Formulation stage stability testing

Those stages after the preclinical discovery and evaluation that involve technical development. These processes include formulation work, stability testing, scaling-up the compound for larger-scale synthesis, and providing analytical support. Clinical trials are not included in this definition. 

There are a number of crystal aspects of the API that should be briefly examined. Knowledge of crystal habit, particle size distribution, surface area, and optical properties are important because these characteristics will affect the stability of all solid dosage forms in excipient compatibility testing (9,10). Although single crystal data may not be available at early formulation stages, predicted data may be available, based on powder x-ray diffraction (PXRD) studies, and should be considered (11). 

Reasons for chopping clinical candidates at any stage of the drug approval process included (1) stability, formulation, or other pharmaceutical development issues, (2) renal toxicity or neurotoxicity, and (3) insufficient advantage over current chugs. Since 1997, the NCI has also operated a screen for compounds active against the cytotoxic effects of HIV in CEM cells. Of 80,000 compounds tested, 4050 (or about 5%) were active. Of the compounds tested, 2291 have included metals. Of those, 136 (about 6%) were active, and two became clinical candidates. Both were chopped due to toxicity problems. One clinical candidate was a polyoxometallate, and therefore about 80 other similar molecules were tested. These were found to be strongly active in vitro, but too toxic in animal models in vivo. If a way around the toxicity problem can be found, interest in these... 

The evolution and optimisation of a formulation is an experimental stage that will be conducted on small batches of the material. For a drug with a tablet weight of 250 mg, test batches would t)rpically be 0.5-1 kg, providing up to 4000 tablets for analysis, performance testing and initial stability studies. Similar scales will be used in the optimisation of the product s packaging. 

Analytical procedures have to be developed for the active ingredient as well as for starting materials and the excipients used in the final formulation. These tests should be able to specify and confirm the identity, purity, potency, stability and consistency of these materials. If significant impurities, degradation products or critical metabolites occur, analytical methods for these will also be required. In-process control methods must be devised and developed to observe all relevant steps of the manufacturing process in order to have adequate control over the inherent variants and to detect potentially harmful contaminants at a stage where they may be easier to trace. 

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