The FDA has issued the document, Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products (January 2015).
This guidance describes and explains the final rule on current good manufacturing practice (CGMP) requirements for combination products, issued January, 2013.
This draft guidance document is being distributed for comment purposes only. It describes and explains the final rule on current good manufacturing practice (CGMP) requirements for combination products, issued January, 2013. The FDA is accepting comments on this draft for 60 days.
Under 21 CFR 3.2(e), a combination product includes:
- A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity (a “single entity” combination product, such as a prefilled syringe or drug-eluting stent);
- Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products (a “co-packaged” combination product, such as a surgical or first-aid kit);
- A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved, individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose) (a “cross-labeled” combination product, as might be the case for a light-emitting device and a light-activated drug); or
- Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect (another type of cross-labeled combination product).
The following remains an important area for companies to comply with when developing their quality systems:
Specifically, the streamlined approach under 21 CFR 4.4(b) provides that combination product manufacturers may meet the requirements of both the drug CGMPs and device QS regulation by designing and implementing a CGMP operating system that is demonstrated to comply with either of the following:
- The drug CGMPs and the following provisions from the QS regulation in accordance with 21 CFR 4.4(b)(1) (considered a drug CGMP-based streamlining approach):
(i) 21 CFR 820.20. Management responsibility
(ii) 21 CFR 820.30. Design controls
(iii) 21 CFR 820.50. Purchasing controls
(iv) 21 CFR 820.100. Corrective and preventive action
(v) 21 CFR 820.170. Installation
(vi) 21 CFR 820.200. Servicing
- The QS regulation and the following provisions from the drug CGMPs in accordance with 21 CFR 4.4(b)(2) (considered a QS regulation-based streamlining approach):
(i) 21 CFR 211.84. Testing and approval or rejection of components, drug product containers, and closures
(ii) 21 CFR 211.103. Calculation of yield
(iii) 21 CFR 211.132. Tamper-evident packaging requirements for over-the-counter (OTC) human drug products
(iv) 21 CFR 211.137. Expiration dating
(v) 21 CFR 211.165. Testing and release for distribution
(vi) 21 CFR 211.166. Stability testing
(vii) 21 CFR 211.167. Special testing requirements
(viii) 21 CFR 211.170. Reserve samples
Chapter 5 should be understood thoroughly. This chapter gives detailed hypothetical scenarios on the approach to CGMP compliance based on three types of combination products, a pre-filled syringe, a drug-coated mesh, and a drug-eluting stent. The change for drug manufacturers will be the importance of focusing on design controls and risk analysis, a familiar activity for medical device manufacturers, but an unfamiliar activity for drug manufacturers.
Read the entire draft guidance here.