Download PQRI Work Project Concept

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?