1-7.The ICH Q8 “Minimal Approach” to Pharmaceutical Development

1. 1-7.The ICH Q8 “Minimal Approach” to Pharmaceutical Development Satish Mallya January , 2011

2. Pharmaceutical Development Q8(R2) • The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. • The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. January 19-22, 2011

3. Pharmaceutical Development Q8(R2) • At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. • Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product. January 19-22, 2011

4. ICHQ8 Empirical (Minimal) Essential product development for all productsvs Enhanced (QbD) Quality by Design Critical understanding of product and process January 19-22, 2011

5. Approaches & Outcomes January 19-22, 2011

6. “Minimal” Approach • Establish Quality Target Product Profile (QTPP) • Identify Critical Quality Attributes (CQA) of the FPP • Investigate quality attributes of the API and formulation ingredients • Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). • Outline pertinent control strategies. January 19-22, 2011

7. “Minimal” Approach • Establish Quality Target Product Profile (QTPP) • Identify Critical Quality Attributes (CQA) of the FPP • Investigate quality attributes of the API and formulation ingredients • Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). • Outline pertinent control strategies. January 19-22, 2011

8. Quality Target Product Profile (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. January 19-22, 2011

9. Quality Target Product Profile (QTPP) • QTPP is the basis of design for the development of the product • Considerations for establishing QTPP: • Indication & route of administration • Dosage form & strength(s) • Container closure system • Attributes affecting pharmacokinetic characteristics (e.g., dissolution) • FPP quality criteria (e.g., sterility, purity, stability and drug release) January 19-22, 2011

10. Quality Target Product Profile (QTPP) • The following are generally identified as elements of QTPP: • Assay of API in the FPP • Purity • Content Uniformity of API in the FPP • Disintegration/Dissolution of FPP • Tablet Friability & Hardness • Stability/Suitability of Container Closure System • Bioequivalence Various formulations are investigated in order to obtain similar dissolution patterns as for the innovator product and to improve the disintegration time. On achieving satisfactory results in the lab scale batches scale up is undertaken to ensure reproducibility of results on larger scales. January 19-22, 2011

11. Quality Target Product Profile January 19-22, 2011

12. “Minimal” Approach • Establish Quality Target Product Profile (QTPP) • Identify Critical Quality Attributes (CQA) of the FPP • Investigate quality attributes of the API and formulation ingredients • Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). • Outline pertinent control strategies. January 19-22, 2011

13. Critical Quality Attribute (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. January 19-22, 2011

14. Critical Quality Attribute (CQA) • Additional CQAs for APIs, raw materials and intermediates: properties that affect FPP CQAs (e.g., particle size distribution, bulk density) . • Potential drug product CQAs are utilized to guide the product and process development. The list of potential CQAs may be modified as product knowledge and process understanding increase. January 19-22, 2011

15. “Minimal” Approach • Establish Quality Target Product Profile (QTPP) • Identify Critical Quality Attributes (CQA) of the FPP • Investigate quality attributes of the API and formulation ingredients • Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). • Outline pertinent control strategies. January 19-22, 2011

16. Quality Attributes of the API • API Characterization • Physical • Chemical • Biological • For FDC products, evaluate the compatibility of the APIs with each other. The knowledge gained from the studies investigating the potential effect of API properties on FPP performance can be used to justify tests in the API specification January 19-22, 2011

17. API Characterization • Physical properties: • Appearance • Particle size • Bulk and tap densities • Crystalline form • Hygroscopicity & water content • Solubility and pH profile of solution/dispersion January 19-22, 2011

18. API Characterization • Chemical properties • Stability • temperature • humidity • oxidative • photolytic • Biological properties • permeability • partition coefficient • BCS January 19-22, 2011

19. Excipients • Function in formulation • Affect on performance of FPP • Stability • Bioavailability • Affect on manufacturability of FPP • Ability to perform during shelf-life • Disintegrants • Preservatives • Antioxidants • Safety of Novel Excipients January 19-22, 2011

20. FPP • Identification of attributes critical to the quality of the drug product • Justification for choice of drug product components • properties of the drug substance • Properties of excipients • Suitability of container closure system • Justification for choice of the manufacturing process • Summary of formulations used in bioequivalence studies • justification for changes between the proposed commercial formulation and those formulations used in bioequivalence batches and primary stability batches • Justification for score line • Justification for overages January 19-22, 2011

21. Container Closure System • Rationale for selection of the container closure system • Safety of packaging material • Suitability of the container closure system for storage and transportation, including the storage and shipping container for bulk PP • Compatibility of the FPP with packaging materials • Integrity of the container and closure • Justification for the use of secondary packaging materials January 19-22, 2011

22. Compatibility • Compatibility of the drug product with reconstitution diluents • Range of diluents • Range of dilutions • Container types • Storage recommendations • Compatibility and stability of admixtures obtained from further dilution of reconstituted products prior to administration. January 19-22, 2011

23. Microbiological Attributes • Rationale for performing or not performing microbial limit testing for non sterile drug products • Evidence of effectiveness of preservative • At the lowest specified concentration • Over shelf-life • Antimicrobial effectiveness of products that are inherently antimicrobial January 19-22, 2011

24. “Minimal” Approach • Establish Quality Target Product Profile (QTPP) • Identify Critical Quality Attributes (CQA) of the FPP • Investigate quality attributes of the API and formulation ingredients • Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). • Outline pertinent control strategies. January 19-22, 2011

25. 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. Collection of process monitoring data during the development of the manufacturing process can provide useful information to enhance process understanding. January 19-22, 2011

26. 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. January 19-22, 2011

27. Critical Process Parameter (CPP) • Blending • Granulation • Drying (LOD) • Compression • Filtration • Sterilization January 19-22, 2011

28. “Minimal” Approach • Establish Quality Target Product Profile (QTPP) • Identify Critical Quality Attributes (CQA) of the FPP • Investigate quality attributes of the API and formulation ingredients • Select an appropriate manufacturing process and establish the Critical Process Parameters (CPP). • Outline pertinent control strategies. January 19-22, 2011

29. Control Strategy • A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. • Is intended to ensure that a product of required quality will be produced consistently Sources of variability that can impact product quality should be identified, thoroughly understood and appropriately controlled January 19-22, 2011

30. Thanks