eBook: Analytical Method and QC Testing Strategies for Biologics Production - 34

of elemental impurities. Unlike ICH Q3C,12
there is
no expectation to tighten limits based on process
capability concerns, provided that PDE values are
not exceeded. However, levels below the PDE may
be justified when existing levels negatively impact
on other critical quality attributes (CQAs) of the drug
product, e.g. metal catalyzed drug degradation.16
Residual elements are classified into 5 different
categories: class 1, 2a, 2b, 3 and others.
Although, the guidance highlights the risks inherent
from both API and particularly excipients, the reality
based on a multi-product assessment is that the risk
is low. Li et al.17
tested 190 samples from 31 different
excipients and 15 samples from 8 different APIs
and they showed relatively low levels of elemental
impurities, typically < PDE.
Residual Mutagenic Impurities
(ICH M7)
ICH M76 is focused on mutagenic impurities (MIs) that
can potentially cause cancer in man. A Threshold
of
Toxicological
Concern
(TTC)
approach was
introduced to describe an acceptable intake for any
new MI, equating to a virtually safe dose (VSD). A
default TTC value of 1.5 μg/day, which corresponds
to a theoretical 10-5
excess lifetime risk of getting
cancer was introduced for MIs. The acceptable intakes
for MIs are based on established risk assessment
approaches.13
Importantly, the acceptable risk can
be higher, i.e. 1 in 106 for early development phases.
For later stages in development and for commercial
products, the risk level is reduced to 1 in 105
* Class 1, known mutagenic carcinogens. Control
at or below compound specific acceptable limit,
i.e. AIs18
or PDEs
. New
impurities are then categorized into five different
classes in order of decreasing regulatory concern:
* Class 2, known mutagens with unknown
carcinogenic potential. Control at or below
acceptable limits, i.e. Less Than Lifetime (LTL)
or TTC
* Class 3, show alerting structures (un-related
to drug substance) with no supporting
mutagenicity data. Control at or below
acceptable limits, i.e. LTL or TTC. Or conduct
bacterial mutagenicity assay; If non-mutagenic
= Class 5, If mutagenic = Class 2
* Class 4, show alerting structures (related to (API)
which is itself non-mutagenic). Treat as nonmutagenic
impurity, i.e. use default ICH Q3A/
Q3B limits
* Class 5, show no alerting structures. Treat as
non-mutagenic impurity, i.e. use default ICH
Q3A/Q3B limits
ICH M76 proposed four control options for MIs, of
these only one includes control of the MI on the API
specification (option 1). Options 2 and 3 identify
some levels of in-process control; whereas, option 4
is focused on process understanding alone, typically
termed " Purge Arguments. " 19
These risk assessments are based on lifetime
exposures, i.e. 70 years. LTL exposure based limits
can be implemented both during development and
commercial use and still maintain comparable risk
levels using Haber's law.20
Thus for example, " if the
compound specific acceptable intake is 15 µg/day
for lifetime exposure, the less than lifetime limits can
be increased to a daily intake of 100 µg (> 1-10 years
treatment duration), 200 µg (> 1-12 months) or 1200
µg (< 1 month). " 6
ICH M7 also covers changes to marketed products,
including new marketing
approval submissions.21
applications and post34
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