QUALITY ASSESSMENT METHODS FOR NEW PRODUCT LAUNCHES:

PROCESS VALIDATION LIFECYCLE

CANADIAN SOCIETY FOR QUALITY9TH QUALITY CONGRESSSEPTEMBER 7-8, 2017

NAHEED SAYEED-DESTA

APOTEX INC.

OUTLINE

Introduction to Apotex

Process Validation Lifecycle

Stage 1 ICH Q12 PACM

Stage 2B Methodologies

Stage 3A Methodologies

Stage 3B Methodologies

Lifecycle Control Strategy

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Employment+10,000 employees globally

Capabilities+300 medicines in approximately +4,000 dosage forms

Global PresencePresent in +115 countries with affiliate offices and distribution networks

Canadian-owned largest pharmaceutical company in Canada

Apotex Overview

3

Sales >$2 billion/year from Apotex

group of companies

Apotex Global Manufacturing Sites

4

MEXICO

(API)

CHINA(API)

CANADA(SD, LD)

INDIA (SD, API)

USA(Transdermal)

Netherlands(SD)

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….

PROCESS VALIDATION LIFECYCLE – REGULATORY LANDSCAPE

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

PROCESS VALIDATION LIFECYCLE APPROACH

Stage 1

PROCESS VALIDATION LIFECYCLE

Stage 2B

Stage 3A 3B

Process Performance Qualification

Continued Process VerificationProcess Design

QTPPDoE- DESIGN SPACECQA, IPCCPP, KPP CONTROL STRATEGY

DETERMINE PPQ VERIFY CPP-NORPROCESS CAPABILITYCOMMERCIALIZATION

ENHANCED CONTROL STRATEGYCAPABILITY ASSESSMENTSTATISTICAL PROCESS CONTROLCONTINUOUS IMPROVEMENTCONTINUOUS PRODUCT SUPPLY

RISK ASSESSMENT: Mitigate Residual Risks at Each Stage

KNOWLEDGE ATTAINMENT : Stage 1, Stage 2, Stage 3, History, Similar Product / Process

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

STAGE 2B

The number of Stage 2B PPQ batches required is the number of batches when the projected “bestestimate” confidence interval of the product quality attribute measurements (which is a combinationof the CI of the process mean and the CI of the process standard deviation) resides completely in thespecification 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 (Pa) Analysis of Stage 2B PPQ Data:

Pa, 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.

STAGE 3A

Stage 3A is the initial assessment post new product launchthat 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 InitiativeAdditional sampling and testing may be required for Stage 3A.

STAGE 3A

Stage 3A systematically evaluates:Material attributesProcess parametersQuality characteristics Drug release profilesEnhance Control Strategy3B 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.

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.

S2Overall = S2

Process + S2Analytical

* 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.

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.*

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 = IPVP/ IPVB

where, IPVB is the Benchmark and IPVp 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 IPVp it indicates that there is an opportunity for reducing process variability of the current product through continuous improvement.

A corporate IPVB can be established based on dosage form and process

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.

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:

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.

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

Core assumptions in SPC are that the data is Normally distributed.

Stage 3B

Investigation / Stats Analysis

Product Performance & Capability (PP&C) Review Board

Proposed Path 3Continuous Improvement Project

Assessment

Stage 2 PPQ Study

Software System Flag

Out of Specification Out of Trend

Out of Statistical Control

Trend Confirmation Ex. WECO Rules

OOS QMS

System Automated Stage 3B

Proposed Path 2Immediate Action

Ex. communication to floor

Proposed Path 1No Action Required

Ex. equipment issue addressed

Automated Notification

Path 2 ImplementationPath 1 Continued Monitoring Path 3 Stage 1 - Optimization Studies

Pre- Stage 2 Risk Assessment

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.

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”

Q A&

THANK YOU