EMERGING ISSUES AND CONSIDERATIONS IN MANUFACTURING QUALITY CONTROL AND ASSURANCE OF DRUG PRODUCTS <ul><li>Yi Tsong, Ph.D....
Three Dimensions of the Critical Path <ul><li>Assessment of Safety – how to predict if a potential product will be harmful...
Working in Three Dimensions on the Critical Path
Statistical Chemical Manufacturing Control and Assurance Programs Shelf  Life Determination  & Stability Acceptance  Tests...
<ul><li>Pre-Marketing Shelf Life Determination </li></ul><ul><ul><li>Single factor design  -> Multiple Factor Design </li>...
<ul><li>Postmarketing stability </li></ul><ul><ul><li>Scale up </li></ul></ul><ul><ul><li>Mixed effect design (batch is ra...
II. Acceptance Tests of Finished Product <ul><li>For general tablets: </li></ul><ul><ul><li>Blend uniformity </li></ul></u...
USPXXIII 3-stage Dissolution Test Acceptance Rule Step 1, 6 tablets No <ul><ul><li>Accept </li></ul></ul>Yes Step 2, addit...
Japan 2-Stage Dissolution Test Rule Step 1, 6 tablets No Accept Yes Step 2, additional 6 tablets Yes Accept No Reject Tson...
Tsong, Shen, Shah, JBS, 2004
3-Stage Dissolution Acceptance Test Based on Sequential Tolerance Interval  Step 1, 6 tablets No Accept Yes Step 2, additi...
Tsong, Shen, Shah, JBS, 2004
Tsong, Shen, Shah, JBS,   2004
Tsong, Shen, Shah, JBS, 2004
Tsong, Shen, Shah, JBS, 2004
Tsong, Shen, Shah, JBS, 2004
FDA 2-Stage Delivery Dose Uniformity Acceptance Test Tsong & Shen, 2004
Step 1, 10 tablets No Accept Yes NMT 1  outside 85-115% All 10 within 75-125% Yes Reject No Step 2, additional 20 tablets ...
<ul><li>Parametric Tolerance Interval Approach </li></ul><ul><ul><li>Adjusted for sequential tests </li></ul></ul><ul><ul>...
Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th  Pharm. Technologies Conf., Jan. 2004 Current State: <ul><li>“...
Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th  Pharm. Technologies Conf., Jan. 2004 Desired State: <ul><li>1...
Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th  Pharm. Technologies Conf., Jan. 2004 <ul><li>DOE Optimization...
Typical Solid Dosage Process Wet  Granulation Milling/ Sizing Blending Tablet Press Coating Inspection & Release Cogdill, ...
Fluidized Bed Drying <ul><li>Input factors: </li></ul><ul><ul><li>Input air volume, humidity, temperature </li></ul></ul><...
Wet Granulation <ul><li>Input factors: </li></ul><ul><ul><li>Rotational speed </li></ul></ul><ul><ul><li>Process scale </l...
<ul><li>Factors varied: </li></ul><ul><ul><li>Drug concentration </li></ul></ul><ul><ul><li>Rotational speed </li></ul></u...
Tablet Compression <ul><li>Input factors: </li></ul><ul><ul><li>Compression force </li></ul></ul><ul><ul><li>Dwell time </...
Blend Uniformity & PAT Univariate Testing to Document Quality Approach Multivariate Quality-by Design Approach Traditional...
<ul><li>8-qt plastic V-blender (Patterson-Kelly) </li></ul><ul><li>Blend composition </li></ul><ul><ul><li>Salicyclic acid...
<ul><li>Sampling method </li></ul><ul><ul><li>Blend process monitored for 50 minutes </li></ul></ul><ul><ul><li>Stopped at...
Powder Blending <ul><li>Typical powder blend profiles </li></ul>Cogdill, et al, Fall Tech. Conf., 2004
<ul><li>3 Factors </li></ul><ul><ul><li>Humidity </li></ul></ul><ul><ul><li>Blender speed </li></ul></ul><ul><ul><li>Salic...
Cogdill, et al, Fall Tech. Conf., 2004 * Blender speed measured in rpm 12.8 3% 60% XVI 12.8 7% 60% XV 20.3 3% 60% XIV 12.8...
Thief-Sample Position Dependency <ul><li>Outliers were flagged during UV analysis as samples exceeding 1.5x IQR </li></ul>...
Results P = 0.0002 P = 0.002 P = 0.0331 Cogdill, et al, Fall Tech. Conf., 2004
<ul><li>Optimal Design of Experiment </li></ul><ul><li>Collect Data to Establish Control Chart </li></ul><ul><ul><li>Univa...
<ul><li>Generic Product Requirement </li></ul><ul><li>SUPAC (Scale-up and Post Approval Changes) Requirement </li></ul><ul...
<ul><li>Dissolution Profile Similarity Test </li></ul><ul><li>Particle Size Distribution Profile Equivalence </li></ul><ul...
Dissolution Profile Similarity
Dissolution Profile Similarity <ul><li>The U.S. FDA Guidance, (SUPAC – IR), 1997 </li></ul><ul><li>The U.S. FDA Guidance, ...
Particle Size Distribution Profile Equivalence Test of Inhaler Products
Particle Size Distribution Profile Equivalence Test of Inhaler Products
Particle Size Distribution Profile Equivalence Test of Inhaler Products
Challenges and Opportunities in CMC <ul><li>Shelf Life and Stability </li></ul><ul><ul><li>Pooling batches by equivalence ...
<ul><li>PAT </li></ul><ul><ul><li>From acceptance test to quality by design </li></ul></ul><ul><ul><li>To identify, manage...
Thank You For Your Interest!!!
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Manufacturing QC and QA

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Manufacturing QC and QA

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Manufacturing QC and QA

  1. 1. EMERGING ISSUES AND CONSIDERATIONS IN MANUFACTURING QUALITY CONTROL AND ASSURANCE OF DRUG PRODUCTS <ul><li>Yi Tsong, Ph.D., Acting Deputy Director </li></ul><ul><li>Quantitative Methods and Research Staff </li></ul><ul><li>OB, OPaSS, CDER, FDA </li></ul>This presentation does not necessarily represent the official position of FDA
  2. 2. Three Dimensions of the Critical Path <ul><li>Assessment of Safety – how to predict if a potential product will be harmful? </li></ul><ul><li>Proof of Efficacy -- how to determine if a potential product will have medical benefit? </li></ul><ul><li>Industrialization – how to manufacture a product at commercial scale with consistently high quality? </li></ul>
  3. 3. Working in Three Dimensions on the Critical Path
  4. 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
  5. 5. <ul><li>Pre-Marketing Shelf Life Determination </li></ul><ul><ul><li>Single factor design -> Multiple Factor Design </li></ul></ul><ul><ul><li>ICH Guidance (2001) </li></ul></ul><ul><ul><li>Optimal matrix design (Lin & Chen, JBS 2003) </li></ul></ul><ul><ul><li>Significance level (Chen & Tsong, JBS, 2003) </li></ul></ul><ul><ul><li>Shelf life determination of multi-factor design (Tsong & Chen, JBS, 2003) </li></ul></ul><ul><ul><li>Equivalence approach (Tsong, Chen, Lin & Chen, JBS, 2003) </li></ul></ul><ul><ul><li>General Issues </li></ul></ul><ul><ul><ul><li>Statistical Methods in Pharmaceutical Industry, 3 rd edition, 2004; </li></ul></ul></ul><ul><ul><ul><li>Encyclopedia of Biopharmaceutical Stat. 2004; </li></ul></ul></ul><ul><ul><ul><li>Encyclopedia of Clinical trials, 2005) </li></ul></ul></ul>I. Shelf Life Determination & Stability
  6. 6. <ul><li>Postmarketing stability </li></ul><ul><ul><li>Scale up </li></ul></ul><ul><ul><li>Mixed effect design (batch is random) </li></ul></ul><ul><ul><li>Nested factor design (specific levels of factors within a batch) </li></ul></ul><ul><ul><li>Compliance of stability batches </li></ul></ul><ul><li>Web tool </li></ul><ul><ul><li>User friendly stability analysis tool for FDA reviewers </li></ul></ul>Shelf Life Determination & Stability (2)
  7. 7. II. Acceptance Tests of Finished Product <ul><li>For general tablets: </li></ul><ul><ul><li>Blend uniformity </li></ul></ul><ul><ul><li>Dose content uniformity </li></ul></ul><ul><ul><li>Dissolution test </li></ul></ul><ul><ul><li>Purity test </li></ul></ul><ul><li>For inhaler/unit dose delivery system </li></ul><ul><ul><li>Delivery dose uniformity test </li></ul></ul><ul><ul><ul><li>Single dose system </li></ul></ul></ul><ul><ul><ul><li>Multiple dose system </li></ul></ul></ul><ul><li>Almost all tests are established at 2 nd WW </li></ul><ul><ul><li>Without batch specification </li></ul></ul><ul><ul><li>Sample size restricted </li></ul></ul><ul><ul><li>Lack of inference consideration </li></ul></ul>
  8. 8. USPXXIII 3-stage Dissolution Test Acceptance Rule Step 1, 6 tablets No <ul><ul><li>Accept </li></ul></ul>Yes Step 2, additional 6 tablets Yes No Step 3, additional 12 tablets Yes No Reject <ul><ul><li>Accept </li></ul></ul><ul><ul><li>Accept </li></ul></ul>Tsong, Shen, Shah, JBS, 2004
  9. 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. 10. Tsong, Shen, Shah, JBS, 2004
  11. 11. 3-Stage Dissolution Acceptance Test Based on Sequential Tolerance Interval Step 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. 12. Tsong, Shen, Shah, JBS, 2004
  13. 13. Tsong, Shen, Shah, JBS, 2004
  14. 14. Tsong, Shen, Shah, JBS, 2004
  15. 15. Tsong, Shen, Shah, JBS, 2004
  16. 16. Tsong, Shen, Shah, JBS, 2004
  17. 17. FDA 2-Stage Delivery Dose Uniformity Acceptance Test Tsong & Shen, 2004
  18. 18. Step 1, 10 tablets No Accept Yes NMT 1 outside 85-115% All 10 within 75-125% Yes Reject No Step 2, additional 20 tablets NMT 1 outside 85-115% All 30 within 75-125% RSD  7.8% Yes Reject Accept All 10 within 85-115% RSD  6% No USP <905>, Content Uniformity Test (n = 30 units) Tsong, Shen, JBS, 2006
  19. 19. <ul><li>Parametric Tolerance Interval Approach </li></ul><ul><ul><li>Adjusted for sequential tests </li></ul></ul><ul><ul><li>Unified OC curve against coverage </li></ul></ul><ul><ul><li>Various sample sizes </li></ul></ul><ul><ul><ul><li>Small sample – acceptance test </li></ul></ul></ul><ul><ul><ul><li>Large sample – compliance study </li></ul></ul></ul><ul><ul><ul><li>Very large sample size – process monitoring </li></ul></ul></ul><ul><li>Delivery Dose uniformity Test </li></ul><ul><ul><li>Collaborating with IPAC </li></ul></ul><ul><li>Dose Content Uniformity Test </li></ul><ul><li>Multivariate adjustment </li></ul><ul><li>Repeated test adjustment & Process control chart </li></ul>Researches in Acceptance Tests of Finished Product
  20. 20. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th Pharm. Technologies Conf., Jan. 2004 Current State: <ul><li>“ Trial-n-Error” </li></ul><ul><li>Batch Processes </li></ul><ul><ul><li>‘ silo’ conditions </li></ul></ul><ul><ul><li>‘ black-box’ controls </li></ul></ul><ul><li>Quality-by-Inspection </li></ul>III. Process Analysis Technology
  21. 21. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th Pharm. Technologies Conf., Jan. 2004 Desired State: <ul><li>1st Principles Understanding </li></ul><ul><li>Robust Processes </li></ul><ul><li>Total Quality Control </li></ul>
  22. 22. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th Pharm. Technologies Conf., Jan. 2004 <ul><li>DOE Optimization </li></ul><ul><li>Mechanistic Understanding </li></ul><ul><li>Process Analytical Technology (PAT) </li></ul><ul><li>Feed-forward control </li></ul><ul><li>Real-Time-Release (RTR) </li></ul><ul><li>Quality-by-Design </li></ul>Intermediate State:
  23. 23. Typical Solid Dosage Process Wet Granulation 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. 24. Fluidized Bed Drying <ul><li>Input factors: </li></ul><ul><ul><li>Input air volume, humidity, temperature </li></ul></ul><ul><ul><li>Product moisture content </li></ul></ul><ul><ul><li>Material properties </li></ul></ul><ul><ul><li>Loading </li></ul></ul><ul><li>Output factors: </li></ul><ul><ul><li>Drying time </li></ul></ul><ul><ul><li>Material properties </li></ul></ul><ul><li>Used for other operations such as coating and granulation </li></ul>Cogdill, et al, Fall Tech. Conf., 2004
  25. 25. Wet Granulation <ul><li>Input factors: </li></ul><ul><ul><li>Rotational speed </li></ul></ul><ul><ul><li>Process scale </li></ul></ul><ul><ul><li>Product moisture content </li></ul></ul><ul><ul><li>Binder fluid application </li></ul></ul><ul><ul><li>Material properties </li></ul></ul><ul><li>Output factors: </li></ul><ul><ul><li>Granulation time </li></ul></ul><ul><ul><li>Particle size distribution </li></ul></ul><ul><ul><li>Material properties </li></ul></ul><ul><ul><li>Tablet performance </li></ul></ul>Cogdill, et al, Fall Tech. Conf., 2004
  26. 26. <ul><li>Factors varied: </li></ul><ul><ul><li>Drug concentration </li></ul></ul><ul><ul><li>Rotational speed </li></ul></ul><ul><ul><li>Humidity </li></ul></ul><ul><li>Factors held constant </li></ul><ul><ul><li>Material properties </li></ul></ul><ul><ul><li>Temperature </li></ul></ul><ul><ul><li>Fill level </li></ul></ul><ul><ul><li>Loading scheme </li></ul></ul>Powder Blending Cogdill, et al, Fall Tech. Conf., 2004
  27. 27. Tablet Compression <ul><li>Input factors: </li></ul><ul><ul><li>Compression force </li></ul></ul><ul><ul><li>Dwell time </li></ul></ul><ul><ul><li>Tablet size & shape </li></ul></ul><ul><ul><li>Material properties </li></ul></ul><ul><li>Output factors: </li></ul><ul><ul><li>Tablet hardness </li></ul></ul><ul><ul><li>Friability </li></ul></ul><ul><ul><li>Tablet performance </li></ul></ul><ul><ul><li>Uniformity </li></ul></ul>Cogdill, et al, Fall Tech. Conf., 2004
  28. 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 proposal and draft Guidance Draft Guidance may include information on the use of NIR methods Proposed PAT Guidance Incentive? Higher efficiency Lower “risk” leading to lower regulatory concern Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004
  29. 29. <ul><li>8-qt plastic V-blender (Patterson-Kelly) </li></ul><ul><li>Blend composition </li></ul><ul><ul><li>Salicyclic acid (SA), 30.5 mm particle size </li></ul></ul><ul><ul><li>Lactose, 115.5 mm particle size </li></ul></ul><ul><li>Input factor levels </li></ul><ul><ul><li>Relative humidity: 20%, 60% </li></ul></ul><ul><ul><li>SA concentration: 3%, 7%, 11% </li></ul></ul><ul><ul><li>Rotation speed: 12.8, 20.3 rpm </li></ul></ul>Powder Blending Cogdill, et al, Fall Tech. Conf., 2004
  30. 30. <ul><li>Sampling method </li></ul><ul><ul><li>Blend process monitored for 50 minutes </li></ul></ul><ul><ul><li>Stopped at pre-determined time intervals for sampling with thief probe and NIR analysis </li></ul></ul><ul><ul><li>Thief samples analyzed via UV spectroscopy (296.9 nm) </li></ul></ul>Powder Blending Cogdill, et al, Fall Tech. Conf., 2004
  31. 31. Powder Blending <ul><li>Typical powder blend profiles </li></ul>Cogdill, et al, Fall Tech. Conf., 2004
  32. 32. <ul><li>3 Factors </li></ul><ul><ul><li>Humidity </li></ul></ul><ul><ul><li>Blender speed </li></ul></ul><ul><ul><li>Salicylic acid Concentration </li></ul></ul><ul><li>Experimental design generated using JMP </li></ul><ul><li>ND = 16 experiments </li></ul>D-Optimal Design of Experiment Cogdill, et al, Fall Tech. Conf., 2004
  33. 33. Cogdill, et al, Fall Tech. Conf., 2004 * Blender speed measured in rpm 12.8 3% 60% XVI 12.8 7% 60% XV 20.3 3% 60% XIV 12.8 11% 60% XIII 20.3 7% 60% XII 20.3 7% 60% XI 12.8 7% 60% X 20.3 11% 60% IX 20.3 3% 60% VIII 12.8 11% 20% VII 20.3 11% 20% VI 20.3 7% 20% V 12.8 7% 20% IV 20.3 3% 20% III 12.8 11% 20% II 12.8 3% 20% I Blender Speed * Salicylic acid Concentration Humidity Experimental Conditions Order
  34. 34. Thief-Sample Position Dependency <ul><li>Outliers were flagged during UV analysis as samples exceeding 1.5x IQR </li></ul>Cogdill, et al, Fall Tech. Conf., 2004 R L 1 2 3 4 5 0 5 10 15 20 25 30 35 40 1 2 3 4 5 Location % Outliers B A
  35. 35. Results P = 0.0002 P = 0.002 P = 0.0331 Cogdill, et al, Fall Tech. Conf., 2004
  36. 36. <ul><li>Optimal Design of Experiment </li></ul><ul><li>Collect Data to Establish Control Chart </li></ul><ul><ul><li>Univariate </li></ul></ul><ul><ul><li>Multivariate </li></ul></ul><ul><ul><li>PCA </li></ul></ul><ul><ul><li>Profile </li></ul></ul><ul><li>Application of Multi-level Control </li></ul><ul><ul><li>Specification </li></ul></ul><ul><ul><li>Trend </li></ul></ul><ul><li>Statistical Monitoring and Feedback System </li></ul><ul><li>Similar concepts are applicable also to batch-to-batch control of finished products </li></ul>PAT (Process Analytical Technology)
  37. 37. <ul><li>Generic Product Requirement </li></ul><ul><li>SUPAC (Scale-up and Post Approval Changes) Requirement </li></ul><ul><ul><li>Biowaiver </li></ul></ul><ul><ul><li>Comparability of new suppliers </li></ul></ul><ul><ul><li>Formulation change </li></ul></ul><ul><ul><li>Manufacturer site Change </li></ul></ul>IV. In Vitro Equivalence Tests
  38. 38. <ul><li>Dissolution Profile Similarity Test </li></ul><ul><li>Particle Size Distribution Profile Equivalence </li></ul><ul><li>Pharmaceutical Equivalence </li></ul>In Vitro Equivalence Tests
  39. 39. Dissolution Profile Similarity
  40. 40. Dissolution Profile Similarity <ul><li>The U.S. FDA Guidance, (SUPAC – IR), 1997 </li></ul><ul><li>The U.S. FDA Guidance, (SUPAC – MR), 1997 </li></ul><ul><li>The U.S. FDA Guidance, (SUPAC – ER), 1997 </li></ul><ul><li>Sathe, Tsong, Shah, In Vitro-In Vivo Correlation, ed. Young D., Devane J.D., and Butler J., Plenum Publishing Corp., 1996. </li></ul><ul><li>Tsong, Hammerstrom, Sathe, Shah. Proceedings of the Biopharmaceutical Section of ASA, pp. 129-134, 1996. </li></ul><ul><li>Tsong, Hammerstrom, Sathe, Shah. DIJ, 30: 1105-1112, 1996. </li></ul><ul><li>Shah, Tsong, Sathe, Liu. Pharmaceutical Research, 15: 889-896, 1998. </li></ul><ul><li>Ma, Wang, Liu, Tsong. JBS, 10(2):229-249, 2000. </li></ul>
  41. 41. Particle Size Distribution Profile Equivalence Test of Inhaler Products
  42. 42. Particle Size Distribution Profile Equivalence Test of Inhaler Products
  43. 43. Particle Size Distribution Profile Equivalence Test of Inhaler Products
  44. 44. Challenges and Opportunities in CMC <ul><li>Shelf Life and Stability </li></ul><ul><ul><li>Pooling batches by equivalence </li></ul></ul><ul><ul><li>Pre-marketing to Scale-up, postmarketing </li></ul></ul><ul><ul><li>Measurements difference between stability and compliance </li></ul></ul><ul><li>Quality of finished products </li></ul><ul><ul><li>WWII compendia to modern inference </li></ul></ul><ul><ul><li>From mean and STD to tolerance interval </li></ul></ul><ul><ul><li>Multiple and repeated tests </li></ul></ul><ul><ul><li>Restricted sample size to unrestricted sample size </li></ul></ul><ul><ul><li>Batch test versus test during process </li></ul></ul>
  45. 45. <ul><li>PAT </li></ul><ul><ul><li>From acceptance test to quality by design </li></ul></ul><ul><ul><li>To identify, manage, monitor, and control critical variables of the manufacturing process </li></ul></ul><ul><ul><li>Statistical expertise in process control </li></ul></ul><ul><li>In-vitro equivalence </li></ul><ul><ul><li>Variation between laboratories, technicians, and environmental conditions </li></ul></ul><ul><ul><li>No conventional statistics and critical values </li></ul></ul>Challenges and Opportunities in CMC
  46. 46. Thank You For Your Interest!!!

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