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

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?)

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

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

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

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

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

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

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

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