Biomedical Engineering Reference
In-Depth Information
Full implementation of PAToccurs when product quality attributes are used directly
to make control decisions during processing. UV is widely used as a general protein
detection system, but it does not discriminate between product and nonproduct peaks.
Analytical methods need to be very rapid to cope with the flow rates used in process
chromatography. Online HPLC has been used to analyze process streams and make
decisions with respect to peak cutting, but provision has to be made to provide sufficient
lag between the sampling point and the valve for switching between collection and waste
[37]. Feed-forward control based on analysis of the sample before loading on to the
column has been proposed as a way of responding to variability of glycosyation in a
highly glycosylated product [38], see Fig. 13.7. Decisions to start and stop peak
collection are based on the most conservative conditions for product quality
(Fig. 13.7a). If peak collection decisions were instead based on a prospective analysis
of the product pool before loading on to the column, the process would deliver more
consistent product quality. A more recent proposal couples analysis of process streams
with predictive models and feed-forward control of sample collection [39]. In this
example a predictive model was developed that would determine if collection of fraction
N was appropriate based on analysis of the N-1 peak. It is worth noting that in both these
cases this strategy could introduce greater variability in yields for the step in question.
This may raise concerns at first glance for those who use yield as a measure of process
Figure
13.7.
(a) Fractionation of a highly glycosylated product by a column chromatography
step. Peak collection points are indicated by arrows and are set based on “worst-case” scenarios
(with thanks toDr Duane Bonam, Ref. [38]). (b) Fractionation of a highly glycosylated product by
a column chromatography step. Analysis of the product pool before loading gives an indication
of where the peak cut should be made to deliver consistent quality. Lower glycosylation levels
would indicate delaying the stop collection point to ensure a product pool of consistent quality
and permitting the collection of more product.
