Implementing continuous process and real time release as a supplemental application change of an approved manufacturing product (a Case Study) Eric Sanchez, MS Global Technical Services, Director Solids Platform Janssen Ortho, LLC
Presentation content The business case for continuous process and real time release Strategic approach for the process transformation Creating a multifunctional team and project management Continuous Process and PAT Development strategy Partnership with academia Project progress status Process development PAT development Line integration and qualification
Why pursuing continuous process transformation? It makes sense from many important aspects of a pharmaceutical production! A continuous process greatly improve material handling and is an enabler for JIT and demand pull Move to Area Move to Area FIFO Weight / Dispense Kanban Move to Area Weight / Dispense Delumping/ Milling Blending Multiple Areas and Handoffs FIFO Move to Area One Room, No Handoffs Move to Area Move to Area FIFO Packaging Kanban Tablet Coating Tablet Compression
Continuous Process and Real Time Release Business Case A quantum leap in process knowledge Quality and Savings Source Batch process Continuous Testing In-process tests & release tests with a cycle time of +30 days On line, at line tests: Cycle time of 5 days Smaller Footprint 7 rooms, 6 discrete pieces of equipment, 80% cost reduction 2 room, 1 equipment train 60% cost reduction Waste 3% 1% 66% yield improvement Capital Investment (for same capacity) $24 MM (est.) $12.4 MM 50% cost reduction
Continuous process Business Case- Reliability of Supply Source Current Future Mfg cycle time (dispensing thru coating) 13 days/1000 kg 1.1 days/1000 kg > 90% reduction Release 30+ days 5 days >80% reduction Flexibility of Supply Batch size changes require exp and validation batches No scale up/down Quality control Process Knowledge and controls Ca 10 out of 265,000 tablets measured/examined (for a 600 mg batch) Limited based on unit operation and in process control (IPC s) On/at line measurement measures CU directly, assay continuously! Full controls integration with PAT capability provides process information real time with capabilities of advanced process control More informtion than ever
Development strategy Industry / Academia / Government collaboration
Development strategy Use of ERC resources Raw material characterization Equipment characterization PAT interface development Continuous process DOE Continuous process samples for in vitro dissolution study Spectroscopic methods evaluation and selection NIR calibration method development for blend and tablets Development of dynamic blend sensing requirements and PAT interface development
Full application of Quality by Design Principles Risk Assessment DOE proposal Model base control DOE analysis
Quality by Design Considerations: Raw Materials Raw materials properties Raw material physical characteristics Materials flow, compressibility, material shear and electrical properties evaluation Safety aspects of materials handling (explosion mitigation)
Quality by Design considerations: Feeding Feeding system Feeding systems optional design aspects selection for each raw materials (feeders screw design (size or type), use of screen at outlet spout)
Quality by Design Considarations: Feeding Feeding system Feeding adequacy assessment Feeders re-fill strategy Allowable perturbation levels (minor and major components) Effect of material transfer on feeding consistency and materials mass balance Feeders variation filterability (Blender-Feeder relationship)
Quality by Design considerations: Blending Blending system Blend system adequacy Selection of Optional blender blade design and configuration Residence time distribution studies Blend transfer and evaluation of blend (IP test and sensing) Blend parametric DoE aspects in design space study e.g, Throughput, Blender RPM
Quality by Design Considerations: Compression Tablet compression process Compression control considerations Effect on compression properties with composition variation (compressibility modeling) Residence time distribution studies Design space aspects of compression (e.g. Throughput = compression speed, composition variation, feed frame RPM, compression force and tablet properties)
Quality by Design Considerations: Compression Tablet compression IPC Compression IPC considerations IPC design = physical properties, NIR models (Calibration and ID) NIR Model development aspects Demonstrated Intended use: Real time measurement (effect of time and environment on either model predictions = method ruggedness) Final concentration and content uniformity for acceptance (e.g. Demonstrated adequacy of Calibration model precision, intermediate precision, accuracy, statistical similarity and method concordance with HPLC methodology) Final product identity for acceptance (e.g. Foreign material identification, raw material (active and excipients) concentration out of limits)
Quality by Design Considerations: Compression Tablet transfer and film coating considerations Tablet relaxation dynamics considerations Time to coat vs Time to expand Design aspects of tablet transfer coordination and integration of tablet transfer elements to allow tablet acceptance/rejection safeguards and relaxation dynamics requirements Film coating process DoE aspects (weight gain, process thermodynamic balance, tablets appearance as a response) Overall DoE considerations (effect on dissolution at variable tablet properties)
Quality by Design Considerations: Compression Parametric controls CPP definition, DoE based PAR and Equipment Variation Range definitions Feeders = Scada system controls limits based on DoE and Feeders characterization study results CPP = Rate of Feeding, re-fill levels, screw speed, Blender = DoE blending study, blender speed (RPM) Tablet press = Throughput speed, feed frame speed, compression force, fill depth, in process physical properties (Multivariable control scheme) Coating = Process thermodynamic balance
Quality by Design Considerations: Compression Model Based controls (future goal) Use predictive models for control assessment and actions real time Feeders = Fourier transformed on feeders rate variation Blender = Taylor dispersion model, mean center variance on residence time distribution Tablet press = multivariable models, density base models Coating = Process thermodynamic models
Process and PAT development status Development milestones achieved Raw material characterization Automated dispensing (feeders) characterization Continuous blending design and characterization NIR PCA identity model and PLS Calibration model for API (blend and tablets) Use of Rutgers pilot line for the selected product Continuous Process Development DOE (Throughput, Blender Speed and configuration, Compression force) In vitro comparability completed, F1 and F2 comparability requirements pass DOE analysis completed 18
% LC % LC % LC % LC In vitro comparability results 120.00 100.00 Regulatory Method 120.00 100.00 0.1N HCL 80.00 80.00 60.00 40.00 20.00 f2 75 f1 4 60.00 40.00 20.00 f2 99 f1 0 0.00 5 10 15 20 30 45 60 Lot: Current 12MG0048 process Lot Run: 0-B 0.00 5 10 15 20 30 45 60 120 Lot. Current 12MG0048 process Lot Run: 0-B 120.00 100.00 80.00 0.05M Phophate Buffer ph 3.0 70.00 0.05M Phophate Buffer ph 4.5, 6.5, 6.8 and 7.5 Max F1 = 13 Min F2 = 68 60.00 40.00 20.00 f2 69 f1 5 5 10 15 20 30 45 60 120 0.00 5 10 15 20 30 45 60 120 Lot: Current 12MG0048 process Lot Run: 0-B -30.00 Reference: Phosphate buffer ph 4.5 New Process: Phosphate buffer ph 4.5 Reference: Phosphate Buffer ph 6.5 Reference: Phosphate Buffer ph 6.8 Reference - Phosphate Buffer ph 7.5 New Process - Phosphate Buffer ph 6.5 New Process - Phosphate buffer ph 6.8 19
Dissolution Prediction and Controls = Surrogated Dissolution Proposal Dissolution predictive elements Dissolution Control Elements Multivariable thermodynamic control, empirical DS control API API Particle Size (COA) and Concentration control Film coating factors PAT? Disintegrant efficiency Disintegrant moisture and concentration control Multivariate (tablet IP, CPP, IPP) control Compression factors Blend lubrication Blender and feed frame shear control
Thanks to the teams!
Project status Project milestones achieved (JSC Gurabo facility) Facility construction completed Equipment installation completed Equipment qualification completed Controls design completed Controls testing (SAT on going) DoE design space confirmation on going Next steps Line integration, and PQ Registration lost manufacturing FDA s pre-operational meeting snda submission 22
The line at a glance (pre equipment installation)
The line at a glance (during equipment installation) Third Level First Level Panoramic View First Level Second Level First Level