Analytical Method Validation Module

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
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.
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.
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
Fusion Method Validation
FMV

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)
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.
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
10
Fusion Method Validation Example Experiment Type Selection
11
FMV


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.
13
FMV


14
21 CFR 11 Support
User Management
User-specific Password Options
Application Module Access Permissions
Role Assignments
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
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.
17
21 CFR 11 Support
Auditing
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.
19
FMV


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)
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

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

23
Supported Chromatography Data Software
Agilent ChemStation / OpenLAB
Thermo Scientific Dionex Chromeleon
Waters Empower 2 and 3
24
FMV

Rigorous QbD-aligned Robustness Optimization
25
Demonstration Study Simple Workflow with Complete QbD Reporting
26
Linearity Example Experiment Setup Template
Define Acceptance Criteria

for each Key Result for each
Compound.
27
Linearity Example Standards Setup Options
Flexible setup of the

required Standards
Strategy.
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
29
Linearity Example Fusion QbD Output Reports
Fusion QbD instantly creates formal

reports with all required tables and graphs.
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.
31
Method Validation Linearity Example
Reports can be
augmented with
images of relevant
chromatograms.
32
Linearity Example Fusion QbD Compiled Report Generator
Reports meet
all output format
requirements:
.TXT
.RTF
.DOC
.PDF
.HTML
.XML
33
FMV

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.
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
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)
37
Method Robustness
1.
1.
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
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
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
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.
42
Method Robustness
2.
2.
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).
44
Method Robustness
3.
II. QbD aligned strategy for validating method robustness
3.
45
Demonstration Example Experiment Type Selection
46
Experiment Setup Template
47
QbD-aligned Study Ranges

Fusion QbD Optimization Design Formatted for Export to the CDS
48
QbD-aligned Study Ranges

Peak Results Data Automatically Imported From the CDS
49
Robustness Assessment Settings

Expected LC Parameter Variation Limits Worst-case Scenario
50
Robustness Assessment Settings

Response Performance Limits Required for Robust Method
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.
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.
53
Robustness Visualization Proven Robust Operating Ranges
54
Robustness Visualization Proven Robust Operating Ranges
55
FMVRobustness Summary
1.
2.
3.

1.
2.
3.

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.
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.
58
Wrap Up
59
End of Presentation
S-Matrix Corporation
1594 Myrtle Avenue
Eureka, CA 95501
USA
Phone: 707-441-0404
URL: www.smatrix.com
60

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Analytical Method Validation Module

Fusion QbD Software Platform

Full Support for

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation Module (FMV)

Full Support for

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Key Benefits of FMV

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Key Benefits of FMV

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Critical QbD Capability

Completely Aligned with Regulatory Requirements

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation

Critical QbD Capability

Completely Aligned with Regulatory Requirements

Supports All Install Environments (Citrix Certified)

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Regulatory Statements and Expectations

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Regulatory Statements and Expectations

PhRMAs Analytical Technical Group

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation Experiment Suite

Early Phase Specific Experiments (Performance Characterization)

Early Phase and Final Phase (FDA / ICH Submittal Quality)

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation Example Experiment Type Selection

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation

Critical QbD Capability

Completely Aligned with Regulatory Requirements

Full 21 CFR Part 11 Compliance Support

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation Scalability

* - Fusion QbD is operating in the GxP environments of many

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation

Critical QbD Capability

Completely Aligned with Regulatory Requirements

Automated DOE Experimenting & Testing on LC

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

User-specific Password Options

Application Module Access Permissions

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Role-based Permissions & Authorities settings for all operations

E-Review and e-Approve

Vertical sequence of auditable operations

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Bookkeeping All Instruments folder lists all currently-defined instruments by

Associations Common Instruments folder makes instruments available to

Bookkeeping accounting of available and used licenses.

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Management administrator notification and

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation

Critical QbD Capability

Completely Aligned with Regulatory Requirements

Simple Workflow with Complete QbD Reporting

Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion Method Validation Automation Workflow