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Revision of ICH Q2(R1) and new ICH Q14 guidance Opportunities for the life cycle management of analytical procedures

Christof Finkler, F. Hoffmann-La Roche

CASSS, Netherlands Area Biotech Discussion Group, December 2019

Scope of Q2/Q14 Expert Working Group

• Develop new Quality Guideline on Analytical Procedure Development

• Revise Q2(R1) Guideline on Validation of Analytical Procedures: Text and Methodology

• Compliment with – Q8 – Q11

• Applicable to products mostly in the scope of Q6A and Q6B

• Either as 2 separate or 1 combined document –to be determined

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_Q14/Q2R2Q14EWG_ConceptPaper_2018_1115.pdf

Why is ICH working on this?

• Proposed by MHLW/PMDA and FDA in 2017

• No ICH guideline on analytical procedure development – Validation results are presented in the absence of development data

– Regulatory communication is ineffective, especially for non-conventional methods

– Applicants do not have opportunity to present scientific basis to justify flexible regulatory approaches to post-approval Analytical Procedure changes

• Facilitate efficient and science-based change management by improving communication between industry and regulators

Why revise Q2 again?

• Q2 (“text” Q2A) was drafted and adopted in the early/mid 1990s

• Q2(R1), which combined Q2A with the “guideline” Q2B, was adopted in the mid-2000s

• ICH Q2 has been a very successful and beneficial guideline over 2 decades

• New technologies arising (e.g. biological tests, immunochemical tests, multivariate tests, hyphenated test) and associated new validation methodology

• Q2(R1) lacks guidance around newer technologies– leading to incomplete submission data and additional requests and potentially approval

delays

– Guidance in Q2(R1) may be insufficient to establish suitability

What are the opportunities for revision of Q2(R1)?

• Define the common validation characteristics for more recent procedures– E.g. NIR, NMR, and hyphenated techniques

• Clarify for procedures reliant on multivariate methods:– Important method parameters to be investigated during method development

– Requirements for validation data sets

– Definition of validation characteristics which may differ with the area of application

• For example batch vs. continuous process

– Demonstration of Robustness

– Inclusion of post-approval verification and maintenance considerations as a part of the validation

What are the goals of ICHQ14• Harmonization of scientific approaches of Analytical Procedure

Development

• Providing the principles relating to the description of Analytical Procedure Development process

o In line with ICH Q8 and ICH Q11

o Improvement of regulatory communication between industry and regulators

o Submission of analytical procedure development and related information in CTD format

• Facilitation of more efficient, sound scientific and risk-based approval as well as post-approval change management of analytical procedures.

• Alignment on key elements and terminology

• Guidance on demonstration of suitability for real time release testing.

A Complex landscape of guidelines

7

ICH Q12• Approval

Procedures for Analytical Procedure Changes

ICH Q14• Analytical

Procedure development

• Analytical Procedure risk assessment

ICH Q2• Validation of

analytical proceduresTerminology, Methodology and examples

ICH Q13• Application of

Process Analytical technology

And there are more….

… and more complex relationships

Page 8

ICH Q12• Approval








Process Analytical technologyRisk of change versus

established conditons

Expected Performance versus Validation

Methodology

Developemnt of prcoedures for RTRT, validation of multivariate procedures,

application as PAT or release

… and even more expectations

9

ICH Q12• Approval








Process Analytical technology

Enable harmonized

change procedures

Allow innovation

Increase scientific

understanding

Connect Process/Product

and Analytical Procedure

Harmonized methodology to

manage and categorize risks

Include present and future Techniques

Keep the excellent

elements of previousversion

From Checklist to Toolbox

Enable RTRT

Expectations on Analytical Methods

How can we learn from development approaches described in ICH Q 8, 9 and 11?

11

What are the Outputs of QbD

Systematic definition of critical quality attributes (CQAs) for our molecules (variants, impurities…)

Systematic studies how CQAs are influenced by process parameters

Definition of critical process parameters (CPPs = those that influence the CQAs) and their allowed ranges

Risk based design of a control system that addresses all residual risks

(release, IPC, and monitoring testing)

Applying QbD Principles to Analytical Procedures

Quality Target Product Profile

Quality Target Product Profile

Risk AssessmentRisk Assessment

Critical Quality AttributesCritical Quality Attributes

Design SpaceDesign Space

Continued Process Verification

Continued Process Verification

Control StrategyControl Strategy

Analytical Target ProfileAnalytical Target Profile

Risk AssessmentRisk Assessment

Critical Procedure Attributes

Critical Procedure Attributes

Method Operable Design Region

Method Operable Design Region

Continued Procedure Verification

Continued Procedure Verification

Analytical Procedure Control Strategy


Product DevelopmentAnalytical Procedure

Development

From QTPP to ATP

Drives CMC Development

QTPP

• Quality characteristics to ensure safety and efficacy as promised in the label

CQA 1

CQA 2

CQA 3

CQA 4

Drives Identificationof CQAs

Drives ControlStrategy

Control of CQA#1Requirements of the reportable result, based on • patient need (Safety/Efficacy) • specification limits/ranges• compendial or regulatory

requirements• technology platform• process capability

Analytical TargetProfile

The QbD Approach

Analytical Target Profile


Analytical TechnologyAnalytical

Technology

• Procedure Performance criteria

• Intended Purpose

Analytical ProcedureAnalytical Procedure

• ProcedureDevelopment

• Procedure Qualification

• Set Point, Ranges, MODR

• Most suitable to fulfillATP requirements

Control Strategy HierachyPe

rfor

man

ce L

evel

QTPP

CQA1

HMW Forms

CQA-AC1≤ 1,5 %

Performance Target1

Technology SE-HPLC

Method 1-1

Technology

SE-UPLC

Method 1-2

CQA2LMW Forms

CAQ-AC2

≤ 3,5 %

Performance Target 2

Technology

SE-HPLC

Method 2-2

Technology

CE-SDS

Method 2-2

CQA3

Potency

CQA-AC3

80 - 120 %rel Potency

Performance Target 3

Technology 3-1

ADCC Assay

Method 3-1

Tech

nolo

hy L

evel

ATP Level

MODRLevel

CQA Level

Product Level

What does analytical QbD stand for?

Good Procedure Design

Good Procedure Design

Good Procedure Understanding

Good Procedure Understanding

Good Procedure Risk Control

Good Procedure Risk Control

Procedure performance criteria

Analytical Target Profile (ATP)

Risk mapping

Multivariate statistical Analysis

?

Procedure Control Strategy:•Risk based SST•Parameter Ranges

Good Operational Flexibility

Good Operational Flexibility

Good Change Control

Good Change Control

Method Development

Report

Change versus ATP

Knowledge Management

Prior knowledge

Risk Management

The Analytical Target Profile (ATP)

PharmTech 42 (12), 2018, pg. 18-23: “Analytical Procedure Lifecycle Management: Current Status and Opportunities”

The combination of all performance criteria required to ensure the measurement of a quality attribute is fit for the intended purpose and produces data which can be used with the required confidence to support for example:• specification pass/fail decisions. • Other quality decisions during development (e.g. process definition) and across

the lifecycle

ATP can be used to:• direct the selection of an appropriate analytical technique. • support risk assessment and rigorous systematic evaluation of procedure

variables. • develop a full understanding of how input parameters affect the reportable result • serve as the focal point for continuous improvement and change control

An ATP would be developed for each of the attributes defined in the control strategy


Accuracy, precision, specificity, range (QL, calibration model…)

- Identity, Purity , Assay, Potency

- CQAs: glycosylation, size variants

- charge variants, oxidation, etc- IPC, realease stability

Intended

Purpose

Performance

Target

Technology

Method Parameters

Performance Requirements for Analytical Procedures

M

Intended

Purpose

Performance

Target

Technology

Method Parameters

IEC, CIEF, iCIEF, CZE,

SEC, CE-SDS etc

ATP

Accuracy, precision, specificity, (QL, calibration model…)

Identity, Purity , Assay, Potency

CQAs: glycosylation, size variants

charge variants, oxidation, etc

Column, flow rate,

Gradient, ampholyte etc

Business, operational or SHE requirement may be added on demand

Factors influencing ATP Generation

ATP

Critical Quality Attribute requirements of Product (Specifications)Statistical requirements for

measurement resultStatistical requirements for measurement result

Toxicological Considerations / Qualification

Toxicological Considerations / Qualification

Regulatory requirements, e.g. • ICH Guidelines • Pharmacopoeias• EMA Guidelines

Regulatory requirements, e.g. • ICH Guidelines • Pharmacopoeias• EMA Guidelines

Direct link

Measurement Context, e.g. Type of testOperating environment

Measurement Context, e.g. Type of testOperating environment

Benefits using the ATP concept

Method Selection and Development

• Facilitation of technology selection and guidance for method development

• Correct use of the ATP ensures that the method selected and developed is fit for the required purpose

• Clear link between method performance and CQAs and their acceptance criteria

Method Validation

• The ATP provides purpose driven (and not technology driven) criteria for validation

• ATP will drive value added validation above tick-box generic validation

Method Lifecycle

• Ensures robust fit for purpose analytical procedures are used as part of the control strategy for marketed products throughout the lifecycle of a marketed product.

• ATP provides criteria for purpose- driven comparison between current and new analytical procedures/ technologies

Analytical Target Profile Charge Heterogeneity for a MAb in Early Stage Development

ATP PerformanceCharacteristic

ATP Performance Criteria

SpecificityDetermination of Acidic Region and Basic Region and Main Peak Stability indicating properties

Accuracy Main Peak: 90.0-100.0 % of assumed true value (area%)

Precision ofreportable result

Main Peak: ≤ 6.0 % RSD (consider extent of Main Peak)

RangeMain Peak: at least 80%-120% of nominal protein concentrationOther components: QL- 120% of upper spec limit

Additional technology dependent performance requirements

Robustness

Based on HPLC Technology: • The analytical procedure must be suitable for at least 2 HPLC platforms

used in IMP-QC• To be tested among different columns, LC systems, sites• The Analytical procedure must be stable for at least 48 h of consecutive

Analyses.

Perf. Characteristic ATP Performance CriteriaIntended PurposeCQA

DS/DP IPC, release and stabilityDetermination of the acidic and basic variants of the native moleculeLC/LC dimer

Specificity Determination of Acidic Region and Basic Region from Main Peak Determination of acidic peak 2 (increases during stability)Stability indicating propoteriesDetermination of LC/LC2No significant interference from stressed and non-stressed reagent blank and other matrix components

Sensitivity QL< 1%

Accuracy Main Peak: 94.0-106.0 % of assumed true value (area%)No carry over detectable

Precision of reportable result

Main Peak: ≤ 3.0 % RSD (consider extent of Main Peak)

Range Main Peak: at least 80%-120% of nominal protein concentrationOther components: QL- 120% of upper spec limit

ATP Charge Heterogeneity for Late Stage Development

Linearity Main Peak: r ≥ 0.99Determination of Product/Process Related Substances/Impurities: r ≥ 0.98

Operating conditions and Environment

Based on HPLC technology:The analytical procedure must be suitable for HPLC platforms used in QC network. Column from established vendor with globally availabilityAcceptable performance for min. 3 resin batchesThe Analytical procedure must be stable for at least 48 h of consecutive analysesShort sample to sample run time Acceptable method performance for least two column types from established vendors.Preferably, the method should work without harmful ingredients

Robustness Robustness proven for critical method parameters identified during primary hazard analysis (flow rate, slope of gradient, injected amount, column oven temperature, buffer concentration and pH), Establishment of MODR

Additional technology dependent performance requirements

Demonstration of Robustness in an Enhanced Approach

PHA1 PHA2 PHA1 PHA2# Category Factor Classif. PRN PRN

1 Method flow rate X C 12 122 Method predilution X X 12 123 Method detection wavelength C C 12 124 Method sample preparation: diluent X C 60 125 Method sample preparation: final concentration X X 36 126 Method sample preparation: storage of diluted sample - temperature X C 60 127 Method sample preparation: storage of diluted sample - time X C 36 128 Method sample preparation: volumentric dilution X X 12 129 Method sample preparation: CpB digestion X X 12 1210 Method RS: # of references X X 12 1211 Method RS: sample bracketing X X 12 1212 Method integration: approach manual/ automatic X C 36 1213 Method integration: tangential/ exponential X C 12 1214 Method integration: one baseline vs. multiple enforced integration X C 60 3615 Method mobile phase: buffer substance X C 60 1216 Method mobile phase: pH X C 60 1217 Method mobile phase: buffer concentration X C 36 1218 Method mobile phase: ionic strength X C 60 1219 Method mobile phase: water X C 12 1220 Method mobile phase: filtration X C 36 3621 Method gradient X C 60 1222 Method column temperature X C 60 1223 Method autosampler temperature X C 12 1224 Method injection: volume X X 12 1225 Method injection: amount X C 36 3626 Method injection: No. of sample injections per sequence X X 12 1227 Method separation time X C 36 1228 Method column: rinse pressure & time X X 12 1229 Method sample loop: rinse pressure & time X X 12 1230 Method column (type) X C 60 12

faktors

flow rate

gradient lope

injected amount

oven temp.

buffer conc.

pH

Output:- identification of critical- and non critical procedure parameters- informs parameter range setting and procedure control strategy

Method Operable Design Region (MODR)

The combination of parameter ranges which have been evaluated and verified as meeting the ATP criteriafor an analytical procedure

• Relationship between method input and method output is understood

• Constitutes a region within which changes can be made without impacton the reportable result

• Based on multivariate experimental design approaches

Remaining Challenge:• How can an MODR be validated• How can risk assessment support to identify the

extend of validation studies


• System Suitability Test (SST)Confirm measurement system performance prior to and/or during analysis

• Detailed set of instructions that clearly specify parameters requiring control(written procedure, parameter setting, operator training… )

• Defined replication strategy, i.e. the number of example injections/sample preparations required for the reportable result

• Quality system aspects e.g. instrument qualification, change management, facility controls

• Ongoing monitoring of critical predefined criteria or procedure outputs

ensures that ATP criteria are consistently met

Changes to analytical procedures

External factors:

• Change in legal / regulatory requirements, or new/revised pharmacopoeia monograph

• environmental considerations may lead to change to methods with less impact on the environment

• Non Availability of instruments or supplies (e.g. HPLC column)

• …

Drivers for Change

Internal factors:

• technological development / progress, e.g. replacement with new analytical technology

• cost / efficiency

• outcome of the continual performance assessment of the analytical method, e.g. reduction of SST failure rates

• …

Changes to analytical procedures

Identifying and generating the required data set in time to support the change

– May include: purchase and qualification of new equipment, procedure development, validation and transfer of analytical procedure,

– method bridging activities, impact assessment on reportable results or specifications

Challenges

Global implementation is time consuming and costly

– change regulation differ in different regions

– criticallity of change may be assessed differently in different regions

– Different implementation timelines is leading to parallel testing and increase of cost for medicines

How can Q14 support facilitation of post approval change management?

Changes During the Analytical Lifecycle

ATP Procedure Development

Procedure DesignScoutingEvaluation

Procedure PerformanceControl Strategy

Procedure Validation

Transfer toCommercial

Procedure Design, Development & Validation Procedure Lifecycle Management

ProcedureMonitoringContinualImprovement

CQA

Scenario1: Changes within MODR are considered adjustments and do not require a procedure performance qualification study to be performed before returning to routine monitoring.

Scenario 1








MonitoringContinualImprovement

CQAScenario 2

Scenario1

Scenario 2: These are changes that are outside the already proven ranges but require only confirmation that the procedure continues to generate data that meet ATP requirements. Full procedure redevelopment is not required


ATP ProcedureDevelopment






ProcedureMonitoringContinualImprovement

CQAScenario 2

Scenario 1

Scenario 3

Scenario 3: This is a change that may require a new analytical procedure, but the ATP remains the same. The procedure will return to the procedure development stage.








Procedure MonitoringContinualImprovement

CQAScenario 2

Scenario1

Scenario 3

Scenario 4

Scenario 4: This change involves e.g. tightening a specification limit or a change to the intended purpose of the procedure to measure additional attributes. These changes result in a new ATP being defined.

Q2(R2)/Q14 Planned Milestones

Nov 2018:

Concept Paper and Business Plan

endorsed

June 2019:

Structured draft texts for EWG review

Nov 2019Drafts of Q2(R2) and

Q14 for intra party consultation

(moved to March)

May 2020:

Step 1 sign-off

Step 2a/2b endorsement

Q3/Q4 2020:

Public consultation

Q2 2021:

Step 3 sign-off

Step 4 adoption

• Link to expected analytical procedure performance

• Updated glossary Q2/Q14 with additional elements in alignment with principles Q8,9,10

• Validation examples beyond Chromatography

• Methodology modernized to include newer technologies

• Streamlined structure by methodology

Status Q2

34

- Emphasis on analytical procedure objectives to define „fit for purpose“

- In alignment with Q8,Q9,Q10

- Elements

- Risk management

- Robustness and operable ranges

- Analytical procedure control strategy

- Change management

- RTRT

- Guidance on how to present knowledge from analytical procedure development in CTD

Status Q14

35

What will success look like?

• Increased scope of analytical procedures to which Q2(R2) and Q14 can be directly applied

• Q2(R2) and Q14 are sustainable and can be applied to technologies to be developed in the future without recursive revision

• Increased understanding on the part of applicants of

• What is required for development and validation of robust analytical methods

• What information reviewers need to fully assess suitability analytical methods as part of an application

• How to communicate development process and justification of decisions regarding analytical method development and validation

• Increased assurance on the part of regulators that applicants have developed and validated suitable analytical methods

• Harmonized definitions for enhanced analytical procedure development approaches and streamlined review processes and lifecycle management for analytical methods

• Increased harmonization among global regulators of expectations for analytical method

Our 2020 mission…

37

Dealing with „General Specific“ (…paradigm)

Doing now what patients need next

ich q2r1 revision and new ichq14 guidance christof finkler ...€¦ · :k\ lv ,&+ zrunlqj rq...

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