Process analytical technology (PAT) (1) is a landmark in the acceptance of process systems engineering tools in modern biopharmaceutical
and pharmaceutical manufacturing. It is often said that PAT has already matured in many other processing areas and that it
is up to industries like pharma to adopt those best-established practices. In actuality, this is not completely true. Many
chemical processes use on-line monitoring for control purposes, but the in-process control specifications (IPC) measured are
typically univariate and limited in information content about the product and process (for example, temperature or single
compositions). By contrast, the aim of PAT is to use high-level quality specifications typically obtained by multiparametric
in-situ, on-line techniques such as process spectroscopies (for example, manipulating a process based upon the entire sample
matrix spectra and not a single compound signal).
Furthermore, any PAT strategy developed for a dynamic process whose trajectory strongly depends upon the starting conditions
(for example, complex and natural raw materials, as in biofuel production) must take into account information from previous
processing stages if a precise endpoint is to be achieved consistently after processing.
Figure 1
One possible and obvious general strategy to develop PAT applications should therefore involve monitoring intensification
(that is, multiple quality specifications measured simultaneously and more frequently in all relevant processing steps); tools
to pull together the information of several processing batches (building a design space); and systems engineering tools to
analyze several runs of the entire process (thus describing the interactions between process components). We have developed
and applied such a strategy successfully in the biomanufacturing of small and large molecules for some years already (2,3)
and have tested its general value in other processes also involving natural and complex starting materials (crude oil refining,
biodiesel production, beer brewing, and so forth) (4–7).
Figure 2
Biofuels are produced in a sequence of large batch operations involving multiple phases, a biochemical reaction, and several
separation–purification steps. The final product must comply with multiple quality specifications despite the variability
in the raw materials and the complexity in the unit operations used in their processing. Overall, biofuels production is amenable
to PAT implementation in the same manner as a pharmaceutical process — given the correlation between stages and the carryover
of fingerprints — or even more so if one examines process economics and its associated logistics. In fact, a recent study
by the U.S. Department of Agriculture (8) has shown that storage tanks make up for one third of new biodiesel facility construction
costs. So streamlining raw material acceptance and final product release (shipping out) would mean that storage capacity and
its associated costs could be cut down from about a month to a few days. Also, the final product cost structure shows that
there is a strong case in favor of using PAT throughout raw materials qualification, production process monitoring and supervision,
and end-product multiparametric release (Figure 1). The logistics associated with the production of large quantities of a
commodity-type product by batch operations, with strict quality specifications, increases the need to reduce end-product variability
as well to use fast multiparametric quality control to achieve safe and fast release and reduce inventory. Once an overall
quantitative description of a process is in place, a PAT strategy for closed loop control and overall process management can
be devised based upon the elements in Figure 2, applied on a plantwide perspective.
