Theoretical purge argumentation for Genotoxic Impurities European Lhasa ICGM 13th October 2016, Basel Jens-Christoph Baumann, Rolf Schulte Oestrich
Theoretical purge argumentation for
Genotoxic Impurities
European Lhasa ICGM 13th October 2016, Basel
Jens-Christoph Baumann, Rolf Schulte Oestrich
Technical Aspects of Control Strategies
Technical Regulatory Considerations
GTIs in Chemical Processes
• Commonly used as reagents, intermediates, bye-products
• Always assessed
• Sometimes sought
• Rarely found
How can we focus our energy on value-adding activities?
Control strategy
Assess structures
Identify structures
ICH M7 provides
• Impurity assessment
– Synthetic impurities
– Degradation products
• Hazard Assessment Elements
– 5 classes wrt mutagenicity, cancerogenicity, structure/structural alerts
• Risk characterization
– TTC, LTL exposure, clinic vs. market phase, multiple impurities
• Control
– Impurities, periodic testing, Lifecycle Management, Clinical
• Documentation
– CTA (IMPD, IND); CTD (NDA, MAA)
Control of Process Related impurities (ICH M7)
Option Impurity level tested at Acceptance
criterion
Required
process
knowledge
Routine
testing/Anal
ytical Data
1 API ≤ acceptable
limit
2 Raw Material
Regulatory Starting Material,
Intermediate
≤ acceptable
limit
3 Raw Material
Regulatory Starting Material,
Intermediate
> acceptable
limit
4 No test implemented,
rationale provided
Theoretically:
Acceptable
limit
Exploring Option 4
• Profound process knowledge required
– Analytical testing
– Procedural controls
• Experimental data
– Fate of impurity studies
– Purge studies
• Scientific risk assessment
– Physico-chemical properties
– Reactivity
– Solubility
– Volatility
Experimental Approach
• Develop analytical tools
– Trace analytics in interfering matrix
– Unstable analytes
– Reference standards
• GC- or LC-MS coupling
– Low LOQ
– High sensitivity
• Conduct experiments at lab-scale or plant scale
Depleting Impurities during the Process
• Reactivity
• Solubility
• Volatility
• Physico-chemical properties
H2O
EtOH
EtCl, bp 12.3 °C
Acidic extraction of anilines
Purification by recrystallization
Acceptable Limit in API
Purge Factors
Theoretical approach
• Estimate depletion/purging
– Analyze process to unit operations
– Assign individual theoretical purge factor to unit operations
– Calculate overall purging power of the process
– Will be high for impurities originating early in the synthesis
• Assess risk of theoretical vs. experimental approach
– Consider combination
Manual Assessment
Purge Table for ethyl chloride (calculated PF)
Real life - Option 2: Limited at early step according to TTC
Experimental Fate & Purge Study
• Requires Analytical Method and Testing
• «n.d» is a frequent result
• Use spiking experiments to establish safety margins
700 ppm
nd<10 ppm
Calculated PF:
1000
(Option 1,
limit 100ppm)
mPF:
> 70
Option 4 examples – Limit > ADI in the process
• Oxalylchloride - Option 4
– Limit during synthesis > acceptable limit (Reaction monitoring)
– Demonstrated process understanding
– Theoreticl purge 1014
• Epichlorohydrine - Option 4
– Used in the synthesis of a starting material
– Not found in raw material batches for representative campaign
– Theoretical purge 1021
In silico
Control strategy
Assess structures
Identify structures
Technical Aspects of Control Strategies
Technical Regulatory Considerations
Technical Regulatory Considerations
• Genotox assessment / Control Strategy required for setting of specification
for drug substance and drug product in all phases of product lifecylce
• Specifications for potential genotoxic compounds are set following the
‘less-than-lifetime’-exposure model provided in ICH M7
• Required grade of detail and supportive data to justify proposed control
strategy depending on development phase
P1<P2<P3<<<NDA/MAA
Commercial
Post-Marketing lifecyle
Divestment
Discontinuation
Clinical Development
Phase I Phase II Phase IIIPre-clinical
phase
New Drug
Application
ApprovalSubmission
NME
Entry-into-human
Review
IND/QIMPD
Technical Regulatory Considerations
• Currently, Health Authorities accept sound scientific rationales for
genotoxic impurities based on
– Theoretical purge argumentation
– Supportive analytical data
Sole Acceptance of Theoretical Purge Argumentation as
Control Strategy is currently not yet full established
Technical Regulatory Considerations
• Measures to increase acceptance from Health Authorities
– Consistent use of theoretical purge elements in control strategies
provided in regulatory dossiers with transparent justifications
– Interaction with and Influencing of Health Authorities/Reviewers
during conferences and dedicated trainings offered (Lhasa?)
– Validation of Theoretical Purge Argumentation with ‘real’ experimental
data from purge studies is essential to achieve high level of
acceptance
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