Impurity Lifecycle Management - ACD/Labs · 2016-06-06 · Impurity Lifecycle Management:...
Transcript of Impurity Lifecycle Management - ACD/Labs · 2016-06-06 · Impurity Lifecycle Management:...
Impurity Lifecycle Management:Visualising a vast array of analytical data
Steve CoombesAstraZeneca, Macclesfield, UK.
20th April 2016
Knowledge Management – what does it mean?
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c500BC
Pharmaceutical DevelopmentInformation overload
• The drug development process takes years, with huge amounts of information being generated
• Thousands of individual experiments/tests• Hundreds of reports, Tbytes of data• Most concise summary is the marketing application but typically still
runs to hundreds of pages to describe impurity control strategy
• There will be dozens of analytical chemists working on a project supporting medicinal and process chemists as the project moves through development
• Also need to communicate this information to multiple stakeholders• Process Chemists• Formulators• Toxicology / QA• Operations
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LaunchPhase 1Toxicological testingFirst into man
Phase 2Early clinical trials
Phase 3 / Technology TransferFull clinical trialsPrepare for launch
Discovery
Why is impurity profile important?
Limited knowledge Known impurity
• Name• Structure• Amount
• Formation• Removal
• Specification
The challenge?• A large amount of complex data is generated• Information stored in multiple computer systems• Many people work on our projects in different groups
and locations
Why?• To ensure our medicines are safe
by controlling our process• To meet regulatory requirements
Information overloadPassing it on
• In a global workplace, project transfers are inevitable and managing this transition poses multiple problems
• Trying to share data or pass on project understanding to a new team is difficult
• Methods / Specifications• Knowledge transfers
• So, can we make this transfer of knowledge more manageable / efficient?
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?
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What questions do we want to answer and how might we view the information?
What is the current route? Route (Commercial)Route (Development)
How are they formed and controlled?
Fate of impurity BFate of impurity A
What impurities do we see and how much?
Impurities in PhenolImpurities in MethylImpurities in AcetateImpurities in Asprin
0.12
Batch 123
<0.050.080.20
Have we seen this impurity before and where does it elute?
What is this other peak?
Where has it come from and is it a concern?
What is this new peak?
What does the spectrum look like?Pharmaceutical Technology & Development
Information and data capture toolsWhat’s already used?
• ELN• Excellent repository for experimental detail and observations• Difficult to browse/find data unless you have specific identifiers
• LIMS• Great for tracking analysis, batches and numerical results, but difficult to
extract knowledge• Spreadsheets – everyone loves a spreadsheet
• Record batch details & analytical results (imps, assay, water, solvents, etc)• Doesn’t link stages/batches together, not particularly visual, difficult to
understand rejection• Access Databases
• Like spreadsheets but better...• Ability to link data together (eg batch history)• Limited searching & no overview
• Global Document Management Systems• Normally only generated at key time points in development (not living
documents) summarising established knowledge
Discrete results
Grouped / linked results
Summary results
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In reality…
ELN / LIMSOther
GDMS Excel
dil. H2SO4
NaNO3
NaBH4
?
Data to Knowledge – building your control strategy
Quality controlProcess understanding
Data
Knowledge
InstrumentLC, MS, NMR, IR, TGA
Samples containing impurities Sample preparation
Lab PC or CDSChromatogram, UV spectra, Mass
spectra, NMR, IR, TGA
ELNExperimental details, method,
sample prep, results, discussion, conclusions
LIMSExperimental details, method, sample prep
GDMSCMC modules, methods, process descriptions,
reports, data summaries, justifications
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In reality we will need multiple elements
• This starts to throw up some more questions…….• How do we find what we want?• If searching doesn’t always make sense then we will need to browse
(knowledge sharing vs answering a specific question)• How do we view the data?• How do we manage multiple techniques and multiple vendors?• IT infrastructure?
• User access / licensing• Where do we store data? (network issues!) • Oracle v’s local databases?
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Routes, spectra, results, chromatograms...
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Accurate MassMSMSMass spectrum
NMR (2D)NMR (Cabon)NMR (Proton)
Route (Commercial)Route (Development)
Fate of impurity BFate of impurity A
ELSDPDAChromatogram (UV at 254nm)
SST
Name Structure Mol Wt Formula
We need the flexibility to easily navigate around our data and view the results
ACD/Labs SpectrusDB EnterpriseImpurity Resolution Management• The result of cross industry development has been the
creation of “IRM”, a customisable integrated multi database SpectrusDB Enterprise platform
• The 4 individual, but linked databases are:• IRM Reactions - Synthetic routes• IRM Molecules - Individual structures (+ chromatograms & spectra)• IRM Impurities - Impurity structures (+ chromatograms & spectra)• IRM Impurity reactions - Impurity formation and onward reaction
• Enables collation of analytical data, but now with the associated chemical context
Searchable by browsing or by:• Structure or substructure• Any user defined fields, eg compound name• Spectra• MH+, molecular weight or NMR chemical shift• Project name / therapeutic target
•Also has the ability to build links between other IT systems
IRM Impurities Reaction database
IRM Reaction database IRM Molecule database
IRM Impurity database
ACD/Labs IRM - 4 interlinked databases
IRM Impurities Reaction database
IRM Reaction database IRM Molecule database
IRM Impurity database
Workflow optimisation – database population
1. Script imports main reaction scheme from .sk2 file
2. Script creates individual molecules from main route
3. User creates impurities for each stage
4. User creates Reaction scheme for each impurity
IRM Reactions - Customised view
IRM Molecules databaseTabbed view for analytical
reference data
IRM Molecules database
IRM Molecules database
IRM Molecules database
IRM Impurities database
IRM Impurities Reaction database
IRM Reactions - Customised view
Critical importance – connectivity to other systems
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Critical importance – connectivity to other systems
AZ has been using structural databases for yearsBut now we’re fully integrated
Where does this database fit in?
• There isn’t (and won’t be) a single solution to knowledge capture
• ELN/LIMS will be driven by the business as primary repositories for laboratory information
• GDMS will contain the summary information and documentation required for formal submission & approval for regulatory authorities
• The IRM database is a living / working tool that can grow over the development lifecycle from Discovery to LCM
• Enables the visualisation of many separate and discrete elements• Eg synthetic routes, spectra, chromatograms, impurity structures & levels and
fate/purge profiles• The ability to link between our different IT systems is critical for optimal operational performance
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Acknowledgements
Thanks to:• John Nightingale• Kevin Sutcliffe• Martin Hayes
• Albert Van Wyk• Peter Russell• Dimitris Argyropoulos• Stephane Albrecht
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