A new definition of pharmaceutical quality: Assembly of a risk simulation platform to investigate the impact of manufacturing/product variability on clinical performance
✍ Scribed by Steven M. Short; Robert P. Cogdill; Frank D'Amico; James K. Drennen III; Carl A. Anderson
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 477 KB
- Volume
- 99
- Category
- Article
- ISSN
- 0022-3549
No coin nor oath required. For personal study only.
✦ Synopsis
The absence of a unanimous, industry-specific definition of quality is, to a certain degree, impeding the progress of ongoing efforts to "modernize" the pharmaceutical industry. This work was predicated on requests by Dr. Woodcock (FDA) to re-define pharmaceutical quality in terms of risk by linking production characteristics to clinical attributes. A risk simulation platform that integrates population statistics, drug delivery system characteristics, dosing guidelines, patient compliance estimates, production metrics, and pharmacokinetic, pharmacodynamic, and in vitro-in vivo correlation models to investigate the impact of manufacturing variability on clinical performance of a model extended-release theophylline solid oral dosage system was developed. Manufacturing was characterized by inter- and intra-batch content uniformity and dissolution variability metrics, while clinical performance was described by a probabilistic pharmacodynamic model that expressed the probability of inefficacy and toxicity as a function of plasma concentrations. Least-squares regression revealed that both patient compliance variables, percent of doses taken and dosing time variability, significantly impacted efficacy and toxicity. Additionally, intra-batch content uniformity variability elicited a significant change in risk scores for the two adverse events and, therefore, was identified as a critical quality attribute. The proposed methodology demonstrates that pharmaceutical quality can be recast to explicitly reflect clinical performance.