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?

9

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

22

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

27