PQRI Project Update Fundamental Understanding of Sulfonate Ester-Forming Reactions Date of Original Submission: April 2006 Date of Current Report: February 2009

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 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

Members of Working Group Bob Evans, AAPS, synthetic chemist Sue Jones, PDA, analytical chemist George Smith, FDA, CDER Etc.

Status of Work Project Overall work is on time and on budget Stage 1 completed An analytical procedure was developed to monitor ethyl methane sulfonate in ethanol/methane sulfonic acid reaction mixtures The method was found to be sufficiently robust to be used in synthetic studies Stage 2 completed The mechanism of reaction was determined using isotope labeled studies

Status of Work Project Stage 3 underway The kinetics of formation of ethyl methane sulfonate from methane sulfonic acid and ethanol is being studied Thus far the effects of temperature and pH have been evaluated It was determined that decreased amounts of methane sulfonate formed with decreasing temperature and higher pH This is important because it leads to an understanding of process chemistry controls/conditions which minimize or quench methane sulfonate formation Next step is to evaluate the effect of the presence of water (to be completed by June 2009)

Impact of Work Project Based on results obtained thus far, the Working Group believes that this project will positively impact product quality in that Industry will be able to make use of the analytical method and kinetic information to evaluate specific synthetic conditions to determine the extent of sulfonate ester formation in proposed synthetic routes Regulators will have a scientific basis for assessing the appropriateness of synthetic pathways in which sulfonate esters may be formed

Communication of Work Project A paper was submitted to xx on development of the analytical methodology A paper will be submitted to xx on the outcome of the kinetic studies (draft to be available by August 2009) Presentations have been given at conference X and Y An email was sent to all PQRI stakeholders with an update of the project at the end of 2008 Are there other opportunities for communication?

Funding Total of $200,000 raised for project (70K from PQRI; remainder from member organizations) Thus far $150,000 has been spent; by the end of the project all funds will be consumed

Support Needed FDA involvement in the WG has waned; is this an important element that should be pursued? Should they be engaged prior to publication?

Other Opportunities? This work may be extended to other relevant solvent systems What is the cost/benefit ratio of doing so?