1. Lhasa ICH M7 Database – Use Cases Dr Angela White

2. Database Overview 2 Lhasa Database Assay data: -Results +/-S9 - Study number -Batch numbers -Positive controls -Comments section Compound details: -Structure -CAS numbers -Compound name -Molecular weight SAR: -Derek predictions (automatic) -QSAR -In house QSAR predictions ICH M7 class Comments stored e.g. expert opinion/PDE/AI Search via (Q)SAR call Search via structure Exact Similarity Substructure Search by Data By study type Endpoint Batch number Logs origin of each compound e.g. degradant, impurity SDF upload or add data via interface Word, SDF or Excel export of search results

3. Use Case 1: ICH M7 Compliant Assessment of API Chemistry 3 –ICH M7 requires “...assessment and control of mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product.” –To comply with ICH M7, potential sources of impurities i.e. synthetic intermediates, reagents, degradants need to be assessed. –Existing mutagenicity data identified –SAR assessment (QSAR and knowledge based tool) –(Q)SAR outcome examined alongside “expert knowledge” –ICH M7 class 1-5 assigned –Identify the need for Ames testing or control –This database can help with ICH M7 assessments by reducing duplication of effort: –Holds all (Q)SAR information –Holds mutagenicity/carcinogenicity data –Store ICH M7 class –Store additional information e.g. PDE, expert knowledge assessment –Provides visibility and traceability

4. Tracking ICH M7 Assessments 4

5. –For some compounds SAR assessment may need to be supplemented with expert knowledge e.g. Unclassified features/Out of Domain. –The database can be used to help answer: –Do we have structurally similar compounds with Ames data? –Does the Ames data suggest a risk with my compound? –Knowledge and ‘expert opinion’ can be stored in the database for future reference –Visible to all users – no duplication of effort Applying Expert Knowledge Unclassified Features/Out of Domain Assessments 5

6. Ames Testing Compounds –Decide to Ames test compound –Is the test compound common to another API program? –What is the impact on the other project if the Ames result is positive? –Allows tracking of data so risk management plans can be put in place prior to Ames testing. 6

7. Preparing an ICH M7 Table for Regulatory Submission 7

8. Use Case 2: Working in Non-mutagenic Chemical Space –As the database houses both structural and mutagenicity data it can be a resource for medicinal chemists –Search for motif of interest: –Exact search – do we have Ames data on this specific fragment? –Substructure/similarity search – Do we have Ames data for structurally similar compounds? –e.g. which aromatic amine building blocks are Ames negative –Allows proactive selection i.e. work in lower risk chemical space 8

9. Concluding Remarks – The database allows the tracking and traceability of (Q)SAR assessments and Genotoxicity data –Which programs are associated with each compound – understanding the impact of new data –Prevents duplication of effort: –External data searches/Ames data captured –Provides consistency of conclusions – stores expert opinions –Allows quick access to information and retrieval of information –Exports can be used as a basis for ICH M7 submissions –Data can be used by medicinal chemists to support low risk drug design –Can promote interrogation of data to improve (Q)SAR –e.g. How many compounds associated with an alert/QSAR call are Ames positive vs Ames negative? 9