ICH M7 Workflow Supporting your expert review

Dr Nicholas Marchetti Product Manager

nik.marchetti@lhasalimited.org

ICH M7 Guidelines

ICH M7 says…

• Hazard assessment involves an initial analysis of actual and potential impurities by conducting database and literature searches for carcinogenicity and bacterial mutagenicity data • in order to classify them as Class 1, 2, or 5....

• If data for such a classification are not available, an assessment of Structure-Activity Relationships (SAR) that focuses on bacterial mutagenicity predictions should be performed. • This could lead to a classification into Class 3, 4, or 5.

ICH M7 says.....

• “If warranted, the outcome of any computer system-based

analysis can be reviewed with the use of expert

knowledge in order to provide additional supportive

evidence on relevance of any positive, negative,

conflicting or inconclusive prediction and provide a

rationale to support the final conclusion.”

• http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Gudelines/Multidisciplinary/M7/M7_Step_4.pdf

What questions do you ask?

• What do I know about this compound? • Is there any public data? • Is there any in-house data? • What do the in silico systems say?

• Is there a consensus between Derek and Sarah? • If there are any concerns, are they more concerning than

the API itself? • What do you think as an expert? Can you add more

knowledge? • Should you test (Ames), control, limit according to TTC or

make an argument for Purge?

How can we help?

• Assist users in presenting relevant information for ICH M7 submission

• Where possible, gather or predict the appropriate information

Key Functionality

• Users can enhance their ICH-M7 prediction with a Classification

• All relevant information to an impurity assessment for a synthetic route will be available within the interface

• Vitic will be used to access relevant user’s data • Where Vitic is not available, data can be supplied by the user

• The system will automatically search relevant public data • Lhasa data will be used for Mutagenicity • Carcinogenic Potency Project data will be used for

Carcinogenicity

What is Müller Classification?

Known mutagen

Class 1 Control < compound-specific limit

Contains structural alert

Known carcinogen

Unknown carcinogen

Same as API (non-mutagenic)

Alert not in API No mutagenicity data

No structural alert or

negative Ames

Class 2 Control < generic or adjusted TTC limits

Class 3 Control < generic or adjusted TTC limits or run Ames

Class 4 Treat as non-mutagenic

Class 5 Treat as non-mutagenic

Known non carcinogen Class 5 Treat as non-mutagenic

Non-mutagen Class 5 Treat as non-mutagenic

Same as API (mutagenic) Unknown

Inputs

• User supplied inputs • User must supply at

least two compounds • API • Impurity/Impurities

• Synthetic route information

Database Lookup

• Use appropriate records from Vitic Nexus to populate table

• Allow entry of information from other data sources

Add predictions

• Derek and Sarah Predictions complete the table

• Other systems can be entered as required

Disclaimer

• The following screenshots are from a development version of Nexus

• Interface and functionality are subject to change up until the date of release

How does it work in practice?

What Information is available?

What Information is available?

ICH M7 Addendum

ICH M7 Addendum

• Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk • Application of the Principles of the ICH M7 Guideline to

Calculation of Compound Specific Acceptable Intakes • Section 7.2.1 of the Guideline states "Compound-specific

risk assessments to derive acceptable intakes should be applied instead of the TTC-based (Threshold of Toxicological Concern-based) acceptable intakes where sufficient carcinogenicity data exist."

• These compound-specific acceptable intakes (AIs) can be calculated for known mutagenic carcinogens by linear extrapolation based on their carcinogenic potency

ICH M7 Addendum

• 17 Compounds have been identified and have Acceptable

Intakes (AIs) or Permissible Daily Exposures (PDEs)

calculated as part of the Addendum

• Information will be made available in the ICH M7

classification table

Summary

• Automated system to assist your expert review

• Supplements Derek and Sarah predictions with public

and in-house data

• Calculates ICH M7 classification

• Expert review comments can be saved and the entire

table retrieved at a later date

Questions?

Work in progress disclaimer

30

This document is intended to outline our general product direction and is for information purposes only, and may not be incorporated into any contract. It is not a commitment to deliver any material, code, or functionality, and should not be relied upon. The development, release, and timing of any features or functionality described for Lhasa Limited’s products remains at the sole discretion of Lhasa Limited.