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Questions and Answers August 2016

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 We have new dissolution equipment with an autosampler that gives satisfactory results in the performance verification test (PVT) using the autosampler feature. This equipment has the option of manual sampling. We would like to know if we should do an independent PVT taking samples manually or if should do a single PVT taking concomitant samples automatically and manually and compare them?
A The PVT procedure found on the certificate for the current lot of Prednisone Tablets RS is written in the context of the apparatus description in USP General Chapter <711>. The procedure in <711> does not specify manual sampling but rather the position and timing of the sampling. The use of any sampling device and filter is subject to evaluation to determine if there is interference with the response of the analyte, typically by adsorptive loss. Manual sampling has no pump, tubing, or inline analytical measurement. From that standpoint, the PVT might be simpler to perform if the sampling is done manually. From another perspective, the individual variations from the operator are minimized when the automated system is properly calibrated and programmed for the task. In either possible approach, the object of the PVT experiment is to determine the ability of the vessel, stirring element, and mechanical support to produce samples from the standard material that conform with the expectations developed in the USP collaborative study for the current Prednisone Tablets RS. The rest of the analytical system has an important role but primarily serves to give reliable analysis of the samples. As with any analytical system, qualification is needed to demonstrate that the sample concentration is correctly determined. You may also want to review USP General Chapter <1092> The Dissolution Procedure: Development and Validation for information on automation (Section 4 of the chapter).
Each approach, manual or automated sample processing, presents some challenge, and neither should be taken without critical evaluation. One final issue that may cause a difference in the sample concentrations is the possibility of resident probes. If the automated system uses sampling probes that remain in the dissolution medium throughout the test, you may want to determine that they do not increase or decrease the dissolution results or contribute to the variability of sample concentration within a single run. As you would need to keep the probes in the vessel during the automated run, the only way to determine if there is an effect is to compare the probe-in run with results from a manual run. Analysis of variance can help with data analysis, and it is possible that more than one run will be needed for each condition. Again, this might be another indication in favor of the use of manual sampling for your PVT experiments.

Q Is it a requirement to keep vessels and stirring elements in the same position every time to considerthe apparatus to be calibrated? We found the followingstatement in the USP Dissolution Toolkit 2.0 (http://www.usp.org/sites/default/files/usp_pdf/EN/dissolutionProcedureToolkit2010-03.pdf): “Assembly&mdashAll vessels and individual parts of the stirring elements (shafts, baskets, paddles or paddle blades) should be uniquely identified, documented, and kept in the same position in the same test assembly for all dissolution runs. For ease of identification and record keeping, apparatus positions on the vessel support plate of the dissolution test assembly should be identified systematically.” However, we were not able to find any other references that require the vessels and stirring elements be kept in the same location, either in USP general chapters related to dissolution or on the FDA website.
A There is no official requirement about keeping the parts in the same position, but it is a current practice because it facilitates any investigation or evaluation of any unusual behavior or results.

Q The USP General Chapter <724> Drug Release states that to evaluate the apparatus suitability of USP Apparatus 5 (paddle over disk), the procedure for USP Apparatus 2 (paddle) should be used. According to our interpretation, we have to do the test using the disk assembly and the shaft of USP Apparatus 5. Is this interpretation correct?
A No. If you remove the disk assembly from Apparatus 5 it becomes Apparatus 2. You remove the disk assembly, adjust the height of the paddle as for Apparatus 2, and carry out the performance verification test (PVT) following the instructions for Apparatus 2.

Q Are there any requirements for the type of measuring cylinders that can be used for dissolution purposes? Can Class A or Class B plastic cylinders be used?
A See USP General Chapter <711> Dissolution, under Procedure, Apparatus 1 and 2, Immediate-Release Dosage Forms, first line in the first paragraph. The range for the measurement of the volume of dissolution medium is ±1%. You need to use a measuring container that can give you at least this range. Check the catalogs or websites of laboratory containers suppliers that have tables with the error associated with each type and size of measuring containers. It is up to you to verify if the material of construction should be plastic or glass. There are drug substances and formulations that may adsorb on glass or plastic. You need to make this selection in a case-by-case approach.

Q For a product applied to the skin, is it possible to run the drug release test at 37 °C instead of 32 °C to obtain a better release rate?
A The temperature of the dissolution or drug release test should be the temperature of the site of administration of the product. Skin temperature is 32 °C for products that will be applied dermally. If the product will have internal use, the temperature of the test should be 37 °C. Temperatures deviating from these recommendations are used only with appropriate justification. It should be demonstrated that higher temperatures do not affect the structure or the release mechanism of the dosage form.

Q We saw some advertisements for dissolution equipment that use a heating jacket instead of a water bath to maintain the dissolution medium in the vessels at the appropriate temperature. Are they in compliance with USP?
A Yes, they are in compliance with the USP General Chapter <711> Dissolution, under Apparatus, Apparatus 1 (basket apparatus), where it is stated that the vessel is partially immersed in a suitable water bath of any convenient size or heated by a suitable device, such as a heating jacket.

Q What is the appropriate temperature at which any dissolution medium should be measured by volume to fill the vessel? I think it should be measured and transferred at 20-25 °C and then equilibrated to 37 °C in the vessel and not measured and transferred to the vessels at 37 °C.
A The USP General Chapter <711> Dissolution, under Procedure, Apparatus 1 and Apparatus 2, Immediate- Release Dosage Forms, states that the volume for dissolution medium stated in monographs refers to measurements made between 20 and 25 °C. If the medium is deaerated using the procedure stated in USP, the medium will be at 41 °C at the end of the procedure and its transfer to the vessel should be done by weight.