PQRI Work Project Concept

1. PQRI Work Project Concept Fundamental Understanding of Sulfonate Ester-Forming Reactions April 2006

2. Objective of Work Project • Description of overall objective of work project • What are the challenges (issues with product quality) the project (deliverable) is intended to address? • Is this problem worth solving and if so, Why? • Definition of key stakeholders (i.e., what is the target audience; who will be interested in the results?)

3. Background of Work Project • Concern exists that sulfonate esters may be genotoxic impurities and are potentially formed during drug substance manufacturing when sulfonic acids are used in the presence alcoholic solvents • The elimination of sulfonic acids from drug substance manufacturing would be highly undesirable due to its useful synthetic properties • This is a potential regulatory outcome if the issue is not addressed • The amount of sulfonate esters formed under synthetically relevant conditions is currently unclear

4. Objective of Work Project • To scientifically demonstrate that sulfonic acids can safely be used in drug substance manufacturing by • Understanding the kinetics of formation and decomposition of sulfonate esters during drug substance manufacture under synthetically relevant conditions • Demonstrating that conditions can be manipulated to control the levels of sulfonate esters formed

5. Key Stakeholders • Global regulatory agencies • The question of potentially genotoxic impurities is of significant concern to them, this adds to the body of available knowledge and allows them to use science to make better decisions • Pharmaceutical manufacturers • Data on impurity formation would allow the possibility of a scientific discussion with regulators on required controls and support continued use of sulfonic acids • Would also provide useful synthetic knowledge to allow minimization of the formation of sulfonate esters

6. Key Deliverables and Outcomes • Definition of key deliverables and approximate timeline required to achieve each deliverable • Method development (timing depends on difficulties encountered) • Experimental protocol design • Execution of experiments to demonstrate impact of synthetic parameters on formation of sulfonate esters • Final output available in March of 2009 • What are the potential risks involved with the project? • Data collected is not valuable in answering the question • Considered to be highly unlikely, i.e. project should have a meaningful outcome

7. Impact of Work Project • If this project is successful, what would be the impact on product quality? • Data would be available that would demonstrate how the formation of sulfonate esters can be controlled and thus allow the continued use of sulfonic acids in synthesis • Discussion with regulators on controls necessary to mitigate the risk of sulfonate esters, including specifications, can be based on science

8. Communication of Work Project • Description of intent of external communication (e.g., to provide best practice, to influence regulatory policy, etc.) • To influence regulatory expectations, as described earlier • Description of internal and external communication plan (e.g., white paper, published article, workshop, etc.) • It is expected that several technical papers in peer-reviewed journals will be published

9. Funding Requirements • It is estimated that somewhere between 100K and 300K will be required to fund this project through to completion (spread over about 2 years) • It is anticipated that a contract lab will be hired to perform the method development and subsequent experiments • It may be necessary to hire a project manager • Funds will be needed from PQRI but there is a possibility that member organizations will partially fund due to high interest level

10. Skill/Knowledge Set • Define the skills/knowledge sets necessary to complete the work project • Synthetic and analytical chemists • Outline the plan for obtaining necessary skills (e.g., contract with external expert, utilize member organization expertise, etc.) • May be a combination of internal and external expertise; plan to investigate possibility of contract lab and project manager