(238a) Managing Residual Risk Via the Control Strategy: A Case Study

There appears to be consensus that a science and risk based development approach  such as QbD helps deliver robust, productive processes that assure product quality attributes are consistently met.   While QbD has become a more mature concept within the pharmaceutical industry, some questions remain regarding implementation.  This presentation will address how ultimately it is within the context of the control strategy that answers are best provided to questions of when continued investment in risk management activities no longer support a proportional benefit to the patient, and how can residual risks (such as scale sensitivity, or the potential process vulnerability to parameters not studied in great detail) be effectively managed.   Furthermore, the presentation will highlight how the output of QbD activities, when coupled with considerations for the commercial production facility, can identify multiple options for how to define a control strategy that assures quality attributes are consistently achieved.  The important considerations for the commercial production facility can include items such as:  

-          managing rate limiting steps and vessel utilization towards optimized process time cycle

-          balancing the cost of expensive reagents against product yield gains

-          evaluating existing equipment capabilities

-          requirements for automation systems

-          approaches for in-process testing

The case study will focus on one specific quality attribute, namely the impurity profile, as impacted by a GMP coupling reaction.  This will include an overview of the iterative nature of the risk assessment process, where assumptions about the risks change as new information regarding processes is gained.   The development activities and results driven by the risk assessment process will also be reviewed in order to highlight how information from various steps is compiled to work towards a final, comprehensive control strategy that considers each synthetic step.  Finally, it will be reviewed how the multifactor process understanding along with the three key elements of control  (raw materials specifications, in process testing, and control by process design) can be formulated into a control strategy that assures final quality attributes are met via a robust, productive process that fits within the anticipated commercial production facility.