Case Study 4: Challenges in the Implementation of Model Based and PAT based RTRT for a new Product PDA: A Global Gorm Herlev Jørgensen, Association Head of Unit, PharmaBiotech, Danish Health and Medicines Authority. Theodora Kourti, NPI OSD Center of Excellence, GSK Joint Regulators / Industry QbD Workshop 28-29 January 2014 London, UK
The TEAM Gorm Herlev Jørgensen , Head of Unit, PharmaBiotech, Danish Health and Medicines Authority. Keith Pugh, MHRA, UK Sean Jones, Quality assessor, MHRA, UK Theodora Kourti , New Product Introduction OSD CoE, GMS, GSK Manish Gupta , Global Formulation Division, R&D, GSK Sherry Watson , CMC Pre-Approval, Chief Regulatory Office, GSK Dimitris Alexandrakis , Chemometrics, GMS, GSK Louise Fido, PAT, GMS, GSK Helen Birkett , Qualified Person, GMS, GSK Paul Frake , Technical , GMS, GSK 2
Case Study Main Points RTRT as part of the control strategy for multiple CQA’s • Description • Identification and Content • Drug-related impurities • Uniformity of dosage • Dissolution End Point Detection supports / integrates into RTRT • Granulation • Drying • Blending Design Space Across Unit Operations at Commercial Scale Lifecycle Support Considerations
Overview of Product: Drug AA Tablets Drug AA Drug Substance • – Four stage manufacturing process with particle size reduction by micronization – Drug substance present as the hydrochloride salt (BCS Class II) – Submission contains enhanced product development approach Drug AA Tablets • – Film-coated immediate release tablet for oral administration – 200 mg and 400 mg strengths; conventional wet granulation process – High Drug Content (66%) in the Tablets – Submission contains: enhanced product development approach control strategy based on comprehensive process understanding real time assurance proposal for real time release process qualification and ongoing quality assessment using lifecycle validation approach Development and submission for this product preceded ICH Q8/Q9/Q10 • implementation activities and uses terms that GSK subsequently updated to align with ICH QbD terms
Drug AA PAT within the control strategy 100 NIR NIR F-value 90 DCS Endpoint Control 80 70 IP21 data capture 60 50 40 Pazopanib Granulation 40 0 30 -2 35 20 -4 30 10 -6 Solution vessel weight [kg] 25 0 Impeller Load [%] -8 0 50 100 150 200 250 Rotation 20 -10 -12 15 -14 10 -16 Granulation 5 -18 Blending Compression 0 -20 0 1 2 3 4 5 6 7 8 9 10 Time [min] Endpoint - Dissolution Impeller Load Solution vessel weight Homogeneity NIR -Content & ID NIR Drying Time (t) Drying Compression 3.0 t=0 Moisture content Main compression force for UDU 2.0 Standard Normal Variate Thickness for dissolution 1.0 0.0 Compression Force Pazaponib Compression 11 -1.0 t=end 10.5 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 Wavelegth [nm] 10 Batch R310401 Campaign Jul'07 Main Compression Force [kN] Date 14-Jul-07 4 3.75 9.5 3.5 3.25 PREDICTED LOD% (w/w) 3 9 2.75 2.5 2.25 2 8.5 1.75 1.5 End-Point Value 1.25 Repeatability around end-point = 1 1 8 0.75 0 10 20 30 40 50 60 70 80 90 100 Time [min] 0.5 08:49:01 08:49:42 08:50:23 08:51:04 08:51:45 08:52:25 08:53:06 08:53:47 08:54:28 08:55:09 08:55:50 08:56:31 08:57:12 08:57:52 08:58:33 08:59:14 Main Compression Force TIME
Traditional Release Proposed RTR Testing Approach Approach Work based granulation end point Granulation to control dissolution Milling NIR based granule drying LOD endpoint endpoint Drying NIR based endpoint for blend Milling uniformity Blending Weight, thickness, hardness, -NIR composite assay disintegration, friability -On-line dosage uniformity by tablet Lubrication press weight control -Main compression height to control AQL dissolution (thickness) Compression DP release tests Film Coating Description -Description by inspection ID - NIR for ID Content (HPLC) Impurity (HPLC) Laboratory Uniformity (Mass) Dissolution
Risk Assessment was performed for All Unit Operations - Example Unit in this slide: Granulation - Fishbone/Ishikawa Diagram for the Drug AA Granulation Transformation Flow Sheet Granulation/Wet Milling/Drying/Dry Milling Process Generated from BRITEST Review Man Man Method Method Materials Materials U6 U6 SOPs, batch record SOPs, batch record U1 U1 micronized drug substance micronized drug substance U8 U8 operator training operator training arm position/orientation arm position/orientation microcrystalline cellulose microcrystalline cellulose (insufficient atomizing) (insufficient atomizing) operator experience operator experience spray rate calibration spray rate calibration (over wetting) (over wetting) sodium starch glycolate sodium starch glycolate (loss through filter) (loss through filter) utilities maintenance utilities maintenance (large droplets) (large droplets) spray rate/time setting spray rate/time setting povidone povidone (high water to (high water to (mostly dry - mix) (mostly dry - mix) drying endpoint drying endpoint anti-static socks/lay flat tubing anti-static socks/lay flat tubing powder ratio locally) powder ratio locally) granulation endpoint/P0 granulation endpoint/P0 water temperature water temperature pre-heating FBD pre-heating FBD cleaning cleaning shake frequency/duration shake frequency/duration scrape-down scrape-down discharge method discharge method loading/dry blending loading/dry blending hold-times hold-times U4 U4 U9 U9 cleaning frequency cleaning frequency (wetting wall) (wetting wall) transfer method transfer method (insufficient atomizing) (insufficient atomizing) (spray arm height) (spray arm height) inlet air humidity inlet air humidity (large droplets) (large droplets) nozzle size nozzle size inlet temperature inlet temperature spray arm spray arm product/exhaust temperature product/exhaust temperature U2 U2 U5 U5 fill(max): 2/3 fill(max): 2/3 solution pump solution pump inlet air volumetric flow inlet air volumetric flow tubing tubing (overwetting) (overwetting) filter/mesh DP filter/mesh DP (under wetting) (under wetting) granulator seal granulator seal vessel weight vessel weight (high spray/impact) (high spray/impact) outside temperature outside temperature wet comil/screen size/spacer wet comil/screen size/spacer (low powder area covered) (low powder area covered) moisture content moisture content inlet humidity inlet humidity comil/screen size/spacer comil/screen size/spacer (fines/coarse generation) (fines/coarse generation) fill(min): 1/3 fill(min): 1/3 granule size, density (porosity) granule size, density (porosity) purge rate purge rate impeller load, Work calculation impeller load, Work calculation “ tophat ” assembly “ tophat ” assembly impeller speed/setting impeller speed/setting rapid transfer port rapid transfer port U7 U7 wet mill current wet mill current chopper speed/setting chopper speed/setting (formation of “balls”) (formation of “balls”) electrostatics electrostatics (maldistribution) (maldistribution) Mother nature Machine Mother nature Machine Measurement Measurement U3 U3 (overwetting) (overwetting) IPO Diagram for Drug AA Granulation Process D2 D2 (located near dispersion zone) (located near dispersion zone) D1 D1 (uniform wetted powder) (uniform wetted powder) (side impeller) (side impeller) (spray on (spray on (mechanical dispersion (mechanical dispersion homogenized mass) homogenized mass) if required) if required) IPO Diagram for the Granulation Process Controllable Parameters Granulation chopper speed Granulation impeller speed Preblend chopper speed Preblend impeller speed Granulation endpoint GRANULATION GRANULATION Processing humidity Water temperature Spray arm position Comil screen size Spray arm height Water spray time Order of addition Water spray rate Impeller recipe Preblend time Water amount Nozzle design Spray recipe Batch size Inputs Outputs High Shear Granulation Process GW786034B physical properties BRITEST performed on all Drug Product unit Microcrystalline cellulose Yield Pazopanib Sodium starch glycolate 1. Material Transfer Granule uniformity Povidone Granule water content 2. Preblend operations Water 3. Water Spray Granule porosity Raw material supplier Granule shape 4. Wet Massing Solution Pump 5. Wet Milling Granule density Granule size distribution 6. Transfer to fluid bed dryer Adhesion to granulator bowl Electrostatic charge Milling Time Non - Controllable Parameters (Noise) Risk Assessments performed on all unit operations to justify decisions
Process Understanding and Control Design of Experiments (evaluated ranges were provided at submission, omitted here) • Granulation and Compression – Water Amount – Granulation End point – Tablet Thickness • Compression – Press speed – Filomatic speed – Tablet Thickness • Blending – Time • Lubrication – Time • Coating – Spray Rate – Inlet Air Temperature • Micronization – Feed Rate (specific Energy model included)
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