Disolución Con Multivariado

Journal of Biopharmaceutical Statistics, 15: 265–278, 2005 Copyright © Taylor & Francis, Inc. ISSN: 1054-3406 print/1520-5711 online DOI: 10.1081/BIP-200049832

A MULTIVARIATE TEST FOR SIMILARITY OF TWO DISSOLUTION PROFILES
H. Saranadasa
Ortho McNeil Pharmaceutical, Inc., Raritan, New Jersey, USA

K. Krishnamoorthy
University of Louisiana at Lafayette, Lafayette, Louisiana, USA
Amultivariate test of size for assessing the similarity of two dissolution profiles is proposed. The inferential procedure is developed by using the approach for the common mean problem in a multivariate setup due to Halperin (1961). The performance of the proposed method is compared with Intersection Union Test as well as f2 criterion recommended by the FDA through a simulation study. All the methods areillustrated with real examples. Key Words: Common mean; f2 factor; Intersection Union Test; Profile similarity; Size Student’s t variable. test;

1. INTRODUCTION Dissolution testing is performed on 6 or 12 dosage units (assume tablets or capsules are the dosage form) and placing them in agitated media. The dissolution test system has six vessels, each holding a liter of media. A rotating basketor paddle is lowered to agitate the contents, after which a tablet is dropped into the vessel and dissolution samples are collected at different time points (e.g., every 15 minutes in the first hour and every 60 minutes after the first hour) and analyzed, usually via chromatography or UV spectroscopy. The response at time t is the cumulative amount (%) of drug released into the media. Thedissolution profiles for solid dosage forms are developed in connection with observations taken on tablets or capsules over time. It is the curve of the mean dissolution rate (cumulative % dissolved) over time. The pharmaceutical scientists are interested in a comparision of these profiles under different conditions related to formulation forms, lot-to-lot and brand-to-brand variation. For example, ifdissolution profile similarity is demonstrated between the prechange drug product and the postchange formulation, in vivo bioequivalence testing can be waived for most changes.
Received January 14, 2004; Accepted November 9, 2004 Address correspondence to H. Saranadasa, Pharmaceutical Sourcing Group Americas, A Division of Ortho McNeil Pharmaceutical, Inc. Johnson & Johnson Company, 1000 Route 202,P.O. Box 300, Raritan, NJ 08869-0602, USA; Fax: (908) 218-0230; E-mail: hsaranad@psgus.jnj.com 265

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It is a big advantage for the industry to avoid conducting clinical studies to demonstrate bioequivalency, and these studies are not only time-consuming but also expensive. For some drugs, bioavailability needs to be demonstrated only if the product failsto achieve adequate dissolution compared with a test standard. Also in the manufacturing phase, dissolution profile of a new lot (may be some changes with respect to chemical manufacturing and control) will be tested against the validation lots for similar dissolution profiles to ensure the compliance. Therefore, it is of great interest to the pharmaceutical scientist to compare dissolution profiles.The statistical challenge is how to define and test the two population dissolution profiles that are “similar” based on the sample dissolution data collected over time. The U.S. Food and Drug Administration (FDA) has issued several guidelines describing circumstances for which scale-up and postapproval change (SUPAC) in the components of drug product manufacturing site or the manufacturing processand equipment of formulation are acceptable. One requirement is to establish the similarity of dissolution across a suitable time interval. The U.S. FDA’s guidance for industry on dissolution testing of immediaterelease (IR) solid oral dose forms (1997), as well as SUPAC-IR (1995), SUPACMR (1997), and bioavailability and bioequivalence study guidance for oral dosage forms, describes the model...