eBook: Analytical Method and QC Testing Strategies for Biologics Production - 33

the same for all treatment regimens. Amitriptyline has
a maximum therapeutic dose of 300mg per day for
inpatient use (150mg/day for outpatient use); whereas,
the highest dose strength is 150mg/tablet.8
However,
all tablet strengths (i.e. 10 mg, 25 mg, 50 mg, 75 mg,
100 mg, 150 mg/tablet) are tested and released to the
same impurity specification.
ICH Q3B reporting thresholds are reported as
percentage values and aligned with method capability;
whereas, ICH Q3B identification and qualification
thresholds are measured in either percentage or mg/
day values. Additionally, safety based impurity limits
do not reflect the duration of treatment,
resulting
in the same limits irrespective of whether the drug
is proscribed " as required " (pro ne rata (PRN)) or
" throughout life time " .
ICH Q3A3
and Q3B7 were intended for marketed
products. However, they are routinely applied during
clinical development and regulatory expectations
during this phase often surpass the actual
requirements. For example, it isn't unusual to see the
following regulatory expectations.9
For Phase I expect structure (or identifier) and origin.
For Phase II expect Limit of Detection and Quantification
and actual impurity levels to be established (aligned
with ICH Q3A, Q3B, etc.).
Unfortunately, the final synthetic route and process
of the API are rarely identified or optimized by Phase
II, and the attrition rate is still high.10
The ICH M3
regulatory guidance11 states that, " If specific studies
are warranted to qualify an impurity or degradant,
generally these studies are not warranted before Phase
3 unless there are changes that result in a significant
new impurity profile (e.g., a new synthetic pathway, a
new degradant formed by interactions between the
ICH Q3D15 provides safety based guidance on allowable
limits of residual elements within pharmaceuticals. ICH
Q3D addresses derivation and assessment of toxicity
data; establishment of a PDE for different routes of
administration, i.e. oral, inhaled and parenteral; and
introduction of a risk based approach13
for the control
Residual Solvent Impurities
(ICH Q3C)
ICH Q3C12
provides safety based guidance on
permissible limits of common residual solvents within
pharmaceuticals. ICH Q3C identifies three different
solvent classes based on toxicity; i.e. class 1 > class
2 > class 3. ICH Q3C recommends the use of less
toxic solvents (class 3) in place of toxic solvents, i.e.
substitution and avoidance of highly toxic solvents
(Class 1) unless their use is warranted via risk-based
evaluations.13
Additionally, certain solvents with
intermediate toxicity (Class 2) should also be restricted
from a patient safety perspective. Moreover, the
concept of " as low as reasonably practicable " (ALARP)
was also introduced for class 2 solvents. Indeed,
regulatory agencies will frequently use process
capability arguments to reduce residual solvent levels
below the ICH Q3C safety based limits.14
Although tolerable daily intake (TDI), acceptable
intake (AI), and acceptable daily intake (ADI) were all in
common usage at the time of the guidance; ICH Q3C12
uses permitted daily exposure (PDE) to avoid confusion.
Residual Elemental Impurities
(ICH Q3D)
components of the formulation). In these latter cases,
appropriate qualification studies can be warranted to
support Phase 2 or later stages of development "
33
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