Analytical Method Validation Module
S-Matrix Corporation
1594 Myrtle Avenue
Eureka, CA 95501
USA
Phone: 707-441-0404
URL: www.smatrix.com
Fusion QbD Software Platform
Full Support for
Part 11
Compliance
Citrix-Ready
Certified
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
Fusion Method Validation Module (FMV)
Full Support for
Part 11
Compliance
Citrix-Ready
Certified
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
Key Benefits of FMV
1. Consistency Workflow and Reporting.
Work is standardized done the same way every time. Reporting is
standardized, complete, easy to communicate.
2. Simplicity
Tremendous ease of use. Very brief learning curve. Clearly defined
templatable workflows with built-in workflow management.
3. Speed (Productivity)
Automation and simplified workflows dramatically increase productivity.
Review process is minimized and simplified.
4. Regulatory Alignment and Completeness
All required validation experiment types are supported. Reporting
meets regulatory requirements. Reports can be attached to Project
specific narrative documents.
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
Key Benefits of FMV
5. Platform Independence
Support for Empower, ChemStation, and Chromeleon means that the
standardized workflows and reporting can be easily extended to users
of other platforms at other sites or other companies (e.g. CMOs).
6. Customer Support
Our support is top-rated worldwide. S-Matrix and our local distributors
have a multi-year history of proven ability to meet all our customers
support needs.
7. Flexible Licensing
S-Matrix can provide corporate licensing based on a Named User
model or a Concurrent Use model with very competitive pricing.
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
Presentation Outline
Critical QbD Capability
FMV
Completely Aligned with Regulatory Requirements
Supports All Install Environments (Citrix Certified)
Full 21 CFR Part 11 Compliance Support
Automated DOE Experimenting & Testing on LC
Simple Workflow with Complete QbD Reporting
Rigorous QbD-aligned Robustness Validation
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
Fusion Method Validation
Critical QbD Capability
FMV
Completely Aligned with Regulatory Requirements
Supports All Install Environments (Citrix Certified)
Full 21 CFR Part 11 Compliance Support
Automated DOE Experimenting & Testing on LC
Simple Workflow with Complete QbD Reporting
Rigorous QbD-aligned Robustness Validation
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
Regulatory Statements and Expectations
ICH Q2(R1)
The objective of validation of an analytical procedure is to
demonstrate that it is suitable for its intended purpose. A tabular
summation of the characteristics applicable to identification, control of
impurities and assay procedures is included.
Method Validation is a regulatory requirement as much as a scientific
necessity. A well executed method validation effort:
provides scientific credence for the method.
(statistical confidence in the data)
defines the limit of acceptable performance of the method.
(Low and high limits of identification and quantitation)
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
Regulatory Statements and Expectations
PhRMAs Analytical Technical Group
Recommends a phased approach to analytical method validation in which
early phase validation efforts are done upstream on a reduced set of
validation elements appropriate to the stage of method development.
Early Phase Validation experiments are structured for internal
consumption to support and guide method development.
Final Phase Validation experiments are structured with the rigor and
regulatory compliance overlay required of results that may be exported
outside the lab.
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
Fusion Method Validation Experiment Suite
Early Phase Specific Experiments (Performance Characterization)
Specificity
Filter Validation
Early Phase and Final Phase (FDA / ICH Submittal Quality)
Accuracy
Linearity and Range
LOQ, LOD
Repeatability* (intra-assay precision)
Accuracy/Linearity and Range/Repeatability Combined Design
(ICH-Q2(R1) Accuracy, Linearity, and Repeatability can be done together as
a single combined experiment).
Sample Solution Stability (stability for a given time period under prescribed
conditions)
Intermediate Precision and Reproducibility (USP Ruggedness)
Robustness
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10
Fusion Method Validation Example Experiment Type Selection
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11
Fusion Method Validation
Critical QbD Capability
FMV
Completely Aligned with Regulatory Requirements
Supports All Install Environments (Citrix Certified)
Full 21 CFR Part 11 Compliance Support
Automated DOE Experimenting & Testing on LC
Simple Workflow with Complete QbD Reporting
Rigorous QbD-aligned Robustness Validation
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
12
Fusion Method Validation Scalability
Supported Environments
Standalone (Workstation)
Workgroup
Network
Citrix Metaframe & XenApp
Fully Qualifiable for GxP *
FMV
* - Fusion QbD is operating in the GxP environments of many
international pharmaceutical companies worldwide. A complete
Software Qualification Package and Support Services are available.
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
13
Fusion Method Validation
Critical QbD Capability
FMV
Completely Aligned with Regulatory Requirements
Supports All Install Environments (Citrix Certified)
Full 21 CFR Part 11 Compliance Support
Automated DOE Experimenting & Testing on LC
Simple Workflow with Complete QbD Reporting
Rigorous QbD-aligned Robustness Validation
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
14
21 CFR 11 Support
User Management
User-specific Password Options
Application Module Access Permissions
Role Assignments
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15
21 CFR 11 Support
Roles Management
Role-based Permissions & Authorities settings for all operations
E-Review and e-Approve
control loops with built-in email notification.
Vertical sequence of auditable operations
= normal software operating workflow
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
16
21 CFR 11 Support
Instrument Management
Bookkeeping All Instruments folder lists all currently-defined instruments by
type.
Associations Common Instruments folder makes instruments available to
any active Fusion QbD user.
Bookkeeping accounting of available and used licenses.
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17
21 CFR 11 Support
Auditing
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18
21 CFR 11 Support
Access Management
Management administrator notification and
unlock Fusion QbD application nodes locked
down due to failed log on attempts.
Administration user
application suspend mode.
Administration global
default password
settings.
Administration
company logo image for
report headers.
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
19
Fusion Method Validation
Critical QbD Capability
FMV
Completely Aligned with Regulatory Requirements
Supports All Install Environments (Citrix Certified)
Full 21 CFR Part 11 Compliance Support
Automated DOE Experimenting & Testing on LC
Simple Workflow with Complete QbD Reporting
Rigorous QbD-aligned Robustness Validation
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
20
Fusion Method Validation Automation Workflow
1. Complete the Fusion QbD template with the relevant information
2. Fusion QbD creates a Validation Experimental Design
3. Fusion QbD exports the design to the CDS
The CDS runs the validation experiment sequence
4. Fusion QbD imports and analyzes the CDS results
5. Fusion QbD creates final reports and graphs
(See next slides)
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
21
Automated FMV Experiment Workflow
Steps 1 and 2
Step 3
Chromatography Data Software (CDS)
Generates QbD-aligned
DOE Experiment
Automatically Builds
Sequence and All
Instrument Methods
Automated, Audited Data Exchange Preserves Data Integrity
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22
Automated FMV Experiment Workflow
Chromatography Data Software (CDS)
Step 4
Automatically Retrieve All
Chromatogram Results Da
Step 5
Automated analysis,
graphing, and reporting.
Report formats:
RTF, DOC, HTML, PDF,
XLSX, XML
Automated, Audited Data Exchange Preserves Data Integrity
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23
Supported Chromatography Data Software
Agilent ChemStation / OpenLAB
Thermo Scientific Dionex Chromeleon
Waters Empower 2 and 3
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24
Fusion Method Validation
Critical QbD Capability
FMV
Completely Aligned with Regulatory Requirements
Supports All Install Environments (Citrix Certified)
Full 21 CFR Part 11 Compliance Support
Automated DOE Experimenting & Testing on LC
Simple Workflow with Complete QbD Reporting
Rigorous QbD-aligned Robustness Optimization
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
25
Demonstration Study Simple Workflow with Complete QbD Reporting
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26
Linearity Example Experiment Setup Template
Define Acceptance Criteria
for each Key Result for each
Compound.
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27
Linearity Example Standards Setup Options
Flexible setup of the
required Standards
Strategy.
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28
Linearity Example Reporting Requirements
ICH Q2(R1).
III. LINEARITY
If there is a linear relationship, test results should be evaluated by appropriate
statistical methods, for example, by calculation of a regression line by the method of
least squares The correlation coefficient, y-intercept, slope of the regression line,
and residual sum of squares should be submitted. A plot of the data should be
included. In addition, an analysis of the deviation of the actual data points from the
regression line may also be helpful for evaluating linearity.
Calculation of a regression line by the method of least squares:
correlation coefficient
y-intercept
slope of the regression line
residual sum of squares
plot of the data
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29
Linearity Example Fusion QbD Output Reports
Fusion QbD instantly creates formal
reports with all required tables and graphs.
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30
Method Validation Linearity Example
ICH Q2(R1):
For chromatographic
procedures,
representative
chromatograms should
be used to
demonstrate specificity,
and individual
components should be
appropriately labeled.
If DL is determined
based on visual
evaluation or based on
signal-to-noise
ratio, the presentation of
the relevant
chromatograms is
considered acceptable
for justification.
Reports can be augmented with images of
relevant chromatograms.
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31
Method Validation Linearity Example
Reports can be
augmented with
images of relevant
chromatograms.
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32
Linearity Example Fusion QbD Compiled Report Generator
Reports meet
all output format
requirements:
.TXT
.RTF
.DOC
.PDF
.HTML
.XML
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33
Fusion Method Validation
Critical QbD Capability
FMV
Completely Aligned with Regulatory Requirements
Supports All Install Environments (Citrix Certified)
Full 21 CFR Part 11 Compliance Support
Automated DOE Experimenting & Testing on LC
Simple Workflow with Complete QbD Reporting
Rigorous QbD-aligned Robustness Validation
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
34
ICH Q2 Robustness
ICH Q2(R1):
The robustness of an analytical procedure is a measure of its capacity to remain
unaffected by small, but deliberate variations in method parameters and
provides an indication of its reliability during normal usage.
In the case of liquid chromatography, examples of typical variations are:
Influence of variations of pH in a mobile phase
Influence of variations in mobile phase composition
Different columns (different lots and/or suppliers)
Temperature
Flow rate
Note the text but deliberate refers to the deliberate perturbation
of critical instrument parameters about their method setpoints
done as part of a Validation-Robustness experiment.
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35
Mean Performance Versus Robustness
Methods A and B
Identical Mean Performance
Good mean performance
good robustness
Method A Good Robustness
Method B Poor Robustness
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36
Method Robustness
I. Potential Sources of Risk in Current Practice
1.
2.
3.
Experimental ranges a Signal/Noise source of risk
Experimental design selection an information content source of risk
Performance requirements a performance variation source of risk
II. QbD-aligned strategy for validating method robustness
1.
2.
3.
Define valid study ranges for critical instrument parameters (CPPs)
Select the right experimental design
Specify risk-based method performance requirements (CQAs)
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
37
Method Robustness
I. Potential Sources of Risk in Current Practice
1.
Experimental ranges a Signal/Noise source of risk
II. QbD-aligned strategy for validating method robustness
1.
Define valid study ranges for critical instrument parameters (CPPs)
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
38
Small Range Poor Effects Estimation
Traditional Range is Within Setpoint Error Range. The most likely result is that
the study factor effects will be UNDERESTIMATED.
The Result methods which are NOT robust will pass the robustness test.
Response
-3
L1
+3
L2
L3
Study Factor
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39
Best Practice Large Ranges = High Signal/Noise
General Guideline: Minimum Study Range for 3 Level Designs Should be >12
Response
-3
+3
>12
L1
L2
L3
L4
L5
Study Factor
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40
Best Practice Large Ranges = High Signal/Noise
General Guideline: Minimum Study Range for 5 Level Designs Should be >24
Response
-3
+3
>24
L1
L2
L3
L4
L5
Study Factor
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41
Comparative Study Ranges Around Method Setpoints
Factor
Method
Nominal
1.0
Traditional
Range*
0.025
QbD-aligned
Range
0.125
% Strong Solvent (%)
80.0
2.0
5.0
Temperature (C)
35.0
2.0
10.0
pH (*)
5.5
0.15
0.5
Pump Flow Rate (mL/min)
* worst-case scenario considered.
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
42
Method Robustness
I. Potential Sources of Risk in Current Practice
2.
Experimental design selection an information content source of risk
II. QbD-aligned strategy for validating method robustness
2.
Select the right experimental design
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43
Classical / Fusion QbD Optimization Designs
II.
QbD-aligned strategy for validating method robustness
Fusion QbD automatically selects the right experimental
design for the included instrument parameters
Fusion QbD design is efficient and automated
Four variable Robustness Study Efficiency Comparison
Full Factorial 3-Level Design = 81 Runs
Fusion QbD Optimal* Design = 22 Runs
* Optimal designs can support studies with non-numeric
factors (e.g. different columns) and factors that are not
completely independent (e.g. mobile phase blends).
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
44
Method Robustness
I. Potential Sources of Risk in Current Practice
3.
Performance requirements a performance variation source of risk
II. QbD aligned strategy for validating method robustness
3.
Specify risk-based method performance requirements (CQAs)
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45
Demonstration Example Experiment Type Selection
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46
Experiment Setup Template
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47
QbD-aligned Study Ranges
Fusion QbD Optimization Design Formatted for Export to the CDS
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48
QbD-aligned Study Ranges
Peak Results Data Automatically Imported From the CDS
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49
Robustness Assessment Settings
Expected LC Parameter Variation Limits Worst-case Scenario
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50
Robustness Assessment Settings
Response Performance Limits Required for Robust Method
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51
Robustness Assessment Results
Statistical Significance Testing Model Coefficients
Failing this test means that the
effect of the parameter across its
Robustness assessment range is
statistically larger than
experimental error.
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52
Robustness Assessment Results
Practical Significance Testing Effects Magnitude
Passing this test means that the
method is robust to the specified
maximum variations in the study
parameters.
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53
Robustness Visualization Proven Robust Operating Ranges
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54
Robustness Visualization Proven Robust Operating Ranges
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55
FMVRobustness Summary
I. Potential Sources of Risk in Current Practice
1.
2.
3.
Experimental ranges a Signal/Noise source of risk
Experimental design selection an information content source of risk
Performance requirements a performance variation source of risk
II. QbD-aligned strategy for validating method robustness
1.
2.
3.
Define valid study ranges for critical instrument parameters (CPPs)
Select the right experimental design
Specify risk-based method performance requirements (CQAs)
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
56
Method Validation Benefits of Fusion QbD
Standardized workflow across platforms CDS Independent.
Agilent OpenLab.
ThermoFisher Dionex Chromeleon.
Waters Empower 2 and 3.
21 CFR 11 compliance support toolset
Including E-records and E-signatures, Audit Logging.
Workflow Management with E-review and E-approve Loops.
Easy setup of experiments
Create standardized workflow templates.
Facilitate rigorous practice and defensibility.
Simple documentation review easy to defend and communicate.
Standardized reporting reports meet all FDA and ICH guidelines.
Method Robustness experimental approach is a reliable gatekeeper.
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
57
Fusion Method Validation Proven ROI
International Pharma Co. Benchmarking Project
Realized Time Savings = 85%.
Using historical records* and adjusting for project complexity
Average Expected Time Savings per Project = 70%.
Minimum Expected Time Savings per Project = 60%.
* - on average 2.5 FTE equivalent years spent in method validation support
work over 10 year life span of drug.
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
58
Wrap Up
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
59
End of Presentation
S-Matrix Corporation
1594 Myrtle Avenue
Eureka, CA 95501
USA
Phone: 707-441-0404
URL: www.smatrix.com
Copyright 2016 S-Matrix Corporation. All Rights Reserved.
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