Question and Answer Section

William Brown and Margareth Marques
The following questions have been submitted by readers of Dissolution Technologies. Margareth Marques, Ph.D. and Will Brown, United States Phamacopeia, authored responses to each of the questions.
*Note: These are opinions and interpretations of the authors, and are not necessarily the official viewpoints of the USP
Email for correspondence: web@usp.org

Q Is it necessary to use both USP Dissolution Calibrator, Disintegrating Type,and USP Dissolution Calibrator,Nondisintegrating Type, for suitability test of dissolution equipment during performance qualification?
A The USP general chapter <711> Dissolution requires that a demonstration of apparatus suitability include the testing of the disintegrating as well as the nondisintegrating reference standards tablets for each apparatus (basket or paddle) that will be used in a USP monograph dissolution test.Use the conditions and acceptance criteria stated in the data sheet for the lot of USP Reference Standards being used,available at http://www.usp.org/referenceStandards/useAndStorage/calibrators.html.

Q How should the suitability of peak vessels be demonstrated? Can the USP Dissolution Calibrator, Disintegrating Type,and USP Dissolution Calibrator, Nondisintegrating Type,be used?
A
Peak vessels are not compendial and their use must be justified,showing an improvement over the compendial vessels.There are no data available to demonstrate the suitability of the USP dissolution calibrator tablets to evaluate the peak vessels. It is up to the user to demonstrate,by any means, the suitability of this equipment.Typical attributes will include repeatability and reproducibility of dissolution results from a well-characterized dosage form such as the USP RS tablets.

Q When using automated sampling in the dissolution test, is it appropriate to prime the filter prior to sample withdrawal? Is it necessary to pre-wet filters before sampling?
A A filter material that is immersed in the dissolution medium may still need to be conditioned to allow flow of the medium in sampling or to eliminate interference due to adsorption of the analyte.Typically,the autosampler can be programmed to send the first portion withdrawn to waste,or if sample is delivered to a UV-Vis flowcell,a lag time can be programmed so the absorption is not measured until the filter interference is overcome. If there is a problem with flow of the medium through the filter,the filter can be conditioned prior to placing it on the sampling cannula. If this is done and the filter is immersed in the medium through the test period, no flow problems due to physical interaction with the medium should be encountered.Always bear in mind the need to use the same filter type that was identified in the method development and validation.

Q Is it necessary to replace the dissolution medium withdrawn when doing dissolution profiling?
A The USP general chapter <711> Dissolution states “where multiple sampling times are specified,replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution media at 37 °C or,where it can be shown that replacement of the medium is not necessary,correct for the volume change in the calculation�.” You just need to be sure that the sink conditions are still being satisfied and that you have enough volume of medium in the vessels to have a good agitation.

Q How are the dissolution tolerances,the Q value, established for noncompendial products?
A The FDA approach is to make the Q or acceptance criteria tight enough to separate the bioequivalent lots from the bioinequivalent lots. Keep in mind that the dissolution test is considered the eventual link from commercial batches to the pivotal biobatch.The FDA does not consider going to Stage 2 and testing 6 more dosage units indicative of an unacceptable batch. In fact,they encourage the tolerances or Q value to be tight enough that going to Stage 2 around 20% of the time is not unusual.The approach of the industry,however, especially if the Quality Control or manufacturing departments are the strongest voice when setting acceptance criteria,is to choose the Q value in such a way that going to Stage 2 is unusual and normally just 6 dosage units will be tested on release testing.The data upon which the tolerances are chosen will come from all lots contained in the documentation submitted to the regulatory agency.This will typically include the relevant clinical lots,manufacturing lots,and the stability data from those lots,including those obtained from the accelerated-condition studies.The stability studies should have been done on lots packed in the final packaging configuration. One approach that could be used to evaluate the dissolution data from all these lots is to tabulate the results for all the individual dosage forms at all time points.A visual inspection of these tables can be performed to find the lowest individual dissolution values at the primary time points (usually 30 or 45 minutes). For example,if the lowest point at 30 minutes is 81% dissolved,then select a Q value that this value of 81% will pass when it is at Stage 1 (not less than or equal to Q + 5%). A Q value of 75% could be chosen, so at Stage 1 (Q + 5% = 80%),the 81% will pass.Other approaches include statistical evaluation of the data points. A visual representation of the data in the form of histograms gives a very good representation of the distribution of the data.

Q How is the volume of the dissolution medium required in a dissolution test defined?
A The volume of dissolution medium to be used is defined by the sink condition. Determine the volume of dissolution medium necessary to obtain a saturated solution of your drug considering the highest strength of your product,and try to work as far as possible from this volume. In general,the volume is three times the volume to obtain a saturated condition, but you can work with 5 times or even 10 times this volume.The volume will be product dependent.

Q Could any tablet other than the USP Reference Standard tablets be used to verify the suitability of the dissolution equipment?
A The USP calibrator tablets are especially sensitive to certain deviations in the dissolution equipment,mainly vibration and deaeration but also vessel geometry. It is not easy to determine vibration mechanically in your equipment because it should be measured where the dosage form sits during the test. In addition,USP calibrator tablets are highly characterized.These tablets are evaluated through collaborative studies with participants from all over the world. If any other tablet will be used,a demonstration of the reproducibility of its performance under controlled conditions as well as its ability to detect perturbed conditions or deviations in your dissolution system is a logical necessity.

Q When should baskets or paddles be used?
A Baskets are generally used for dosage forms that float or that stick in different regions in the dissolution vessel. It is necessary to verify that the formulation is not clogging the mesh wire.The USP general chapter <711> Dissolution calls for baskets with wire openings of 0.36�0.44 mm.Other openings could be used if properly justified and validated. If the formulation clogs the wire,paddles could be used,but sinkers will be required to keep the dosage unit in a fixed position underneath the agitation device. Paddles may be used with capsules,tablets,and suspensions.