Revision of ICH Q2(R1) and new ICH Q14 guidance - Opportunities for the life cycle management of analytical procedures
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Revision of ICH Q2(R1) and new ICH Q14 guidance Opportunities for the life cycle management of analytical procedures CASSS, Netherlands Area Biotech Discussion Group, December 2019 Christof Finkler, F. Hoffmann-La Roche
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_Q
14/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
ICH Q12 ICH Q14 ICH Q2 ICH Q13
• Approval • Analytical • Validation of • Application of
Procedures Procedure analytical Process
for Analytical development procedures Analytical
Procedure • Analytical Terminology, technology
Changes Procedure Methodology
risk and
assessment examples
And there are more….
7
… and more complex relationships
ICH Q12 ICH Q14 ICH Q2 ICH Q13
• Approval • Analytical • Validation of • Application of
Procedures Procedure analytical Process
for Analytical development procedures
Expected Performance Analytical
Risk of change
Procedure versus technology
established conditons
• Analytical versus Validation
Terminology,
Changes Procedure Methodology
Methodology
risk and
assessment examples
Developemnt of prcoedures for RTRT,
validation of multivariate procedures,
application as PAT or release
Page 8
… and even more expectations
Enable Increase Include present
harmonized scientific and future
ICHchange
Q12 ICH Q14
understanding ICH Q2
Techniques ICH Q13
procedures
• Approval • Analytical • Validation of • Application of
Procedures Procedure analytical Process
for Analytical development procedures
Keep the Analytical
Procedure Connect technology
• Analytical Terminology,
excellent
Changes Process/Product
Procedure Methodology
elements of Enable RTRT
and
riskAnalytical and
previous
Procedure
assessment examples
version
Allow
innovation Harmonized
methodology to From Checklist
manage and to Toolbox
categorize risks
9
Expectations on Analytical Methods How can we learn from development approaches described in ICH Q 8, 9 and 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)
11Applying QbD Principles to Analytical Procedures
Analytical Procedure
Product Development
Development
Quality Target Product
Analytical Target Profile
Profile
Risk Assessment Risk Assessment
Critical Procedure
Critical Quality Attributes
Attributes
Method Operable Design
Design Space
Region
Analytical Procedure
Control Strategy
Control Strategy
Continued Process Continued Procedure
Verification VerificationFrom QTPP to ATP
Drives CMC Drives Identification Drives Control
Development of CQAs Strategy
Control of CQA#1
Requirements of the reportable result,
based on
CQA 1
• patient need (Safety/Efficacy)
QTPP • specification limits/ranges
CQA 2
• compendial or regulatory
• Quality characteristics requirements
to ensure safety and CQA 3 • technology platform
efficacy as promised • process capability
in the label CQA 4
Analytical Target
ProfileThe QbD Approach
• Procedure
Analytical Performance criteria
Target Profile • Intended Purpose
• Most suitable to fulfill
Analytical ATP requirements
Technology
• Procedure
Development
• Procedure
Analytical Qualification
Procedure • Set Point,
Ranges,
MODRControl Strategy Hierachy
QTPP Product Level
Performance Level
CQA1
HMW Forms
CQA2
LMW Forms
CQA3
Potency CQA Level
CQA-AC3
CQA-AC1 CAQ-AC2
≤ 1,5 % 80 - 120 %
≤ 3,5 %
rel Potency
Performance Performance Performance
Target1 Target 2 Target 3 ATP Level
Technolohy Level
Technology Technology Technology Technology Technology 3-1
SE-HPLC SE-UPLC SE-HPLC CE-SDS ADCC Assay
Method 1-1 Method 1-2 Method 2-2 Method 2-2 Method 3-1
MODR
LevelWhat does analytical QbD stand for?
Good
Good Procedure Good Procedure Good Procedure Good Change
Operational
Design Understanding Risk Control Control
Flexibility
Change
Method
versus ATP
Development
Report
Risk mapping
Procedure Procedure Control
performance Strategy:
criteria •Risk based SST
? •Parameter Ranges
Analytical Target
Profile (ATP) Multivariate statistical
Analysis
Prior knowledge
Knowledge Management
Risk ManagementThe Analytical Target Profile (ATP)
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
An ATP would be developed for each of the attributes defined in the control strategy
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
PharmTech 42 (12), 2018, pg. 18-23: “Analytical Procedure Lifecycle Management: Current Status and Opportunities”Analytical Target Profile
- Identity, Purity , Assay, Potency
- CQAs: glycosylation, size variants
Intended - charge variants, oxidation, etc
- IPC, realease stability
Purpose
Accuracy, precision, specificity,
Performance range (QL, calibration model…)
Target
Technology
Method ParametersPerformance Requirements
M for Analytical
Procedures
Intended Identity, Purity , Assay, Potency
Purpose CQAs: glycosylation, size variants
charge variants, oxidation, etc
ATP
Performance
Accuracy, precision,
Target
specificity, (QL, calibration
model…)
Technology IEC, CIEF, iCIEF, CZE,
SEC, CE-SDS etc
Method Parameters
Column, flow rate,
Gradient, ampholyte etc
Business, operational or SHE requirement may be added on demandFactors influencing ATP Generation
Critical Quality Attribute
requirements of Product
Statistical requirements for (Specifications)
measurement result Regulatory requirements,
e.g.
• ICH Guidelines
• Pharmacopoeias
• EMA Guidelines
Direct link
Toxicological
Considerations / ATP
Qualification
Measurement Context, e.g.
Type of test
Operating environmentBenefits 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 Performance ATP Performance Criteria
Characteristic
Determination of Acidic Region and Basic Region and Main Peak
Specificity
Stability indicating properties
Accuracy Main Peak: 90.0-100.0 % of assumed true value (area%)
Precision of
Main Peak: ≤ 6.0 % RSD (consider extent of Main Peak)
reportable result
Main Peak: at least 80%-120% of nominal protein concentration
Range
Other components: QL- 120% of upper spec limit
Additional technology dependent performance requirements
Based on HPLC Technology:
• The analytical procedure must be suitable for at least 2 HPLC platforms
used in IMP-QC
Robustness
• To be tested among different columns, LC systems, sites
• The Analytical procedure must be stable for at least 48 h of consecutive
Analyses.ATP Charge Heterogeneity for Late Stage Development
Perf. Characteristic ATP Performance Criteria
Intended Purpose DS/DP IPC, release and stability
CQA Determination of the acidic and basic variants of the native molecule
LC/LC dimer
Specificity Determination of Acidic Region and Basic Region from Main Peak
Determination of acidic peak 2 (increases during stability)
Stability indicating propoteries
Determination of LC/LC2
No 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 Main Peak: ≤ 3.0 % RSD (consider extent of Main Peak)
result
Range Main Peak: at least 80%-120% of nominal protein concentration
Other components: QL- 120% of upper spec limit
Additional technology dependent performance requirements
Linearity Main Peak: r ≥ 0.99
Determination of Product/Process Related Substances/Impurities: r ≥ 0.98
Operating conditions Based on HPLC technology:
and Environment The analytical procedure must be suitable for HPLC platforms used in QC network.
Column from established vendor with globally availability
Acceptable performance for min. 3 resin batches
The Analytical procedure must be stable for at least 48 h of consecutive analyses
Short 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 MODRDemonstration of Robustness in an Enhanced Approach
PHA1 PHA2 PHA1 PHA2
# Category Factor Classif. PRN PRN
1 Method flow rate X C 12 12
2 Method predilution X X 12 12
3 Method detection wavelength C C 12 12
4 Method sample preparation: diluent X C 60 12
5 Method sample preparation: final concentration X X 36 12
6 Method sample preparation: storage of diluted sample - temperature X C 60 12
7 Method sample preparation: storage of diluted sample - time X C 36 12
8 Method sample preparation: volumentric dilution X X 12 12
9 Method sample preparation: CpB digestion X X 12 12
10 Method RS: # of references X X 12 12
11 Method RS: sample bracketing X X 12 12
12 Method integration: approach manual/ automatic X C 36 12
13 Method integration: tangential/ exponential X C 12 12
14 Method integration: one baseline vs. multiple enforced integration X C 60 36
15 Method mobile phase: buffer substance X C 60 12
16 Method mobile phase: pH X C 60 12
17 Method mobile phase: buffer concentration X C 36 12
18 Method mobile phase: ionic strength X C 60 12
19 Method mobile phase: water X C 12 12
20 Method mobile phase: filtration X C 36 36
21 Method gradient X C 60 12
22 Method column temperature X C 60 12
23 Method autosampler temperature X C 12 12
24 Method injection: volume X X 12 12
25 Method injection: amount X C 36 36
26 Method injection: No. of sample injections per sequence X X 12 12
27 Method separation time X C 36 12
28 Method column: rinse pressure & time X X 12 12
29 Method sample loop: rinse pressure & time X X 12 12
30 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 strategyMethod Operable Design Region (MODR)
The combination of parameter ranges which have been
evaluated and verified as meeting the ATP criteria
for an analytical procedure
• Relationship between method input and method output is understood
• Constitutes a region within which changes can be made without impact
on 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 studiesAnalytical Procedure Control Strategy
ensures that ATP criteria are consistently met
• 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 outputsChanges to analytical procedures
Drivers for Change
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)
• …
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
Challenges
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
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
CQA
Scenario 1
Procedure Design Procedure Procedure
Procedure Procedure Transfer to
ATP Scouting Performance Monitoring
Development Validation Commercial
Evaluation Control Strategy Continual
Improvement
Procedure Design, Development & Validation Procedure Lifecycle Management
Scenario1: Changes within MODR are considered adjustments and do
not require a procedure performance qualification study to be performed
before returning to routine monitoring.Changes During the Analytical Lifecycle
Scenario 2
CQA
Scenario1
Procedure Design Procedure
Procedure Procedure Transfer to
ATP Scouting Performance Monitoring
Development Validation Commercial
Evaluation Control Strategy Continual
Improvement
Procedure Design, Development & Validation Procedure Lifecycle Management
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 requiredChanges During the Analytical Lifecycle
Scenario 3
Scenario 2
CQA
Scenario 1
Procedure Design Procedure Procedure
Procedure Procedure Transfer to
ATP Scouting Performance Monitoring
Development Validation Commercial
Evaluation Control Strategy Continual
Improvement
Procedure Design, Development & Validation Procedure Lifecycle Management
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
Scenario 4
Scenario 3
Scenario 2
CQA
Scenario1
Procedure Design Procedure Procedure
Procedure Procedure Transfer to
ATP Scouting Performance Monitoring
Development Validation Commercial
Evaluation Control Strategy Continual
Improvement
Procedure Design, Development & Validation Procedure Lifecycle Management
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 2019
Nov 2018: Drafts of Q2(R2) and Q2 2021:
Concept Paper and Q14 for intra party
Business Plan consultation Step 3 sign-off
endorsed (moved to March) Step 4 adoption
June 2019: May 2020:
Structured draft texts Step 1 sign-off
for EWG review
Step 2a/2b
endorsement
Q3/Q4 2020:
Public consultationStatus Q2
• 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
34Status Q14
- 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
35What 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 methodOur 2020 mission…
Dealing with
„General Specific“
(…paradigm)
37Doing now what patients need next
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