In early phase development, there is limited exposure to the clinical candidate and low numbers of individuals participate
in these early clinical studies. The risk to patient safety is relatively low compared to late stage development (7, 8). Therefore,
this IQ working group proposes controlling impurities in early stage DS at levels that are three times (3X) higher than those
defined in ICH Q3 guidelines (9, 10). As clarified in the preamble of these guidance documents, the ICH impurity guidelines
are intended for pharmaceuticals approaching the point of final commercial application submission. It is inappropriate to
apply these commercial ICH expectations during early clinical development based on the shorter duration of exposure during
these earlier clinical studies. This 3X ICH recommendation for DS impurities in early development translates to a qualification
threshold for individual impurities being three times the commercial ICH Q3A limit. Specifically, the early phase DS impurity
qualification threshold is proposed to be 0.5% or 3 mg per day intake, whichever is lower, for a maximum daily dose ≤ 2 g/day.
It is recognized that individual companies within industry may choose to apply different impurity qualification thresholds
in early development based on an assessment of safety in the context of the individual development program.
Similarly, an identification (ID) threshold of three times the ICH Q3A limit (0.3%) is proposed for unknown impurities that
have not been qualified by toxicology studies. This ID threshold can be set higher for unknown impurities that have already
been qualified. It is expected that as development progresses, impurities would be assessed from a toxicological perspective,
appropriately qualified as necessary, and the relevant specifications updated accordingly. Later in development (Phase 2b
and beyond), when a larger patient population is exposed to the clinical candidate for longer durations of time, the DS specifications
for unqualified impurities should be narrowed to approach the limits outlined in the commercial ICH guidelines. Table II provides examples of various impurity scenarios to illustrate the utilization of the proposed early clinical identification
and qualification thresholds and their potential impact on the acceptability of several example DS lots. All of the included
examples assume a maximum daily dose of < 2 g/day and that the individual impurities are nongenotoxic.
Table II: Example of drug substance (DS) impurity scenario data in early development.1
For individual impurities that exceed the 0.5% threshold but are supported by toxicology data, an upper limit of not more
than (NMT) 1.0% in the DS is appropriate for this stage of development. In some situations, an upper limit greater than 1.0%
can be justified if the impurities are qualified at a higher level or if it is evident that the specific compound is also
a known metabolite. In either case, a close review of the impurity profiles is required to ensure the quality of the clinical
lot(s) is appropriate for the intended use and comparable based on projected exposure levels to the tox lot impurity profile.
This may be triggered through the use of internal targets with alerts corresponding to the identification or qualification
levels discussed above. For total impurities, the acceptance criterion often correlates with what is known about the individual
impurities. An upper limit of 3.0% for total impurities is proposed as suitable for this stage of development. However, a
higher upper limit for total impurities may be justified if there are a number of qualified impurities present in the DS.
Chiral impurities are usually held to the same criteria as any other impurity or degradation product with a known structural
identification, leading to a proposed specification of NMT 1.0%. However, the target limit for the minor enantiomer can vary
based on understanding of its pharmacological activity, toxicological qualification, metabolism pathway, and purging capabilities
of the synthetic process. Sometimes it is difficult to determine the absolute chiral purity of a DS that has multiple chiral
centers due to chromatographic separation challenges. For these molecules, specific rotation can be used to monitor the chiral
purity in early as well as late development. Another acceptable approach to controlling chiral impurities in the DS is to
monitor the chiral purity of the starting material or at an intermediate stage, where the corresponding isomers can be readily
prepared and chiral chromatographic methods developed.
The early development specifications for residual-solvent control are often set using the ICH established limits, including
the consideration of maximum daily dose for Class 2 solvents (Option 2) (11). If the residual-solvent levels are likely to
exceed the ICH limits, the specification limits in early development may be set higher than these ICH limits if they are realistically
based on the manufacturing process capabilities and if there is low toxicity potential (e.g., Class 3 solvents that form solvates
with the DS). In lieu of setting the standard ICH acceptance criteria, evaluation of known safety data are normally provided
and justified by the appropriate drug-safety organization. It is also common practice to only set acceptance criteria on non-Class
I solvents used in later steps of the synthetic process (e.g., final recrystallization and last synthetic steps) while assuring
all solvents are purged through internal/characterization testing of intermediates and/or final DS.