QbD/PAT Implementation: The Road to RTR From Science to Compliance

Transcription

1 Quality by Design China 2013 April 17-18, 2013 Shanghai, China Pedro Hernandez, PhD 何盼多博士 Senior Director Quality Assurance - China pedrohernandez@frontagelab.com.cn

2 Background Development Overview Quality Risk Assessment FMEA Risk Prioritization Matrix Pareto Chart Ishikawa diagram PAT Implementation Strategy Process Flow - Opportunities Blending - NIR Instrumentation, Technology and Development Roller Compactor/Milling - LLD Instrumentation, Technology and Development Compression - NIR Fette 3090 Tablet Press Control Loops Instrumentation, Technology and Development Strategy for Implementation Conclusions

3 Product Summary Relatively High Dose Compound Extended Release Formulation Required for Once-a-Day Dosing HPMC based formulation Dissolution Rate Controlled by HPMC Concentration Surface Area/Volume Ratio

4 Design Space: Multi-dimensional space that encompasses combinations of product design, manufacturing process design, manufacturing process parameters and component attributes that provide assurance of suitable product quality and performance. Control Space: Multi-dimensional space that encompasses process operating parameters and component quality measurements that assure process or product quality. The Control space is a sub-set of the design space. Control Strategy : A strategy/methodology to mitigate the risks associated with the batch failure when the critical and non-critical parameters fall outside the control space but within the design space.

5 Defined experimental design space dimension for HPMC Viscosity Polymer substitution Water content Defined roller compaction design space dimension Roll force Roll gap Polymer concentration Defined tablet compression design space dimension Pre-compression force Compression force Tableting speed

6 Design Space

7 Summary Manufacturing design space based on DOE has been established and discussed Next step in implementation process: Incorporation of PAT techniques into the manufacturing process. Goal: Real Time Release of drug product based on QbD principles and real time monitoring of the manufacturing process

8 Background Development Overview Quality Risk Assessment FMEA Risk Prioritization Matrix Pareto Chart Ishikawa diagram PAT Implementation Strategy Process Flow - Opportunities Blending - NIR Instrumentation, Technology and Development Roller Compactor/Milling - LLD Instrumentation, Technology and Development Compression - NIR Fette 3090 Tablet Press Control Loops Instrumentation, Technology and Development Strategy for Implementation Conclusions

9 Quality Risk Assessment (QRA) Fish bone or Ishikawa diagram Solid dosage quality risk assessment uses Failure Mode and Effect Analysis (FMEA) FMEA: Risk scores based on probability, severity, and detectability Risk Prioritization Matrix Pareto Chart

10 Ishikawa: Fishbone Diagram Compression Blending Raw Material Tooling Cam selection Surface Discharge rate Fill Weight Feed frame setting Mg. Stea TALC Fill Vol. Order of ddn. Material addition Feeder speed Blend time Blend rpm HPMC API Press speed Pre & Post Compression Hardness of Tablet (Friability) Storage Discharge Roll force Roll Gap Transport Moisture PSD Porosity (den) Humidity Temp. Ribbon strength Material Transfer Environmental Roller Compaction

11 FMEA for Roller Compaction and Compression Process Steps Roller Compaction Potential Failure Mode No Roll Gap Control Potential Effect of Failure SEV Cause of Failure OCR Current Process Control DET RPN Recommended Action Reject Batch 3 Porosity & Roll gap 4 Control particle size 3 36 PAT for porosity not controlled control Reject batch 3 API particle size; morphology 2 Raw material physical characteristics 1 6 Moisture, double sampling Reject Batch 3 Flow of blend 3 Raw material characteristics Milling/ Granulation Reject Batch 3 Flow issues of blend; excess fines 3 Monitor particle size, use of force feeder 2 27 Reduce roll speed to improve densification 2 18 Control particle size; control roll gap Tablet Compression Loss in Hardness Reject Batch 4 Loss in compressibility; over lubrication 4 Control particle size; compressibility & lube time 3 48 PAT- porosity control Weight Variation Scrap batch 2 Flow & fill weight variability due to PSD Sticking of tablets Reject 4 Over lubrication, feeder causing over lubrication 3 In-Process sampling 3 18 Double sampling Control PSD 3 Control Lube times 3 36 Feeder speed & setting control.

12 Risk Prioritization Matrix

13 HPMC K 100 CR POROSITY PRESS SPEED COMPRESSION FORCE FEEDER SPEED LUBE TIME PSD OF INTRA- GRANULAR BLEND API PARTICLE SIZE BLEND TIME PRE-COMP FORCE EXCIPIENT PARTICLE SIZE 14.00% Pareto Chart: Relative Importance of Inputs 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00%

14 Background Development Overview Quality Risk Assessment FMEA Risk Prioritization Matrix Pareto Chart Ishikawa diagram PAT Implementation Strategy Process Flow - Opportunities Blending - NIR Instrumentation, Technology and Development Roller Compactor/Milling - LLD Instrumentation, Technology and Development Compression - NIR Fette 3090 Tablet Press Control Loops Instrumentation, Technology and Development Strategy for Implementation Conclusions

15 PAT Pyramid NIR Monitoring Blend Uniformity of API and HPMC Initial Blend Control of Manufacturing Ingredients QbD ` All raw materials are released and dispensed against established specifications to verify identity and quality. Compression PAT Laser Diffraction Monitoring Particle Size Roller Compactor Milling Fette Control Loops Monitoring Weight and NIR Monitoring Identity and Assay of API and HPMC Process Stage Quality Control or PAT

16 Implementation Strategy Stage 1: Identify and develop a feasibility (proof of principle) study for PAT use in critical steps of the drug product manufacturing process Stage 2: Application development to further refine the technique and demonstrate its robustness to assure data quality Stage 3: Monitor and analyze data of at commercial scale to demonstrate applicability of the PAT techniques Stage 4: Formal submission to agency to allow for real time release of the finished drug product and implementation of Continual Process Improvement

17 Background Development Overview Quality Risk Assessment FMEA Risk Prioritization Matrix Pareto Chart Ishikawa diagram PAT Implementation Strategy Process Flow - Opportunities Blending - NIR Instrumentation, Technology and Development Roller Compactor/Milling - LLD Instrumentation, Technology and Development Compression - NIR Fette 3090 Tablet Press Control Loops Instrumentation, Technology and Development Strategy for Implementation Conclusions

18 NIR Tools Process Unit Granulation Tablet Compression Critical Quality Attribute Blend Uniformity Assay and ID (AP I and HPMC) Instrument Brimrose: Luminar 4030 Bruker: MPA Process AOTF-NIR FT-NIR Mode Reflectance Transmission Range nm nm Scans 50 per revolution 128 per tablet Chemometric PLS, First Derivative PLS, First Derivative NIR data can serve as a surrogate for dissolution performance (i.e. ratio of API/HPMC).

19 Brimrose: Luminar 4030 NIR NIR Tools Brimrose: Luminar 5030 NIR Proper blending is critical to consistent product quality in solid dose manufacturing. NIR spectroscopy provides a real time window into your blending process for improved end-point determination even with variability in raw materials.

20 NIR spectra: 90% (blue) and 100% (red) strength

21 HPMC NIR spectra

22 NIR for Blend Uniformity Benefits Real time monitoring of the blending process and End Point determination. Non-invasive and non-intrusive. No sampling or sample preparation artifacts to affect the data. Summary Method development validated the NIR method(s) for monitoring Blend Uniformity (API and HPMC)

23 Background Development Overview Quality Risk Assessment FMEA Risk Prioritization Matrix Pareto Chart Ishikawa diagram PAT Implementation Strategy Process Flow - Opportunities Blending - NIR Instrumentation, Technology and Development Roller Compactor/Milling - LLD Instrumentation, Technology and Development Compression - NIR Fette 3090 Tablet Press Control Loops Instrumentation, Technology and Development Strategy for Implementation Conclusions

24 Roller Compaction Roll force Roll gap

25 Design of Experiments and Design Space The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. ICH Q8 (R2)

26 Tablet Development - Summary of DoE There was good control of key attributes within the design space studied. DOE demonstrates robustness of tablet compressibility within the manufacturing design space Variation in roller compaction force and tablet compression force gave essentially the same dissolution Batches manufactured outside of the roll compaction design space are within the clinical pharmacokinetic design space but fail tablet compression (Failure mode did not achieve desired hardness)

27 Malvern Insitec: Laser Diffraction for On-line Particle Size Analysis System Description The system consists of a computer, an Automation Control Panel, and Interface Panel and a bypass arrangement using a venturi eductor to draw a small amount of particulate from the discharge of the roller compactor. The eductor also provides a dispersion mechanism for the powder to separate agglomerated particles. Material drawn out of the process flow is returned to the process flow downstream from the sampling point.

28 % in RANGE QbD/PAT Implementation: The Road to RTR Particle Size Distribution: Range by Dose A + A - B + B - C + C - D + D - 0 % > 1000m (%) 840m > 1000m (%) 350m > 840m (%) 177m > 350m (%) 149m > 177m (%) PS RANGE 74m > 149m (%) 44m > 74m (%) % < 44m (%) Maximum: (+), Minimum (-)

29 Benefits Particle Size Analysis in real time Non-destructive sampling. Flow problems can be visually monitored and addressed Summary Laser Diffraction for Particle Size Analysis Each formulation has its own PSD profile but all four exhibit a similar bimodal profile. The axis for the bimodal distribution is in the microns in all four doses. Control of particle size at the roller compaction stage of the process may be needed for processing purposes (i.e. manufacturability). Particle size distribution does not impact dissolution

30 Background Development Overview Quality Risk Assessment FMEA Risk Prioritization Matrix Pareto Chart Ishikawa diagram PAT Implementation Strategy Process Flow - Opportunities Blending - NIR Instrumentation, Technology and Development Roller Compactor/Milling - LLD Instrumentation, Technology and Development Compression - NIR Fette 3090 Tablet Press Control Loops Instrumentation, Technology and Development Strategy for Implementation Conclusions

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33 NIR will be used to assess tablet assay of API and HPMC Bruker Optics Model MPA FT-NIR

34 Tablet NIR Spectra of Calibration Standards: First Derivative/MSC* *Multiplicative Scatter Correction

35 API Model Prediction versus calibration tablets API

36 HPMC Model Prediction versus calibration tablets

37 Benefits Identity and Assay in real time Non-destructive sampling. NIR for Assay of core tablets The final coating stage is for cosmetic purposes and dose differentiation, and has no impact on product performance. Desired Objective: NIR analysis at the compression stage on uncoated tablets will eventually replace current HPLC release testing. Summary The NIR methods has been validated for identity and assay for for both, API and HPMC In summary, NIR will be used to assess tablet assay of API and HPMC

38 Background Development Overview Quality Risk Assessment FMEA Risk Prioritization Matrix Pareto Chart Ishikawa diagram PAT Implementation Strategy Process Flow - Opportunities Blending - NIR Instrumentation, Technology and Development Roller Compactor/Milling - LLD Instrumentation, Technology and Development Compression - NIR Fette 3090 Tablet Press Control Loops Instrumentation, Technology and Development Strategy for Implementation Conclusions

39 Strategy for Implementation PAT deployment during the monitoring stage In-line blend uniformity measurements Using NIR On-Line Particle size monitoring using Laser Light Diffraction At-line NIR measurements for API and HPMC content in tablets (n = 90) NIR Assay: n= average of 10 tablets beginning, middle and end Tablets weights using an automatic weight checker Over 180 batches monitored

40 Feasibility Application Development Monitoring Implementation PAT TOOLS 1Q Brimrose Luminar 4030/5030 NIR On-Line Monitoring of Blend Uniformity Malvern Insitec T Particle Size Analyzer In-Line Monitoring of Particle Size in the Roller Compactor/Milling Process Bruker MPA NIR At-Line Monitoring of ID, Assay and API to HPMC ratio

41 Fit For Purpose Development cgmp Continual Improvement and Process Control Implementation Process Data gathering for statistical analysis Monitoring Method/Technology optimization In Process Application Development/Deployment Feasibility Proof of Concept for the Technology Risk Analysis Identify Critical Process Steps and PAT Technologies

42 Fit For Purpose Development cgmp Risk Analysis Feasibility Monitoring Implementation Application Development General Method Validation Requirements per ICH Q2A & Q2B These requirements are Scientific and Fit for Purpose, they are not based in a compliance status. The compliance status is determined by the environment. Specificity Linearity Range Accuracy Precision Repeatability Intermediate Precision Robustness Detection Limit Quantitation Limit

43 Fit For Purpose Development cgmp Application Risk Analysis Feasibility Monitoring Implementation Development PAT Development Proof of Concept with R&D During TT PAT Deployment at Manufacture Installation, IQ/OQ/CSV SOPs Method Optimization Validation Update Real Time Release Methods, SOPs and trainings are developed, verified and implemented with team inputs from R&D, TT, PPU, Quality, Regulatory, IT, Engineering and EHS support.

44 PAT Implementation Plan Feasibility Application Development Monitoring TASKS Risk assessment Tool selection NIR - Blend uniformity of API and HPMC Particle size - Roller Compactor NIR compression potency determination Feasibility protocol / report Experimental studies (lab. Scale) Method development Plan and build up chemometric models robustness Application development report PAT Comparability Protocol for FDA Build up chemometric models robustness commercial scale Data analysis / process variability Training strategy Determine other process variables that can indirectly support product release testing Revise SOP s / product spec as applicable for reduce testing PAT development report

45 Start System Integration Process Understanding PAT Implementation Plan Ownership Transition Technology to PPU/Quality Deployment TASKS commercial scale System integration for blend stage only. End point determination. Operation strategy, revise SOP Training strategy PAT and critical process data will be reviewed. Revise SOP s / product spec as applicable for reduced testing and Update PBR/MES Define Data Custody Chain based on level of integration and compliance requirements Approve SOPs for Data Custody Chain Write and Submit Comparability Protocol Real Time Release Degradation every 10 lots Continuous process monitoring Define future integration on a need and ROI basis

46 Background Development Overview Quality Risk Assessment FMEA Risk Prioritization Matrix Pareto Chart Ishikawa diagram PAT Implementation Strategy Process Flow - Opportunities Blending - NIR Instrumentation, Technology and Development Roller Compactor/Milling - LLD Instrumentation, Technology and Development Compression - NIR Fette 3090 Tablet Press Control Loops Instrumentation, Technology and Development Strategy for Implementation Conclusions

47 Conclusions Optimal Design Space Criteria for Hypromellose ensures consistent performance Blend monitoring by NIR will insure consistent uniformity of the granulation Particle Size distribution monitoring will insure processability of the granulation Compression NIR monitoring of Identity and Assay of API and HPMC together with Weight Analysis assures that quality is built into the product QbD + PAT = Real Time Release THE DESIRED STATE FOR QUALITY BY DESIGN MANUFACTURING

48 Guidance for Industry: PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, September pdf Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, September pdf Guidance for Industry: Q9 Quality Risk Management, June pdf Guidance for Industry: Q8(R2) Pharmaceutical Development Revision 2, November pdf Guidance for Industry: Q10 Pharmaceutical Quality System,April pdf Guidance for Industry: Process Validation: General Principles and Practices, January pdf References

49 谢谢 Acknowledgments Guayama-PR Ernesto Perez Reinaldo Vazquez Hector Garcia Gladys Collazo Lind Claudio Carlos Conde Pearl River-NY Carl Longfellow Saeed Hashemi Peter Larkin Eileen Fruhling Shailesh Singh Collegeville-PA Dominic Ventura Doug Becker Lou Sivieri T.G. Venkateshwaran

50 问题? Hesitating to act because the whole vision might not be achieved, or because others do not yet share it, is an attitude that only hinders progress. M. K. Gandhi