Biomedical Engineering Reference
In-Depth Information
Patient
PAT
Product
Process
Systems
Facilities, etc.
QbD
Figure
13.4.
Relationships between different levels of the sequence between patient, product,
process, andmanufacturing components. PAT canbe applied to areas that donot directly impact
the process, such as environmental control.
interaction between the product, the process, and the materials from which it is made.
Screening incoming materials for identity, contaminants, and possible adulterants
ensures the integrity of the process from the outset and can now be performed at line
with hand-held monitors. Monitoring and controlling pH and conductivity eliminate
variability in raw materials or operator errors in the makeup of media and buffers.
The fitness for use of pumps and processing equipment such as columns can be assessed
through vibration monitors (on pumps) or by tracking transitional analysis (on columns).
These parameters are not always directlywithin scope for QbD although theymay enable
the final outcome of the process. Equipment automationwill be increasingly important as
higher titers will result in greater dependence on the use of concentrates in downstream
processing, requiring the use of automated in-line dilution systems.
There are several examples elsewhere in this topic for where and how design space
can be developed and PAT tools can be deployed, so we shall limit our discussion to two
unit operations, one for drug substance and another for drug product, to give an
interpretation as to how the tools can be used.
13.5.5 Drug Substance Purification
Chromatography is a critical purification tool in biotechnology. The development of a
design space for a chromatography operation is described elsewhere in this topic, so we
shall focus on implementation aspects.
Assuming that there has been an initial risk assessment of the process, and that the
basic conditions have been developed in such a way that CQA's have been identified and
their dependency on process parameters is at least partially understood, what is the role of
the manufacturing engineer in applying PAT principles to ensure the process remains
within the design space and delivers product of desired quality? What opportunities are
there for further refinement of the process and for continuous improvement through
