Components Of The Finished Pharmaceutical Product and API (Active Pharmaceutical Ingredient):
3.1 Components Of The Finished Pharmaceutical Product:
3.2.P.2.1 The components of the FPP are the ingredients listed under section 3.2.1.P.1 (Description and composition of the FPP in the PD). The components thus include the API(s) and all the excipients, as well as those excipients that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. water for granulation) and any others (e.g. nitrogen or silicone for stoppers).
3.1.1 (API) Active Pharmaceutical Ingredient:
3.2.P.2.1.1 The compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed.
Physicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.
Information on the intrinsic physicochemical properties of the molecule, e.g. solubility, solid-state properties, including polymorphism and habit, melting range, pK_a and hygroscopicity, is needed for the development of the product to allow the manufacturer of the FPP to take full responsibility for the quality and quality control (QC) of the API and the FPP.
Additionally, the manufacturer will need information (either from the API manufacturer, or gathered by another party, or by itself) on potentially critical properties of the API, together with specifications, as applicable, e.g. solubility at 37 °C at relevant physiological pH values to permit BCS classification of the API, partition coefficient (octanol/water) at 37 °C and particle size distribution, which may affect dissolution rate and bioavailability, as well as density, bulk and tapped density, flowability, compressibility, and other factors which may influence processibility. The above-mentioned properties of the API should usually be supported by experimental data (or by information from peerreviewed literature) and discussed with respect to CQAs and CPPs.
The specifications of the API manufacturer and the retest period or expiry date derived from formal regulatory stability studies should also be available to the manufacturer of the FPP.
Guidance on compatibility studies is provided in Appendix 3 of the WHO Guidelines for registration of fixed-dose combination medicinal products (6). In addition to visual examination, chromatography results (assay, purity) are required to demonstrate API–API and API–excipient compatibility. In general, API–excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.
Stress testing of the API should be designed to include simulation, as far as possible, of the conditions that may be encountered during the manufacturing process of the FPP. An example is provided in Appendix 1.
Pharmaceutical Development of multi source (generic) Finished Pharmaceutical Products - points to consider, (Annex 3, WHO Technical Report Series 970, 2012)
