The rapid development of combination products—biologics, pharmaceuticals and their devices—provides great opportunity for technological advancement, opening new doors for patient health and improved compliance with administration requirements. The complexity of these systems often requires the device to be developed alongside the drug that it will contain. Whether wearables, injectables or transdermal delivery systems, concerns of maintaining a firm grip on quality and stability throughout the design, manufacturing and product lifecycle process means understanding the GMP requirements of each component. Both are critical to product and compliance success.

Combination drug/device products as defined by FDA’s 21 CFR part 3 must comply with 21 CFR part 4 subpart A, current Good Manufacturing Practice (GMP) requirements for combination products (see January 2017 Final Guidance, Current Good Manufacturing Practice Requirements for Combination Products). Whether approved by CDRH, CDER or CBER, (generally only one approval is required based on the product’s most “significant” attribute or mode of action), device design controls (21 CFR part 820.30) must confirm there are no negative interactions between constituent parts and assure the combination product is safe and effective, performing as expected. Additionally, pharmaceutical quality must also address product design and development procedures, so it is critical that both sets of requirements are coordinated in the design and development stage. A reminder that cGMPs are minimum standards by which products shall be manufactured.

Oftentimes during development of combination products each product side understands their own regulatory requirements better than that of their combination component. From formulation, excipient selection, manufacturing controls, appropriate storage conditions and more, every facet of development must be considered in totality with the requirements for both aspects of the drug (or biologic) and its combination device. Properties that influence the rate of delivery, including characteristics of the drug substance such as particle size, must be considered with optimum product quality attributes and evaluated in terms of product performance. The principles of Quality by Design through In-process controls (IPCs) should be applied throughout the lifecycle to ensure products have the identity and strength, and meet quality and purity characteristics as required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. It should be noted that the constituent parts of a combination product will retain their regulatory status (e.g., as a drug or device) even after they are combined and it is recommended that manufacturers implement a streamlined regulatory approach that demonstrates compliance with either the drug cGMPs (21 CFR parts 210 and 211) or the device Quality System (QS) regulation (21 CFR part 820) and also demonstrate compliance with any specified provisions of cGMP requirements.

Per FDA’s 2017 Final Guidance on GMPs, combination product manufacturers may meet the requirements of both drug cGMPs and device QS regulation by designing and implementing a cGMP operating system that demonstrates the most efficient compliance. While compliance with all cGMP regulations applicable to their combination product under 21 CFR 4.3 must be demonstrated, a streamlined approach may be used under 21 CFR 4.4(b).

For example, drug cGMPs may use the following provisions from the device QS regulation in accordance with 21 CFR 4.4(b)(1) (drug cGMP-based streamlined approach):¹

1. 21 CFR 820.20 Management responsibility
2. 21 CFR 820.30 Design controls
3. 21 CFR 820.50 Purchasing controls
4. 21 CFR 820.100 Corrective and preventive action
5. 21 CFR 820.170 Installation
6. 21 CFR 820.200 Servicing

OR

Device QS regulation may use the following provisions from the drug cGMPs in accordance with 21 CFR 4.4(b)(2) (device QS regulation-based streamlined approach):¹

1. 21 CFR 211.84 Testing and approval or rejection of components, drug product containers, and closures
2. 21 CFR 211.103 Calculation of yield
3. 21 CFR 211.132 Tamper-evident packaging requirements for over-the counter (OTC) human drug products
4. 21 CFR 211.137 Expiration dating
5. 21 CFR 211.165 Testing and release for distribution
6. 21 CFR 211.166 Stability testing
7. 21 CFR 211.167 Special testing requirements
8. 21 CFR 211.170 Reserve samples

Both options are viable, depending on the manufacturer’s circumstances, however, the facility’s quality system documentation should identify which cGMP operating system is utilized for the combination product(s) manufactured at that facility.

To that end, FDA has been working to facilitate partnership, collaboration and coordinated development of combination products with the publication of various guidance documents including GMPs, postmarket safety and surveillance, human factor and transdermal delivery systems. The Office of Combination Products, which assigns the appropriate regulatory review office, and the Combination Products Policy Council (CPPC), which acts as an intermediary between industry and the FDA, ensure good communication and facilitate resolution of disputes.

It is imperative that management are actively engaged in oversight of the quality system and demonstrate an active, ongoing commitment to the quality system’s development and implementation. Particularly in the case of combination products, understanding how to comply with both sets of cGMPs and which should take precedence can be confusing at best and warrant and injunction order at worst. As your product development team begins the process of creating or reviewing policies and procedures that ensures operation under the correct GMP systems, invite both the drug and device side of the business to the table so that each set of regulatory requirements is met or exceeded, and done so with integrity.

Reference

1. FDA. (January 2017). Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products. Final Guidance.