Purpose Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. Methods Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients. Results The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher. Conclusion The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.

The new USP General Chapter <1724> Semisolid Drug Products-Performance Tests will be official in the First Supplement to USP 36 on August 1, 2013.This chapter covers the equipment (vertical diffusion cell, immersion cell, and cell for USP Apparatus 4) and the procedures that can be used to evaluate drug release from semisolid drug products such as creams, ointments, gels, and lotions.Currently, this test is not used routinely for batch release but is an important tool during product development and for post-approval changes (see FDA Guidance for Industry: Nonsterile Semisolid Dosage Forms-Scale-Up and Postapproval Changes

The selection of media in dissolution method development can sometimes be an arbitrary decision.The case studies in this article give a practical rationale that should help in selecting media, especially surfactants.Three cases were studied: (1) the role of surfactants versus compound stability in the dissolution medium during dissolution method development, (2) the selection of a surfactant based on interactions between the dissolution medium and the drug substance, and (3) the selection of media based on formulation properties.In the first case study, the choice of surfactant in relation to solubility and physical stability of the drug substance is shown.The second revealed an unexpected synergy between polysorbate 20 (Tween) and acetic acid solution that caused an unusual increase in the dissolution rate compared with these media used separately.In the last case study, the medium was modified by addition of surfactant to reflect a change in the formulation.The selection of a dissolution medium should be based on drug substance and formulation characteristics as well as on interactions among components.

Dissolution testing of dosage forms is an activity in continuous development, both for improving equipment and its performance qualification and for selecting the best test conditions. The U. S. Pharmacopeia (USP) held a workshop coordinated by some USP expert panels at its headquarters in Rockville, MD, on June 11 and 12, 2012, to present and discuss the ongoing projects related to dissolution. This paper presents a summary of the discussions held at this meeting.

On 1 March 2010, the US Pharmacopeial Convention released into commerce Lot P1I300 of its Prednisone Tablets Reference Standard for use in periodic performance verification testing (PVT) of dissolution Apparatus 1 and 2. This report presents the collaborative study data, development of the acceptance limits, and results from supporting work for this Lot.

Purpose. Beyond instrumental qualification, proficiency testing is not usually a prerequisite for many analytical procedures, given reliance on a manufacturer's assay validation coupled with regulatory review and inspection. Given the special features of the dissolution procedure, proficiency testing was put in place initially by pharmaceutical manufacturers and carried on by USP. Proficiency testing is designed to help ensure that execution of a dissolution procedure for solid oral dosage forms adequately supports administrative and legal decisions so that measurements made at different times, by different analysts, or with different methods can be confidently compared. USP has applied metrological principles to aid practitioners in carrying out the dissolution procedure alone and in collaborative studies to facilitate understanding potential sources of variability.Materials and Methods. The present study aimed to identify key dissolution variables associated with USP Lot P Prednisone Tablets in conjunction with the USP Performance Verification Test (PVT). Using five dissolution test assemblies from different manufacturers, at least four of six analysts determined percents prednisone dissolved on dissolution Apparatus 1 (basket) and Apparatus 2 (paddle) on each assembly. Six replicate experiments were performed on each analyst-assembly combination with a set of six to eight tablets in each experiment.Results and Conclusions. Statistical analysis demonstrated that dissolution test assemblies were the largest factor contributing to dissolution variability. Inherent tablet variability was low, and USP Lot P Prednisone Tablets did not contribute importantly to dissolution variability. Contributions from analyst and analytical procedure also were estimated to be low.

PURPOSE:Periodic performance verification testing (PVT) is used by laboratories to assess and demonstrate proficiency and for other purposes as well. For dissolution, the PVT is specified in the US Pharmacopeia General Chapter Dissolution <711> under the title Apparatus Suitability Test. For Apparatus 1 and 2, USP provides two reference standard tablets for this purpose. For each new lot of these reference standards, USP conducts a collaborative study. METHODS:For new USP Lot P Prednisone Tablets, 28 collaborating laboratories provided data. The study was conducted with three sets of tablets: Lot O open label, Lot O blinded, and Lot P blinded. The blinded Lot O data were used for apparatus suitability testing. RESULTS:Acceptance limits were determined after dropping data due to failure of apparatus suitability, identification of data as unusual on control charts, or protocol violations. CONCLUSIONS:Results yielded acceptance criteria of (47, 82) for Apparatus 1 and (37, 70) for Apparatus 2. Results generally were similar for Lot P compared to results from Lot O except that the average percent dissolved for Lot P is greater than for Lot O with Apparatus 2.

Pharmacopeial Forum 33(3) [May-June 2007] included a Stimuli article titled "Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing."This Stimuli article proposed changing the form of the acceptance criteria for the Performance Verification Test (PVT) associated with USP Dissolution < 711 > to make the PVT consistent with the International Organization for Standardization's recommendations for proficiency testing.The article elicited five comments, which are abstracted here with USP responses.

Dissolution testing of solid oral dosage forms plays a critical role in product development by providing a link (1) between drug release and bioavailability (BA) and bioequivalence (BE) and (2) between drug release and formulation and manufacturing process variables (1–4). The importance of dissolution in quality assurance and regulatory science is well known (5–7). In vivo–in vitro correlations and relationships (IVIVC/R) can be established when in vivo absorption is solubility- or dissolution rate-limited. A correlated dissolution test allows waiver of clinical studies for the documentation of BA, BE, and, scale-up and post-approval changes (SUPAC; 5,7). USP dissolution apparatus 1 and 2 are widely used for testing solid oral dosage forms (8). As with any analytical equipment, and perhaps particularly with dissolution assemblies, installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) are important. For a dissolution assembly, mechanical calibration provides OQ. For the assembly, analysis, and analytical procedure, the USP dissolution procedure as described in General Chapter Dissolution and other General Chapters, together with USP Prednisone Reference Standard (RS) and other Reference Standard Tablets provides PQ (9). Beyond these cGMP approaches, USP’s physical tablets support proficiency testing, thus leading to USP’s new term Performance Verification Test (PVT) for the term apparatus suitability in (10,11). USP has extensively studied the quality attributes of USP Lot P Prednisone RS Tablets and their sensitivity to selected variables of the dissolution test procedure using apparatus 1 and 2 (12–14). Some have argued that dissolution testing is specific to a particular product and thus have recommended the use of in-house standards for PQ of dissolution equipment (15,16). Some members of the scientific community are also of the opinion that USP RS Tablets contribute much of the variability observed in dissolution testing (17). The purpose of the study reported here was to determine the dissolution variability associated with selected commercial dosage forms in comparison to USP Lot P Prednisone RS Tablets. The secondary purpose was to gain data that would inform the process of choosing an RS for dissolution PQ. A product that displayed low variability (repeatability) and sensitivity to selected variables during dissolution testing would be an ideal dissolution RS. This study did not attempt to evaluate the quality of the commercial medicines for their intended therapeutic use.

The specifications and acceptable ranges for nine critical dissolution apparatus variables were examined during a perturbation study of LISP dissolution Apparatus 2 using LISP Prednisone Reference Standard (RS)Tablets. A Design of Experiment (1) approach was used to screen the nine variables to determine the contribution of each,alone and in combination, to mean percent dissolved and standard deviation results. We observed a wide range of dissolution results, including several values that fell outside of current acceptance limits,even though the variables were kept within currently acceptable ranges. When we analyzed mean percent dissolved results,we found three variables that were statistically significant: level of deaeration,vessel type, and rotation speed. When we examined standard deviation results, we found that five variables or combinations of variables were statistically significant: vessel type, level of deaeration, paddle height, paddle height-vessel type interaction, and paddle height-level of deaeration interaction. We also found that the other variables examined-temperature, shaft wobble, vessel centering, vessel tilt, and base plate levelness-were not statistically significant within the ranges explored in this study. Acceptance ranges for several assembly variables may need to be more stringent or more precisely defined in order to decrease inter-and intralaboratory variability (reproducibility and repeatability) in dissolution testing.

Introduction Used in the private or public USP Performance test, dissolution testing plays an important role in both product development and quality assurance for nonsolution oral dosage forms. The dissolution procedure itself,as described in USP General Chapter Dissolution , is sensitive and specific but requires special care in execution. Results of a recent USP collaborative study of new Lot P Prednisone Reference Standard Tablets indicate much higher reproducibility (interlaboratory variance) than repeatability (intralaboratory variance) (1,2). To improve reproducibility,the USP Biopharmaceutics Expert Committee recommends careful IQ,OQ,and PQ (mechanical calibration),as well as a Performance Verification Test (PVT); the latter two typically are performed at six-month intervals. Several variables such as shaft rotation speed,shaft and vessel alignment,basket/paddle height,and bath levelness have been cited as factors that contribute to high variability of the dissolution procedure. Missing from this list are factors relating to vessel dimension and irregularities,which are the subject of this report.

USP Dissolution specifies performance verification testing (PVT) of dissolution Apparatus 1 and 2. Acceptance criteria are determined from a collaborative study and apply per tablet; i.e., each of the six tablets tested must fall within the specified acceptance criteria in order to pass. In this Stimuli article, USP proposes changing the form of the acceptance criteria to one that is consistent with the International Organization for Standardization’s (ISO’s) recommendations for proficiency testing. The new criteria would apply to the laboratory’s average and standard deviation of the tablets tested. The article explains the rationale and shows the criteria that would be applied to USP Lot P Prednisone Reference Standard (RS) Tablets and USP Lot Q Salicylic Acid RS Tablets.

This study evaluated the sensitivity of USP Prednisone tablets (Reference Standard Lot P0E203) to dissolved gas in the medium in USP Apparatus 2. This lot will be introduced into commerce over the summer of 2006 as a replacement for current Lot O0C056. The effect of deaeration techniques and water purification methods on dissolution was also studied. Dissolution tests were performed in water containing nine different concentrations of dissolved gas. The oxygen and total dissolved gas pressure was monitored using a dissolved gas and oxygen meter. Other experimental variables such as the equipment,shaft position,and vessel position were kept constant throughout the study. The same analyst performed all studies. The study tablets were highly sensitive to dissolved gas in USP Apparatus 2. An increase in both the amount of prednisone dissolved and the variability of results was observed when the dissolved oxygen concentration exceeded 6 mg/L. The corresponding sum of the partial pressure of gases other than oxygen and the percent saturation were 510 mm Hg and 68%,respectively.

he text of the USP general test chapter <711> Dissolution requires the use of calibrator tablets as a part of the system suitability of a dissolution test apparatus.Only a suitable apparatus may be used in dissolution testing.Failures to meet the calibrator requirements not only put data obtained on the failing assembly in doubt but cost resources in failure investigation and may ultimately lead to the assembly being taken out of service.A high rate of failures perceived by users has been ascribed to the variability of the tablets.The entire dissolution community (USP staff and experts,industry and regulators) wants to ensure that dissolution calibration is a value-added activity.The USP Project Team on Dissolution Calibration was formed to initiate dialog and advance that concept.The Project Team represents PhRMA,GPhA,FDA,CVG,and dissolution apparatus manufacturers.All are recognized as stakeholders in the USP dissolution calibrator program.The Council of Experts is represented on the Project Team by Thomas Foster,chair of the Biopharmaceutics Expert Committee,and by Vivian Gray,John Mauger,and Lewis Leeson,members of the Expert Committee.The

The performance test is one of a series of tests that compose the specification in a United States Pharmacopeia (USP) dosage form monograph. For an orally administered, nonsolution dosage form, it is usually satisfied by either a dissolution or disintegration procedure. Dissolution acceptance criteria are usually set in private negotiations between an applicant and a regulatory agency. With information about this private agreement and other information provided in a sponsor's Request for Revision to USP, the USP's Council of Experts elaborates a public dosage form monograph. Based on the relationship between the regulatory decisions and the Request for Revision, the USP dissolution procedure links to a regulatory judgment about bioavailability and bioequivalence and, ultimately, to a judgment about safety and efficacy. The current dissolution procedure and acceptance criteria are perceived as having worked well over the years and are generally accepted. This article discusses new approaches that merit consideration. These approaches focus on a) explicit use of hypothesis testing, b) use of parametric tolerance intervals, c) improved ways to set dissolution acceptance criteria, and d) a more flexible protocol to assess conformity. Application of the proposed approaches may better assess, manage, and communicate both manufacturer and consumer risk for dissolution testing.

Contributors Jean-Marc Aiache, Nobuo Aoyagi, Dennis Bashaw, Cynthia Brown, William Brown, Diane Burgess, John Crison, Patrick DeLuca, Ruzica Djerki, Jennifer Dressman, Thomas Foster, Kirsti Gjellan, Vivian Gray, Ajaz Hussain, Tom Ingallinera, James Klancke, Johannes Kraemer, Henning Kristensen, Kofi Kumi, Christian Leuner, Jobst Limberg, Petra Loos, Lenny Margulis, Patrick Marroum, Helga Moeller, Bernd Mueller, Martin Mueller-Zsigmondy, Ngozi Okafo, Larry Ouderkirk, Shravan Parsi, Saeed Qureshi, Joseph Robinson, Vinod Shah, Martin Siewert, Ramana Uppoor, and Roger Williams. Aventis, Frankfurt, Germany JW Goethe University, Frankfurt, Germany Eli Lilly and Company, Indianapolis, IN Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD Universite d'Auvergne, Clermont-Ferrand Cedex, France National Institute of Health Sciences, Division of Drugs, Tokyo, Japan US Pharmacopeia, Rockville, MD University of Connecticut, Storrs Mansfield, CT Pfizer, Inc, La Jolla, CA University of Kentucky, Lexington, KY Novartis Pharma, Basel, Switzerland AstraZeneca, Sodertalje, Sweden V.A. Gray Consulting, Inc, Hockessin, DE AAI International, Charleston, SC CIMA Laboratories, Inc, Minneapolis, MN Laboratory and Quality Services, Eschborn, Germany University of Copenhagen, Denmark Bundesinstitut fur Arzneimittel, Bonn, Germany Aventis Pharmaceuticals, Bridgewater, NJ Pfizer, Groton, CT Zentrallaboratorium Deutscher Apotheker, Eschborn, Germany Kiel University, Kiel, Germany Alza Corporation, Mountain View, CA DPT Laboratories, Ltd, San Antonio, TX Health Protection Branch, Ottawa, Canada University of Wisconsin, WI