1. Finished Pharmaceutical Product Specifications Rutendo Kuwana Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Control of FPP Four subsections Specifications Analytical procedures Validation of analytical procedures Batch analysis (against full set of specifications) Full info on three or more batches e.g. Batch number and size Date/place of manufacture and QC testing Purpose of batches Batch number of API 2

3. Specifications for the FPP Specifications are one part of a total control strategy for the FPP designed to ensure product quality and consistency Others include sound development studies and adherence to GMP; e.g., suitable facilities, a validated manufacturing process, in-process testing, stability testing, API testing, etc. 3

4. Biobatch vs Specifications For the PQP, specifications should be designed to ensure consistency with the biobatch. This then becomes the starting and central point for dossier assessment

5. Steps in setting specifications • Identify critical product and process atributes • Evaluate regulatory requirements • Evaluate stability trends

6. Critical Product Attributes • Safety • Efficacy • Quality • Physical • Chemical • Microbiological • Biological • Functionality

7. Product Attributes – Example, Oral Suspension • Presentation to the Patient • Child resistant closure • Tamper evident packaging • Accurate dosing of correct medication • Description (appearance, colour, odour) • Identification (API, Preservatives) • Dose delivery device (Physical characteristics of liquid – viscocity, particle size) • Uniformity of content, resuspendability, dissolution

8. Specifications for the FPP Should be as stated in the Pharmacopoeia; or Release End of shelf life the concept applies only to products and establishes more restrictive criteria for the release of the product Compendial requirements – General chapters e.g. Dissolution, residual solvents AND specific monographs 8

9. FPP specifications (2) Important reading for setting specifications: ICH guideline Q6A (also good for generics):Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. ICH Q3B (R2): impurities in new drug products ICH Q3C (R3): Impurities – Guidelines for Residual Solvents ICH Q8 (2): Pharmaceutical development ICH Q10: Pharmaceutical quality system 9

10. Specifications based on Compendial monographs • Additional product related specifications, e.g. • Those standard for the type of dosage form (e.g. friability, tablet hardness, mass uniformity, viscosity) • ID of colorants (skip testing?) • microbial limits (skip testing?) • ID and assay of preservatives • Limits may be tighter than in monograph

11. FPP specificationsTypical parameters (2) Appearance Identification of the following in FPP APIs Colorants (skip testing possible) Preservatives Physical tests appropriate to dosage form e.g. LOD, friability, hardness (tabs) Uniformity of dosage units (mass / content) Pharmaceutical tests, e.g. dissolution Each API in FDC products 11

12. FPP specificationsTypical parameters (3) Purity tests Degradation products (related substances) Special attention to API-API degradation products Residual solvents (solvents used in process) Microbial count / sterility / bacterial endotoxins Content of APIs in FPP (assay) Limits 95.0% – 105.0%, unless justified Content of preservatives Limits 90.0% – 110.0%, generally acceptable 12

13. FPP specificationsExample for uncoated tablets (1) 13

14. FPP specificationsExample for uncoated tablets (2) 14

15. Analytical procedures • Should be presented with sufficient detail to enable the procedure to be repeated by another laboratory • If a test is based on a Pharmacopieal monograph, a copy of the monograph + any methods referenced in the monograph must be submitted • Details of any specifications and test methods additional to those in the pharmacopoiea must be submitted

16. General Requirements for justification of specifications • It is normally not necessary to test the FPP for synthesis impurities that are controlled in the API and are not degradation products • When a specification is first proposed, justification should be presented for each procedure and each acceptance criterion included. The justification should refer to relevant development data, pharmacopoeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long term stability studies, as appropriate • Test results from stability and scale-up / validation batches, with emphasis on the primary stability batches, should be considered in setting and justifying specifications.

17. Use of reference standards • If a primary reference standard is available, then it should be used • When not available, then a reference standard should be developed and qualified (See ICH Q6A) – information on tests to establish identity, purity and assay value should be provided • Secondary working standards – content should be assayed relative to the primary reference standard using the same assay method