Product Robustness: Reducing Variability and Ensuring Delivery of Superior Quality Products to Patients

Transcription

1 Product Robustness: Reducing Variability and Ensuring Delivery of Superior Quality Products to Patients Dafni Bika, Jennifer Walsh and Tara Nestor Global Manufacturing Science and Technology Bristol-Myers Squibb 1

2 What is Process Robustness? Robustness is the ability of a process to demonstrate acceptable quality & performance while tolerating input variability Attribute or Parameter Statistica l Control Limits Specification Limit Robust Process = In control + Capable Within or across batches What is the source of variability? 2

3 Variability: A Day to Day Challenge Raw material properties Fluctuations in Humidity Unqualified test methods Storage conditions Tool wear New operators Undefined processes Complex machine settings Temperature cycling Supplier changeover With multiple sources of variability, how to achieve robustness? Categorize sources of variation to optimize approach Raw materials + Processes + Environment + Supply = Quality, Yield Variations 3

4 Robustness Is A Strategic Imperative Process monitoring reveals risks that create threats to supply and enables addressing them in a proactive manner Robustness addresses GMP expectations of Continued Process Verification Supply Risk Management Compliance Quality Robustness is the life cycle extension of QbD, continuing to build our process understanding and refine our control strategy and is not optional 4

5 Product Robustness spans the value chain Supplier Robustness Equipment Robustness Process Robustness Distribution Robustness People Business Processes Technology 5

6 What is a monitoring plan? Defines all product and material attributes and in-process parameters that are robustness indicators based on the product risk assessment and product development knowledge (includes all CPPs and CQAs) Implemented as a sampling, testing and analysis protocol for all robustness indicators Is the data source for the batch/campaign robustness and capability report 6

7 Example of How to Develop A Monitoring Plan 7

8 Example of A Monitoring Plan 8

9 Product Robustness Realization Roadmap Product Prioritization Develop and Approve Monitoring Plans Implement Monitoring Plans Initial data gathering Continuous Verification Locked Control Limits Process Capability Reporting At validation of new products Data gathering & analysis is manual or automated Monitoring plans across multiple products On initial assessment 70% of CQAs are capable Mitigation plans in place for the less capable ones Statistical process control and common metrics established across operations and quality Aligned R&D and manufacturing cooperation goals on robustness 9

10 PROCESS ROBUSTNESS RESULTS Process Capability Sixpack of D90 Individual Value P I Chart P UCL=87.58 _ X=68.51 LCL= Capability Histogram USL 97.5 Specifications USL 100 Moving Range Moving Range Chart P9 P7 UCL=23.43 MR=7.17 Normal Prob Plot A D: 0.409, P: LCL= Values Last 25 Observations Observation Within StDev Cp * Cpk 1.65 PPM 0.37 Capability Plot Within Overall Specs Overall StDev Pp * Ppk 1.49 Cpm * PPM 3.91 Product Performance Awareness Manufacturing Sites Proactive response 10

11 Monitoring Example: Assay Year-wise N = 168 PpK = 1.57 Ave. = UCL = LCL = N = 180 PpK = 1.08 Ave. = UCL = LCL = N = 286 PpK = 1.33 Ave. = UCL = LCL = N = 318 PpK = 1.63 Ave. = UCL = LCL =

12 Monitoring Example: Dissolution S1 Year-wise I Chart of Disso Min (2011 & 0.5 mg) 105 In d iv id u a l V a lu e _ X= lots_1 S2 = 3 out of 84 S2 = 1 out of 90 S2 = 5 out of 143 S2 = 3 out of 159 N = 84 PpK = 0.87 Ave. = N = 90 PpK = 0.67 Ave. = N = 143 PpK = 0.69 Ave. = N = 159 PpK = 0.64 Ave. =

13 Monitoring Example: Dissolution Vessel Capability comparison Concern: High instance of S2 Dissolution.* Impact: QC testing/release time QC Data collection: Date, Time, Equipment No., Model, Location (Vessel No.), Maintenance history, Analyst Assessment: Correlation 1: Vessel 1 has lowest capability compared to others Correlation 2: Some equipments showed high variability than others Strategies: GR&R study Analytical Equipment robustness *S2 frequency requires increased lab resources & time to patient. Product capable to S2 release criteria. 13

14 What Do We Do With The Data High Cpk/Ppk, Low shift Report Only Marginal capability, Mid - high degree of shift. Sufficient Safety Margin vs Specs Low-Mid Investigation Low capability, High degree of shift, Near proximity to specs Trackwise CAPA Expected 14

15 Product Robustness Status Examples Growth Product A Assay & Dissolution (S1) Actions: *Intensive monitoring plan developed. *Monitoring of drying uniformity. *Drying model & IPC evaluation. *Analytical impacts under evaluation. *Disso spec basis under evaluation. New Combination Product B Monotherapy Product Assay (1.28) FDC Assay/CU Actions: *Assay IPC control limits to alert of process/analytical outliers. *IPC control strategy & filing update under evaluation. *API analytical robustness ID of 1% recovery improvement w/ alternate pipette. *Predicting capability modeling *Intensive monitoring plan implemented RMs & PPs. 15

16 PRODUCT ROBUSTNESS OUTCOMES Reduce # of investigations and rejected batches No robustness related recalls In control and capable processes Leverage design data Support Change Control QUALITY COMPLIANCE Apply CPV guideline Respond to agency questions PAI readiness Reduce Investigations and APQRs cycle time Improve yield and reduce cycle time Reliable and timely tech transfers Expedite source and screening of raw materials CYCLE TIME 16 CULTURE Engagement at all levels Proactive intervention and prevention Continuous improvement Product Ownership

17 BMS Global Product Robustness Program Comprehensive industry benchmark E2E program driven by a highly collaborative cross-divisional team, which seeks to continually reduce variability in the processes, products and supply. Build Quality In, Ensure Supply and Prevent Investigations Sites with no investigations and no recalls 17