When different types of medical products (drugs, devices, and/or biologics) are combined into a single product, the regulatory framework becomes more complex — as diverse sets of regulations begin to overlap. Dspite the fact that these combination products are becoming more prevalent, there are many areas where FDA has yet to establish a clear method for satisfying overlapping and diverse regulations. or example, in the area of good manufacturing practices ("GMPs"), different combination product requirements (current good manufacturing practices ("cGMPs") for pharmaceuticals vs. Quality System regulations for medical devices) overlap, and the lack of a clear regulatory framework can hamper a manufacturer's ability to ensure that its GMP system adequately complies with those requirements. The following are 10 best practices for sorting through and applying GMPs to combination products.
Determine What GMP Requirements Apply
1. Review applicability by constituent parts. To determine which GMP requirements apply to the manufacture of a combination product, manufacturers should first consider the requirements for each of the product's constituent parts. Under FDA's interpretation of existing regulations, constituent parts of a combination product are only subject to their individual governing GMPs prior to being combined, merged, or joined together. When different types of constituent parts are joined together, however, all sets of the individual governing GMPs become applicable.
2. Define the general requirements. For manufacturing stages where all sets of individual GMPs apply (i.e., during and after joining constituent parts),FDA has said that compliance with multiple sets of GMP regulations "can generally be achieved by following one set because under a more general requirement in one set of regulations, it will be possible to develop and implement a practice that complies with a more specific requirement." Manufacturers should begin by considering those GMP provisions that differ in specificity. For a drug-device combination product, for example, a manufacturer should define the key elements of both the pharmaceutical cGMPs and medical device Quality System regulations in relationship to the proposed combination product. Table 1 of FDA's Draft Guidance, Current Good Manufacturing Practice for Combination Products, outlines some of these key areas.
3. Consider any specific requirements. Manufacturers should consider whether there are product-specific requirements that must be satisfied in order to comply with GMP regulations. These types of requirements, which are often determined by the constituent parts incorporated into the combination product, can add a level of complexity to complying with GMPs. Examples of such requirements include good tissue practice regulations and aseptic control assurance for drug and biological product constituent parts unable to withstand terminal sterilization. FDA recommends that manufacturers facing these types of requirements engage in an early conversation with the Agency about achieving compliance with each set of regulations.
4. Outline differences between the applicable quality system regulations. Manufacturers should not seek to implement duplicative or overlapping regulatory requirements. Outlining the differences between applicable GMP requirements can direct manufacturers toward grouping the GMP regulations that are especially relevant to a combination product.
5. Address the gaps. Manufacturers operating under an existing GMP system should consider whether their current system is sufficient to ensure the quality of a combination product. To address gaps in its current GMP system, a manufacturer may need to incorporate elements from other GMP regulations. For example, a drug-device combination product manufacturer may need to adapt portions of the Quality System regulations to supplement an existing pharmaceutical cGMP system. Manufacturers without a GMP system in place should consider how to combine elements of the GMP regulations in order to fully address all aspects of combination product quality.
6. Engage in early discussions with FDA. To assist the regulated community in determining which regulations apply to their products, FDA encourages manufacturers to "discuss with the Agency how current good manufacturing practice regulations apply to their products." Manufacturers should seek FDA's input on implementing a compliant GMP system throughout the development lifecycle. Early collaborations with FDA (during pre-investigational meetings, for example) can help prevent future misunderstandings about which regulations apply.
7. Consider the entire product life. Manufacturers are currently not required to implement provisions of more than one GMP system before joining or merging constituent parts. However, the design control provisions of the Quality System regulations (21 CFR 820.30) are an exception to this rule. A drug-device combination product manufacturer operating under an existing pharmaceutical GMP system, for example, would still need to comply with the design control provisions even prior to joining the constituent parts of the combination product. Thus, it is often advisable for manufacturers to take certain steps in order to achieve compliance once the constituent parts are joined. Manufacturers of combination products should consider laying the groundwork early in the production cycle of a constituent part to ensure compliance with requirements which apply once that part is incorporated into a combination product.
8. Develop a quality plan. Quality planning is “a management activity that sets quality objectives and defines the operational and/or quality system processes and the resources needed to fulfill the objectives.” Manufacturers should establish a quality plan that will help them outline how they will satisfy the applicable GMP requirements.
9. Audit the system regularly. Manufacturers should conduct internal audits in accordance with the schedule specified by the GMP system. Conducting internal audits is one of the best ways to evaluate the adequacy of the existing GMP system. The system should be audited against the applicable GMP regulations as defined in the quality plan. In order to maintain compliance with GMPs, manufacturers must ensure that standard operating procedures ("SOPs") and internal procedures are revised/updated in accordance with audit findings. Manufacturers may need to conduct additional training to help ensure that all personnel are aware of their roles within the combined GMP system.
10. Stay current with the regulatory environment. Being up-to-date with changes in the regulatory environment is a key way to ensure that the GMP system is compliant with FDA's current views. Forthcoming proposed rules from FDA may offer more clarity on how the GMP regulatory framework applies to combination products. In addition to being aware of new and proposed rules, manufacturers should take advantage of the electronic resources that FDA has made available through its website. The most recent versions of FDA guidance documents, for example, can be very useful in understanding the Agency's current thinking. Manufacturers are also encouraged to review FDA's Inspection Guides and Compliance Manuals for specific details on what to expect from FDA during a GMP inspection. Deficiencies cited in recently issued warning letters (e.g.,2006 warning letter from FDA's Los Angeles District Office) can be used as a tool for avoiding potential pitfalls. Involvement in industry groups with a shared product focus or interest can also be a great avenue for anticipating and influencing changes within the regulatory environment.
