The document summarizes a case study on the implementation of Quality by Design (QbD) principles in developing a film-coated tablet with an active layer to protect an unstable drug. Key aspects included identifying critical quality attributes of content uniformity and potency. Design of experiments was used to establish a design space. In-line monitoring techniques like Raman spectroscopy were utilized to ensure consistent coating quality during scale-up.
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Implementation of Design Space Concepts in Active-Coated Tablet Development
1. Case Study: Implementation of Design Space Concepts in Development of an Active-Coated Tablet Robert A. Lipper, Ph.D., Divyakant Desai, Ph.D., San Kiang, Ph.D. Bristol-Myers Squibb Pharmaceutical Research Institute Real World Applications of PAT and QbD in Drug Process Development and Approval – September 11, 2006 – Arlington, VA
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8. Manufacturing Process Conventional Excipients Lubricant COURT OY R - 100 COURT OY R - 100 COURT OY R - 100 200 mg tablet cores Polymer coat pH 2 Polymer coat pH 2 API Polymer coat pH 2 Tablet Printing Blend (5 minutes) Blend (3 minutes) Tablet Compression Middle Layer Coat Outer Layer Coat In process monitoring: Weight gain Weight gain Weight gain Raman HPLC Inner Layer Coat
14. Comparison of Nozzle Types I and II : Selection criteria: flat, focused spray pattern with uniform droplet size and intensity. Cone angle of (A) Type I and (B) Type II nozzles Effect of Nozzle Type A B
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16. Coating Control: Use of Raman to Monitor the Inner Layer A U Wave number (cm-1) Opadry A.U. Coating Progress Tablet Core
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18. Coating Kinetics of the Inner Layer Followed by In-Line Raman Spectroscopy El Hagrasy, A., Chang S-Y., Desai, D. and Kiang, S. American Pharmaceutical Review 9(1):40-45 (2006) Bed Temperature Adjustment Coating Initiated
20. Raman Prediction of the Inner Layer from Different Spatial Locations 60”(I) 48” (I) 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 1 2 3 4 5 6 Location % Weight Gain Location % Weight Gain 60” (II) 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 1 2 3 4 5 6 Location % Weight Gain 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 1 2 3 4 5 6 Location % Weight Gain 48” (II) 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 1 2 3 4 5 6 El Hagrasy, A., Chang S-Y., Desai, D. and Kiang, S. Journal of Pharmaceutical Innovation. Accepted (2006) Raman Gravimetric Raman Gravimetric Raman Gravimetric Raman Gravimetric
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22. Classification of Process Variables PAR = Proven Acceptable Range; NOR = Normal Operating Range; EOF = Edge of Failure *If frank failures are observed, EOF should be estimated Inherently Variable Tightly Controllable Non-Critical Critical Fix Fix, determine PAR (EOF*) Determine target, NOR and PAR Determine target, NOR, PAR (EOF*)
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24. Formulation and Process Optimization DOE Design: API Film Coated Tablets 2^(5-1) Fractional Factorial with 3 Center Points Designs – 19 Runs
25. Creating the Process Design Space: Process Parameters Studied Screening for Parameter Ranges for Optimal Content Uniformity Atomizing/Pattern Air Volume Air Volume Inlet Air Temperature Spray rate % API in suspension API/Opadry Ratio Spray rate % API in suspension Critical Parameters: API application rate was most critical for content uniformity . 60 75 0.75 5 0.75 8 1:1 1:8 200 300 525 600 50 55 60 105 DOE
26. Summary of Potency and Content Uniformity Results of Second Layer Coated Tablets
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29. DEM-1M model PBE-2 zone model RSD model for Production Coater Workflow for Coating Process Model PAT applications Thermodynamics & mass transfer Formulation 1.Predict RSD 2.Reduce DoE batches 3.Provide added insight to design space for CMC Nozzle optimization Feed tank optimization and scale-up At-line uniformity analysis tablet velocity characterization
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31. Project Leads: Divyakant Desai San Kiang Formulation and Drug Product Process: William Early Charles Van Kirk Howard Stamato Srinivasa Paruchuri Sanjeev Kothari API Process: Steven Chan John Korzun Analytical R&D: Harshad Patel Leon Liang Xujin Lu PAT: Arwa El-Hagrasy Don Kientzler Wei Chen Shih-Ying Chang Technical Operations: Howard Miller Megan Schroeder DEM modeling: Fernando Muzzio (Rutgers University) Regulatory Sciences: Steve Liebowitz Acknowledgements
34. Formulation and Process Optimization DOE - API versus Polymer Amounts -- Each batch was coated up to 10-mg potency. Tablets corresponding to 2.5-mg and 5-mg were collected at the appropriate times (theoretical weight gain) and results were treated separately. -- Effectively, three separate DOEs were performed for the three strengths: 2.5 mg, 5 mg and 10-mg, respectively. 20 16 2 1:8 20 16 4 1:4 16 8 8 1:1 Total Solids Dissolved / Suspended Opadry II White API % w/w in Coating Suspension API/Polymer Ratio 10 10 5 5 2.5 2.5 40 10 20 5 10 2.5 80 10 40 5 20 2.5 Opadry II White API Opadry II White API Opadry II White API 10 mg Tablets 5 mg Tablets 2.5 mg Tablets Amount per Tablet (mg)
35. Representative Tablet Formulations 7 mg Color D 7 mg Color C 7 mg Color B 7 mg Color A Opadry II Color 200 mg 200 mg 200 mg 200 mg Inert Core Outer Layer 10 mg 20 mg 20 mg 8 mg Opadry II White 10 mg 5 mg 2.5 mg 1 mg API Middle Layer 6 mg 6 mg 6 mg 6 mg Opadry II White Inner Layer 10 mg 5 mg 2.5 mg 1 mg Ingredient