title: Integrating biopharmaceutics risk assessment and in vivo absorption model in formulation development of BCS class I drug using the QbD approach.
abstract: OBJECTIVE
  Clinically relevant critical quality attributes (CQA's) were identified for the development of generic drug products containing fluconazole and potential design spaces relevant to the clinical application of the drug candidate was explored.
  
  
  CONCLUSIONS
  A simplified scoring system for the biopharmaceutics risk assessment roadmap (BioRAM) is proposed to guide product development.
  
  
  METHODS
  Factorial design of experiments was employed to study the effect of formulation and process variables on CQA's. The in vivo model was developed for predicting the fraction of drug absorbed and to identify the effect of formulation components on drug absorption.
  
  
  RESULTS
  BioRAM yielded low scores for fluconazole absorption with respect to severity (risks of sub and supra-bioavailable drug products), probability of incidence of bioinequivalent results and capacity of detection. The results demonstrated that dissolution was highly influenced by the active pharmaceutical ingredient (API) polymorphism and the ratio of diluents. Process variables (mixing time, lubricant concentration, lubrication time and filling speed) did not impact the clinical outcome of the formulation with respect to dissolution and content uniformity.
  
  
  CONCLUSIONS
  Understanding the clinical implications of the adopted formulation approach led to the construction of purposeful design space and control strategy.
authors.affiliation: a Zeino Therapeutics , Khalifa Industrial Zone , Abu Dhabi , United Arab Emirates.
authors.forename: Naseem A
authors.initials: NA
authors.lastname: Charoo
authors.affiliation: b Division of Therapeutic Equivalence , Brazilian Health Surveillance Agency (ANVISA) , Brasilia , Brazil.|c Institute of Pharmaceutical Technology, Goethe University , Frankfurt am Main , Germany.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Cristofoletti
authors.affiliation: d QbD Works LLC , Fremont , CA , USA.
authors.forename: Sun K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D001702:Biopharmaceutics / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016568:Drugs, Generic / Q000737:chemistry*; D015725:Fluconazole / Q000737:chemistry*; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D018570:Risk Assessment; D012995:Solubility
chemical_list: D016568:Drugs, Generic; D015725:Fluconazole
keywords: Biopharmaceutics risk assessment; absorption models; fluconazole; formulation development; quality by design