impurity lifecycle management - acd/labs · 2016-10-18 · impurity lifecycle...
TRANSCRIPT
Impurity Lifecycle
Management:Visualising a vast array of
analytical data
Steve CoombesAstraZeneca, Macclesfield, UK.
ACD/Labs UKUM
27th Sept 2016
Introduction
Information 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
2 Pharmaceutical Technology & Development
LaunchPhase 1
Toxicological testing
First into man
Phase 2
Early clinical trials
Phase 3 / Technology Transfer
Full clinical trials
Prepare 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 overload
Passing 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?
4
?
Pharmaceutical Technology & Development
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 tools
What’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
resultsPharmaceutical Technology & Development
In reality…
ELN / LIMSOther
GDMS Excel
dil. H2SO4
NaNO3
NaBH4
?
Data to Knowledge – building your control strategy
Quality control
Process understanding
Data
Knowledge
InstrumentLC, MS, NMR, IR, TGA
Samples containing
impuritiesSample 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
Pharmaceutical Technology & Development
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...
Pharmaceutical Technology & Development
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
Impurity Resolution Management
• The result of cross industry development has been the creation of “IRM”, a customisable integrated multi database SpectrusDB 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 years
But now we’re fully integrated
Get a summer student – it’s much easier!!
• IRM Reactions database • Chemical routes for 21 compounds
• 70 records (including routes to starting materials)
• IRM Molecules database • 373 records - raw materials, intermediates, Drug Substance
• NMR and MS data
• Impurities
• IRM Impurity database• 126 records if individual impurities
• IRM Impurities Reaction database• 71 impurity reactions added
• Also helped to establish ways of working and drafting training material for roll out
Populating the IRM database
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
26 Pharmaceutical Technology & Development
Acknowledgements
Thanks to:• John Nightingale• Kevin Sutcliffe• Martin Hayes• Azalea Micottis• Mary Rozier• Rose Lau
• Albert Van Wyk• Peter Russell• Dimitris Argyropoulos• Stephane Albrecht
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