Q: What are the regulations that govern CGMP requirements for investigational combination products? For example, we are developing a pen injector and need to determine what the regulations say for CGMP requirements for a Phase 1 clinical trial.
A: I love this question. I love it because prior to this month, it was unanswerable or answerable only with "I believe that . . ." without sufficient justification. I specifically selected this question because two of my last three clients have been combination product manufacturers who had the same exact question.
Over the past two years, when those clients asked me the same question posited above, I essentially made an educated guess and indicated that depending on the product's primary mode of action (PMOA), the CGMP requirements for an investigation product's trials were different. But lets back up a bit . . .
Primary mode of action as defined by FDA is ""the single mode of action of a combination product that provides the most important therapeutic action of the combination product" (first defined in the Federal Register in Aug 2005). What this means, in a nutshell, is that you must determine how exactly your product works. Does the drug, device, or biologic have the most therapeutic effect? When in doubt, a company can always submit a request for designation (RFD), but more and more combination product submissions also mean increasing clarity about classification. In the pen injector case, the PMOA is clearly "drug," as the device--the injector--is primarily a delivery mechanism or vehicle.
|Don't miss David Amor's session on "Overcoming Combination Product Risk and Quality Challenges" at the MD&M East Conference in New York City on Tuesday, June 14, 2016.|
In the question above, the pen injector is a single-entity drug-device combination product. This means the product is bundled up as one "thing" (hence, single entity). If an injector comes packaged as a drug (in a vial or other container) and the injector (barrel, pen, etc.) separately, it is considered a copackaged product. FDA released its draft guidance for CGMPs for combination products in January 2015, which now paints a clearer picture of the answer to this question.
For investigation devices, FDA indicates that 21 CFR Part 4 (combination products regulation) does not alter the applicability of each independent set of regulations on investigational combination products.
What does this mean? Let's review for the drug-device combination product:
- Drug: IND, Phase drugs must comply with 21 U.S.C. 351(a)(2)(B) but generally exempt from most 21 CFR Part 210 and Part 211 requirements (except as described below).
- Device: Investigational Device Exemption (IDE) devices are exempt from 21 CFR 820 regulations--as a rule--except 21 CFR 820.30 design controls.
If we interpret the guidance, I would advise that companies design the device portion of the combination product compliant to 21 CFR 820.30, including design inputs, outputs, review, and verification. Thus, other QSR elements such as process validation and test method validation may not be explicitly applicable. The drug portion of the product should be compliant to investigational drug requirements in 21 CFR 210.2(c), 21 CFR 820.1, and 61 FR 52,616-52,617, and Guidance for Industry on CGMP for Phase 1 Investigational Drugs (July 2008), for Phase 1 IND applications.
In Phase 2 and Phase 3, drugs must meet most sections of 21 CFR 210/211 and applicable section of 21 CFR 820. Long story short, that's when full compliance is critical.
QuickConsult (www.myquickconsult.com) is an online consulting marketplace for the medical device industry where clients can engage experts in short, flexible engagements (ask a question, get an answer in 48 hours) or small project-based work. Each month, cofounder David Amor takes a client-asked question and answers it in QuickConsult Grab Bag. For more information, visit the QuickConsult website www.myquickconsult.com or email David at [email protected]
[image courtesy of MASTER ISOLATED IMAGES/FREEDIGITALPHOTOS.NET]