title: A new definition of pharmaceutical quality: assembly of a risk simulation platform to investigate the impact of manufacturing/product variability on clinical performance.
abstract: 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.
authors.affiliation: Duquesne University Graduate School of Pharmaceutical Sciences, 410A Mellon Hall, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Short
authors.forename: Robert P
authors.initials: RP
authors.lastname: Cogdill
authors.forename: Frank
authors.initials: F
authors.lastname: D'Amico
authors.forename: James K
authors.initials: JK
authors.lastname: Drennen
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D001249:Asthma / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000592:standards; D003132:Commerce; D003257:Consumer Product Safety; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004339:Drug Compounding / Q000592:standards; D016503:Drug Delivery Systems; D004345:Drug Industry / Q000706:statistics & numerical data; D005079:Excipients; D017408:Guidelines as Topic; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method; D010349:Patient Compliance; D012306:Risk; D012995:Solubility; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000592:standards*; D013806:Theophylline / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D001993:Bronchodilator Agents; D005079:Excipients; D013607:Tablets; D013806:Theophylline