Analytical Method Validation Module - S-matrix...Analytical Method Validation Module S-Matrix Corporation 1594 Myrtle Avenue Eureka, CA 95501 USA Phone: 707-441-0404 URL: 5. Platform

Analytical Method Validation Module

S-Matrix Corporation1594 Myrtle AvenueEureka, CA 95501USAPhone: 707-441-0404URL: www.smatrix.com

2Copyright 2016 S-Matrix Corporation. All Rights Reserved.

Fusion QbD Software Platform

Full Support for Part 11

Compliance

Citrix-ReadyCertified


Fusion Method Validation Module (FMV)

Full Support for Part 11

Compliance

Citrix-ReadyCertified


1. Consistency – Workflow and Reporting. Work is standardized – done the same way every time. Reporting is standardized, complete, easy to communicate.

2. SimplicityTremendous 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 CompletenessAll required validation experiment types are supported. Reporting meets regulatory requirements. Reports can be attached to Project specific narrative documents.

Key Benefits of FMV


Key Benefits of FMV

5. Platform IndependenceSupport 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 customer’s support needs.

7. Flexible LicensingS-Matrix can provide corporate licensing based on a Named User model or a Concurrent Use model with very competitive pricing.


Presentation Outline

FMV

Critical QbD Capability

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


FMV








Fusion Method Validation


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


PhRMA’s 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.

Regulatory Statements and Expectations


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

Fusion Method Validation Experiment Suite


Fusion Method Validation Example – Experiment Type Selection


FMV










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.

Fusion Method Validation – Scalability


FMV










User-specific Password Options

Application Module Access Permissions

Role Assignments

21 CFR 11 Support – User Management


Vertical sequence of auditable operations= normal software operating workflow

E-Review and e-Approve control loops with built-in e-mail notification.

Role-based Permissions & Authorities settings for all operations

21 CFR 11 Support – Roles Management


Bookkeeping – accounting of available and used licenses.

Bookkeeping – “All Instruments” folder lists all currently-defined instruments by type.

Associations – “Common Instruments” folder makes instruments available to any active Fusion QbD user.

21 CFR 11 Support – Instrument Management


21 CFR 11 Support – Auditing


Management – administrator notification and unlock Fusion QbD application nodes locked down due to failed log on attempts.

Administration – global default password settings.

Administration – user application suspend mode.

Administration –company logo image for report headers.

21 CFR 11 Support – Access Management



FMV









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)

Fusion Method Validation – Automation Workflow


Chromatography Data Software (CDS)

Automated, Audited Data Exchange Preserves Data Integrity

Generates QbD-aligned DOE Experiment

Automated FMV Experiment Workflow

Automatically BuildsSequence and All

Instrument Methods

Steps 1 and 2 Step 3


Automated analysis, graphing, and reporting.

Report formats:RTF, DOC, HTML, PDF, XLSX, XML

Chromatography Data Software (CDS)

Automated FMV Experiment Workflow

Automatically Retrieve AllChromatogram Results Da

Automated, Audited Data Exchange Preserves Data Integrity

Step 4

Step 5


Supported Chromatography Data Software

Agilent ChemStation / OpenLAB

Waters Empower 2 and 3

Thermo Scientific Dionex Chromeleon








Rigorous QbD-aligned Robustness Optimization


FMV


Demonstration Study – Simple Workflow with Complete QbD Reporting


Linearity Example – Experiment Setup Template

Define Acceptance Criteria for each Key Result for each Compound.


Linearity Example – Standards Setup Options

Flexible setup of the required Standards Strategy.


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…

Linearity Example – Reporting Requirements


Linearity Example – Fusion QbD Output Reports

Fusion QbD instantly creates formal reports with all required tables and graphs.


Method Validation – Linearity Example

ICH Q2(R1):

For chromatographic procedures, representative chromatograms should be used todemonstrate specificity, and individual components should be appropriately labeled.

If DL is determined based on visual evaluation or based on signal-to-noiseratio, the presentation of the relevant chromatograms is considered acceptable for justification.

Reports can be augmented with images of relevant chromatograms.


Method Validation – Linearity Example

Reports can be augmented with images of relevant chromatograms.


Reports meetall output format requirements:

.TXT

.RTF

.DOC

.PDF

.HTML

.XML

Linearity Example – Fusion QbD Compiled Report Generator










FMV


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 setpointsdone as part of a Validation-Robustness experiment.


Mean Performance Versus Robustness

Method A – Good RobustnessMethod B – Poor Robustness

Methods A and B –

Identical Mean Performance –

Good mean performance ≠ good robustness


Method Robustness

I. Potential Sources of Risk in Current Practice

1. Experimental ranges – a “Signal/Noise” source of risk

2. Experimental design selection – an information content source of risk

3. Performance requirements – a performance variation source of risk

II. QbD-aligned strategy for validating method robustness

1. Define valid study ranges for critical instrument parameters (CPPs)

2. Select the right experimental design

3. Specify risk-based method performance requirements (CQAs)


Method Robustness






Study Factor

Res

pons

eSmall Range – Poor Effects Estimation

L1 L2 L3

6σ

-3σ +3σ

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.


Study Factor

Res

pons

eBest Practice – Large Ranges = High Signal/Noise

L1 L2 L3 L4 L5

>12σ

6σ

-3σ +3σ

General Guideline: Minimum Study Range for 3 Level Designs Should be >12σ


Study Factor

Res

pons

eBest Practice – Large Ranges = High Signal/Noise

L1 L2 L3 L4 L5

>24σ

6σ

-3σ +3σ

General Guideline: Minimum Study Range for 5 Level Designs Should be >24σ


Factor Method Nominal

Traditional Range*

QbD-aligned Range

Pump Flow Rate (mL/min) 1.0 ±0.025 ±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

Comparative Study Ranges Around Method Setpoints

* – worst-case scenario considered.


Method Robustness






Classical / Fusion QbD Optimization Designs

Full Factorial 3-Level Design = 81 Runs

Fusion QbD Optimal* Design = 22 Runs

Four variable Robustness Study – Efficiency Comparison

* – 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).


• Fusion QbD automatically selects the right experimental design for the included instrument parameters

• Fusion QbD design is efficient and automated


Method Robustness



II. QbD aligned strategy for validating method robustness



Demonstration Example – Experiment Type Selection


Experiment Setup Template


Fusion QbD Optimization Design Formatted for Export to the CDS

QbD-aligned Study Ranges


Peak Results Data Automatically Imported From the CDS

QbD-aligned Study Ranges


Expected LC Parameter Variation Limits – Worst-case Scenario

Robustness Assessment Settings


Response Performance Limits Required for Robust Method

Robustness Assessment Settings


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.

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.

Robustness Assessment Results


Robustness Visualization – Proven Robust Operating Ranges


Robustness Visualization – Proven Robust Operating Ranges


FMV–Robustness – Summary










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.

21 CFR 11 compliance support toolset –Including E-records and E-signatures, Audit Logging.Workflow Management with E-review and E-approve Loops.

Standardized workflow across platforms – CDS Independent.Agilent OpenLab.ThermoFisher Dionex Chromeleon.Waters Empower 2 and 3.

Method Validation – Benefits of Fusion QbD

Method Robustness – experimental approach is a reliable gatekeeper.


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 supportwork over 10 year life span of drug.

Fusion Method Validation – Proven ROI


Wrap Up


S-Matrix Corporation1594 Myrtle AvenueEureka, CA 95501USAPhone: 707-441-0404URL: www.smatrix.com

End of Presentation

Documents

Analytical Method Validation Module - S-matrix...Analytical Method Validation Module S-Matrix Corporation 1594 Myrtle Avenue Eureka, CA 95501 USA Phone: 707-441-0404 URL: 5. Platform