(Slightly More) Options for cGMP for Combination Products: FDA Describes Alternative or Streamlined Mechanisms for Compliance

FDA recently published Alternative or Streamlined Mechanisms for Complying with the Current Good Manufacturing Practice Requirements for Combination Products; List under the 21st Century Cures Act in the Federal Register (FR Notice).  By way of background, 21 C.F.R. § 4.3 requires generally that manufacturing of a combination product (CP) must comply with the applicable current Good Manufacturing Practice regulations (cGMPs) for all of its components (i.e., a drug/device CP must follow the cGMPs for drugs as well as those for medical devices).  21 C.F.R. § 4.4 provides an optional alternative streamlined approach for current good manufacturing practices (cGMPs) for manufacturers of drug-device combination products (CPs).  The 21st Century Cures Act required FDA to publish in the Federal Register a list identifying types of CPs and manufacturing processes that may vary from the requirements of § 4.4, or that FDA proposes can satisfy the requirements in § 4.4 through alternative or streamlined mechanisms.  FDA must also review the list periodically.  FDA published a proposed list on June 13, 2018 (83 FR 27609), which we blogged about here.

The recent FR Notice does not modify § 4.4, but instead describes FDA policy on applying § 4.4, much like an FDA guidance document.  The FR Notice also emphasizes in several places that interaction with the Agency may be needed when applying alternative or streamlined mechanisms for complying with cGMP requirements for CPs.

For manufacturers of CPs that have established a quality system that complies with the full requirements of 21 C.F.R. Part 820 Quality System Regulation and additional provisions from 21 C.F.R. Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, the list describes alternative mechanisms for complying with the requirements in § 211.165 Testing and Release for Distribution, § 211.166 Stability Testing, § 211.167 Special Testing Requirements, and § 211.170 Reserve Samples.

The list of alternative mechanisms for complying with Part 211 in this FR Notice is not different from what was proposed in the 2018 FR Notice.  Of the six comments FDA received on the 2018 FR Notice (five were published), only one raised Part 211. FDA added some clarifying language or examples (shown below in italics) to the Part 211 list:

• Section 21 C.F.R 211.165 – Testing and Release for Distribution: Manufacturers may be able to use product samples that are not finished combination products when performing the required testing, but they would need to establish that any differences in the manufacturing process for the sample used, as compared to the finished combination product, do not affect the drug constituent part (i.e., there is no difference in the quality attributes related to the drug constituent part in the representative sample as compared to the attributes related to the drug constituent part in the finished combination product).

• Section 21 C.F.R 211.166 – Stability Testing: Manufacturers may be able to leverage stability knowledge, data, or information for an already marketed combination product, for example, when the new combination product is a modification of an already marketed product and the modification does not impact the stability of the drug constituent part.
• Section 21 C.F.R 211.167 – Special Testing Requirements: Manufacturers may be able to define “batch” based on the drug constituent part rather than the finished combination product for purposes of special testing requirements involving pyrogens and endotoxins. This mechanism would only potentially be available if there would be no impact on the endotoxin and pyrogen levels for the finished combination product from subsequent manufacturing processes, including when the constituent parts are combined to produce the final combination product (e.g., there are no statistically significant differences in pyrogen or endotoxin test results for the combination product immediately following a drug coating process step as compared to the finished combination product).
• Section 21 C.F.R 211.170 – Reserve Samples: Manufacturers may be able to use validated surrogates as representative samples to meet the requirements of this regulation, provided the surrogate is appropriate, both in terms of the manufacturing process and the characteristics of the container closure. It may be permissible to maintain as a reserve sample only the drug-containing subassembly of a single-entity combination product, such as only the distal tip subassembly (with drug-containing collar) of a pacemaker lead without the associated internal electronic components, or the drug constituent part of a co-packaged combination product, such as the prefilled cartridge of a combination product that is distributed as a prefilled cartridge with an injector system.

For manufacturers of CPs that have established a quality system that complies with the full requirements of 21 C.F.R. Part 211 and additional provisions from 21 C.F.R. Part 820, the list provides information on integration of the design control requirements within a pharmaceutical development program and discussion of exemption from cGMP requirements for applicable device constituents.

The FR Notice notes that many design control requirements may be addressed by a robust pharmaceutical development program, but adds that it is important to align terminology with design control principles and ensure that any design control elements not covered by pharmaceutical development procedures are documented.  Emphasis is placed on ensuring that management of postmarket design changes to the CP follows the requirements of § 820.30.

Some low-risk devices  are exempt from cGMPs except for complaint handling and record keeping requirements, e.g., a liquid medication dispenser (21 C.F.R. § 880.6430).  The FR Notice clarifies that these devices may also be exempt from the provisions of Part 820 called out in §4.4.  For determining if the device constituent of a CP is GMP exempt, the FR Notice references the .9 regulations (e.g. § 880.9).  Although the .9 regulations describe limitations for 510(k) exemption and not GMP exemption, FDA intends to apply the same exemptions for purposes of determining if the device constituent of a CP is GMP exempt.

For any specific CP there can be nuances, so interaction with the Agency may be warranted to obtain FDA feedback prior to making a premarket submission or submitting a postmarket supplement.  The FR Notice provides guidelines on types of interactions and information to provide in a request.

Overall, the FR Notice provides additional options for CP manufacturers to reduce burdens by streamlining their approach to cGMPs, but FDA wants to be involved in decisions to use these approaches.