Questions and Answers February 2025

Margareth R. Marques, Ph.D. and Mark Liddell, Ph.D.
The following questions have been submitted by readers of Dissolution Technologies. Margareth R. Marques, Ph.D., and Mark Liddell, Ph.D., United States Pharmacopeia (USP), 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: mrm@usp.org

Q What is the definition of automated systems in dissolution?
A Automated systems in dissolution are considered where any of the test steps, i.e., sampling, tablet drop, filtration, etc., are performed by programable robotic or motorized equipment and not manually. Although there are fully automated dissolution systems available, in practice, most automated dissolution systems are actually semi-automated, that is, some portion of the dissolution test is performed by an analyst or technician. There are some automated systems where only the sampling (removal of the appropriate volume of the solution under test from the dissolution vessel) is done by automation. This situation is very useful when collecting dissolution profiles and when sampling is done with high frequency. There are also some automated systems where all the steps are done by programmable equipment, including introduction of the sample, sample collection, filtration, transfer to the analytical instrument to perform the quantitative determination (e.g., spectrophotometer, HPLC, etc.), calculating the percent drug release, and reporting the data. For more information see the USP general chapter <1092> The Dissolution Procedure - Development and Validation.

Q Does USP have any recommendations about how much time can pass from when the DPVS - Prednisone tablet is removed from the blister and sachet until it is placed in the vessel or basket to start the Performance Verification Test (PVT)?
A The intention of the push-through blister packaging is that the dosage form can be pushed directly through the foil backing and dropped into the vessel when using USP apparatus 2 (paddle). When using USP apparatus 1 (basket), the tablet should be placed in the basket and the dissolution test should be conducted as soon as possible to avoid contamination and adsorption of moisture.

Q Regarding the calculation tool for the Performance Verification Test (PVT), how many decimal places should be provided for the data that the user enters in the calculation tool?
A The calculation tool allows the inclusion of individual dissolution values with up to three decimal places. Data entered with more than three decimal places will be rounded using USP rounding rules. At the end of the calculation of the geometric mean (GM) and % coefficient of variation (%CV), the final result is rounded and expressed with the same number of decimal places as the acceptance criteria. Rounding data early, i.e., before the final calculation of the GM and %CV, may lead to failing results.

Q Regarding the disintegration test, is it correct to consider the average disintegration time from the six vessels?
A Although the acceptance criteria for disintegration is specific to the type of dosage form, in all cases the disintegration time specification is intended to be applied to each individual dosage unit.

Q Is it necessary to validate repeatability and intermediate precision when validating dissolution tests?
A Yes, repeatability and intermediate precision need to be validated. Both are key validation parameters needed to evaluate the precision of the dissolution method. To evaluate the repeatability, a single analyst will evaluate several replicate of the standard, spiked placebo, and/or standard addition solutions and use the data to calculate the standard deviation. For intermediate precision, one approach is to have 2 or more analysts perform the dissolution procedure and use the data to estimate the magnitude of random and controlled sources of variance. This is typically done later in the dissolution method validation after other validation parameters have been confirmed for the method in question. See USP general chapter <1092> The Dissolution Procedure - Development and Validation for more details.

Q Is it possible to validate repeatability using only the finished product, running the dissolution test with six units and only one determination per vessel?
A Yes, it is possible, but it will depend on the type of data that is being collected for the dissolution method in question. According to general chapter <1092>, the ICH guidance, “Q2(R1) Validation of Analytical Procedures: Text and Methodology,” recommends that repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure (i.e., three concentrations and three replicates of each concentration) or using a minimum of six determinations at 100% of the test concentration. Consequently, if collecting dissolution profile data, satisfying the minimum of nine determinations is fairly straightforward. If collecting single point dissolution data, you would most likely need to use infinity dissolution data and collect multiple samples from a single vessel to have a minimum of six determinations at 100% of the concentration.

Q With respect to the validation of intermediate precision in the dissolution testing of extended-release dosage forms, in describing the acceptance criterion as indicated in the USP general chapter <1092> The Dissolution Procedure - Development and Validation, it is stated: “A typical acceptance criterion for ruggedness is that the difference in the mean value for dissolution results between any two conditions, using the same dosage strength, does not exceed an absolute 10% at time points with < 85% dissolved and does not exceed 5% for time points NLT 85%. Acceptance criteria may be product specific, and other statistical tests and limits may be used.” Does the established criterion refer to the last sampling time for extended-release pharmaceutical formulations? Is it possible to demonstrate only with the last sampling time?
A Because extended-release formulations are likely to require the percent release to be evaluated at multiple time points throughout the dissolution profile, the evaluation of intermediate precision for this type of dosage form shall be performed considering the entire dissolution profile. This is a requirement because the variability may be different at each time point and tends to decrease at later times in the dissolution profile.

Q If a stability study fails to meet the tier I specification at a specified interval due to crosslinking in the gelatin capsules (e.g., at 9 months), must the remainder of the stability study (months 12-18) be conducted for tier I specifications at each timepoint? Or can a tier II analysis be performed immediately?
A USP general chapter <1094> Capsules - Dissolution Testing and Related Quality Attributes, under Dissolution Testing During Stability Studies states: “The dissolution testing during stability studies should start with the dissolution medium stated in the original method without the enzyme. When evidence of cross-linking is found, the test should be done with the addition of the appropriate enzyme to the dissolution medium. As cross-linking does not stop even if the agent causing it is removed, from this time point forward, the dissolution testing of stability samples can be carried out with the addition of the appropriate enzyme to the dissolution medium.”