It was difficult to formulate telaprevir into a medicine since its crystalline form suggests low aqueous solubility and has physicochemical characteristics that violate the majority of Lipinski's rule of five for molecules pharmaceuticals. For toxicity and examinations of the first man exposed to a lower and implicitly variable of the lower rate than anticipated, the aqueous, spray-dried, amorphous suspension was selected. As a result, it was expected that the amorphous solution would crystallize and induce a reduction in pressure when exposed. A more physical formulation that could be developed without extending the timeframe for development and was stable for toxicological stage and solid oral dosage in clinical research was desired (Kwong, et al., 2015). The formulation team adopted the multipronged approach to research an important formulation that would improve enhanced solubility and physical stability which resulted in bio-availability that was efficient for clinical and toxicology use. Screening of small scales was adopted to explore approaches of various solubility and bio-availability enhancements. The study noted that changing of amorphous of the drug substance with polymer stabilizer was the most effective approach to achieve appropriate exposure. In the bid to develop the formulation which is physically stable, multiple approaches were used in finding mechanisms of crystallization transformation and evaluation of prototype formulation physical stability. Calorimetric isothermal titration was primary in elucidating crystallization mechanisms and differentiation of roles of different surfactants and polymers in either nucleation inhibition or accelerating and growth of crystals (Kwong, et al., 2015). Based on these studies, the new formulation was chosen that had shown effective physical stability during the storage of drug products, toxicology studies on dosing suspension and physiologic fluids which are simulated.
Quality by design concept was discussed in different at different conferences of pharmaceutical across the globe. It focused on building quality through the scientific understanding of the product and process of manufacture and development. CMC Vertex development activities used the scientific approach. The outcome was the process which yielded full amorphous powered with low variability of batch-to-batch in characteristics of the powder. Since the physical stability is an identifiable amorphous product concern, further research was conducted to characterize physical relaxation, kinetics crystallization and effects of seeding on physical stability in both solid states and stimulated. They established that telaprevir commercial formulation was stable (Kwong, et al., 2015).
A mathematic model which predicted the rates of chemical degradation of the spayed dried tablet and dispersion as temperature function, excipient and moisture characteristics was developed to ensure that factors affecting the stability of chemical were controlled. The model was merged with different elements to predict the kinetic uptake of moisture in the proposed package of commercial blister o predict the stability of chemical at the intended conditions of storage during commercial packaging where the rate of moisture varied. The predictions of the model were in agreements with results of formal stability test which was conducted under harmonization format during the traditional international conference. The large volume of materials produced in support of clinical trials showed a confidence of high level that the drug substance, spray dried tablet and dispersion process of manufacturing was commercially able to produce quantities of produced important for commercialization(Kwong, et al., 2015).
The challenges of CMC for telaprevir were many. The decision of attempting quality by design compliant of application of new drug filling had the higher risk. Quality by design outlined rational scientific approach with an attempt of understanding the fundamental phenomena where possible. Flexibility was said to be primary reason as to why quality by design was used. One of the primary benefits is that it results in product improvement and understanding of process which results in products of high-quality inconsistency with the lower risk of the batch to batch failure (Kwong, et al., 2015).
Reference
Kwong, A.; Kauffman, R.; Hurter, P. and Mueller, P. (2015). Discovery and development of
telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nature Biotechnology, 29 (11): pp. 993 – 1002.
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