title: Development of performance matrix for generic product equivalence of acyclovir topical creams.
abstract: The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax®). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted. The formulations were subjected to physicochemical characterization (drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase) and in vitro drug release studies against RLD. The results demonstrated that DOE formulations were structurally and functionally (e.g., drug release) similar (Q3) to RLD. Moreover, in vitro drug permeation studies showed that extent of drug bioavailability/retention in human epidermis from F-12-F-14 were similar to RLD, although differed in rate of permeation. The results suggested generic acyclovir creams can be manufactured to obtain identical performance as that of RLD with Q1/Q2/Q3.
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yellela S R
authors.initials: YS
authors.lastname: Krishnaiah
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Usha
authors.initials: U
authors.lastname: Katragadda
authors.affiliation: Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lionberger
authors.affiliation: Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Peters
authors.affiliation: Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Uhl
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. Electronic address: mansoor.khan@fda.hhs.gov.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D000212:Acyclovir / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D000998:Antiviral Agents / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D002102:Cadaver; D055598:Chemical Phenomena; D017277:Drug Approval / Q000379:methods*; D004339:Drug Compounding; D016568:Drugs, Generic / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D004655:Emulsions; D004817:Epidermis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D010316:Particle Size; D010539:Permeability; D063465:Skin Cream / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D044366:Transition Temperature; D014481:United States; D014486:United States Food and Drug Administration; D014783:Viscosity
chemical_list: D000998:Antiviral Agents; D016568:Drugs, Generic; D004655:Emulsions; D000212:Acyclovir
keywords: Acyclovir; Process variables; Q1/Q2/Q3; Quality metrics; Sameness; Topical cream