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Questions and Answers August 2019

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 evaluate amber and colorless vessels during physical and chemical verification of the dissolution apparatus?
A Any vessel needs to be verified regardless of color. The most critical parameters for vessels are dimensions and shape.

Q When evaluating a batch of a product, it was observed at the S1 stage that this batch would not meet S2 criteria. Therefore, we are planning to skip the S2 stage and go directly to S3. However, according to the USP general chapter <711> Dissolution, the S3 stage requires an average of 24 units. Do we need to conduct testing on 12 units or 18? If testing is done on 12 units, can the average of 18 units be reported?
A To evaluate the dissolution results at the S3 stage, 24 results are needed, and the average of those 24 unit results must meet the S3 stage requirements in the acceptance table.

Q What would be the appropriate performance verification procedure when using USP apparatus 5 or 6?
A Please, refer to the USP general chapter <724> Drug release. For USP apparatus 5, the procedure for the verification of USP apparatus 2 (paddle) should be used. For USP apparatus 6, the procedure for the verification of USP apparatus 1 (basket) should be used.

Q We are developing a bilayer tablet formulation and collecting dissolution data for submission to the regulatory agency. Currently all USP acceptance tables specify to use 6 units at S1/L1 stage, an additional 6 at S2/L2 stage, and additional 12 units at S3/L3 stage. Therefore, we would like to understand the justification for the number of units, i.e., 6, 6, and 12. Similarly, we would like to understand the approach used for the acceptance criteria, i.e., number of units outside of the range.
A The acceptance tables in USP are for quality control evaluation. To support your submission, you need to have more data than stated in the acceptance tables. The number of additional units will depend on how the product behaves during dissolution profiling (variability of the results, types of batches being evaluated, disintegration behavior, etc.). In most cases, the acceptance criteria are defined using dissolution profiles from all the batches evaluated during product development, including batches that did not have good in-vivo performance. The dissolution procedure and acceptance criteria should be discriminative for the critical quality attributes of the formulation. Also, the probability of going to the second stage will be important information during negotiation with the regulatory agency over the acceptance criteria. There are several papers in the literature that discuss different approaches to evaluate the probability of going to the second stage.

Q Can USP give guidance on how to prepare the dissolution medium containing pepsin at a concentration of NLT 750,000 Units/L? USP general chapter <711> Dissolution indicates that the pepsin concentration cannot be greater than 750,000 Units/L. Is there any guidance on what a lower limit (in Units/L) would be for the test to perform as expected?
A The activity of the pepsin to be used needs to be determined by the procedure under the “Pepsin, Purified in the Reagent Specifications” section of USP-NF. Using this value, the amount of powder to be weighed can be determined. The amount of pepsin needs to be as close as possible to 750,000 Units/L. Given the trivial lower limit that no pepsin results in no activity, we do not have any data to support a lower limit for this purpose.

Q We developed a generic soft gelatin capsule product. The dissolution method was developed based on the one recommended in the US FDA Dissolution Methods database. This method has a Tier 2 pretreatment step using pepsin. During the evaluation of the dossier by a regulatory agency, we were requested to provide the discriminatory power of both methods (without and with pepsin). During the development of the product we demonstrated the discriminatory power of the test without the enzyme. However, as the enzyme is only used when there is evidence of gelatin cross-linking, we consider that it is not necessary to evaluate the discriminatory power with the enzyme in the same way without it. Would you give your opinion?
A The composition of the dissolution medium to be used in the case of evidence of cross-linking is exactly the same as the original method. The only difference is the addition of the appropriate enzyme. The role of the enzyme is to digest the cross-linked gelatin, allowing the contents of the capsule to be released into the dissolution medium. As the basic composition of both media is the same and the only role of the enzyme is to digest the cross-linked gelatin, it is our opinion that there is no need to demonstrate the discriminatory power of the dissolution test with the use of the enzyme.

Q I am currently working on the addition of surfactant to a dissolution medium, and I am looking for a justification on the level of surfactant to use. What do you recommend?
A Surfactants can be added to the dissolution medium when the drug substance(s) present in the dosage form has/ have low solubility in aqueous solvents. Before going further with your project, check with your R&D group to understand how this product is being formulated. If the formulation will have any excipients that may increase the solubility of the drug substance, then surfactants may not be necessary. If you are going to add surfactant to the dissolution medium, then you need to justify the type and amount of surfactant used. It needs to be the smallest amount that does not interfere with the discriminatory power of the test. Have a look at USP general chapter <1092> The Dissolution Procedure - Development and Validation and at the paper by Noory C, Tran N, Ouderkirk L, Shah V. Steps for development of a dissolution test for sparingly water-soluble drug products. Dissolution Technol. 2000, 7, 16. dx.doi.org/10.14227/DT070100P16.

Q The “Dissolution Toolkit Procedures for Mechanical Calibration and Performance Verification Test Apparatus 1 and Apparatus 2” (available at https://www.usp.org/resources/compendial-tools) requires that all vessels and individual parts of the stirring elements (shafts, baskets, paddles) should be uniquely identified, documented, and kept in the same position in the same test assembly for all dissolution runs. Is this procedure also required in routine analysis? Where is this approach described in USP?
A This procedure is recommended even for routine analysis because it is going to facilitate any investigations in case of abnormal results/behaviors. It is not described in USP; however, it may be part of the cGLP.

Q Are there any specific apparatus for the dissolution testing of vaginal inserts?
A No, there are no specific dissolution apparatus for vaginal inserts. Based on the shape and release mechanism of the particular insert, you are free to use any of the apparatus described in the USP general chapters <711> Dissolution or <724> Drug Release.

Q For dissolution equipment with 7 vessels, can the performance verification (PVT) be done in only one step or is it mandatory to run it in two steps? We carry out the performance evaluation of dissolution equipment every 6 months. We would like to extend this period to every year. Is this acceptable? Also, in USP general chapters <711> Dissolution and <724> Drug release, there are measurements for all parts that constitute the dissolution apparatus, but there are no recommendations on at when these measurements should be verified. Currently, we are verifying these measurements every 6 months. We would like to extent this period to every 5 years when we do the installation qualification. Any comments?
A The PVT can be performed as a two-stage or single-stage procedure. The two-stage procedure is only available for test assemblies with 6, 7, or 8 positions. The single-stage procedure is available for those with 6, 7, 8, 12, and 14 positions. For a test assembly with 7 positions, the single-stage procedure requires two runs (2 x 7). The decision on the frequency of qualification for a test assembly involves a decision on risk tolerance. The problem is that an out of range observation casts doubt on the quality of data collected for the apparatus over the preceding period. Moving from a 6-month to a 12-month interval would increase the amount of data at risk. Chapter <711> describes the dissolution apparatus used in a USP monograph dissolution test. When used for a USP dissolution test procedure, the apparatus must conform with the description in the chapter and with any specific details given in the monograph. The specified measurements that are part of the apparatus description given in <711> would be checked as part of operational qualification. USP does not separate these measurements from apparatus suitability. You can find a complete discussion of mechanical qualification and performance verification at https://www.usp.org/chemicalmedicines/pvt.