Dissolution Modeling for Real Time Release Testing (RTRT)

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1 Dissolution Modeling for Real Time Release Testing (RTRT) Hanlin Li, Justin Prichard, Kelly A. Swinney 2016 Vertex Pharmaceuticals Incorporated

2 Outline Introduction to continuous manufacturing and RTRT at Vertex RTRT for dissolution model development approach Case Study Vertex Pharmaceuticals Incorporated

3 Vertex Business Drivers for Continuous Manufacturing Early finalization of formulation/process on commercial scale Data rich QbD commercial design space High quality, consistent product Vertex Pharmaceuticals Incorporated

4 Vertex s Continuous Manufacturing Rig Powder In Multi-product Line Day 1 AM Smaller scale equipment All unit ops in one facility Day 1 AM Coated Tablets Out Vertex Pharmaceuticals Incorporated 2012 Vertex Pharmaceuticals Incorporated. PAT Automated Control Strategy => IPCs + RTRT

5 Tablet Press PAT Locations Available for IPC and RTRT Measurements PAT1 NIR, measures material attributes during screening of raw materials PAT2, NIR, measures composition and BU PAT3a, NIR, measures granule uniformity, LOD, solid state form and physical attributes of granules PAT3b, Laser Diffraction, measures particle size distribution NIR Laser Diffraction 100L 1000L 1000L 1000L HC STEP 4, MILLING 100L 100L PAT4, NIR, measures composition and BU PAT5a, Raman, measures assay and CU PAT5b, Weight, hardness, thickness 10L PAT3b Mill PAT3a LHP 10L 10L Loss In Weight Feeders PAT6, Raman, measures coat thickness NIR STEP 5, FEEDER/BLENDER 2 STEP 1, FEEDER/BLENDER 1 STEP 1, FEEDER /BLENDER 1 PAT4 LHP Bucket Lift Granulation liquid 1 STEP 2, TWIN SCREW GRANULATOR STEP 7, COATING MC Waste STEP 6, COMPRESSION PFLS drying air out Dryer Thermocouple Deduster Fluid Bed Dryer STEP 3, FLUIDIZED BED DRYER W Th H drying air in PAT5a PAT5b Coating Liquid Finished Product Tablet Tester Raman Vertex Pharmaceuticals Incorporated

6 CM Control Strategy Building Blocks RTRT Material considered for release is manufactured within the DS (CPPs) and conforms to IPC criteria In-Process Controls Design Space Monitoring IPC failure Outside DSL Material is segregated from the process Unit Operation Control to Set Point Vertex Pharmaceuticals Incorporated Vertex Confidential Information

7 Example of RTRT for Continuous Manufacturing Critical Quality Attribute PAT Technology RTRT Method Material Identification Raman Confirm presence of API Core Tablet Assay NIR Weight API Content Tablet Weight Final Blend Core Tablet Dissolution Laser Diffraction NIR WTH Granule Particle Size API Content, Water Content Tablet Weight, Hardness, Thickness Milled Granules Final Blend Core Tablet Water Content NIR Water Content Final Blend Content Uniformity NIR Weight Variance in API Content Variance in Tablet weight Final Blend Core Tablet Physical Form Raman API physical form Core Tablet 7

8 RTRT for Dissolution Tablet Weight Final Blend Water Content Final Blend API Content Dryer inlet air temp Paddle speed Drying Time Dryer inlet air flow rate Individual components & granule powder feed rate DS bulk density Dryer Fill time Granule Water Content Blender speed Dissolution VX-770 DS Bulk SDD bulk Density density Compression Force Compression Force Paddle speed DS bulk density Paddle speed Granulation Solution Pump Rate DS Particle Size Granulation Powder Feed Rate Mill Speed Thickness Hardness Granule Particle Size The inputs are based on knowledge of the process and factors influencing dissolution performance at the time of batch release Vertex Pharmaceuticals Incorporated

9 Dissolution Model Development Approach 1. Determine the dissolution rate from the reference dissolution profiles 2. Model Z using measured attribute data Core Tablet (PAT 5 - Kraemer): Hardness, Thickness, Weight Final Blend (PAT 4 - NIR): water content, API content Granules (PAT 3b Malvern): particle size distribution 3. For routine use, Z is predicted and used to predict the a dissolution profile Vertex Pharmaceuticals Incorporated

10 Step 1: Determine the dissolution rate from the reference dissolution profiles dddddd dddd = zz pp LLLL nn (SS DDDDDDDD VVVVVV LLLL) LC: dissolution % at time t Dose: dose Fixed parameters n: shape factor Vol: volume S: solubility Parameters to be fitted: z: rate (scale) factor p: plateau Vertex Pharmaceuticals Incorporated

11 Step 2: Model dissolution rate using measured attribute data Predicted Dissolution Rate Reference Dissolution Rate Vertex Pharmaceuticals Incorporated

12 Reconstruct Dissolution Curve using Predicted Dissolution Rate 12

13 RTRT Dissolution Model: Case Study Batch 1 Batch % Dissolved QC Method % D issolved QC Method 40 RTRT Model 40 RTRT Model Tim e Tim e USP <1092>: Absolute difference not more than 5% for time points > 85% released Vertex Pharmaceuticals Incorporated

14 In Summary Process knowledge and identified factors influencing dissolution performance used to develop RTRT dissolution method Dissolution Rate PLS Model Modified Noyes- Whitney Equation RTRT Result 14

15 Acknowledgements Vertex Team Pharmaceutical and Preclinical Science Technical Operations Supply Chain Management Quality CMC Regulatory Facilities Global Information Systems Equipment Manufacturers Our CMOs, Suppliers, and Research Collaborators Regulatory Agencies (FDA, EMA, MHRA, etc) Vertex Pharmaceuticals Incorporated