Download PQRI Work Project Concept

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