EMERGING ISSUES AND CONSIDERATIONS IN MANUFACTURING QUALITY CONTROL AND ASSURANCE OF DRUG PRODUCTS

1. EMERGING ISSUES AND CONSIDERATIONS IN MANUFACTURING QUALITY CONTROL AND ASSURANCE OF DRUG PRODUCTS Yi Tsong, Ph.D., Acting Deputy Director Quantitative Methods and Research Staff OB, OPaSS, CDER, FDA This presentation does not necessarily represent the official position of FDA BASS XI

2. Three Dimensions of the Critical Path Assessment of Safety – how to predict if a potential product will be harmful? Proof of Efficacy -- how to determine if a potential product will have medical benefit? Industrialization – how to manufacture a product at commercial scale with consistently high quality? BASS XI

3. Working in Three Dimensions on the Critical Path BASS XI

4. Statistical Chemical Manufacturing Control and Assurance Programs Shelf Life Determination & Stability Acceptance Tests of Finished Product PAT (Process Analytical Technology) In Vitro Equivalence Tests BASS XI

5. I. Shelf Life Determination & Stability • Pre-Marketing Shelf Life Determination • Single factor design → Multiple Factor Design • ICH Guidance (2001) • Optimal matrix design (Lin & Chen, JBS 2003) • Significance level (Chen & Tsong, JBS, 2003) • Shelf life determination of multi-factor design (Tsong & Chen, JBS, 2003) • Equivalence approach (Tsong, Chen, Lin & Chen, JBS, 2003) • General Issues • Statistical Methods in Pharmaceutical Industry, 3rd edition, 2004; • Encyclopedia of Biopharmaceutical Stat. 2004; • Encyclopedia of Clinical trials, 2005) BASS XI

6. Shelf Life Determination & Stability (2) • Postmarketing stability • Scale up • Mixed effect design (batch is random) • Nested factor design (specific levels of factors within a batch) • Compliance of stability batches • Web tool • User friendly stability analysis tool for FDA reviewers BASS XI

7. II. Acceptance Tests of Finished Product • For general tablets: • Blend uniformity • Dose content uniformity • Dissolution test • Purity test • For inhaler/unit dose delivery system • Delivery dose uniformity test • Single dose system • Multiple dose system • Almost all tests are established at 2nd WW • Without batch specification • Sample size restricted • Lack of inference consideration BASS XI

8. USPXXIII 3-stage Dissolution Test Acceptance Rule Step 1, 6 tablets No Step 2, additional 6 tablets Yes No • Accept Step 3, additional 12 tablets Yes • Accept No Reject BASS XI Yes Tsong, Shen, Shah, JBS, 2004 • Accept

9. Japan 2-Stage Dissolution Test Rule Step 1, 6 tablets No Step 2, additional 6 tablets Yes No Accept Reject Yes Accept BASS XI Tsong, Shen, Shah, JBS, 2004

10. BASS XI Tsong, Shen, Shah, JBS, 2004

11. 3-Stage Dissolution Acceptance TestBased on Sequential Tolerance Interval Step 1, 6 tablets No Step 2, additional 6 tablets Yes Accept Step 3, additional 12 tablets Yes Accept No Reject BASS XI Yes Accept Tsong, Shen, Shah, JBS, 2004

12. BASS XI Tsong, Shen, Shah, JBS, 2004

13. BASS XI Tsong, Shen, Shah, JBS,2004

14. BASS XI Tsong, Shen, Shah, JBS, 2004

15. BASS XI Tsong, Shen, Shah, JBS, 2004

16. BASS XI Tsong, Shen, Shah, JBS, 2004

17. FDA 2-Stage Delivery Dose Uniformity Acceptance Test BASS XI Tsong & Shen, 2004

18. USP <905>, Content Uniformity Test (n = 30 units) Step 1, 10 tablets No All 10 within 85-115% RSD  6% NMT 1 outside 85-115% All 10 within 75-125% Yes Yes Step 2, additional 20 tablets No Accept Reject NMT 1 outside 85-115% All 30 within 75-125% RSD  7.8% No Reject Yes BASS XI Accept Tsong, Shen, JBS, 2006

19. Researches in Acceptance Tests of Finished Product • Parametric Tolerance Interval Approach • Adjusted for sequential tests • Unified OC curve against coverage • Various sample sizes • Small sample – acceptance test • Large sample – compliance study • Very large sample size – process monitoring • Delivery Dose uniformity Test • Collaborating with IPAC • Dose Content Uniformity Test • Multivariate adjustment • Repeated test adjustment & Process control chart BASS XI

20. Hierarchy of Process Understanding III. Process Analysis Technology Current State: • “Trial-n-Error” • Batch Processes • ‘silo’ conditions • ‘black-box’ controls • Quality-by-Inspection Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004 BASS XI

21. Hierarchy of Process Understanding Desired State: • 1st Principles Understanding • Robust Processes • Total Quality Control Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004 BASS XI

22. Hierarchy of Process Understanding Intermediate State: • DOE Optimization • Mechanistic Understanding • Process Analytical Technology (PAT) • Feed-forward control • Real-Time-Release (RTR) • Quality-by-Design Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004 BASS XI

23. Dispensory FB Drier PAT PAT PAT PAT PAT PAT PAT Typical Solid Dosage Process Wet Granulation Milling/ Sizing Inspection & Release Blending Coating Tablet Press BASS XI Cogdill, et al, Fall Tech. Conf., 2004

24. Fluidized Bed Drying • Input factors: • Input air volume, humidity, temperature • Product moisture content • Material properties • Loading • Output factors: • Drying time • Material properties • Used for other operations such as coating and granulation BASS XI Cogdill, et al, Fall Tech. Conf., 2004

25. Wet Granulation • Input factors: • Rotational speed • Process scale • Product moisture content • Binder fluid application • Material properties • Output factors: • Granulation time • Particle size distribution • Material properties • Tablet performance Cogdill, et al, Fall Tech. Conf., 2004 BASS XI

26. Powder Blending • Factors varied: • Drug concentration • Rotational speed • Humidity • Factors held constant • Material properties • Temperature • Fill level • Loading scheme BASS XI Cogdill, et al, Fall Tech. Conf., 2004

27. Tablet Compression • Input factors: • Compression force • Dwell time • Tablet size & shape • Material properties • Output factors: • Tablet hardness • Friability • Tablet performance • Uniformity BASS XI Cogdill, et al, Fall Tech. Conf., 2004

28. Blend Uniformity & PAT Traditional test methods Current PQRI proposal and draft Guidance Univariate Testing to Document Quality Approach Draft Guidance may include information on the use of NIR methods At-line test methods On- and/or At-line test methods for all critical components and processes Proposed PAT Guidance Incentive? Higher efficiency Lower “risk” leading to lower regulatory concern Multivariate Quality-by Design Approach Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004 BASS XI

29. Powder Blending • 8-qt plastic V-blender (Patterson-Kelly) • Blend composition • Salicyclic acid (SA), 30.5 mm particle size • Lactose, 115.5 mm particle size • Input factor levels • Relative humidity: 20%, 60% • SA concentration: 3%, 7%, 11% • Rotation speed: 12.8, 20.3 rpm BASS XI Cogdill, et al, Fall Tech. Conf., 2004

30. Powder Blending • Sampling method • Blend process monitored for 50 minutes • Stopped at pre-determined time intervals for sampling with thief probe and NIR analysis • Thief samples analyzed via UV spectroscopy (296.9 nm) BASS XI Cogdill, et al, Fall Tech. Conf., 2004

31. Powder Blending • Typical powder blend profiles BASS XI Cogdill, et al, Fall Tech. Conf., 2004

32. D-Optimal Design of Experiment • 3 Factors • Humidity • Blender speed • Salicylic acid Concentration • Experimental design generated using JMP • ND = 16 experiments Cogdill, et al, Fall Tech. Conf., 2004 BASS XI

33. BASS XI Cogdill, et al, Fall Tech. Conf., 2004

34. A B 40 35 30 2 1 25 3 4 % Outliers 20 5 15 10 L R 5 0 1 2 3 4 5 Location Thief-Sample Position Dependency • Outliers were flagged during UV analysis as samples exceeding 1.5x IQR BASS XI Cogdill, et al, Fall Tech. Conf., 2004

35. Results P = 0.0002 P = 0.002 P = 0.0331 BASS XI Cogdill, et al, Fall Tech. Conf., 2004

36. PAT (Process Analytical Technology) Optimal Design of Experiment Collect Data to Establish Control Chart Univariate Multivariate PCA Profile Application of Multi-level Control Specification Trend Statistical Monitoring and Feedback System Similar concepts are applicable also to batch-to-batch control of finished products BASS XI

37. IV. In Vitro Equivalence Tests • Generic Product Requirement • SUPAC (Scale-up and Post Approval Changes) Requirement • Biowaiver • Comparability of new suppliers • Formulation change • Manufacturer site Change BASS XI

38. In Vitro Equivalence Tests • Dissolution Profile Similarity Test • Particle Size Distribution Profile Equivalence • Pharmaceutical Equivalence BASS XI

39. Dissolution Profile Similarity BASS XI

40. Dissolution Profile Similarity • The U.S. FDA Guidance, (SUPAC – IR), 1997 • The U.S. FDA Guidance, (SUPAC – MR), 1997 • The U.S. FDA Guidance, (SUPAC – ER), 1997 • Sathe, Tsong, Shah, In Vitro-In Vivo Correlation, ed. Young D., Devane J.D., and Butler J., Plenum Publishing Corp., 1996. • Tsong, Hammerstrom, Sathe, Shah. Proceedings of the Biopharmaceutical Section of ASA, pp. 129-134, 1996. • Tsong, Hammerstrom, Sathe, Shah. DIJ, 30: 1105-1112, 1996. • Shah, Tsong, Sathe, Liu. Pharmaceutical Research, 15: 889-896, 1998. • Ma, Wang, Liu, Tsong. JBS, 10(2):229-249, 2000. BASS XI

41. Particle Size Distribution Profile Equivalence Test of Inhaler Products BASS XI

42. Particle Size Distribution Profile Equivalence Test of Inhaler Products BASS XI

43. Particle Size Distribution Profile Equivalence Test of Inhaler Products BASS XI

44. Challenges and Opportunities in CMC • Shelf Life and Stability • Pooling batches by equivalence • Pre-marketing to Scale-up, postmarketing • Measurements difference between stability and compliance • Quality of finished products • WWII compendia to modern inference • From mean and STD to tolerance interval • Multiple and repeated tests • Restricted sample size to unrestricted sample size • Batch test versus test during process BASS XI

45. Challenges and Opportunities in CMC • PAT • From acceptance test to quality by design • To identify, manage, monitor, and control critical variables of the manufacturing process • Statistical expertise in process control • In-vitro equivalence • Variation between laboratories, technicians, and environmental conditions • No conventional statistics and critical values BASS XI

46. Thank You For Your Interest!!! BASS XI