Stability assessments of preclinical dosing formulations need to consider conditions that are representative of the formulation
process used for preparing the dose preparation. Specifically, preparations manufactured in an analytical laboratory to evaluate
method performance may not be representative of the process used in the formulation laboratory and, therefore, may not be
appropriate for use in assessing stability. Differences in scale, equipment, and mixing methods may need to be considered.
For example, heat generated from the use of high-speed mixers in a dosing batch may not have been apparent during the preparation
of a small-scale batch. As such, direct heating of the dosing batch may be required. Extended or overnight mixing times also
may be required for a dosing batch where they may not be required for a small-scale validation batch. These variables need
to be considered when establishing an appropriate stability protocol to ensure stability batches are representative of dosing
Stability data need to cover the conditions encountered during dosing in the in vivo studies. Related to dosing, physical stability becomes just as crucial as chemical stability. Questions related to maintaining
a viable suspension or homogeneous mixture during the dosing period may need to be considered and addressed. In situations
where dosing formulations have known stability issues, either chemical or physical adjustments may be needed for dosing. Conditions
such as preparing the dose formulation under yellow light, temperature control, continuous stirring, and timed dosing are
all strategies that may be used to ensure that the integrity of the dosing formulation material remains intact. For example,
a dose formulation was found to be chemically stable for 48 hours at ambient temperature and observed recoveries were near
100% of the time-zero value. An optimal dosing viscosity, however, could not be maintained at ambient temperature and the
material required heating before and during dosing. As a consequence, heating was incorporated into the original stability
Consistent with stability assessment for drug products, storage of preclinical dose formulations needs to be considered when
evaluating stability. This evaluation may range from a simple assessment of material at ambient or refrigerated conditions
or for material being used over multiple dosing days and include evaluation of freeze/thaw cycles. Extensive stability programs,
comparable to those designed for drug substances and drug products, are not required as storage and use are tightly controlled.
Stability studies on dose formulations are required to support preclinical regulated studies. While stability protocols for
preclinical dose formulations are not as comprehensive as their subsequent drug-substance and drug-product programs, the information
they provide to support an in vivo study is critical. Development of stability studies requires consideration of formulation, dosing, and storage to ensure
the stability data collected are directly relevant to the in vivo study conditions.
Amy Smith is director of analytical laboratory operations, and Melissa Whitsel is analytical manager both with MPI Research; headquarters located at 54943 North Main Street, Mattawan, MI 49071.
1. FDA, 21 CFR Part 58 Good Laboratory Practice Regulations Final Rule (Rockville, MD, 1987).
2. M.B. Whitmire, AAPS Jrnl.
12 (4), (2010).
3. ICH, Q1A(R2) Stability Testing of New Drug Substances and Products (2003).
4. ICH, Q2(R1) Validation of Analytical Procedures: Text and Methodology (1996).