The Analytical Lifecycle - cbinet.com 15... · The Analytical Lifecycle Starting with Legacy Methods ... •Monograph is revised ... •Curves, DLs, QLs •Software

Nancy & Donna (sisters) Gaucher Disease USJade (with her mother) Fabry disease USA

The Analytical LifecycleStarting with Legacy MethodsDebora Aguiar, Analytical Lifecycle Management Program Director, Genzyme

Analytical LifecycleStarting with Legacy Methods

2

• Contributing factors that may indicate you should consider revalidating

Regulatory Expectations

• Objectives and performance parameters

• Elements of test method assessments

• Considerations

Assessments

• Strategy

• Prioritization

• Benefits and Challenges

• Test Method Validation Master Plan

Remediation

•Elements of a test method monitoring program•An analytical lifecycle process component

Test Method Performance Monitoring

Analytical LifecycleRegulatory Expectations for Test Methods

3

Materials and product testing is a critical control function. It is also good business practice to ensure test methods are suitable for intended use and compliant.

Test methods must be validated to support the safety, identity, strength, quality, purity and potency claims for drug substances and drug products.

The regulations clearly state that test method validation must demonstrate that a test method is reliable, reproducible, linear, specific, and accurate.

The regulations also state that revalidation of a test method should occur under certain conditions.

Analytical LifecycleRegulatory Expectations for Test Methods

4

Regulations and Guidance Documents

FDA Guidance for Industry: Analytical Procedural Method Validation for Drugs and Biologics

ICH Q2(R1), Validation of Analytical Procedures: Text and Methodology

21 CFR Part 211.160, 211.165, cGMP for Finished Pharmaceuticals, Subpart I, Laboratory Controls

USP <1225> Validation of Compendial Procedures

USP <1226> Verification of Compendial Procedures

Also consider method type and other relevant documents

FDA Guidance for Industry: Bioanalytical Method Validation

CDER; Reviewer Guidance: Validation of Chromatographic Methods, 1994

USP <621> Chromatography

USP <851> Spectrophotometry and Light Scattering

Analytical LifecycleContributing Factors for Revalidation

5

• A validation study is a snapshot of test method performance at that point in time.

• Changes in the laboratory or manufacturing process can affect characteristics of a test method.

• Accumulation of minor changes can create a gradual drift.

• Equipment: replaced or repaired

• Reagents: products discontinued and replaced

• Materials: different suppliers are used

• Consumables: manufacturing process changes

• Environment: temperature, humidity, water quality, ventilation

• Personnel: experience, workload, training

• Test Article: manufacturing process changes

Time

Analytical LifecycleContributing Factors for Revalidation

6

• Changes to compendia/regulations

• Monograph is revised

• System suitability is added or revised

Criteria

• A validation study generates performance characteristics for a test method.

• A test method not performing in the same manner in which it was validated may require additional assessment.

• Adverse trends: assay controls, Cpk

• High failure rates

• Operating challenges

Performance

Analytical LifecycleTest Method Assessments: Objectives

BenefitsMethod assessments helps ensure compliance with standards and regulations.

Other benefits include:• Ensures method reliability• Reduces risk to product• Provides quality assurance• Continuous improvement, efficiency• Alignment w/ GMP

ConsequencesConsequences of poor method assessment include:• Unreliable methods• Ineffective or inefficient methods• Releasing product that is not safe, effective, pure• Patient safety risk• Non-compliance• Cost/reworkFinally, non-compliance can have a major cost impact. Inefficient, ineffective methods can lead to OOS results, costly investigations, and rework.

7

Test method assessments should be performed to evaluate appropriateness, identify operating challenges, deficiencies, and compliance risk

Test method assessments should be proceduralized so that they are performed consistently and routinely

Analytical LifecycleTest Method Assessments: Parameters

8

• Purpose• An assessment of what product attributes the method is used to measure

Evaluate Appropriateness

• Usability• An assessment of the method by those who use it regularly

Identify Operating Challenges

• Adequacy• A comparison of the test method procedure to current standards and industry best

practices

Identify Deficiencies

• Validation• A comparison of the test method validation to current standards and industry best

practices

Identify Compliance Risk

• Raw Materials

• In-Process

• Process Characterization

• Lot Release

• Stability

Intended Use

• Identity

• Purity

• Potency

• Impurity

• Content

Critical Quality Attributes

• Ppk

• Stability Specifications

• All JurisdictionsSpecifications

• Product Composition

• Buffer Formulation

• Sample MatrixChanges

Analytical LifecycleTest Method Assessments: Purpose

9

• Laboratory Error Rate

• OOS/OOT Investigations

• Assay Control Trends

• Cpk Value

• Safety Concerns

Performance

• Reagent Availability

• Equipment Availability or Malfunctions

• Compliant Operating Software

• Operating Environment Consumables and Equipment

• Meaningful

• Appropriate

System Suitability

• Test Method Document

• Qualification Procedures

Documentation

Analytical LifecycleTest Method Assessments: Usability

10

• Test Method Content

• Performance vs. Intended Use

Performance

• Ref Standards

• Critical Reagents and Qualified Materials

• Reagents

• Expiration Dates

• Equipment Procedures, Precision

Materials and Equipment

• Documentation clarity

• Curves, DLs, QLs

• SoftwareExecution

• Calculations

• System Suitability

• Acceptance CriteriaEvaluation

Analytical LifecycleTest Method Assessments: Adequacy

11

Analytical LifecycleTest Method Assessments: Validation

• Development and Qualification

• Validation vs. Intended Use

• Recommendations

• System SuitabilityFit for Use

• Protocols

• Reports

• Data

• Calculations

• Changes

Documentation

• Critical Reagents

• Qualified Materials

• Reagents

• Sample Stability

Materials

Equipment

Laboratory

• Specificity, Linearity, Range, Accuracy, Precision, DL/QL, Robustness

• Compendial requirements

ICH Q2 R1

12

Analytical LifecycleTest Method Assessments: Considerations

13

• Quality Review

• Objective Language

• Sufficient Evidence to Support Ratings

Auditable

• Risk Assessment

• Operating in a State of Control

Suitable for Continued Use

14

Analytical LifecycleTest Method Assessments: Template Bonus Material

Method Assessment Report, <Assessed Method SOP number and version (e.g. QC-XXX-XX v.1.0) here>, <type method SOP title here>

Analytical Life Cycle Management (ALCM)

Method Assessment Report

Method SOP # Version #

Method SOP Title

Date Assessment Completed

Lead Assessor Name

Table of Contents

1.0 Executive Summary 2

2.0 Method Assessment Team Review Results 3

3.0 Assessment Team, References, and Summary of Major Observations 4

4.0 Assessment for Method Purpose 5

5.0 Assessment for Usability 7

6.0 Assessment for Adequacy 10

7.0 Assessment for Validation 15

8.0 Assessment for Regulatory Commitments 22

Analytical LifecycleTest Method Remediation: Strategy

15

• Test method SOPs should be revised to address deficiencies and provide additional clarity and guidance for method performance.

Document Revision


16

• Test method should be validated for applicable process stage matrices according to current standards.

• Opportunities for enhancement/optimization could be incorporated that may require a change control, but not necessarily result in a regulatory filing other than Annual Reportable.

• Additionally, it may not be necessary to do a full revalidation as a modified or reduced validation may be all that is needed.

Revalidate


17

• The test method requires significant changes to the current method.

• Method development and qualification studies prior to method validation are necessary and may lead to the generation of new product testing specifications.

• Regulatory filings are assumed to be required.

Redevelop


18

• The test method requires a change in platform that would replace the current method.

• Method development and qualification studies prior to method validation are necessary and may lead to the generation of new product testing specifications.

• Comparability/crossover studies and/or “double-testing” of both current and replacement methods are presumed.

• Regulatory filings are required and retirement can not occur until replacement approval from required jurisdictions is obtained.

Replace and Retire

Considerations for employing one strategy over another


19

• Post Marketing Commitment

Regulatory Compliance

• Project interdependencies

• Timelines

• Process monitoring

Business Needs

• Expertise

• Operational Support

Resource Availability

• Cost of project

• Risk mitigation

Return on Investment

Analytical LifecycleTest Method Remediation: Prioritization

20

21

Analytical LifecycleTest Method Remediation: Benefits

• Validation

• SST Requirements

• Sample Stability / Reagent Expiry

Compliance (SISPQ)

• Upgrade Technology

• Identify Common Technology Platforms

• Harmonize Methodologies Across Products

• Reduce Method-Related Lab Errors

• Evaluate / Revise Testing Catalogues

Improve Efficiency

• Enablers for Process Change

• Implement Working Standard for Test Method Performance Monitoring

Improve Process Knowledge

22

Analytical LifecycleTest Method Remediation: Challenges

• Compliance

• Improve Efficiency / Reduce Lab Error

• Improve / Support Process Changes

• Improve or Replace the Current Method; Evaluate alternative analytical platforms

Identifying and Fixing the Problem

• Qualification in a GMP Environment

• Revisions to Quality Systems (Define and Refine)

• Multi-Site Coordination

• Multi-Product Methods

• Technical Challenges

• New Lab Equipment: Procurement and Qualification

Duration of Activities

• FTE to perform Assessments, Remediation and Implementation

• Sufficient QTY of Product, Controls, and Reference Material

Resources

• Generating Sufficient Data to support Crossover and /or New Specifications

Regulatory Filing Strategies

Analytical LifecycleTest Method Remediation: Test Method Validation Master Plan

23

The TMVMP is an official document requiring

quality approval, periodic review, and revision

The intent of the TMVMP is to document the strategy for

test method development, qualification, validation, verification, transfer, and lifecycle management

a comprehensive list of validated/verified test methods currently in use

a description of planned activitiesa schedule for lifecycle management for

test methods currently in use

Elements to Consider for a Test Method Monitoring Program

Analytical LifecycleTest Method Performance Monitoring

24

Communicate

•A test method performance review meeting should be held on a routine basis

Statistical Analysis

•The test methods actual performance should be compared to expected or desired performance

•Test method's performance expectations, such as the maximum allowable percent difference (±C%) from the Analytical Target Profile (ATP) and test method performance Right First Time (RFT) target should be defined

•Bias, precision and accuracy of assay control values should be compared across all sites

Practical Analysis

•Trends, investigations, and deviations should be evaluated for commonalities between methods and across sites

•Change controls should be evaluated to determine impact to method performance

Document

•The discussion and action items from the review meeting should be documented and include the test method performance document(s) as attachments.

PDCA (Deming circle) is an iterative four-step management method used in business for the control and continuous improvement of processes and products.

•Study the actual results (measured and collected in "DO" above) and compare against the expected results (targets or goals from the "PLAN") to ascertain any differences.

•the CHECK showed something different than expected (whether better or worse), then there is some more learning to be done

•Implement the plan, execute the process, make the product. Collect data for charting and analysis in the following "CHECK" and "ACT" steps.

•Establish the objectives and processes necessary to deliver results in accordance with the expected output (the target or goals).

Plan Do

CheckAct

25


The analytical lifecycle components; TMVMP, Remediation, Performance Monitoring and Assessments, model the PDCA approach and supports continued maintenance of a test

method in its validated state.

• Test Method Performance Monitoring

• Test Method Assessments

• Test Method Remediation


Plan Do

CheckAct

26


Where are you going to start?

• Test Method Performance Monitoring

• Test Method Assessments

• Test Method Remediation


Plan Do

CheckAct

27


Thank You

28

• Robert Donaldson, Senior Director QSAT, Genzyme

• Mark Kapeckas, Program Manager ALCM, Genzyme

• Isabelle Renaers, ATS Manager, Genzyme

• Helen Smith, Consultant, Quantic

• Melissa Smith, Consultant, Quantic

Acknowledgements

Questions