On Jan. 11, the Food and Drug Administration (FDA) published a final guidance document entitled “Current Good Manufacturing Practice Requirements for Combination Products,” which provides the FDA’s recommendations on how manufacturers of combination products can comply with current good manufacturing product (cGMP) requirements. The guidance follows – and closely adheres to – a 2013 final rule (codified at 21 C.F.R. Part 4) that describes which cGMP requirements — i.e., drug, device or biological product — apply to combination products. The final guidance provides greater detail about how manufacturers can implement a streamlined quality management system.

A Streamlined Approach: FDA Expectations

The guidance reiterates a concept that is central to understanding the FDA’s approach to combination products, namely that “[t]he constituent parts of a combination product retain their regulatory status (as a drug or device, for example) after they are combined.” This concept does not mean, however, that separate quality systems specific to each constituent part of a combination product are necessary. Rather, the guidance describes two ways manufacturers can establish an adequate “cGMP operating system.” On one hand, a manufacturer of a drug/device combination product can demonstrate compliance with all cGMP regulations applicable to each of the product’s constituent parts. Or a manufacturer can opt for a “streamlined approach” that allows the manufacturer to demonstrate compliance with either the drug cGMPs (21 C.F.R. Part 210 and 211) or the device quality system regulation (QSR) (21 C.F.R. Part 820) as well as compliance with several specific provisions from the other set of cGMPs.

For example, a combination product manufacturer can implement a drug-based cGMP system by following all drug cGMP requirements and specific provisions from the QSR, or a manufacturer can implement a device-based cGMP system by following all device QSR requirements and specific provisions from the drug cGMPs. The final rule identifies the cGMP provisions that must be implemented in either system, and the guidance elaborates on the FDA’s expectations for implementing those provisions. The QSR provisions include management responsibility, design controls, purchasing controls and corrective and preventive actions, while the drug cGMP provisions include calculation of yield, stability testing, expiration dating, requirements for reserve samples and more.

The streamlined approach generally is limited to single-entity and co-packaged combination products; the guidance reiterates the principle that each constituent part of a cross-labeled combination product remains subject to the cGMP requirements for that particular part (e.g., part 211 for a drug constituent part or part 820 for a device constituent part). However, if constituent parts of a cross-labeled combination product are manufactured at the same facility, the FDA states it will not object to the implementation of a streamlined cGMP system. Notably, the “primary mode of action” of the combination product, which determines the FDA center that has jurisdiction over the combination product, does not dictate which base cGMP system the manufacturer must implement.

Outside of drug/device combination products, the FDA also provides guidance on specific cGMP provisions that manufacturers must follow when their combination products include biological products or human cell and tissue products (HCT/Ps).

In Practice: Hypotheticals for Certain Combination Products

To illustrate implementation of the streamlined approach, the guidance offers hypothetical scenarios for three types of combination products. The scenarios include:

  • Prefilled syringe: drug-based cGMP system, with device-specific QSR provisions
  • Drug-eluting stent: device-based QSR system, with drug-specific cGMP provisions
  • Drug-coated mesh: compliance with device cGMP regulations after a drug constituent is combined with a device

Compliance Considerations: Specific cGMP Requirements

The FDA suggests that manufacturers identify documentation to demonstrate compliance with 21 C.F.R. Part 4 or document justification why compliance is not necessary. The manufacturer’s quality system documentation should identify the type of cGMP system (i.e., drug-based, device-based or biological product-based) and should be provided to FDA investigators at the initiation of an inspection.

The guidance specifically discusses implementation of purchasing controls (21 C.F.R. § 820.50), which is a provision specific to the device QSR, for manufacturers using a drug-based cGMP system for their combination product. Certainly purchasing controls are not unfamiliar to drug manufacturers, particularly in the context of foreign-supplied active pharmaceutical ingredients, but manufacturers may have to augment their existing procedures to meet the specific requirements of 21 C.F.R. § 820.50. For example, the QSR explicitly requires manufacturers to evaluate potential suppliers, document the evaluations and obtain change notification agreements with suppliers where possible.

The FDA also expects coordination across multiple manufacturers involved in the production of a combination product. Combination product owners assume responsibility for the product, including cGMP compliance, even if they are not directly engaged in the manufacturing process. The FDA recommends that the owner ensure compliance through, for example, quality agreements with contract manufacturers and routine audits of their facilities.

Drug manufacturers that plan to market a combination product should be aware of the administrative and technical requirements of the QSR design control provision (21 C.F.R. § 820.30). Importantly, although design control requirements do not apply to all devices, when applicable, they apply even at the investigational stage. For example, manufacturers of combination products with a device constituent to which design controls apply must create a design history file (DHF), a historical file of a product’s development. A DHF contains, among other things, documentation of periodic design reviews and results of verification and validation testing. The guidance suggests that manufacturers can leverage existing product development documentation to satisfy DHF requirements, but drug manufacturers — which may not be familiar with verification or validation testing — may need to carefully consider the testing necessary to ensure their products meet design control requirements.