3.3 Manufacturing Process Development:
3.2.P.2.3 The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.
For products that meet the criteria of an established multi source product, in order to fulfill the requirements of section P.2.3, section P.2.3 (b) of the dossier should be completed and a product quality review should usually be submitted as outlined in Appendix 2 of the WHO Guidelines on submission of documentation for a multi source (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (1). The guidance below applies to all other products, for which section P.2.3 should be completed in its entirety.
The rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery system) should be provided in the PD. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence quality and performance of the FPP should usually be explained
(e.g. wet granulation using high-shear granulator). The results of an API stress study may be included in the rationale. Any developmental work undertaken on protecting the FPP from deterioration (e.g. protection from light or moisture) should also be included.
The manufacturing process of the multi source FPP should be appropriate for the product that is in development. It does not need to be the same as that of the comparator FPP.
Efforts should be primarily directed towards reducing variability in process and product quality. In order to achieve this, all critical sources of variability should be identified and explained and the sources of variability should be minimized and controlled.
Process development studies should provide the basis for process improvement, process validation and any process control requirements. All CPPs should usually be identified, monitored or controlled to ensure that the product is of the desired quality.
For sterile products an appropriate method of sterilization for the pharmaceutical product and primary packaging material should be chosen. Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided in the PD.
Differences between the manufacturing process(es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3.3 that can influence the performance of the product should be discussed.
The scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should usually be explained, in particular the CPPs (e.g. rate of addition of granulating fluid, massing time, and granulation end-point). A discussion of the CPPs, controls and process robustness with respect to the QTPP and CQA of the product should usually be included (10).
Based on close monitoring of the manufacturing process in the pilot batches, provisional acceptance ranges should be proposed for the CQAs of intermediates and CPPs that impact on downstream processing. Interim acceptance criteria may be approved until enough knowledge is available to
finalize CQAs of intermediates and CPPs for production batches.
The manufacturing process used for pilot batches should be the same as the one proposed to be applied to production batches and should provide product of the same quality and meeting the same specifications as that intended for marketing.
Pharmaceutical Development of Multi source (generic) Finished Pharmaceutical Products – points to consider, (Annex 3, WHO Technical Report Series 970, 2012)
