Questions and Answers August 2020
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.
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Q There is no upper limit in the acceptance criteria for dissolution tests. Should a limit be established to help with the Out-of-Specification (OOS) investigations?
A There is no upper limit for immediate-release dissolution results. The linearity range for any dissolution test should include the upper limit of the uniformity of dose. As the uniformity of dosage units test limits are product dependent, the linearity range is also going to be product dependent. An OOS investigation will be conducted when the product does not meet all stages of the appropriate acceptance table. When this occurs the results of the uniformity of dosage units test should also be considered to determine the range allowed by of the manufacturing process. If dissolution results greater than 100% are observed, very often this is an indication that there is a problem with both the dissolution of the product as well as the uniformity of dosage units. Although it is possible that the problem could be a result of the dissolution test (filter compatibility, sampling, interference of excipients, etc.), the dissolution results should also be considered against other quality attributes of the finished dosage form.
Q In the USP general chapter Drug Release <724> there is the statement under “Apparatus suitability” that says “Proceed as directed for Apparatus 2 in Dissolution <711>, Apparatus Suitability, Performance verification test, Apparatus 1 and Apparatus 2.” Should we run the procedure with the USP Prednisone Tablets RS with the disk assembly.
A No. The performance of the USP apparatus 2 instrument should be verified using the performance verification test (PVT) for USP apparatus 2. Once the performance has been verified using the PVT procedure the test assemble can be modified for use as a USP apparatus 5 assembly.
Q How should the acceptance criteria for an immediate-release tablets be expressed? For an example, should it be “Not less than 70%(Q) in 15 minutes” or “Not less than 75% (Q + 5%) in 15 minutes”?
A Based on the information in the question, the acceptance criteria would be expressed as “Not less than 70% (Q) in 15 minutes”. When evaluating the dissolution results for an immediate-release dosage form for quality control purposes, follow the instructions associated with Acceptance Table 1 in the USP general chapter <711> Dissolution. This table has three stages and the samples need to be evaluated through all three stages unless the results conform at either S1 or S2.
Q As per USP <711>, it is not necessary to continue testing through the last stage (up to 24 units) when criteria are not met during the first stage testing, and evidence of cross-linking is observed. How do we report the results? Do we have to report the results separately for stage 1 and stage-2 using enzyme (or) average both the stage results? How is the acceptance criteria interpretation?
A For products that are susceptible to cross-linking internal discussions and procedures should be discussed before performing dissolution tests at your organization and procedures for reporting the results and observations should be in place before performing the dissolution test. Generally, when cross-linking is observed in the dissolution testing of gelatin capsules, stop the test and document the evidence of cross-linking. Since the evidence of cross-linking (e.g., pellicle formation, polymer strands, and other visual observations) has been documented and used as justification for stopping the test, there are no final dissolution results to report. Next, prepare the dissolution medium with the appropriate enzyme, and start the test with six new units and go through all the necessary stages as instructed in the INTERPRETATION section of USP <711>.
Q In the USP general chapter <711> Dissolution, under delayed-release dosage forms, it is stated that the final results should consider the amounts released in the acid and buffer stages. If the acceptance criterion is, for example, Acid stage: NMT 10% of the labelled amount of XYZ is dissolved in 2 h. Buffer stage: NLT 80% (Q) of the labelled amount of XYZ is dissolved in 45 min. Should the acceptance criteria be modified, based on the text in <711>, to Acid stage: NMT 10% of the labelled amount of XYZ is dissolved in 2 h. Buffer stage: NLT 10 % + 80% (Q) of the labelled amount of XYZ is dissolved in 45 min?
A No. The acceptance criterion remains the same. Using your example, the acceptance criteria remains as Acid stage: NMT 10% of the labelled amount of XYZ is dissolved in 2 h. [Note: the criterion for the acid stage is an upper limit and independent from the criterion for the buffer stage. If the dosage unit fails the acid stage, i.e., releases more than 10%, there is no need to continue to the buffer stage of the test.] Buffer stage: NLT 80% (Q) of the labelled amount of XYZ is dissolved in 45 min. When evaluating the sample results, you are going to add the amount released in the acid stage to the amount released in the buffer stage for each unit being evaluated. The purpose of adding the amount dissolved in the acid stage is simply to account for the entire amount released over both stages of the dissolution test.
Q We are performing the dissolution test of a transdermal system for one of our clients and we are using USP apparatus 5 (paddle over disk) for holding the transdermal patch, mesh 125 µm, which we believe to be what is used in the European Pharmacopoeia dissolution test ‘2.9.4. DISSOLUTION TEST FOR TRANSDERMAL PATCHES’. However, looking at the USP chapter <724> Drug release, under apparatus 5, it refers to a 17-mesh screen with a 90-mm diameter. Do you know if this screen is equivalent to the disk for holding transdermal patch, 125-µm mesh? Also do you know if the USP information in chapter <724> is the same/ harmonized with the information in ‘2.9.4. DISSOLUTION TEST FOR TRANSDERMAL PATCHES’ from the European Pharmacopoeia?
A The USP general chapter <724> Drug release is not harmonized with the European Pharmacopeia or the Japanese Pharmacopoeia. The text in <724> allows the use of any appropriate and validated procedure to keep the transdermal system flat when using the USP apparatus 5.
Q When evaluating the dissolution results should we consider the actual content or the theoretical content of the tablets? Also, should the real mass of the tablets also be included in the calculations?
A All the calculations in dissolution are done considering the product label claim. The exceptions are osmotic pumps and transdermal systems, where the calculations are made considering the dose released from the dosage form. The tablets weights should not be considered.
Q The FDA Dissolution Method database recommends a dissolution test for mesalamine suppositories that is run at 40 °C. What could be the reasons for using this temperature instead of 37 °C?
A One possible reason could be that, in the case of suppositories, the drug release occurs when the suppository is completely melted. The elevated temperature accelerates the melting process and ensures that the suppository is completely melted.