- 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
This presentation does not necessarily representthe official position of FDA 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?
3. Working in Three Dimensions on the Critical Path 4. Statistical Chemical Manufacturing Control and Assurance Programs ShelfLife Determination& Stability AcceptanceTests ofFinishedProduct PAT (ProcessAnalyticalTechnology) In VitroEquivalenceTests 5.
- Pre-Marketing Shelf Life Determination
- Single factor design-> Multiple Factor Design
- 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)
- Statistical Methods in Pharmaceutical Industry, 3 rdedition, 2004;
- Encyclopedia of Biopharmaceutical Stat. 2004;
- Encyclopedia of Clinical trials, 2005)
I. ShelfLife Determination & Stability 6.
- Mixed effect design (batch is random)
- Nested factor design (specific levels of factors within a batch)
- Compliance of stability batches
- User friendly stability analysis tool for FDA reviewers
ShelfLife Determination & Stability (2) 7. II. Acceptance Tests of Finished Product
- For inhaler/unit dose delivery system
- Delivery dose uniformity test
- Almost all tests are established at 2 ndWW
- Without batch specification
- Lack of inference consideration
8. USPXXIII 3-stage Dissolution Test Acceptance Rule Step 1, 6 tablets No
Yes Step 2, additional 6 tablets Yes No Step 3, additional 12 tablets Yes No Reject
Tsong, Shen, Shah, JBS, 2004 9. Japan 2-Stage Dissolution Test Rule Step 1, 6 tablets No Accept Yes Step 2, additional 6 tablets Yes Accept No Reject Tsong, Shen, Shah, JBS, 2004 10. Tsong, Shen, Shah, JBS, 2004 11. 3-Stage Dissolution Acceptance Test Based on Sequential Tolerance IntervalStep 1, 6 tablets No Accept Yes Step 2, additional 6 tablets Yes Accept Step 3, additional 12 tablets Yes No Reject Accept Tsong, Shen, Shah, JBS, 2004 12. Tsong, Shen, Shah, JBS, 2004 13. Tsong, Shen, Shah, JBS, 2004 14. Tsong, Shen, Shah, JBS, 2004 15. Tsong, Shen, Shah, JBS, 2004 16. Tsong, Shen, Shah, JBS, 2004 17. FDA 2-Stage Delivery Dose Uniformity Acceptance Test Tsong & Shen, 2004 18. Step 1, 10 tablets No Accept Yes NMT 1outside 85-115% All 10 within 75-125% Yes Reject No Step 2, additional 20 tablets NMT 1outside 85-115% All 30 within 75-125% RSD7.8% Yes Reject Accept All 10 within 85-115% RSD 6% No USP , Content Uniformity Test (n = 30 units) Tsong, Shen, JBS, 2006 19.
- Parametric Tolerance Interval Approach
- Adjusted for sequential tests
- Unified OC curve against coverage
- Small sample acceptance test
- Large sample compliance study
- Very large sample size process monitoring
- Delivery Dose uniformity Test
- Dose Content Uniformity Test
- Repeated test adjustment & Process control chart
Researches in Acceptance Tests of Finished Product 20. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 thPharm. Technologies Conf., Jan. 2004 Current State:
III.Process Analysis Technology 21. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 thPharm. Technologies Conf., Jan. 2004 Desired State:
- 1st Principles Understanding
22. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 thPharm. Technologies Conf., Jan. 2004
- Mechanistic Understanding
- Process Analytical Technology (PAT)
Intermediate State: 23. Typical Solid Dosage Process WetGranulation Milling/ Sizing Blending Tablet Press Coating Inspection & Release Cogdill, et al, Fall Tech. Conf., 2004 FB Drier Dispensory PAT PAT PAT PAT PAT PAT PAT 24. Fluidized Bed Drying
- Input air volume, humidity, temperature
- Used for other operations such as coating and granulation
Cogdill, et al, Fall Tech. Conf., 2004 25. Wet Granulation
- Particle size distribution
Cogdill, et al, Fall Tech. Conf., 2004 26.
Powder Blending Cogdill, et al, Fall Tech. Conf., 2004 27. Tablet Compression
Cogdill, et al, Fall Tech. Conf., 2004 28. Blend Uniformity & PAT Univariate Testing to Document Quality Approach Multivariate Quality-by Design Approach Traditional test methods At-line test methods On- and/or At-line test methods for all critical components and processes Current PQRI proposaland draft Guidance Draft Guidance mayinclude information on the use of NIR methods Proposed PAT Guidance Incentive? Higher efficiency Lower risk leading tolower regulatory concern Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004 29.
- 8-qt plastic V-blender (Patterson-Kelly)
- Salicyclic acid (SA), 30.5 mm particle size
- Lactose, 115.5 mm particle size