PROCESS DEVELOPMENT AND CLINICAL PRODUCT MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 106

even ensure a margin of safety by requesting that batches which are borderline
are not supplied even if within the defined profile.
Taking another look at the diagram, it seems as if some of the points raised
during the brainstorming are not really hazards, but process control parameters.
However, this is the point of the session. Failure to identify individual process
parameters at this stage (when their criticality is often only vaguely understood)
as being potentially capable of harming a quality attribute will result in the lack
of investigation of that potential during the subsequent development process.
Should the parameter prove to be critical or necessary for process control, failure
to investigate will also result in lack of a control strategy and, ultimately, rejected
product batches.
A word of caution—risk assessment includes tools for expanding thinking
followed by focusing on the perceived risks to identify control strategies. Brain-
storming is intended to expand thinking and participants should be encouraged to
put down apparently “zany” ideas. At the time of focusing, the group will decide
together if there is a real risk behind the thought, but stifling any idea too early
can result in an incomplete or less effective assessment.
6.3 PRODUCT CONTROL STRATEGY
In the QTPP shown in Figure 6.1, the target population is immunocompromised.
The attribute of microbial limits, normally less important, becomes a critical qual-
ity attribute and the limit is considerably more stringent than for most tablets. This
is a very important point and persons involved in development and manufacturing
operations need to be made aware of this CQA in order to ensure the development
of an appropriate microbial control strategy. Making personnel aware of specific
requirements and (C)QAs and translating them into a control strategy is known as
risk communication and is one of the most neglected areas of risk management.
You may never assume that someone is aware of a specific restriction or that the
facility and processes currently in operation are sufficiently forgiving to allow for
successful manufacture of the new product. Most tablets have a microbial specifi-
cation of not more than 1000 CFU/g such that a minimally controlled production
environment, laboratory coats, hairnets, gloves, face masks, as well as routine
cleaning of equipment will suffice to ensure that finished product batches meet
specifications. For the product described in Figure 6.1, potential microbial risks
are far greater and therefore the control strategy will need to consider upgrading
the facility classification, providing additional gowning, disinfection of equip-
ment and facility (sampling, weighing, and production), more stringent microbial
control limits for starting materials, etc. In order to be sure that the controls which
are designed into the process are then functioning correctly, monitoring will be
required. The monitoring will also be designed into the process control strategy
and might include, but not necessarily be limited to, frequent microbial moni-
toring of air, surfaces, and possibly personnel (which is not usual for nonsterile
production); regular oversight (quality assurance) of disinfection procedures to