Pilot Study to Automate Forced Degradation Workflows · Not a new idea! Automating some or all of...
Transcript of Pilot Study to Automate Forced Degradation Workflows · Not a new idea! Automating some or all of...
(very) Pilot Study to Automate Forced Degradation Workflows
David Benstead, AstraZenecaACD/Labs User Group Meeting 27th September 2016
Why Automate Forced Degradation Workflows?
Not a new idea!
Automating some or all of the forced deg workflow has a
large potential payoff
• All development compounds must have a forced deg
• Robust retention of raw data and context is imperative
• Data should be generated as few times as possible to
avoid “surprises”
Forced deg can easily generate 30+ samples per compound
• Significant time cost to manually process them all
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Stability Understanding
From ICH Q1A:
Forced degradation/stress testing forms part of a wider stability
understanding, and the knowledge is used throughout the product
lifecycle
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Drug Candidate
•What do we know?
•Structure
•Lab “lore”
Predictions
•Company knowledge
•Literature sources
•In silicoprediction
Reality
•Forced Degexperiments
•Accelerated stability
•Long term stability
Data
•Process
•Interpret
•Store
Knowledge
•Capture
•Immediate use
•Long term use
Automation
Forced degradation studies generate large numbers of samples and
data, which are time consuming to acquire and process.
Can the acquisition and interpretation process be made easier?
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Drug Candidate
•What do we know?
•Structure
•Lab “lore”
Predictions
•Company knowledge
•Literature sources
•In silicoprediction
Reality
•Forced Degexperiments
•Accelerated stability
•Long term stability
Data
•Process
•Interpret
•Store
Knowledge
•Capture
•Immediate use
•Long term use
Automation
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Structure In silicoprediction*
Forced Degexperiments
•LC-MS
Data Knowledge
What tools are available, and how can we combine them?
* Zeneth 6.0 (Lhasa Limited) used here. For further info see Parenty et al, Mol. Pharmaceutics, 2013, 10 (8), pp 2962–2974,
doi:10.1021/mp400083h
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Rule based prediction of degradation products under a variety of
conditions
Relies on existing knowledge base, which can be added to with
custom knowledge
Degradation map can be exported in a variety of formats, including
.sdf
Zeneth Degradation Map
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Zeneth Degradation Map
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.sdf
Zeneth Degradation Map
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.sdf
Q
D1
Spectrus MetID
Spectrus MetID offers a workflow which is very
relevant to forced deg interpretation
Identification of components from a predicted
metabolic transformation map, component
filtering and databasing of transformation,
structural and spectral information.
Could the Zeneth output be used to input
structures and component relationships into the
MetID workflow?10
DegID
DegID is a script to feed the Zeneth .sdf output
into the MetID workflow
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DegID
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DegID
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DegID
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DegID
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Metasense
Metasense is an evolution of MetID and
incorporates extra features such as time-course
profiling
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Metasense
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Multiple chromatograms with
time-course data
Multiple forced
deg conditions
Doesn’t currently
interface with Zeneth
maps – this example
uses MetID map.
Metasense (current output)
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Degradation
map
Component XIC
TIC
Degradation Profile
Multiple
conditions and
timepoints
Graphical output
for deg map via
Chemsketch
Export as .csv
DegID/”DegSense”
The Good:• Retains reaction information from Zeneth deg map
• Databases reactions, structures, spectra and chromatograms easily with
minimal user data entry.
• Easy visualisation of data.
• Excellent tool for “one place” retention of forced deg data.
The room for improvement: • Use of UV for quantification/retention times
• Isobaric impurities – potentially resolvable with HRMSn data for non-isomers
• Sensible Markush
• Incorporation of non-Zeneth predictions
• Zeneth “intermediates” structures – reactive intermediates contained within
Zeneth .sdf but not part of the degradation map.20
“Degsense” (thoughts on desired output)
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Degradation
map Component XIC
DAD or flat chrom
UV quantitation at
chosen wavelength
Multiple
conditions and
timepoints
Project name field
Component
UV
spectrum
Is there an opportunity to automatically select optimum wavelength?
Deg map at
different
levels
Degradation ProfileDeg map filter –
predicted,
observed etc.Graphical output
for deg map via
Chemsketch
Export as .csv
Conclusions and End game
ACD workflows can provide an opportunity to automate
aspects of forced deg and degradation knowledge
management
What could an automated forced deg workflow look like?
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Low pH T8_3_TIC
Retention Time (min)4.54.03.53.02.52.01.51.00.50
-100
-80
-60
-40
-20
0
20
40
60
80
100
Automated
LC-HRMS2
Autochrom10%?
Best API Generic
MethodNo
Yes
“DegSense”Spectrus DB
Acknowledgements
Peter Russel, Albert van Wyk and Richard Lee Advanced Chemistry Development, Inc. (ACD/Labs)
Alex Harding and Lisa BarrLhasa Limited
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