1. Satish Mallya January 20-22, 2010 1 |1 | 2-3. Pharmaceutical Development Satish Mallya Quality Workshop, Copenhagen May 18-21, 2014 May 18-21,2014

2. Satish Mallya January 20-22, 2010 2 |2 | Outline Focus on immediate release solid dosage forms Guidance Elements Case Studies May 18-21,2014

3. Satish Mallya January 20-22, 2010 3 |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. Satish Mallya January 20-22, 2010 4 |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. Satish Mallya January 20-22, 2010 5 |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. Satish Mallya January 20-22, 2010 6 |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. Satish Mallya January 20-22, 2010 7 |7 | Case Study #1 Identify the QTPPs and CQAs in the following table (product: 100mg IR tablets) May 18-21,2014 Element/AttributeTargetQTPPCQAElement/AttributeTargetQTPPCQA Identificationpositive √ Stability24 M at RT Dosage formTabletDissolutionNLT75%/30min Container/closureBlistersPharmacokineticsBioequivalent to RP Assay100% LCWater contentNMT 4.0% Content uniformityUSP Route of administrationOral √ Strength100 mgRelated substancesInd -NMT0.2% Total:- NMT 1.5% Microbial limitsPh.Eur

8. Satish Mallya January 20-22, 2010 8 |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. Satish Mallya January 20-22, 2010 9 |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. Satish Mallya January 20-22, 2010 10 | Processes Wet granulationDry GranulationDirect Compression MillingMillingMilling Pre-blendingPre-blendingBlending/lubrication Addition of binderSlugging/Roller Compaction Screening wet massDry screening Drying Screening of granulesBlending of lubricant Tablet compressionTablet CompressionTablet Compression May 18-21,2014 What happens to the API

11. Satish Mallya January 20-22, 2010 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. Satish Mallya January 20-22, 2010 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. Satish Mallya January 20-22, 2010 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. Satish Mallya January 20-22, 2010 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. Satish Mallya January 20-22, 2010 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. Satish Mallya January 20-22, 2010 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. Satish Mallya January 20-22, 2010 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 API/ExcipientManufacturing Process CPPOthers TOCWet GranulationBlending (BU)Divisibility: Weight Variation/Content Uniformity XRDDry GranulationGranulationF2 calculations PSDDirect CompressionDrying (LOD)Geometric dilution CompatibilityCompression Coating (spray rate)

18. Satish Mallya January 20-22, 2010 18 | Thanks Questions ? May 18-21,2014