Knowledge Management and Process Monitoring of Pharmaceutical Processes in the Quality by Design Paradigm - Measurement, Monitoring, Modelling, and Control of Bioprocesses - page 240

processes and controls to meet product quality and to identify areas for continual
improvement.'' [ 9 ].
More recently, the newly issued Draft Guidance on Process Validation by the
US FDA makes several references to process monitoring. Some excerpts in this
regard are as follows:
1. Section 211.110(a), Sampling and testing of in-process materials and drug
products, requires that control procedures ''… be established to monitor the
output and to validate the performance of those manufacturing processes that
may be responsible for causing variability in the characteristics of in-process
material and the drug product''.
2. Special attention to control of the process through operational limits and
in-process monitoring is essential (1) where the product attribute is not readily
measurable due to limitations of sampling or detectability (e.g., viral clearance
or microbial contamination), or (2) when intermediates and products cannot be
highly characterized and well-defined quality attributes cannot be identified.
3. In most cases, process qualification (PQ) will have a higher level of sampling,
additional testing, and greater scrutiny of process performance. The level of
monitoring and testing should be sufficient to confirm uniform product quality
throughout the batch during processing. This greater scrutiny accompanied by a
higher level of sampling should continue through the process verification stage,
as appropriate.
4. We recommend continued monitoring and/or sampling at the level established
during the PQ stage until sufficient data is available to generate significant
variability estimates. Once the variability is known, sampling and/or moni-
toring should be adjusted to a statistically appropriate and representative level.
Process variability should be periodically assessed and sampling and/or mon-
itoring adjusted accordingly.
5. Maintenance of the facility, utilities, and equipment is another important aspect
of ensuring that a process remains in control. Once established, qualification
status must be maintained through routine monitoring, maintenance, and cali-
bration procedures and schedules (21 CFR part 211, subparts C and D).
6. Process flow diagrams should describe each unit operation, its placement in the
overall process, monitoring and control points, and the component, as well as
other processing material inputs (e.g., processing aids) and expected outputs
(i.e., in-process materials and finished 611 product).
It is clear from the above references that both the industry and regulators are
opting for implementation of a holistic approach where process characterization,
process validation and process monitoring are closely intertwined, being capable
of initiating one another as needed. The future of process monitoring lies in
combined use of powerful analytical tools capable of supporting real-time decision
making and sophisticated statistical tools that can analyse complex datasets in an
efficient and effective manner [ 3 ]. Several examples in the literature demonstrate
the benefits of such monitoring schemes [ 10 , 21 , 22 , 24 ].