Conclusions
Using on-line HPLC to monitor the eluent from process-scale chromatography columns allows a critical quality attribute (product
purity) to be measured on-line in near–real time. The product purity data generated from an on-line HPLC analyzer can be used
to automate the collection of product pools. Using the measurement of the critical quality attribute to adjust the mainstream
pool collection points allows the process to vary as needed to compensate for variability in the process scale separation.
This flexible process endpoint allows this variability to be accommodated by varying the timing of mainstream pool collection
rather than have it show up as increased variability in the mainstream pool purity.
In addition to reducing product variability, using on-line HPLC also increases product yield; enables the use of increased
levels of automation; reduces opportunities for errors; and reduces overall cycle time.
Obtaining product purity data in near–real time can enable unique approaches to product purification to be implemented. For
example, two process-purification column steps can be combined and their sequencing can be fully automated. When this combination
of column operations was carried out at Eli Lilly and Company process throughput was significantly increased, primarily as
a result of cycle time reduction, allowing the production area to increase its throughput for the process step tenfold.
Acknowledgements
The author thanks Eli Lilly and Company for allowing the use of its process example to demonstrate the value of on-line HPLC
in process scale chromatography operations.
The author would like to particularly acknowledge the invaluable contributions of several scientists, engineers, and technicians
who were involved in the development, implementation, and support of this pioneering work at Eli Lilly and Company: Charles
Stevenson, Danny Johnson, David Crozier, Richard Moss, Michael Hilgert, Robert Wilken, Jim Owens, Jerry Shrake, and Mearl
Gibson. In addition, without the challenging questions of the late Dr. Leroy Baker, the development and use of on-line HPLC
probably would not have been initiated at Eli Lilly and Company in 1980.
RICK E. COOLEY is the manager of process analytics center of excellence at Dionex Corporation, 765.349.6002, rick.cooley@dionex.com
References
1. Cooley RE. Utilizing PAT to monitor and control bulk biotech processes Presentation at University of Michigan Pharmaceutical
Engineering Seminar, 2003 Mar 4. Available from:
http://www.fda.gov/cder/OPS/cooley/index.htm
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