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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