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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
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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
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 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
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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
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
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 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
Analytical Target Profile
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
Analytical Procedure Control Strategy
• 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
Changes During the Analytical Lifecycle
ATP Procedure Development
Procedure DesignScoutingEvaluation
Procedure PerformanceControl Strategy
Procedure Validation
Transfer toCommercial
Procedure Design, Development & Validation Procedure Lifecycle Management
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
Changes During the Analytical Lifecycle
ATP ProcedureDevelopment
Procedure DesignScoutingEvaluation
Procedure PerformanceControl Strategy
Procedure Validation
Transfer toCommercial
Procedure Design, Development & Validation Procedure Lifecycle Management
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.
Changes During the Analytical Lifecycle
ATP Procedure Development
Procedure DesignScoutingEvaluation
Procedure PerformanceControl Strategy
Procedure Validation
Transfer toCommercial
Procedure Design, Development & Validation Procedure Lifecycle Management
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
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- 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
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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…
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Dealing with „General Specific“ (…paradigm)
Doing now what patients need next