eBook: Analytical Method and QC Testing Strategies for Biologics Production - 32

Exposure Based Limits for
Controlling Impurities
D.P. Elder
Introduction
Whereas, the use of medicinal products is always
a compromise between acceptable risks and likely
benefits, the same is not true for impurities.1
However,
it is widely accepted that complex, multi-stage drug
substances cannot be manufactured without the
commensurate formation of impurities or degradation
products.2
The compromise is to develop control
strategies whereby these impurities can be controlled
to appropriate safety based levels.
Impurities in New Drug Substances
and New Drug Products
(ICH Q3A/ ICH Q3B)
The international conference on harmonization
(ICH) first introduced safety based limits. ICH Q3A
summarized the types of impurities found in new drug
substances (or active pharmaceutical ingredients, APIs)
and their controls. Impurities were assessed based on
either chemistry or safety considerations.3
Impurities were additionally differentiated as " identified
and unidentified impurities " , both were incorporated
as separate specification tests onto API specifications.4
API specifications also included those unidentified
impurities that were actually present at levels greater
than the pre-defined reporting, identification and
qualification thresholds.3
Reporting thresholds are linked to analytical capability.5
Identification thresholds are where unknown
impurities require identification and qualification
thresholds " establishes the biological safety of an
individual impurity or a given impurity profile at the
level(s) specified. " 3
The derivation of both identification and qualification
threshold limits were not disclosed; apart from linkage
to the maximum daily dose of the product. For those
impurities " known to be unusually potent or to produce
toxic or unexpected pharmacological effects, the
quantitation/detection limit of the analytical procedures
should be commensurate with the level at which the
impurities should be controlled " ; and this is the origin
for the subsequent ICH M7 guidance.6
Comparable guidance was also introduced for new
drug product impurities.7
There was better delineation
of the various ICH Q3B thresholds; however, it was
never explained why the various ICH Q3B thresholds
could not be better aligned. Therefore, there is the
confusing scenario where the reporting thresholds are
either above or below 1g; whereas, the identification
thresholds are sub-divided into four (> 2 g, >10 mg -
2 g, 1 mg - 10 mg and < 1 mg); whilst, the ICH Q3B
qualification thresholds are different (> 2 g, >100 mg
- 2 g, 10 mg - 100 mg and < 10 mg).7
Additionally, the maximum daily dose (mg/day) and
the maximum strength of a product (mg) are not always
32
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