FusionChromFusionChrom

Analytical Method Development Analytical Method Development And Method Validation And Method Validation

Chemometric platform for analytical method Chemometric platform for analytical method validation.validation.

Auto-control of instrument parameters, external Auto-control of instrument parameters, external solvent selection valves, and column switching.solvent selection valves, and column switching.

Auto-construction and export of methods and Auto-construction and export of methods and sequences sequences to your Chromatography Data System to your Chromatography Data System (CDS).(CDS).

Auto-importing of results from the CDS.Auto-importing of results from the CDS.

Automated analysis and reporting that meet all Automated analysis and reporting that meet all FDA & ICH Guidelines.FDA & ICH Guidelines.

AutomatedAutomatedExperimentationExperimentation

FusionChromFusionChrom

S-Matrix Corporation: S-Matrix Corporation: www.smatrix.comwww.smatrix.com

FusionChromFusionChrom

• Off-the-shelf components:Off-the-shelf components:• PC-controlled HPLC instrumentationPC-controlled HPLC instrumentation• Commercial CDSCommercial CDS• Commercial DOE softwareCommercial DOE software

• Additional components:Additional components:• Software interface: DOE design (*.txt) Software interface: DOE design (*.txt) HPLC (*.mth, *.seq) HPLC (*.mth, *.seq)• Software control: accessory solvent valvesSoftware control: accessory solvent valves• Software control: column switching valveSoftware control: column switching valve

• Early 1990’s – Major Pharma Company Project:Early 1990’s – Major Pharma Company Project:• Sponsored by an International Top 5 Pharma company.Sponsored by an International Top 5 Pharma company.• Carried out by ControlChrom BVCarried out by ControlChrom BV• Transform DOE output into HPLC methods and sequencesTransform DOE output into HPLC methods and sequences

HistoryHistory

• Initially (mid 1990’s) PE Nelson Turbochrom was chosen because the Initially (mid 1990’s) PE Nelson Turbochrom was chosen because the development toolkit had documented HPLC instrument controldevelopment toolkit had documented HPLC instrument control

HistoryHistory

• Peltier column ovenPeltier column oven

• Mobile phase valves:Mobile phase valves:• More phasesMore phases• pHpH• BufferBuffer• ModifierModifier

• Column switcherColumn switcher

• Automated DOE-based HPLC experiments - from design to report - Automated DOE-based HPLC experiments - from design to report - complete successcomplete success

FusionChromFusionChrom

FusionChromFusionChromHistoryHistory

• How could this DOE/HPLC system be improved?How could this DOE/HPLC system be improved?• Ease of use = deeper integrationEase of use = deeper integration

• Chromatography specific DOE interfaceChromatography specific DOE interface

• Wizards for DOE design selectionWizards for DOE design selection

• Adapt DOE to HPLC instrument parametersAdapt DOE to HPLC instrument parameters

• Create a method validation experiment suiteCreate a method validation experiment suite

• Automate data exchange with CDSAutomate data exchange with CDS

• Expanded range of instruments and CDSExpanded range of instruments and CDS

• Improvement requires a partnership:Improvement requires a partnership:• Chromatography/automation expertChromatography/automation expert

• DOE expertDOE expert

FusionChromFusionChrom

• S-Matrix CorporationS-Matrix Corporation• Validated DOE software in Pharmaceutical Validated DOE software in Pharmaceutical

usageusage• Major Pharma customer sponsoring new Major Pharma customer sponsoring new

developmentdevelopment• Looking at new opportunities to expand DOE Looking at new opportunities to expand DOE

applicationsapplications

• Da Vinci Europe (ControlChrom BV)Da Vinci Europe (ControlChrom BV)• Specialists in software development for Specialists in software development for

chromatography systems (CDS)chromatography systems (CDS)• Partnerships with leading HPLC and CDS Partnerships with leading HPLC and CDS

companiescompanies• Validated software in Pharmaceutical usageValidated software in Pharmaceutical usage• Looking to improve DOE prototypeLooking to improve DOE prototype

E-lab notebookE-lab notebookInterface for fast, easyInterface for fast, easyexperiment setupexperiment setupwith correct planningwith correct planningbuilt in. built in.

Automatically builds,Automatically builds,designs and exportsdesigns and exportsexperiments to theexperiments to theCDS as ready-to-run.CDS as ready-to-run.

AutomatedAutomatedExperimentationExperimentation

FusionChromFusionChrom

E-lab notebookE-lab notebookInterface for fast, easyInterface for fast, easyexperiment setupexperiment setupwith correct planningwith correct planningbuilt in. built in.

Automatically builds,Automatically builds,designs and exportsdesigns and exportsexperiments to theexperiments to theCDS as ready-to-run.CDS as ready-to-run.

Auto-analyzesAuto-analyzesresults and createsresults and createsreports that meetreports that meet

FDA and ICHFDA and ICHguidelines.guidelines.

Output formatsOutput formats include RTF, DOC,include RTF, DOC,

HTML, and PDF. HTML, and PDF.

ExperimentsExperimentsrun automaticallyrun automatically

on the CDS.on the CDS.

FusionChromFusionChromauto-imports allauto-imports all

results.results.

AutomatedAutomatedExperimentationExperimentation

FusionChromFusionChrom

FusionChromFusionChrom

• Filter ValidationFilter Validation– Compares the response of the filtrate to that of a centrifuged or other Compares the response of the filtrate to that of a centrifuged or other

appropriate control - quantifies filtration effect on test samples in the appropriate control - quantifies filtration effect on test samples in the response region of interest.response region of interest.

Pharma-guided Development:

Analytical Method Validation

• AccuracyAccuracy– The closeness of agreement between the value which is accepted The closeness of agreement between the value which is accepted

either as a conventional true value or an accepted reference value either as a conventional true value or an accepted reference value and the value found.and the value found.

• Linearity and RangeLinearity and Range– The ability (within a given range) to obtain test results which are The ability (within a given range) to obtain test results which are

directly proportional to the concentration (amount) of analyte in the directly proportional to the concentration (amount) of analyte in the sample.sample.

• RepeatabilityRepeatability– Precision under the same operating conditions over a short interval of Precision under the same operating conditions over a short interval of

time. Repeatability is also termed intra-assay precision.time. Repeatability is also termed intra-assay precision.

FusionChromFusionChromPharma-guided Development:

Analytical Method Validation

• Robustness (requires method development technology)Robustness (requires method development technology)– The system's capacity to remain unaffected by small, but deliberate The system's capacity to remain unaffected by small, but deliberate

variations in method parameters and provides an indication of its variations in method parameters and provides an indication of its reliability during normal usage.reliability during normal usage.

• Sample Solution StabilitySample Solution Stability– Quantifies the solution stability of the drug substance or drug product Quantifies the solution stability of the drug substance or drug product

after preparation according to the test method.after preparation according to the test method.

• RuggednessRuggedness– The degree of reproducibility of the same sample under a variety of The degree of reproducibility of the same sample under a variety of

conditions: analyst, column, equipment, lab, day, etc.conditions: analyst, column, equipment, lab, day, etc.

• SpecificitySpecificity– The ability to assess unequivocally the analyte in the presence of The ability to assess unequivocally the analyte in the presence of

components which may be expected to be present. Typically these components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.might include impurities, degradants, matrix, etc.

FusionChromFusionChrom

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% Time Spent

SPL Prep& Seq.Setup

DataAnalysis &

Stats

ResearchReport

Creation

Activity

% Time Spent per Method Validation Activity

No Automation

Automation

1.1. 2.5 FTE Years method validation (MV) effort per Project Life.2.5 FTE Years method validation (MV) effort per Project Life.

2.2. MV cost per project = $625,000.MV cost per project = $625,000.

3.3. Therefore, Therefore, per projectper project::

MinimumMinimum time saved using FusionChrom = time saved using FusionChrom = 60%60%..

MinimumMinimum dollars saved using FusionChrom = dollars saved using FusionChrom = $375,000$375,000..

Unsurpassed Proven Value:

Automation -Automation - allows for easy tracking of aberrant data. Reduces allows for easy tracking of aberrant data. Reduces the need for costly Analysis Lab Investigation Reports (ALIRs)the need for costly Analysis Lab Investigation Reports (ALIRs)..

Easy setup of DOE-based experiments -Easy setup of DOE-based experiments - tremendously facilitates tremendously facilitates rigorous practicerigorous practice..

Method Connectivity –Method Connectivity – early methods developed using other tools early methods developed using other tools can be optimized and/or validated using FusionChromcan be optimized and/or validated using FusionChrom..

Simple documentation review -Simple documentation review - easy to defend and communicate.easy to defend and communicate.

Platform independence -Platform independence - works with PerkinElmerworks with PerkinElmer TotalChrom TotalChrom, Waters, Waters

MillenniumMillennium3232 and Empower, and Varian and Empower, and Varian Galaxie Galaxie

(and others in 2004).(and others in 2004).

Standardized reporting -Standardized reporting - reports meet all FDA and ICH guidelines.reports meet all FDA and ICH guidelines.

Automated ExperimentationAutomated Experimentation FusionChromFusionChrom

21 CFR 11 Compliant -21 CFR 11 Compliant - compliance features include full audit trail, compliance features include full audit trail, e-signing Permissions/Authorities, and work flow administration.e-signing Permissions/Authorities, and work flow administration.