Other internal/characterization tests
In addition to the specification tests already described, there are several tests routinely performed but not included in
the specifications that are designed to gather information on the DS as the compound advances through process and analytical
development. These tests are often linked to process consistency, and in early phase development there is sometimes a temptation
to set wide limits based on limited manufacturing experience. Instead, it is recommended to gather data through internal/characterization
testing as manufacturing experience is gained. These tests may become part of the formal specifications when meaningful limits
can be introduced based on experience with the compound. These additional characterization tests are discussed below.
Potential mutagenic impurities.
Limits for mutagenic or potentially mutagenic impurities have been the subject of much discussion among the industry because
ICH is currently drafting its M7 guideline on this topic (12). While the landscape for this class of impurities continues
to evolve, the recommendation is to follow existing guidances, such as the 2007 CHMP Guideline on the Limits of Genotoxic
Impurities, until ICH M7 is finalized (13).
Inorganic impurities are typically monitored via Residue on Ignition (ROI) and heavy metals tests using US Pharmacopeia (USP) General Chapters <281> and <231>, respectively. The recommendation for ROI in early development is an internal specification
of NMT 1.0% with the knowledge that this specification may be tightened as development progresses. The current USP heavy metals test is not typically sensitive to many of the metals used in an DS synthetic route and is also currently scheduled
to be retired in the near future. As such, residual metals are often monitored internally by inductively coupled plasma–mass
spectrometry (ICP–MS) or ICP–atomic emission spectroscopy (OES), or some other metal specific test. The recommended limits
for these metals are those set forth in EMA guidance (14). This guidance provides classifications and permitted daily exposures
(PDEs) for many of common metal catalysts and metal reagents. Limits for metals not contained within this guidance should
be discussed with the internal product development team and appropriate drug safety organization.
Water content, polymorphic forms, and particle size.
The proposed internal specifications for water, polymorphic form and particle size distribution (PSD) are all "report results"
for compounds in early development. For water content, there is normally limited information available about a compound's
sensitivity to moisture in early development. Although it is important that data be collected, initially the acceptance criteria
should be "report results" unless the product quality is known to be sensitive to water. In the case where the DS is a known
hydrate or shown to be hygroscopic, a target water content range is typically established in the DS specification.
X-ray diffraction, Raman, and solid-state NMR can be used to monitor the polymorphic form of the DS. Because the polymorphic
form can impact on solubility, stability, and bioavailability, any change in form is typically monitored during stability
Particle-size distribution (PSD) can be crucial to the ability to formulate the DS into the desired dosage form. In early
development, many of the formulations are relatively simple (e.g., powder in a bottle) and the PSD information is normally
gathered for development purposes only as an internal test. However in certain cases (e.g., low dose tablets, inhaled products),
it is worth considering a suitable PSD target which is normally set in collaboration with the formulation development group.
Other tests to consider.
Other tests may be considered as additional specification tests or non-specification tests for data collection purposes. For
example, certain physicochemical properties of the DS, such as pH of an aqueous solution, melting point/range, and refractive
index may be considered depending on the physical nature of the DS and its intended use. Similarly, there may be a need to
specify the total count of aerobic microorganisms, the total count of yeasts and molds, and the absence of specific objectionable
bacteria (e.g., Staphylococcus aureus, Escherichia coli, Salmonella, Pseudomonas aeruginosa) in the DS. If so, these should be suitably determined using pharmacopeial procedures.