(677a) Rapid Risk Assessment and Process Optimization to Enable FIH
AIChE Annual Meeting
2019
2019 AIChE Annual Meeting
Process Development Division
Case Studies in Technology: Design, Risk Reduction and Implementation
Thursday, November 14, 2019 - 12:30pm to 12:52pm
Given the competitive landscape faced by the pharmaceutical industry, rapid delivery of first in human (FIH)
clinical materials through efficient risk identification and process development is critical. Identifying important API
quality attributes and major liabilities that may affect them focuses the development of an enabling process. This
presentation provides a case study on optimization of a complex, fit-for-purpose process to enable scale-up for
an FIH delivery of a small molecule API for parenteral use. Some of the challenges and risks inherent to the process
included the use of hazardous hydrogen fluoride chemistry, unit operations such as prep-HPLC, ion-exchange, and
lyophilization, specific requirements for API material properties, and stringent bioburden and endotoxin control.
Liabilities identified included residual fluoride impacting the API stability, residual modifier from the prep-HPLC
mobile phase impacting potency, water-uptake of API due to its hygroscopicity, and variability in the counterion
content of the API. A control strategy was devised and implemented across the reaction, crude precipitation, prep-
HPLC, concentration, ion-exchange and lyophilization to address these liabilities. Lastly, a risk assessment for
bioburden and endotoxin was carried out, and specific processing requirements were outlined in order to ensure
adequate control. The identification and mitigation of major risks through targeted process development resulted
in successful scale-up production of the drug substance.
clinical materials through efficient risk identification and process development is critical. Identifying important API
quality attributes and major liabilities that may affect them focuses the development of an enabling process. This
presentation provides a case study on optimization of a complex, fit-for-purpose process to enable scale-up for
an FIH delivery of a small molecule API for parenteral use. Some of the challenges and risks inherent to the process
included the use of hazardous hydrogen fluoride chemistry, unit operations such as prep-HPLC, ion-exchange, and
lyophilization, specific requirements for API material properties, and stringent bioburden and endotoxin control.
Liabilities identified included residual fluoride impacting the API stability, residual modifier from the prep-HPLC
mobile phase impacting potency, water-uptake of API due to its hygroscopicity, and variability in the counterion
content of the API. A control strategy was devised and implemented across the reaction, crude precipitation, prep-
HPLC, concentration, ion-exchange and lyophilization to address these liabilities. Lastly, a risk assessment for
bioburden and endotoxin was carried out, and specific processing requirements were outlined in order to ensure
adequate control. The identification and mitigation of major risks through targeted process development resulted
in successful scale-up production of the drug substance.