Biomedical Engineering Reference
In-Depth Information
There are three areas in biologics process development and manufacturing that may
benefit from these techniques. First, upstream processes (cell culture and fermentation)
are demonstrating greater understanding of the nuances of media development as well as
criticality of controlling the timing of process events and parameters (and materials) as a
means of controlling process variability. Much work has been done on optimizing seed
train transfer times using in-line and online techniques to more tightly control biomass.
Second, downstream purification processes (such as chromatography and filtration) are
coupling online FIA, HPLC, and chemometrics to explore what applications are
conducive to relevant time decision making. And finally, formulation development is
using compounding and fill/finish activities, including dosage delivery systems as well as
dosage form processes such as freeze-drying, lyophilization, and crystallization, for
exploring PATapplications to help control product quality attributes such as cake structure
and uniformity, moisture, and other such attributes as excipient concentrations.
There are many challenges that exist during the course of development of these tools
that must be dealt with in the framework of implementing best manufacturing practices.
Most organizations discover that some of the tools are appropriate only in a process
development environment. Typically, tools will be used to gain further process under-
standing and thereby obviating the need to put an equivalent tool in a manufacturing
environment. Enough information about the manufacturing process will have been
gained during the process development phase to allow a simple tactical or procedural
solution to take the place of the tool. A certain subset of these tools may be used as
platforms for cross-validation of a tool that is more conducive to a manufacturing
environment.
As with any biopharmaceutical PAT applications placed in a manufacturing envi-
ronment, the key to implementation is simplicity and reproducibility. The criteria that are
of use in a manufacturing environment must be discussed and agreed upon with parties
involved in the process development, automation engineering, and manufacturing
functions. Additional negotiations will be required with personnel from quality assur-
ance, quality control, and regulatory affairs in terms of how the technology adds value to
the process and how to position the technique for regulatory inspections. Typically, this
will involve presenting the process monitoring data to regulatory agencies within the
framework of Quality by Design and protocol-driven exercises such as comparability. In
the past, this type of datawould have been deemed for information only and not presented
as part of a regulatory filing. The paradigm has shifted and this type of data form the crux
of the argument tomove closer to design space concepts and allow the freedom to operate
within a given range instead of at fixed set points. Further discussion can be found in
Chapter 13.
The end goal of any of these technologies is to control the process in either a manual
or automated fashion. Changes to manufacturing batch records may typically involve a
migration from a process control point being made on a volume or time-point basis to
decisions being made through calculated or empirically derived analytical results.
Process control will then take the form of a trained operator manual switching of a
valve or automated switching through a SCADA system in which the mechanism is
controlled via a signal when the safety margin (upper or lower warning limit) for critical
process parameter has been reached.
