Biomedical Engineering Reference
In-Depth Information
TABLE 6.2 Revised Hazard Analysis with Stability Data Input
Identified Risk
Item # for Revised QTPP
Control
Monitoring
Comment
1.
Moisture absorbed
by tablets—risk
eliminated by
blister pack
Eliminated
Not applicable
2.
Wrong number of
tablets
Eliminated
Not applicable
3.
Absence of
tablet/presence of
broken tablet
Vision camera
Challenge by
deliberately passing
blister with missing
or broken tablet
Part of line
clearance
procedure/set
up
analysis at an early stage followed by formal risk communication to the parallel
project groups can mitigate the possibility of misunderstandings and divergent
rather than interleaved development pathways.
As a result of miscommunication, the start of human trials might be delayed.
This, in turn, can result in financial hardships that bankrupt the company and
cause the potential therapy to be lost. Consider a preclinical study (toxicological
safety studies in animals), where there is no well-characterized reference standard
available. The drug substance assay is performed against a reference material that
is simply an early batch synthesized and put aside for this purpose. It is unlikely
that there will be any reference material for impurities available at this stage. The
major risk is of sending material for testing that is inadequately characterized
with respect to its impurity profile and inadvertently described as purer than it
really is. This could lead to subsequent production of a “dirtier” batch for first-
in-human trial, that is, one where additional impurities are identified, in which
case further toxicology studies would be needed before the human study could
proceed. However, this risk could be mitigated by a simple strategy whereby
material from the toxicology batch is placed at (
)70 C storage. The retained
material can be reanalyzed as the analytical method develops, and if it can be
shown that the “new” impurities were also present in the toxicology batch, then
the initial studies would be valid and the first-in-human trial can proceed as
planned.
To summarize, a preliminary hazard analysis identifies those risks that should
be mitigated in the early stages of product development. Identification of the
risks allows a systematic approach to risk mitigation as well as communication
of the risks to stakeholders. This approach can reduce misunderstandings and
delays that arise from less formal techniques.
Once the QTPP is established, a process flow diagram can be prepared for
drug substance, and usually a little later, for product manufacture and packaging.
The process flows will assist in performance of an initial risk assessment that
might be no more than a brainstorming session using, for example, an Ishikawa
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