2. Designing quality in Colin R Gardner, Currently: CSO, Transform Pharmaceuticals Inc Lexington, MA, 02421 Formerly: VP Global Pharmaceutical R&D Merck & Co Inc. Acknowledgement for useful discussions: Dr. Scott Reynolds, Executive Director, Pharmaceutical Development, Merck and Co Inc. www.transformpharma.com Presentation to Manufacturing Subcommittee of the FDA Advisory Committee for Pharmaceutical Science. Sept 17, 2003

3. Summary Continuum of process development activities from NCE selection through manufacturing Fundamental NCE characterization and process development leads to meaningful control points Success of the scale up exercise is judged by rational comparison of meaningful process and product parameters Fingerprint parameters are identified to monitor process robustness and used to flag issues before control is lost

4. Issues within the industry

5. Lifecycle Management Development 0.5 - 2 yrs1 - 2 yrs1.5 - 3.5 yrs2.5 - 4 yrs0.5-2 yrs R&D takes 6.5 - 13.5 years Up to $800MM Discovery Drug Discovery / Development / Marketing Market 2-5 yrs Submission& Approval 10-20 yrs Source: PRTM Phase 3 Phase 2a/bPhase 1 Pre- clinical Development Targets Hits Leads Candidate Challenges: - Find safe and effective drugs - Speed to market

6. Drug company products Approved label claim used to position product in the market The marketed dosage form(s) The API

7. Drug company products Approved label claim used to position product in the market The marketed dosage form(s) The API

8. Intra-company Consequences R&D heads focus on potency, selectivity, safety and clinical response do not uniformly recognize the importance of investment in process chemistry and formulation development Inexperienced clinical staff often set timelines and targets independent of product development capabilities The goals and rewards of Discovery, Development and Manufacturing staffs are often not aligned CEO’s have not regarded manufacturing excellence as a competitive advantage

9. Issues created by the regulatory agencies Depth of understanding of process engineering Timeframe to review and understand the regulatory filing Training of compliance inspectors – especially for PAI’s

10. PAI examples

11. Scaling up a suspension formulation Batch sizeBiobatch 10 liters Commercial batch 100 liters Mixing time 15 mins45 mins drugexcipients drugexcipients FDA inspector conclusion: “The processes are different”

12. Preparation tank Filling tank Filling points Re-circulating filling line Pump Suspension formulation preparation and filling FDA inspector conclusion: “Any stoppage of the filing process > 15 mins should result in destruction of the entire batch Preservative adsorption to tubing

13. What can we do about this situation? Manufacturing processes start with the choice of the NCE, its form and formulation We must link discovery, early development, process scale-up and manufacturing

14. Develop methodologies to improve: Candidate selection Form selection and Formulation design Process development and optimization Process control Scale-up and tech transfer Process validation Process monitoring and continuous improvement Demonstrate reduced risk to regulatory agencies Obtain regulatory relief Demonstrate value to company management Industry role

15. HOW?

16. Building in “developability” 1. Picking better development candidates:

17. DiscoveryDevelopment Target HTS Synthetic chemistry Scale up 100-500mg Animal model Probe Tox, PK, met Pre-clinical Research & Early Development Process 2-4 cmpds GLP Tox F & F Process chemistry Sample collection in vitro selectivity in vitro metabolism in vitro Tox Animal model efficacy Early Discovery Lead optimization Pharm. Sci. Ph I GenomicsLibraries Hits to Leads Lead optimization

18. New R&D Challenges Drug Discovery Preclinical development Clinical development Resource constraints Time constraints Discovery revolution Pharmaceutical Development

19. DiscoveryDevelopment Target HTS Synthetic chemistry Scale up 100-500mg Animal model Probe Tox, PK, met 2-4 cmpds GLP Tox F & F Process chemistry Sample collection in vitro selectivity in vitro metabolism in vitro Tox Animal model efficacy Early Discovery Lead optimization Pharm. Sci. Ph I GenomicsLibraries Hits to Leads Lead optimization Pre-clinical Research & Early Development Process

20. Candidate selection: Building in “Developability” Lead (active molecule) Metabolism Selectivity Potency LO (optimized molecule) Physical properties Potency Selectivity Metabolism Best leads Physical / chemical properties Biopharmaceutics

21. 2. Form and formulation selection

22. Product Development Timeline Develop Synthetic Route First Supplies Non GLP Probes IND/Phase I/II Safety Drug Substance Transfer to Manufacturing Validation Safety Assessment Extended Safety Studies Degradate Qualification Carcinogenicity PAI Launch Quantities Product Development Preformulation Studies Biopharm Evaluation Formulation Design Phase I/IIA Formulations Analytical Methods Composition & Process Defined Probe Stability $5-10MM Process Development and Scale Up Biobatch Specifications MCSS Transfer to Manufacturing First in Man Phase IIB Approval Develop Process and Scale-up Establish Specifications Phase I/IIA Wide Dose Range Multiple Formulations Phase IIB Dose Range Phase III Final process >1/10 scale PAI Discovery Launch Validation Launch Quantities Clinical Program Phase III $250-800MM 3-10 years 4-8 years File NDA WMA crg development timeline

23. Exploration of solid forms solvent process impurity or degradate process (t,T) Traditional     process (t,T) process impurity or degradate solvent High throughput 

24. Crystalline Trihydrate Solubility ~0.73 mg/mL Weakly Crystalline Anhydrous Form Solubility >100 mg/mL

25. Ritonavir: HIV protease inhibitor  ABT-538 discovered  Launch of semi-solid capsule/polymorph I  Polymorph II appears, <50% solubility  Product pulled from the market  Massive effort to reformulate the product  Reformulated softgel capsule launched Case history: 1992 1996 1998 1998 - 1999 1999

26. Summary of Ritonavir Crystal Forms IV mp 122 °Cmp 125 °Cmp 80 °Cmp 97 °C mp 116 °C Launch in 1996 Summer of 1998 TransForm 2002 – 6 week effort Launch in 1996 Summer of 1998 Morissette et al. PNAS 100, (2003). 2002 5 forms found

27. TPI 745: New salt form with improved solubility Solubility

28. New TPI Form Has Faster Onset Salt form with “solubility modifier” 30 mpk P.O. 0 5000 1 10 4 1.5 10 4 2 10 4 02468 TPI-745A TPI-745B time, hours C max T max AUC TPI-A 23.2±6.2 1.3±1.0 * 139±26 TPI-B 19.6±4.6 2.1±1.1 135±24 T-745 21.4±4.0 2.8±1.6 150±43 Parent

29. Faster Onset, Increased Bioavailability and Linear Dose Response New form & formulation combination significantly improves dissolution, resulting in better onset and bioavailability

30. The current norm     The future  environmental raw material properties process conditions environmental raw material properties process conditions 3. Process development

31. Pharmaceutical Process Development: Objectives Provide a continuous link from early phase characterization to final manufacturing process Define process based on unit operations approach Provide a road map for tracking success of scale up activities and technology transfer Enable effective process monitoring and improvements

32. Pharmaceutical Process Development: Initial Design Identify parts of process which are most susceptible to failure upon scale-up Conceptual “scale down” of the final manufacturing process into the pilot plant and the lab

33. Process Understanding Determine fundamental process constraints –Where appropriate, utilize unit operations which are most forgiving – lower risk Identify underlying principles which control process –Avoid “black box” analysis –Identify appropriate process parameters to monitor and control - value of PAT - provides confidence about process robustness

34.   Pharmaceutical Process Development: Optimization environmental raw material properties process conditions    environmental raw material properties process conditions Optimization Studies –Find regions of process parameters where performance is most stable –Design process to operate within this region.

35. Process optimization Region where process is unstable Process most stable Target values

36.   environmental raw material properties process conditions    Pharmaceutical Process Development: Optimization environmental raw material properties process conditions Optimization Studies –Find regions of process parameters where performance is most stable –Design process to operate within this region. Process Robustness –Stress ranges of variables –Include ranges in materials, environmental conditions, process parameters

37. Region where process is robust Region where process is unstable Process most stable Target values Process optimization

38. Pharmaceutical Process Development: Process Control Define process through measurable, quantitative endpoints – PAT? Eliminate dependence upon qualitative endpoints Evaluate how process can respond to variations in process equipment performance and/or raw materials characteristics Provide continuous fingerprint of process performance – NOT regulatory specifications

39. Pharmaceutical Process Development: Continuous Improvement “Hooks” for future process improvement. –Plan into development program collection of “fingerprint” data for future comparisons –Design validation protocols to collect similar “fingerprints” –Use in manufacturing to continuously monitor process operation and status

40. Process optimization Region where process is unstable Process most stable Target values Region where process is robust Fingerprint region to monitor process robustness and prospectively identify drifts

41. Summary Continuum of process development activities from NCE selection through manufacturing Fundamental NCE characterization and process development leads to meaningful control points Success of the scale up exercise is judged by rational comparison of meaningful process and product parameters Fingerprint parameters are identified to monitor process robustness and used to flag issues before control is lost