Drug candidates, stress testing

At the early stages of optimisation, preformulation studies are usually conducted to screen excipients or packaging materials and to select those compatible with the candidate drug, using accelerated stress testing procedures. More details about the preformulation techniques, which can be employed for compatibility studies, are discussed in Chapter 3. The importance of doing compatibility studies is for reducing the number of excipients and formulation options to test in further product optimisation studies. 

As discussed in Sect. 18.3, several models are available and can be applied with limited amounts of experimental data in combination with calculated molecular descriptors. These models are extremely valuable at the early stage of development of the API. A quick decision can be made regarding if ASD is an applicable approach for the candidate. Once this question is answered, the selection of an appropriate polymer comes in as the next step. If other additives are needed, for example, a surfactant to improve the manufacturability or to enhance the pharmacokinetic (PK) performance, the implication on system stability has to be assessed. The different formulations developed can be rank ordered based on their stability under severe temperature and humidity conditions. When the composition of the ASD is finalized, a more systematic stress test is used to understand the recrystallization risk. Though the changes in physicochemical properties by and large appear in a nonlinear fashion, the stress tests normally are sufficient to assess the risks, thus providing the formulation scientists confidence to estimate the stability of the drug product. 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bioavailable form will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed. 

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