authored by Jim Johnson, Jodi Scott, Scott Kaplan, Chris Fanelli, Daniel Roberts, and Alex Smith