1. The First Conference for Medicines Regulatory Authorities In Sudan and Neighboring Countries Khartoum - 6-8 December 2014 Alain PRAT, Technical Officer, RSS/EMP/HIS Access to good quality generic medicines: Regulation of multi-sourced pharmaceutical products

2. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 2 |2 | Introduction Two products are pharmaceutical equivalent if they have –the same active ingredient, –the same strength, –The same dosage form, and –The same route of administration And if they meet comparable standards

3. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 3 |3 | Introduction Pharmaceutical equivalent is not always a therapeutic equivalent i.e producing same efficacy and safety profiles –Because of  API particle size  Polymorphism  Excipients  Manufacturing equipment or process  Site of manufacture

4. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 4 |4 | Introduction two pharmaceutical products are bioequivalent if – they are pharmaceutically equivalent and – their bioavailabilities in terms of peak and total exposure does not show a significant difference after administration of the same molar dose –under similar experimental conditions

5. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 5 |5 | P reliminary statement Basic regulatory requirements applied Initial marketing authorization requested Variations submitted in case of changes Quality requirements for API and FPP applied Safety and efficacy requirements applied Submission of documentation on Q/S/E in CTD format Labelling and product information requirements applied Pharmacopeia monographs applicable

6. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 6 |6 | P reliminary statement Basic regulatory requirements applied Assessment by NRA of the submitted documentation Manufacturer licensed and inspected by the NRA GMP compliance requested Pharmacovigilance organized by NRA Treatment of quality defects by NRA Post-marketing surveillance activities by NRA

7. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 7 |7 | P reliminary statement Main derogation By way of derogation the applicant is not be required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is interchangeable with a reference medicinal product Sometimes conditions regarding the MA of the reference products e.g. registered by the same NRA Requirements for bioequivalence studies may differ between countries.

8. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 8 |8 | Active Substance Finished Product CTD Stability Control Drug Product Control of excipients Manufacture Pharmaceutical development Characterisation Control drug substance Manufacture General Information Container closing system Guidelines on Impurities Guidelines on Stability studies Guidelines on specifications & analytical methods Pharmacopea Monographies Container closing system Assessment of quality Same quality guidelines applied Guidelines on Pharmaceutical development

9. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 9 |9 | Assessment of Bioequivalence Critical points: BE study Selection of investigator, Ethics clearance Study design: cross-over or parallel Choice of the subjects, number versus statistical power Choice of comparator /reference products and test products Selection of dose, fasting or fed state, standardization of meals, wash out Pharmacokinetics parameters and statistical analysis WHO Guidelines on interchangeability WHO Guidelines on choice of comparator PQP lists of comparators

10. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 10 | Assessment of Bioequivalence Critical points: Bioanalytical methods Sampling biological fluid: anticoagulants, processing, storage, sampling time Assay of parent drug, metabolites, enantiomer(s) Validation –Limit of quantification –Accuracy –Precision –Selectivity –Stability Calibration and quality control samples Bioanalytical Method validation guidelines

11. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 11 | Differences in Bioequivalence criteria Highly variable pharmaceutical products (products exhibiting greater intra-subject variability) Narrow therapeutic index Criteria on fluid intake, posture and physical activity during the study Minimal number of subject Population (age, BMI)

12. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 12 | Assessment of Bioequivalence Critical points: Waiving BA/BE studies Waiver of in vivo bioavailability and bioequivalence studies –for immediate-release solid oral dosage forms –based on a biopharmaceutics classification system (BCS) Derogations: Pharmaceutically equivalent product don't need equivalence studies (administered parenterally)

13. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 13 | Assessment of Bioequivalence Critical points: Implementation of BCS Drug Substance –Solubility –Permeability Drug products –Dissolution –Excipients Risk assessment Provision of data comparing in vitro dissolution data of Test and Reference drug products WHO Guidance on the implementation of BCS concept

14. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 14 | Differences in API eligibility for BCS CLASS ICLASS II High permeability High solubility Poor solubility WHOYES EMAYESNO FDAYESNO CLASS IIICLASS IV Poor permeability High solubility Poor solubility WHOYESNO EMAYESNO FDANO

15. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 15 | Conclusions Same principals requirements and main guidelines are applied Science based criteria for BE and BCS established in guidelines –for which minor differences may exist globally –need for more harmonisation Literature provides evidence of no change in efficacy or safety profiles Critical differences in the assessment procedures and competencies of NRAs

16. Alain PRAT, Regulatory System Strengthening EMP/HIS WHO/HQ Geneva 16 | Thanks for your attention