Proposed drug substance specifications
The DS used in the first-in-human (FIH) enabling GLP drug safety studies, referred to in this article as the "tox batch,"
is a fundamental part of the product lifecycle in defining the specifications for an early phase clinical DS. For the DS used
in the tox batch, internal targets rather than formal specifications are routinely used while gathering knowledge about impurities,
structural identification, process purging capabilities, rework processing procedures, and potential impact to the safety
study. The DS tox batch is typically subjected to a series of tests to confirm description, identity, potency, and purity.
The main goals are to:
- Ensure that the correct DS is administered to the test animals (often done via a spectroscopic analysis such as nuclear magnetic
resonance or infrared)
- Determine the correct potency value of the DS to ensure the proper dosing of the animals
- Quantitate impurities for toxicology qualification.
For DS intended for clinical studies, additional testing and controls beyond those used for the GLP toxicology lot testing
may be required. The testing may be similar to the DS tox batch, but with established acceptance criteria. In early development,
the depth of knowledge regarding the synthetic route is still evolving and the DS has not been fully characterized. Accordingly,
the initial clinical acceptance criteria are often based on target specifications (see Table I), with the safety limits established from the tox batch being evaluated during the disposition process of the GMP clinical
DS. If the tox batch is also intended to be used in a clinical study, there is an advantage in that the qualification of impurities
for the clinical studies is inherently assured. In this case, the formal specification for clinical disposition of the DS
may be established based on the results of tox batch testing. To further highlight the differences in expectations for early
phase DS specifications, the authors propose a standardized set of clinical DS specification attributes in the following sections.
Table I: Proposed specification for clinical drug substance (DS) for use in early development.1
Description, or appearance, is a test describing the visual attributes of the DS. Although technically simple in terms of
the test, it can be the subject of much discussion due to potential discrepancies in visual observations from analyst to analyst.
Important aspects of this specification are to ensure that there is no visible contamination or anomalous appearance within
the DS. The recommended early phase acceptance criteria is often a somewhat broad range of colors (e.g., "white to almost-white
to light yellow powder") because there is typically little batch history in early development related to the color of the
DS. If it is known that the DS has an inherent color, the specification should be adjusted accordingly.
At least one form of discerning chemical identification (ID) testing is performed in the early clinical release DS specifications.
This testing ensures that the drug being dosed is traceable to the same chemical entity that was qualified in the safety studies.
A single ID test by a spectroscopic method such as IR is often employed. Often, the spectroscopic method compares the DS with
a known batch that has been well characterized by several analytical methods.
The counterion, if present, often is a relatively large percentage of the DS and as such is important to understand the overall
potency. The recommended acceptance criteria is "report results" while batch data is accumulated and the variability of the
analytical methods is assessed. If the DS is sensitive to extreme counterion levels (e.g., changes in hygroscopicity), internal
targets may be implemented to prospectively alert the internal product development team of any potential issues.
Assay is a critical DS component used to determine the accurate dosing concentration for the corresponding clinical DP. The
recommended range is 97.0% to 103.0% (wt/wt on a corrected anhydrous basis) based on typical assay variability for an HPLC-UV
method and an acceptable accuracy range required for the early phase clinical studies. This range may be modified with justification
for particular circumstances that require a wider acceptance range (e.g., elevated levels of a qualified impurity). In the
absence of a reference standard, which may be the case for the initial DS lot, the assay value may be derived by using an
assigned chemical potency factor that takes into account related substances, residual solvents, moisture, counterion, and
inorganic impurities present.
Impurities and degradation products.
Controlling organic impurities and degradation products through the DS specification is required during all stages of drug
development, except in initial microdose studies. As discussed, understanding the profile of impurities qualified in the Tox
batch is crucial to establishing acceptance criteria for impurities in early phase clinical DS. It is also important to monitor
degradation products and impurities present in the clinical DS which may not have been qualified in toxicology studies.