QUALITY ASSESSMENT METHODS FOR NEW PRODUCT LAUNCHES: PROCESS VALIDATION LIFECYCLE

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1 QUALITY ASSESSMENT METHODS FOR NEW PRODUCT LAUNCHES: PROCESS VALIDATION LIFECYCLE NAHEED SAYEED-DESTA APOTEX INC. CANADIAN SOCIETY FOR QUALITY 9 TH QUALITY CONGRESS SEPTEMBER 7-8, 2017

2 OUTLINE Introduction to Apotex Process Validation Lifecycle Stage 1 ICH Q12 PACM Stage 2B Methodologies Stage 3A Methodologies Stage 3B Methodologies Lifecycle Control Strategy

3 Apotex Overview Canadian-owned largest pharmaceutical company in Canada Global Presence Present in +115 countries with affiliate offices and distribution networks Capabilities +300 medicines in approximately +4,000 dosage forms Employment +10,000 employees globally Sales >$2 billion/year from Apotex group of companies 3 3

4 Apotex Global Manufacturing Sites Netherlands (SD) CANADA (SD, LD) CHINA (API) USA (Transdermal) MEXICO (API) INDIA (SD, API) 4

5 PROCESS VALIDATION LIFECYCLE REGULATORY LANDSCAPE US FDA PV (2011) The guidance aligns PV activities with a product lifecycle concept and with existing FDA, ICH guidance s for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. EMA PV (2014) Process validation incorporates a lifecycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production. WHO Appendix 7 (2015) The life-cycle approach links product and process development, validation of the commercial manufacturing process and maintaining the process in a state of control during routine commercial production. PIC/S Annex 15 (2015) Requirements for process validation continue throughout the lifecycle of the process. ICH Q8, ICH Q9, ICH Q10, ICH Q12.

6 PROCESS VALIDATION Process Validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process. Process Validation and Drug Quality Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. This principle incorporates the understanding that the following conditions exist: Quality, safety, and efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished-product inspection or testing Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications. Process validation activities are categorized in three stages. FDA (CDER/CBER), Validation Guidance: General Principles and Practices, guidance for Industry, January 2011

7 PROCESS VALIDATION LIFECYCLE APPROACH

8 PROCESS VALIDATION LIFECYCLE RISK ASSESSMENT: Mitigate Residual Risks at Each Stage Stage 1 Stage 2B Stage 3A 3B Process Design QTPP DoE- DESIGN SPACE CQA, IPC CPP, KPP CONTROL STRATEGY Process Performance Qualification DETERMINE PPQ VERIFY CPP-NOR PROCESS CAPABILITY COMMERCIALIZATION Continued Process Verification ENHANCED CONTROL STRATEGY CAPABILITY ASSESSMENT STATISTICAL PROCESS CONTROL CONTINUOUS IMPROVEMENT CONTINUOUS PRODUCT SUPPLY KNOWLEDGE ATTAINMENT : Stage 1, Stage 2, Stage 3, History, Similar Product / Process

9 STAGE 1 ICH Q12 provides a framework to facilitate the management of post-approval CMC changes in a more predictable and efficient manner across the product lifecycle. Full realisation of ICH Q8, Q9, Q10 and Q11 concepts. Post-Approval Change Management Protocol (PACMP) is an ICH Q12 regulatory tool. Proposal will streamline changes to be implemented during lifecycle of a product, ensuring continuous supply. Components: A detailed description and rationale of the change. A list of specific tests and studies to be performed to evaluate the potential impact. Risk assessment methodology. Appropriateness of the approved control strategy to oversee the changes. Supportive data from previous experience, if any. Proposed reporting category. Confirmation of Continued Process Verification plan. ICH Q12 Harmonization promotes continual improvement, reduces regulatory burden, strengthens QA and ensures reliable supply

10 STAGE 2B The number of Stage 2B PPQ batches required is the number of batches when the projected best estimate confidence interval of the product quality attribute measurements (which is a combination of the CI of the process mean and the CI of the process standard deviation) resides completely in the specification range. historical batch-to-batch variability for comparable product/processes based on highest correlation factor: active content product specific information (e.g. data generated from Stage 1 batches produced for the purpose of clinical trials, submission, stability, process scale-up/demonstration) Acceptance Probability (P a ) Analysis of Stage 2B PPQ Data: P a, is designed to provide the probability that a future produced batch will meet the specification acceptance criteria. Traditional capability computations fall short in providing reliable assessment of the ability of the product to meet stage wise acceptance criteria.

11 STAGE 3A Stage 3A is the initial assessment post new product launch that utilizes a substantial body of data for statistical evaluation to gain deeper product understanding. Stage 3A assessment utilizes data from all PV Lifecycle Stages. Stage 3A assessment is pivotal in understanding product variability. Stage 3A evaluation is a valuable resource for product development and risk mitigation of similar products and processes. Defining a Stage 3B monitoring plan is part of Stage 3A. Stage 3A assessment demonstrates the organizations compliance in establishing an enhanced product control strategy and attaining a high level of product understanding and quality. Stage 3A protocol may be initiated upon completion of Stage 2B. ISPE BU/CU Initiative Additional sampling and testing may be required for Stage 3A.

12 STAGE 3A Stage 3A systematically evaluates: Material attributes Process parameters Quality characteristics Drug release profiles Enhance Control Strategy 3B CPV monitoring criteria. Stage 3A assessment is vital for new products in understanding product robustness and managing variability. The conclusions made should provide sufficient information to make a scientific and risk-based decision on Product Robustness and Product Quality. Process Capability and Quality Dashboard (PCQd): A product specific PCQd is a component of Stage 3A assessment in projecting product robustness. The dashboard addresses the elements in the FDA's Guidance: Request for Quality Matrix, where the agency suggests optional metrics as evidence of manufacturing robustness and a commitment to quality.

13 STAGE 3A INDICES FOR BUSINESS Inherent Process Variability (IPV) US FDA recognizes the importance of statistical process control in understanding and managing variability. Understanding the causes of variability allows for control at the source. First step in estimating process variability is to ensure that variability contributing factors are constant. Inherent Process Variability (IPV) is estimated using variance component analysis using a one-way Random effects ANOVA model with 95% CI. IPV is a measure of batch to batch variability while analytical variability is a measure of within batch variability.* S 2 Overall = S 2 Process + S 2 Analytical * Nunnally B, Variance Component Analysis to Determine Sources of Variation for Vaccine Drug Product Assays Journal of Validation Technology, (Summer) 2009 Continuous Improvement strategies may be developed based on observed inherent process variability.

14 STAGE 3A INDICES FOR BUSINESS Once the IPV is calculated for a particular product it can be used to derive a PaCS index. The PaCS index is a derivative of a product s performance measured against a benchmark of similar process. PaCS index empowers management with site specific product performance oversight. PaCS = IPV P / IPV B where, IPV B is the Benchmark and IPV p is the Product Inherent Process Variability A PaCS <1 indicates the process variability is low and a PaCS index > 1 indicates the process variability is high compared to the benchmark. In cases where PaCS > 1, further evaluation may be required. If IPV p it indicates that there is an opportunity for reducing process variability of the current product through continuous improvement. A corporate IPV B can be established based on dosage form and process

15 STAGE 3B Stage 3B assures routine production process remains in a state of control. A system or systems for detecting unplanned departures is essential. Evaluation of process performance data will allow detection of process drift. Will verify CQA s are being appropriately controlled through the process and reduces process failure rate If properly carried out, these efforts can identify variability in the process and/or signal potential process improvements.

16 STAGE 3B - CONTINUED PROCESS VERIFICATION SPC trend limits, coupled with control chart rules alert to potential non-random events. There are a multitude of SPC charting rules. These include, but not limited to: Rule Description Possible Concern Rule 1 One point more than three standard deviations from mean Indicates a statistically anomalous event Rule 2 Nine sequential points on the same side of the mean Potential prolonged bias Rule 3 Six sequential points continually decreasing or increasing A potential trend Rule 4 Fourteen sequential points alternate (oscillate) in direction Potential multiple underlying processes Triggering one of these rules indicates with reasonable statistical confidence that something may have changed within the process that may have an impact on the product robustness and control. Core assumptions in SPC are that the data is Normally distributed.

17 Stage 3B System Automated Stage 3B Software System Flag Automated Notification OOS QMS Out of Specification Out of Trend Out of Statistical Control Trend Confirmation Ex. WECO Rules Investigation / Stats Analysis Proposed Path 1 No Action Required Ex. equipment issue addressed Proposed Path 2 Immediate Action Ex. communication to floor Proposed Path 3 Continuous Improvement Project Assessment Product Performance & Capability (PP&C) Review Board Path 1 Continued Monitoring Path 2 Implementation Path 3 Stage 1 - Optimization Studies Pre- Stage 2 Risk Assessment Stage 2 PPQ Study

18 CONTROL STRATEGY LIFECYCLE DEVELOPMENT OF CONTROL STRATEGY IMPLEMENTATION OF CONTROL STRATEGY CONTINUAL IMPROVEMENT OF CONTROL STRATEGY PRODUCT DEVELOPMENT > SUBMISSION > COMMERCIAL MANUFACTURING Control strategy describes a set of controls ensuring as a whole, product quality and control of the source of variability. Control Strategy established in Stage 1 to ensure that CQAs are met, and hence QTPP is realized. Control strategy is verified during Stage 2 qualification Stage 3A is integral to Control Strategy in detection of variability. Stage 3B allows for continual improvement of the Control Strategy.

19 SUMMARY PV Lifecycle Approach Stage 1 ICH Q12 PACM Protocol Stage 2B Methodologies Stage 3A Methodologies Stage 3B Continued Process Verification Continual Enhancement of Control Strategy Science and risk-based

20 Q & A THANK YOU