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6 Pharmaceutical Technology QUALITY AND REGULATORY SOURCEBOOK EBOOK MARCH 2022 P h a r mTe c h . c o m Quality: Validation drug-embedded/eluting stent. The definition used in the United States for combination products by FDA is found in 21 Code of Federal Regulations (CFR) 3.2(e) (1). FDA has identified nine different possible combination products that fall into the pur- view of the Office of Combination Products. FDA identifies and describes nine different types of combination products, ranging from co-packaged convenience kits; to prefilled delivery device/systems where the sole purpose of the device is to deliver the drug or biologic product; to devices that are coated, impregnated, or otherwise combined with a drug; to coated devices in a device scaffold that have an addi- tional function beyond drug delivery; to drug/biologic combinations; to separate products labeled for use with a specific light source device; to combination products that contain two different combination product types. Of these, the authors consider two different types of combination products. The first concerns drug/ biologic-led combination products: the primary ef- fect of the product is driven by the drug/biologic. An example of this type of combination product is a pre-filled syringe, where the device is used to deliver the drug/biologic to the patient. The second type of combination product consists of a device-led combi- nation product, where the primary effect is related to the device characteristics. An example of a device-led combination product is a drug/biologic-coated stent, where the primary effect of the product is due to the device action. In either case, the tests used to evaluate the products will require a validation of test methods. Product and device design interrelation Medical devices, biologics, drugs, and combination products all require specifications that describe the product's potency, quality, purity, and performance attributes. For drugs and biologics, specifications are established in relation to the quality target product profile as per International Council for Harmonisa- tion (ICH) Q8(R2) guidance (2). For devices, specifica- tions are set according to the design requirements in the device design specification (Design Controls, 21 CFR 820.30) (3). Both sets of requirements should be considered when validating test methods for combi- nation products. Typically, methods used to test com- bination products are evaluated during the discovery and feasibility phases of product development, where it is important to consider the interrelationship between the device and the drug/biologic. Method development Establishing a procedure to test an attribute of a prod- uct using a measurement device or instrument can be simple or complex, depending on the attribute of the product being tested. For example, a method for testing the assay and impurities of a drug substance may not be suitable for the analysis of a combination product. Interactions among the device components may cause additional degradation products to be gen- erated that are not detected with the drug substance method; or the requirements for sample preparation may result in sample concentrations that are lower than the working range of the drug substance method. If one were to validate or verify just the drug sub- stance method, analysis of the manufactured com- bination product with the method would likely be unacceptable. Consequently, the development of com- bination product methods should consider the poten- tial impacts of the drug/biologic and device on the ex- ecution, performance, and output results of the method. Method validation guidelines Validation of analytical methods is expected and re- quired for marketing applications and approval.