The Dried Product - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 151

11.6 Estimation of Useful Shelf Life

Almost all chemical and physical rate processes or phase transitions are
accompanied by energy changes. Thermoanalytical methods are there-
fore potent tools for monitoring such events, although they cannot in
themselves provide any direct information of events at the molecular
level. Three main groups of calorimetric methods find application:
isothermal, adiabatic and temperature scanning. Under the right con-
ditions, scanning methods are economical and convenient as monitors of
overall long-term stability, and thus they find extensive application in
industry. 145
Accelerated chemical stability assays are a popular method for deter-
mining shelf lives of pharmaceutical preparations. A major advantage is
their acceptance by regulatory authorities as a valid method for the
determination of pharmaceutical stability. Samples are exposed to a
range of temperatures above the desired storage temperature, and the
stability is measured over a given length of time, in terms of the retained
biological or biochemical activity. A typical protocol may include
temperatures of -20, þ 4, þ 20, þ 37 and þ 451C and storage periods of
3 and 6 months, followed by 1, 2 and 5 years. Results are usually
extrapolated back to the recommended storage temperature, frequently
251C. An undoubted advantage is the fact that the assay can be made to
be specific for a given chemical change. On the other hand, the uncertain
extrapolation of data, taken at high temperatures, to 251C is a distinct
disadvantage and can lead to considerable uncertainties. The methods
are also time consuming and assays may well be laborious to perform. It
has been shown that even when the loss of a given protein activity
appears to exhibit Arrhenius kinetics, this may hide a combination of
individual degradation mechanisms, although giving rise to an appar-
ently simple overall inactivation profile. 176
By contrast, DSC provides a fast and economical alternative. How-
ever, because of the marginal sensitivities of some commercial instru-
ments, high temperatures and long extrapolations sometimes become
necessary. The method is also non-specific, in the sense that energy
changes, rather than chemical changes, are measured.
Quantities directly measurable by DSC are shown in Figure 9; they
include:

glass transitions and their time dependence, T g (t);
softening points, T s , the temperature at which the viscosity (me-
chanical relaxation) becomes measurable in real time (Z 10 8 D

Pa s), indicated in Figure 5;