Control of a system of loss-in-weight feeders for drug product continuous manufacturing

摘要

Loss-in-weight (LIW) feeders are used to dispense individual materials to the downstream unit operations in continuous drug product manufacturing processes. The purpose of this work was to identify potential material feeding failure modes and demonstrate how a ratio control loop can be used to improve performance for a system of feeders when these disturbances occur and at steady operation. Three feeding failure modes were identified and studied in detail. First, excessive mass flow variability about the setpoint was examined. Next, inaccurate feeding (e.g. consistent over- or under-feeding) relative to setpoint was investigated. Finally, special-cause transient disturbances were explored, which are often generated by hopper refills, external influences to the scale, and/or changes in material properties and flow. These feeding issues impact both the precision and accuracy of the feeding operation. Experiments were executed on a continuous direct compression process utilizing two control modes for the feeders, local (individual feeder control) and ratio (system control in addition to individual feeder control) modes. Ratio mode was proven to be more effective than local mode for feeding the unit formula to the downstream process. Both the precision and accuracy of the output from the system of feeders were improved when using ratio control. For formulas with high feeding variability for drug substances (DS) and excipients, using ratio control improved the DS concentration %RSD at the outlet of the feeders from 5.1% to 2.1% and excipient concentration %RSDs ranging from 23-4.9% to 23-2.7%. For formulas with good dispensing precision but poor accuracy, ratio control was used to demonstrate improved DS Feeding Accuracy from 97.3% to 101.0% of target. Finally, for formulas that encounter transient disturbances while running in the continuous process, ratio control mode was shown to improve both accuracy and precision during the disturbances, improving the DS concentration %RSD5 from 1.9-3.7% to 0.7-1.3% and accuracy values from 104.0-106.5% to 100.2-102.0% of target. Ratio control complements proper equipment configuration selection and individual feeder controller optimization as appropriate techniques used to implement a well performing system of feeders. (C) 2018 Elsevier B.V. All rights reserved.