Your SlideShare is downloading. ×
0
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Manufacturing QC and QA
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

Manufacturing QC and QA

2,489

Published on

Manufacturing QC and QA

Manufacturing QC and QA

Published in: Technology
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
2,489
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
79
Comments
0
Likes
1
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 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
  • 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 Shelf Life Determination & Stability Acceptance Tests of Finished Product PAT (Process Analytical Technology) In Vitro Equivalence Tests
  • 5.
    • 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, 3 rd edition, 2004;
        • Encyclopedia of Biopharmaceutical Stat. 2004;
        • Encyclopedia of Clinical trials, 2005)
    I. Shelf Life Determination & Stability
  • 6.
    • 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
    Shelf Life Determination & Stability (2)
  • 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 2 nd WW
      • Without batch specification
      • Sample size restricted
      • Lack of inference consideration
  • 8. USPXXIII 3-stage Dissolution Test Acceptance Rule Step 1, 6 tablets No
      • Accept
    Yes Step 2, additional 6 tablets Yes No Step 3, additional 12 tablets Yes No Reject
      • Accept
      • Accept
    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 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. 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 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.
    • 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
    Researches in Acceptance Tests of Finished Product
  • 20. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th Pharm. Technologies Conf., Jan. 2004 Current State:
    • “ Trial-n-Error”
    • Batch Processes
      • ‘ silo’ conditions
      • ‘ black-box’ controls
    • Quality-by-Inspection
    III. Process Analysis Technology
  • 21. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th Pharm. Technologies Conf., Jan. 2004 Desired State:
    • 1st Principles Understanding
    • Robust Processes
    • Total Quality Control
  • 22. Hierarchy of Process Understanding Ajaz Hussain, AAPS 39 th Pharm. Technologies Conf., Jan. 2004
    • DOE Optimization
    • Mechanistic Understanding
    • Process Analytical Technology (PAT)
    • Feed-forward control
    • Real-Time-Release (RTR)
    • Quality-by-Design
    Intermediate State:
  • 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. 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
    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
  • 26.
    • Factors varied:
      • Drug concentration
      • Rotational speed
      • Humidity
    • Factors held constant
      • Material properties
      • Temperature
      • Fill level
      • Loading scheme
    Powder Blending 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
    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 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.
    • 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
    Powder Blending Cogdill, et al, Fall Tech. Conf., 2004
  • 30.
    • 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)
    Powder Blending Cogdill, et al, Fall Tech. Conf., 2004
  • 31. Powder Blending
    • Typical powder blend profiles
    Cogdill, et al, Fall Tech. Conf., 2004
  • 32.
    • 3 Factors
      • Humidity
      • Blender speed
      • Salicylic acid Concentration
    • Experimental design generated using JMP
    • ND = 16 experiments
    D-Optimal Design of Experiment Cogdill, et al, Fall Tech. Conf., 2004
  • 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. Thief-Sample Position Dependency
    • Outliers were flagged during UV analysis as samples exceeding 1.5x IQR
    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. Results P = 0.0002 P = 0.002 P = 0.0331 Cogdill, et al, Fall Tech. Conf., 2004
  • 36.
    • 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
    PAT (Process Analytical Technology)
  • 37.
    • Generic Product Requirement
    • SUPAC (Scale-up and Post Approval Changes) Requirement
      • Biowaiver
      • Comparability of new suppliers
      • Formulation change
      • Manufacturer site Change
    IV. In Vitro Equivalence Tests
  • 38.
    • Dissolution Profile Similarity Test
    • Particle Size Distribution Profile Equivalence
    • Pharmaceutical Equivalence
    In Vitro Equivalence Tests
  • 39. Dissolution Profile Similarity
  • 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.
  • 41. Particle Size Distribution Profile Equivalence Test of Inhaler Products
  • 42. Particle Size Distribution Profile Equivalence Test of Inhaler Products
  • 43. Particle Size Distribution Profile Equivalence Test of Inhaler Products
  • 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
  • 45.
    • 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
    Challenges and Opportunities in CMC
  • 46. Thank You For Your Interest!!!

×