The proposed scheme requires that the manufacturing operators be trained to interpret and act upon the data from the HPLC.
Further, since the pooling decision to end the refold is based on HPLC data, it is critical that the analytical methods have
the required robustness. It may be necessary to have redundancy (e.g., duplicate analysis) built into the control scheme to
ensure accuracy of the data. Since the aim is to achieve consistent pool purity by shifting stop collect criteria, recovery
across the chromatographic step is expected to vary from lot to lot. It is seen in Table 3 that when load purity drops from
86% to 78% and the target for pool purity is 94%, column recovery decreases from 99% to 95%.
Table 3. Estimations of recovery from the JMP model for a given load purity and to get a targeted pool purity of 94% (mAU
= milli absorbance unit).
Implementation of a PAT-based control scheme for a process chromatography step is feasible and will offer several benefits.
This would be particularly attractive when a high-performance separation is being accomplished. Then a purity-based pooling
criterion will allow for a dynamic control scheme that can yield consistent pool purity.
For the three unit operations that were examined in this article, we have shown that it is feasible to design control schemes
that rely on measuring product quality attributes. We project gains in consistency and operational efficiencies. However,
these schemes require highly trained operators to deal with complexity. There is likely to be increased variability in step
recovery, a parameter that is commonly considered as an indicator of process consistency. It is evident that adoption of control
schemes such as these presented here will require changes in our approaches toward process and analytical development, manufacturing,
quality assurance, and regulatory filings.
The authors would like to thank Duane Bonham and Duncan Low of Amgen for useful discussions.
Anurag S. Rathore, PhD, is associate director of process development at Amgen Inc., 30W-2-A; One Amgen Center Drive, Thousand Oaks, CA 91320, 805.447.4491,
fax 805.499.5008, email@example.com
Ashutosh Sharma and David Chilin are process development engineers at Amgen Inc.
Anurag Rathore is a member of the Editorial Advisory Board.