Questions and Answers May 2024

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 USP General Chapter <701> Disintegration states that “the use of disks is permitted only where specified or allowed in the monograph.” Can you elaborate on when disks can be applicable, or for which type of formulation disks shall be used?
A The use of disks needs to be defined experimentally using the samples under evaluation. Their use is defined in a case-by-case approach. Generally, disks are used for dosage forms that tend to float in the disintegration media. The disks help to ensure that the dosage form is fully submerged. Also, some disintegration test equipment utilizes a sensor mechanism to determine the end point of the test. In some cases, the function of the endpoint detection depends on the presence of the disk.

Q We are qualifying dissolution equipment with eight positions. Considering the complexity of this equipment, we have classified it as Group C according to USP General Chapter <1058> Analytical Instrument Qualification, and we are going to qualify the installation, operation, and performance. We think design qualification is not needed because we have already acquired the equipment. Is this rationale appropriate? For an equipment with eight positions, which acceptance criteria should be used, 6 or 8 positions?
A It is up to your lab to decide how to classify the equipment. The instrument should be well described, and the user should have thorough knowledge of the equipment capabilities and specifications to ensure that the instrument purchased satisfies the requirements for the intended use. Typically, the detailed design specifications are maintained by the equipment manufacturer, which may satisfy the design qualification for off-the-shelf instruments. The major aspects of operating the dissolution equipment, such as how the samples are introduced into the dissolution media; whether it is possible to stagger both sample introduction and shafts operation; if sampling is going to be manual, semi-automated, or automated; and whether there is a source of vibration near the proposed location for the equipment are the responsibility of the purchaser. The question of which qualification approach should be used is answered by considering the intended use of the equipment. If all eight positions are going to be used for sample evaluation, then all eight positions should be qualified. If only six positions are used for sample evaluation and the remaining two are used as a reservoir for pre-warmed dissolution medium, then the six positions used to evaluate samples must be qualified.

Q In USP General Chapter <711> Dissolution and in the certificate of the USP Dissolution Performance Verification Standard - Prednisone RS, it is stated that the performance verification should be carried out. Is this verification the same as the performance qualification stated in <1058> Analytical Instrument Qualification? For the periodical verification, should the same procedure be used or can a finished product be used?
A Yes, the use of the USP Dissolution Performance Verification Standard - Prednisone RS (DPVS - Prednisone) satisfies the performance qualification phase of the instrument qualification, and it should be followed for dissolution apparatus 1 and 2 equipment verifications. The DPVS - Prednisone tablet is specifically designed to be sensitive to the setup and operational variables of the dissolution equipment. In contrast, most finished products are designed to meet the specific critical quality attributes required for the performance of the product in the patient, be it animal or human. More information on how to qualify the dissolution equipment can be found at www.usp.org/small-molecules/pvt.

Q What is the appropriate technique to validate the precision for a dissolution method?
A Precision has three components: repeatability, intermediate precision, and reproducibility. Repeatability is where the standard deviation of multiple sets of samples is calculated for dissolution experiments conducted by the same analyst on the same equipment. Intermediate precision is where at least two analysts perform the dissolution experiments using samples from the same batch or lot of finished product on two different days and the results compared at each time point in the dissolution profile using an appropriate statistical tool. Reproducibility can be evaluated when the dissolution method is transferred to another lab. See more information in USP General Chapter <1092> The Dissolution Procedure - Development and Validation.

Q When a dissolution method has different timepoints, how should a verification study be carried out? In the dissolution test in the USP monograph for Tamsulosin Hydrochloride Capsules, the sampling times are 2, 3, and 8 hours. Which time point should be used to verify the method?
A First, the dissolution test for Tamsulosin Hydrochloride Capsules is formulation dependent. In the example above, where the monograph method is established and three time points are required, the method verification should be carried out at each time point. For this example, each formulation is going to have its own specific and discriminative dissolution test. Normally, the validation of any dissolution method is done considering the entire dissolution profile, not only the final acceptance criteria. When developing a new method, the dissolution method needs to be validated as soon as it is finalized and prior to the establishment of acceptance criteria.

Q If the assay specification for a particular product is 95-105% and one of the six dissolution results is 135% and the average value is 103%, what should be done? Is there an upper limit for dissolution results?
A There is no upper limit for dissolution tests. Assay and dissolution results cannot be compared, as they measure different characteristics from the same product, and the sample is prepared in a completely different manner for each of these tests. In this scenario, the parameter that is likely to be most useful is to evaluate uniformity of dosage units for the batch in question. If dissolution results above 100% are found, an investigation should be done to identify the possible reasons for high drug content in an individual tablet. If it is determined that the uniformity of dosage units meets the specifications, an investigation to determine the source of high dissolution results could in include the following. The material, construction, and pore size of the filter used to prepare the dissolution samples should be evaluated; sampling should be considered, i.e., whether it was done at the appropriate time and at the appropriate location within the vessel; and potential analytical interference from the other formulation components or possible contamination of the reagents or solutions used in the dissolution test.