2-3. Pharmaceutical Development

1. 2-3. Pharmaceutical Development Satish Mallya Quality Workshop, Copenhagen May 18-21, 2014 May 18-21,2014

2. Outline • Focus on immediate release solid dosage forms • Guidance • Elements • Case Studies May 18-21,2014

3. TRS970 Annex 4 • Overarching Principles: • The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. • Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. May 18-21,2014

4. TRS970 Annex 4/ICH Q8 • Define Quality Target Product Profile (QTPP) as it relates to quality, safety and efficacy considering, for example, the route of administration, dosage form, bioavailability, strength and stability; • Identify Critical Quality Attributes (CQA) of the FPP so as to adequately control the product characteristics that could have an impact on quality; • Discuss CQAs of the API(s), excipients and container-closure system(s)including the selection of the type, grade and amount to deliver drug product of the desired quality; • Discuss the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner. May 18-21,2014

5. QTTP & CQA • Define Quality Target Product Profile (QTPP) as it relates to quality, safety and efficacy considering, for example, the route of administration, dosage form, bioavailability, strength and stability; • Identify Critical Quality Attributes (CQA) of the FPP so as to adequately control the product characteristics that could have an impact on quality; • Discuss CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount to deliver drug product of the desired quality; • Discuss the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner May 18-21,2014

6. QTPP & CQA • QTPP: A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product. • CQA: A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. May 18-21,2014

7. Case Study #1 • Identify the QTPPs and CQAs in the following table (product: 100mg IR tablets) May 18-21,2014

8. TRS970 Annex 4/ICH Q8 • Define Quality Target Product Profile (QTPP) as it relates to quality, safety and efficacy considering, for example, the route of administration, dosage form, bioavailability, strength and stability; • Identify Critical Quality Attributes (CQA) of the FPP so as to adequately control the product characteristics that could have an impact on quality; • Discuss CQAs of the API(s), excipients and container-closure system(s)including the selection of the type, grade and amount to deliver drug product of the desired quality; • Discuss the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner May 18-21,2014

9. CQAs of the API & Excipients • Key physicochemical characteristics of the API that can influence the performance of the FPP: • Physical properties: particle size distribution, bulk and tap densities, crystalline form, hygroscopicity, solubility ; • Chemical properties: stability under temperature, humidity, oxidative, photolytic conditions • Biological properties: permeability, partition coefficient, BCS • The compatibility of the API(s) with each other (FDCs) and with excipients; • The choice of excipients, their concentration and their characteristics that can influence the FPP performance. May 18-21,2014

10. Processes Wet granulation Dry Granulation Direct Compression Milling Milling Milling Pre-blending Pre-blending Blending/lubrication Addition of binder Slugging/Roller Compaction Screening wet mass Dry screening Drying Screening of granules Blending of lubricant Blending of lubricant Tablet compressionTablet Compression Tablet Compression What happens to the API May 18-21,2014

11. CQA of the C/C System • Rationale for selection of the container closure system • Suitability of the container closure system for storage and transportation, including the storage and shipping container for bulk PP • Safety of packaging materials • Protection from moisture and light • Compatibility of the FPP with packaging materials May 18-21,2014

12. TRS970 Annex 4/ICH Q8 • Define Quality Target Product Profile (QTPP) as it relates to quality, safety and efficacy considering, for example, the route of administration, dosage form, bioavailability, strength and stability; • Identify Critical Quality Attributes (CQA) of the FPP so as to adequately control the product characteristics that could have an impact on quality; • Discuss CQAs of the API(s), excipients and container-closure system(s)including the selection of the type, grade and amount to deliver drug product of the desired quality; • Discuss the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner. May 18-21,2014

13. Manufacturing Process Development • Justification for the selection of the manufacturing process and in-process controls; • Appropriateness of the equipment used; • Identification of critical process parameters (CPP) • Justification for differences between the manufacturing processes used to produce batches for bioequivalence studies or primary stability studies and the commercial process. May 18-21,2014

14. Critical Process Parameter (CPP) • A process parameter whose variability has an impact on a critical quality attribute (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality • Blending • Granulation • Drying (LOD) • Compression • Coating May 18-21,2014

15. Other Considerations • Justification for overages • Issues surrounding score line - uniformity testing (i.e. Content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for other situations) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. • In-vitro dissolution • Development of discriminatory method • Generation of dissolution profiles • Optimization and Scale-up May 18-21,2014

16. Optimization Studies • Studies are undertaken to optimize: • quantity of binder • quantity of disintegrant • LOD • Different trial batches having varying amounts of disintegrant and binder are used; • Results of granule flowability, tablet characteristics and comparative dissolution profiles are compared; • Granules with different LOD levels are compressed and results with respect to flowability and tablet characteristics are used to finalize formulation; • The formulation so developed is considered to be optimized when there are no problems (e.g. capping) and the dissolution profile matches the innovator product May 18-21,2014

17. Case Study #2 • Applicant has developed an IR tablet product containing light and moisture sensitive API. The API belongs to BCS class 2 and exists in 2 polymorphic forms. The API constitutes 4% of the formulation. The SmPC reports that the tablets are uncoated and scored bisected May 18-21,2014

18. Thanks Questions ? May 18-21,2014