PROCESS DEVELOPMENT AND CLINICAL PRODUCT MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 110

TABLE 6.5 DOE Matrix for Analytical Method
Development—Column Considerations

Parameter Low Range Mid Range High Range Units

Flow rate A B C

Injection volume A B C

Temperature A B C

Height A B C

Diameter A B C

Packaging volume A B C

Five variables at two levels would result in 64 experiments just for the
column and probably not all the parameters. Some of the parameters can be
eliminated on the basis of prior knowledge of similar methods, but in order
to perform methodical development, which will allow trouble-free analytical
testing, the use of a partial factorial design is needed to select the appropriate
experiments.

6.5 PRECLINICAL STUDIES AND RISK MANAGEMENT FOR
FIRST-IN-HUMAN TRIALS

Those active in the area of clinical trials and investigational medicinal prod-
ucts will remember the phase 1 trial of TGN1412 from March 2006 that took
place at Northwick Park Hospital Research Center. Six patients, participating in
a phase 1 trial to determine the safety of the product, took the drug, while two
were given placebo. The drug initiated a life-threatening cytokine storm in all
six patients, causing horrendous side effects because of an unanticipated biolog-
ical effect. Fortunately, the research unit was adjacent to the main hospital and
all participants received first-class treatment and apparently suffered no long-
term harm. Nevertheless, regulators and industry alike had numerous questions
regarding procedures for first-in-human trials and risk management. The out-
come was a guidance document from the European Medicines Agency (EMA)
on risk management [10] or, specifically, strategies to identify and mitigate risk
for first-in-human trials. The guidance ties in with preclinical studies and prior
knowledge, in particular, requiring the sponsor to demonstrate the relevance of
the animal model.
While not directly related to the risks identified in the aforementioned trial,
from the perspective of the drug product manufacturer, one critical risk control
is to ensure the formulation and analytical methods used to determine the assay
and impurity profile of the preclinical material are comparable to those used
to manufacture products for use in humans. Without this assurance, the animal
studies may not provide an accurate picture of the toxicological profile of the
drug product.