Effective Application of Quality‐by‐Design in Pharmaceutical Development and 
 Product Manufacture

Featured Speaker:


  ...
Sponsoring Partner:

Patheon
Patheon is a leading global provider of contract development and manufacturing services to th...
Effective Application of Quality-by-Design in Pharmaceutical
                      Development and Product Manufacture



...
Effective Application of Quality by Design
in Pharmaceutical Development and Product
Manufacture
Kwok Chow Ph.D., Patheon ...
Why is QbD Important?


• FDA initiative
• Expectation in regulatory guidance
• Wide range of strategies and applications
...
Concept of Quality by Design




                               Moheb M. Nasr, Ph.D.
                               CDER, ...
QbD: Knowledge to Practice




                             7
DfSS vs. Conventional Development


    Resources             DfSS Vision:
     Required
                           Predic...
QbD Strategies




                 9
Product Design Matrix


                                                                                Structural
       ...
Quote
          Characterization                                                Project
              Module              ...
Chemistry with Chemists

        NO 2                                N O2
                    CO 2 Me                     ...
Decision Tree for Low Solubility Drug Formulation

                                            Low solubility molecule    ...
Value of Statistical Design of Experiment




               Against                             For
 Expensive           ...
Defining the Design Space




                            15
Design Space Determination –
 Identification of Process Parameters (Fishbone Diagram)


      Material properties?        ...
Design Space Determination –
Identification of Process Parameters (Fishbone Diagram)

                                    ...
Guideline for Selecting Experimental Design



                                    Three Level Design


           Mixed q...
Granulation End Point Determination




                                      19
Granulation End Point by Size


   (A)                              (B)           (C)




                                ...
Response Surfaces: Influence of Water Addition
  and Massing Time


           D50 (micron)                        Bulk De...
Microcrystalline Cellulose and Water Interaction:
Influence of Flow and Compaction




                         Range for ...
Roller Compaction DOE + PAT




Burke et al 2009 AAPS poster
                               23
Blend Uniformity by Near Infrared (NIR)

                                                                                 ...
Interactions and Polymer Behaviors




               Feature characteristics of polymer surfaces and interfaces
L.H. Sper...
Electrostatic Powder Coating




                                        Electrostatic deposition
                        ...
Electrostatic Powder Coating Systems




                                       27
Integrated QBD Tools


• Material science
• Biopharmaceutics
• Formulation and process designs
• Statistical design of exp...
Contact Information


Thank you for participating! The audio and slides from this
presentation will be available for downl...
Effective Application of Quality-by-Design in Pharmaceutical
                        Development and Product Manufacture

...
Effective Application of Quality-by-Design in Pharmaceutical
                        Development and Product Manufacture

...
Contact Information


Thank you for participating! The audio and slides from this
presentation will be available for downl...
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Transcript of "Effective Application of Quality-by-Design in Pharmaceutical Development and Product Manufacture"

  1. 1. Effective Application of Quality‐by‐Design in Pharmaceutical Development and  Product Manufacture Featured Speaker: Kwok Chow, Ph.D., Senior Director Global Pharmaceutical  Development Technology and Alliances, Patheon Inc. Introduction: Mark Kontny, Ph.D., President of Global Pharmaceutical  Development Services and Chief Scientific Officer, Patheon Inc Copyright © 2010 Honeycomb Xtalks Inc.
  2. 2. Sponsoring Partner: Patheon Patheon is a leading global provider of contract development and manufacturing services to the global pharmaceutical industry. Patheon prides itself in providing the highest quality products and services to approximately 300 of the world’s leading pharmaceutical and biotechnology companies. Patheon’s services range from preclinical development through commercial manufacturing of a full array of dosage forms including parenteral, solid, semi‐solid and liquid forms. Patheon uses many innovative technologies including single‐use disposables, liquid‐filled hard capsules and a variety of modified release technologies. Patheon’s comprehensive range of fully integrated Pharmaceutical Development Services includes pre‐formulation, formulation, analytical development, clinical manufacturing, scale‐up and commercialization. Patheon can take customers direct to clinic with global clinical packaging and distribution services and Patheon’s Quick to Clinic™ programs can accelerate early phase development projects to clinical trials while minimizing the consumption of valuable API. Patheon’s integrated development and manufacturing network of 11 facilities and nine development centers, across North America and Europe, strives to ensure that customer products can be launched timely and confidently anywhere in the world. Copyright © 2010 Honeycomb Xtalks Inc.
  3. 3. Effective Application of Quality-by-Design in Pharmaceutical Development and Product Manufacture Kwok Chow, Ph.D., Senior Director Global Pharmaceutical Development Technology and Alliances, Patheon Dr. Chow joined Patheon as Director, Formulation Development in 2001. He has been serving as the Senior Director of Global PDS Technology and Alliances since 2005. He is responsible for developing/introducing new technologies, establishing strategic technology-alliances and providing scientific input for the pharmaceutical development of challenging molecules. Prior to joining Patheon, Dr. Chow spent 13 years at GlaxoSmithKline (previously Glaxo Wellcome and Glaxo) where he was leading the formulation design and development of a variety of conventional and novel dosage forms. He also played a CMC leadership role in the development of new chemical entities and line extension products for North America, Europe, Australia/New Zealand, Japan and other Asian Pacific countries. He is the author of a number of patents, abstracts and research/review articles. Copyright © 2010 Honeycomb Xtalks Inc.
  4. 4. Effective Application of Quality by Design in Pharmaceutical Development and Product Manufacture Kwok Chow Ph.D., Patheon Inc. Senior Director, Global Pharmaceutical Development Services Technology and Alliances
  5. 5. Why is QbD Important? • FDA initiative • Expectation in regulatory guidance • Wide range of strategies and applications • Significant benefits to improve product quality, plus reduce development/manufacturing risks through enhancing product robustness and ultimately streamlining regulatory interactions 5
  6. 6. Concept of Quality by Design Moheb M. Nasr, Ph.D. CDER, FDA MOHEB.NASR@FDA.HHS.GOV DIA Annual Meeting, Philadelphia, PA June 19, 2006 6
  7. 7. QbD: Knowledge to Practice 7
  8. 8. DfSS vs. Conventional Development Resources DfSS Vision: Required Predictive Design Revenue w/ DFSS Revenue w/o DfSS Launch Launch Time • Early problem identification; solution when costs low • Faster market entry: earlier revenue stream, longer patent coverage • Lower total development cost • Robust product at market entry: delighted customers • Resources available for next game-changer © 2010 Air Academy Associates, LLC. Used with permission. 8
  9. 9. QbD Strategies 9
  10. 10. Product Design Matrix Structural Analysis Chiral Analysis Solid stability Impurities Force identification Chemical Degradation /qualification pK, Stability Partition Dissolution Dynamic Coefficient Simulation Dissolution in Surface Simulated Fast Area Vapor Moisture Fed media Adsorption /Solvent Rule of 5 Content Animal pH Powder Bioavailability Solubility Thermo X-ray Analysis DSC TGA Single Caco2 Cell Bioavailability Process Crystal X-ray pH Log P Stability Capability Crystal Intrinsic Habit Particle Dissolutio Size n pK Human Powder Micronization Flow Microdosing/ Remote Wettability/ Controlled Human Solvent Microbial Surface Capsule Bioavailability Cosolvent Bioburden Tension Solubility Lead Compaction Simulation Optimization Chow et al. 2008 J Pharm Sci, 97 2855-2877 10
  11. 11. Quote Characterization Project Module Initiation Functional Test Modules particle size – sympatec surface area – BET morphology – microscope & image analysis (shape factor) flow – flowdex or volumetric flow rate moisture – TGA/DVM SRPD – if polymorph DSC – crystallinity If materials pass Product Specific Set acceptance criteria Process for incoming lots API check Materials Testing Assess likelihood Preferred particle size of issues with morphology / shape If fails or Flow Adhesion is marginal Product specific: small scale dosator pin tests / mini-tooling / compaction tests Miniaturization Modules: Process Flow & Adhesion Functional specifications for API confirmation Assess for each lot of API Product Specific Miniaturize Modules 11
  12. 12. Chemistry with Chemists NO 2 N O2 CO 2 Me C O 2M e H eat OH NO 2 NO 2 CO 2 Me C O2 H H ydrolysis OH OH N O2 NO 2 CO 2 Me C O2 M e O xidation OH O NO 2 NO CO 2 Me C O2 M e Light OH OH 12
  13. 13. Decision Tree for Low Solubility Drug Formulation Low solubility molecule Dissolution enhancer Expert review Salt and form selection Micronization* Expert review Solubility no enhancer* yes Liquid filled Tablets or capsules capsules* no Target modified release Non-patented Amorphous delivery Liquid, suspension, Absorption system drug mircoemulsion* enhancer Taste masking no Nanoparticles by high energy Patented delivery system milling* Other Nasal Technologies spray/buccal spray yes yes *ED Bioscreen 13
  14. 14. Value of Statistical Design of Experiment Against For Expensive Cost effective Time consuming Save time Standard template job Needs experience and know how Confusing: not one factor at a Powerful tool for robust processes time and products An FDA tool Solutions for complex problems 14
  15. 15. Defining the Design Space 15
  16. 16. Design Space Determination – Identification of Process Parameters (Fishbone Diagram) Material properties? GRANULATION UNIT SCREEN SIZE SCREEN/GRANULATOR GAP ANGLE CCWA CWA GRANULATO R CCWS CWS TYPE MOODE SPEED PRODUCT QUALITY COMPACTION FORCE TORQUE CONTROL SPEED FEEDING AUGUR SPEED TAMPING AUGUR SPEED ROLLER AUGUR TYPE FEEDING/TAMPING SPEED RATIO GAP WIDTH TYPE GAP AGITATOR GAP CONTROL FEEDING UNIT COMPRESSION UNIT 16
  17. 17. Design Space Determination – Identification of Process Parameters (Fishbone Diagram) GRANULATION UNIT Shear rate Impeller, chopper speed Binder dispersion Geometry Temperature Fill ratio GRANULATOR Atomization Feed rate Mixing time DRYING/ATTRITION Power, Torque control PRODUCT QUALITY Surface chemistry Humidity, temperature Viscosity Pre & post compression Press speed Binder Press Yield stress Feed frame setting Particle Size Distribution Fill weight Material Tooling Properties Shape, Roughness COMPRESSION Porosity, Area BLENDING RAW MATERIALS 17
  18. 18. Guideline for Selecting Experimental Design Three Level Design Mixed quantitative/-litative Quantitative only Factors Type Modeling Factors (k) or Screening Screening Modeling k≤3 4≤k≤4 6≤k≤7 k=5 Full Factorial Taguchi L18 Central Composite k = 2, nrep ≥ 7 Screening Box-Behnkin k = 3, nrep ≥ 3 nrep ≥ 4 k = 2, nrep ≥ 9 (CCD) k = 3, nrep ≥ 5 (CCD or BB) k = 4, nrep ≥ 3 (CCD or BB) k = 3, nrep ≥ 3 (CCD) Sample size (nrep) is for 95 % confidence in S-hat and 99.9 % in Y-hat model Sample size (nrep / 2) will provide 75 % confidence in S-hat and 95 % in Y-hat model 28 18
  19. 19. Granulation End Point Determination 19
  20. 20. Granulation End Point by Size (A) (B) (C) • • Microscopic images of wet granules obtained from different granulators (A)KG-5, 10× (B)PMA1, 5× (C) PMA65, 5× Huang et al 2006 AICHE conference 20
  21. 21. Response Surfaces: Influence of Water Addition and Massing Time D50 (micron) Bulk Density (g/ml) FlowDex (mm) Massing Massing Massing Time (s) Time (s) Time (s) Water 0 0 Addition (g) 0 Water Water Addition (g) Addition (g) 21
  22. 22. Microcrystalline Cellulose and Water Interaction: Influence of Flow and Compaction Range for optimized operational parameters Huang et al 2006 AICHE conference 22
  23. 23. Roller Compaction DOE + PAT Burke et al 2009 AAPS poster 23
  24. 24. Blend Uniformity by Near Infrared (NIR) 60 60 Medium EDTA 50 50 NIR EDTA Concentration, % NIR Concentration, % Fine EDTA 40 40 30 30 Linear (Medium 20 EDTA) 20 10 Linear 10 (Fine EDTA) 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Theoretical Concentration, % Theoretical EDTA Concentration, % Coarse EDTA Medium EDTA Fine EDTA Pooled samples Linear (Medium EDTA) Linear (Coarse EDTA) Linear (Fine EDTA) Linear (Pooled samples) NIR measurements generated by PLS model from samples NIR EDTA calibration curve generated using containing medium and fine EDTA samples containing fine, medium or coarse EDTA by MLR method. Each solid line is the line of best fit from one set of samples. Dotted line represents the line of best fit from pooled data Hu et al 2005 AAPS poster 24
  25. 25. Interactions and Polymer Behaviors Feature characteristics of polymer surfaces and interfaces L.H. Sperling: Introduction to Physical Polymer Science (Fourth Edition), Wiley, 2006 25
  26. 26. Electrostatic Powder Coating Electrostatic deposition and charge dissipation Film forming at slightly elevated curing temperature in presence of plasticizer Zhu et al, Tablets and capsules 2010 26
  27. 27. Electrostatic Powder Coating Systems 27
  28. 28. Integrated QBD Tools • Material science • Biopharmaceutics • Formulation and process designs • Statistical design of experiments • Process analytical technology • Innovation solutions • Statistical process control • Quality system 28
  29. 29. Contact Information Thank you for participating! The audio and slides from this presentation will be available for download shortly. Kwok Chow Ph.D., Patheon Inc. Senior Director, Global Pharmaceutical Development Services Technology and Alliances Email: doingbusiness@patheon.com Telephone: 1-866-PATHEON 29
  30. 30. Effective Application of Quality-by-Design in Pharmaceutical Development and Product Manufacture Q&A Session Polling Question: Is your company already doing QBD development? Yes 53% No 47% Copyright © 2010 Honeycomb Xtalks Inc. 30
  31. 31. Effective Application of Quality-by-Design in Pharmaceutical Development and Product Manufacture Q&A Session Polling Question: Based upon the information you’ve learned about QbD today, are you more inclined to use this approach in the future? No 8% Yes 92% Copyright © 2010 Honeycomb Xtalks Inc. 31
  32. 32. Contact Information Thank you for participating! The audio and slides from this presentation will be available for download shortly. Kwok Chow Ph.D., Patheon Inc. Senior Director, Global Pharmaceutical Development Services Technology and Alliances Email: doingbusiness@patheon.com Telephone: 1-866-PATHEON 32

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