eBook: Analytical Method and QC Testing Strategies for Biologics Production - 35

Impurities in Oncology Products
(ICH S9)
Oncology studies often involve cancer patients
whose prognosis is poor and projected lifetime is
short (< 2 years).22
Therefore, ICH S923
seeks to accelerate the development
of anticancer pharmaceuticals whilst protecting patient
safety. Those specific situations where requirements
may diverge from other ICH guidance are described in
ICH S9.23
Historically, limits for impurities have been predicated
on a negligible risk to the patient. In oncology
products this consideration is not as important as
patient wellbeing and higher limits for impurities
may be applicable, with supporting justifications. In
particular, stricter limits for mutagenic impurities6
are
inappropriate and higher limits can be implemented.
New Considerations
Harvey et al.24
lower, for exposure intervals of < 6 months, for general
drug substance impurities, i.e. non-mutagenic.24
Conclusion
Safety based limits for impurities, which are predicated
on daily exposure limits, rather than the more classical
percentage based limits are becoming increasingly
important in the effective reduction and control of toxic
impurities in drug products. Historically, there has been
an evolution in the approaches toward safety based
impurity control. Whereas, ICH Q3A3
and Q3B7
mainly
focused on relative levels of impurities, i.e. percentage
based limits; later guidance i.e. residual solvents,12
residual elemental impurities15
and mutagenic
impurities,6 had a greater focus on daily exposure
limits. This led to the introduction of various impurity
specific limits, such as PDEs, AIs, TTCs and staged TTCs,
all aimed at defining a virtually safe dose (VSD); which
in turn led to LTL limits for MIs.6
Surprisingly, LTLs have
demonstrated that the 1 mg/day
impurity level for an unqualified impurity of unknown
toxicity, proposed by ICH Q3A3
is indeed a VSD for nonmutagenic
impurities. Using a modified Haber's law
approach,20
they determined a VSD for shorter exposure
intervals seen in early clinical studies (< 6 months) of
5 mg/day (i.e. 5 times higher than existing ICH Q3A
limit). The authors also introduced a percentage cut
off based on 5x the ICH Q3A qualification threshold
of 0.15%; i.e. 0.7%. Thus the proposed limits for drug
substances are 5 mg or 0.7%, whichever is lower.
For drug products, similar LTL limits for non-mutagenic
impurities can be derived. The additional constraint of
0.7% need not be applied to drug products. The authors
therefore suggested a limit of 5 mg or 2%, whichever is
not been implemented for the other specific classes
of impurities or indeed general impurities. In order to
address this deficiency, Harvey et al.24
have assessed
the underpinning data behind the current " 1 mg or
1%, whichever is lower " limit in ICH Q3A3
/Q3B,7
and
they proposed an ancillary LTL for general impurities
of 5 mg or 0.7% and 5 mg or 2%, whichever is lower, for
API and drug product, respectively (for clinical studies
with durations of less than 6 months).
From a risk based perspective an overt focus
on impurity control makes little sense if the life
expectancy of the affected patient is short, i.e. less than
2 years.23
It has been reported that the LTL approach
may also be appropriate " in diseases with reduced
life expectancy, limited therapeutic alternatives or
chronic diseases with late onset. " 21
there has been little regulatory appetite for widening
Interestingly,
35
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