Biomedical Engineering Reference
In-Depth Information
6.6 PHASE 1 THROUGH PHASE 3 CLINICAL TRIALS
Risk management for early-stage trials tends to focus primarily on safety. At
this stage, the toxicity profile of the product may not yet be fully understood,
increasing the risks related to exposure of employees (research, manufacturing
and analytical) and of course potentially for the patient. While cleaning equip-
ment, usually the pilot plant, the inherent risks need to be considered, especially
because analytical methods may not be sufficiently developed to provide a full
impurity profile. Controls should focus on worst-case scenarios where clean-
ing is required to remove all traces down to a minimal acceptable level, often
using total organic carbon (TOC) testing and assuming that any measurement
is ascribed to the product, whereas in fact some will be because of detergent
residues or excipients.
Other factors of concern in early-phase trials could include, but are not limited
to, the following:
• level of supplier qualification for active and inactive substances;
• skills and familiarity with the process: may be the first time personnel have
produced at this scale, in which case risk mitigation might involve a “dry
run”—production of a “learning” batch that will not be used in humans;
• how to document production and how to provide written instructions;
• how much qualification of analytical methods; and
• how much stability data and determination of retest date/expiry or use by
date.
Table 6.6 shows an example of a preliminary risk assessment performed in one
company before phase 1 manufacture. At the time the company was only handling
a single API in a novel delivery platform. Since the API was well characterized,
the risks were significantly reduced as compared to a new chemical entity or
unknown molecule. Nevertheless, risk assessment is lengthy as will be the case
for any systematic assessment. This was a start-up company, so some of the
risks may be different (not necessarily greater or lesser) than for a development
department within an existing commercial company.
As can be seen in Table 6.6, a very detailed risk assessment has been con-
ducted, but without adopting a formal risk assessment tool of the type mentioned
in ICH Q9. There is no scoring system, not even low/medium/high. There is, how-
ever, an objective assessment of the risks involved, made by a multidisciplinary
team using a process flow diagram to systematically review the manufacturing
and control process for the batch to be produced for the phase 1 clinical trial.
Mitigation measures are identified and can therefore be communicated to the per-
sonnel responsible for manufacturing and controlling the batch—both as formal,
written instructions and “in frontal training” as well as “on-the job” training.
Table 6.7 shows a full FMEA table for just a few of the points in the
original table, revised for phase 3 production. In this case, the company has
introduced additional APIs so that there are new risks related to cleaning and
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