dx.doi.org/10.14227/DT250218P54

Questions and Answers May 2018

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 How does the Acceptance Table 1 in the USP general chapter <711> Dissolution apply when enzymes are added to the dissolution medium in the presence of cross-linking in gelatin capsules? Should only Stage 1 be used?
A If evidence for the presence of cross-linking in gelatin capsules is found during dissolution testing, then the test should be interrupted. The appropriate enzyme should be selected and added to the dissolution medium in the amounts prescribed in <711> Dissolution, and the test should be run using six new units, starting at the stage 1 and following the other stages according to the appropriate Acceptance Table.

Q When can enzymes be used in the dissolution procedure for hard gelatin capsules? Is it advisable to keep our dissolution procedure with enzymes as an alternative method from batch release? Is forced crosslinking of the gelatin capsules required before adopting the dissolution procedure with enzymes? Are regulators going to accept adopting the alternative method with enzymes without proving forced cross-linking in the gelatin capsules?
A Enzymes can be added to the dissolution medium when there is evidence of the presence of crosslinking in the gelatin capsule. See more information at http://www.dissolutiontech.com/DTresour/201411Articles/DT201411_A01.pdf and at AAPS PharmSciTech 2014, 15(6), 1410-1416. The addition of enzymes to the dissolution medium can be done at any stage in the product life time (batch release, stability studies, etc.) but only if there is evidence for the presence of cross-linking in the gelatin. If the noncompliance is due to other reasons, the addition of enzymes is not appropriate. The addition of enzymes is not considered an alternative method. It is part of your dissolution procedure and it should be employed any time there is evidence for the presence of cross-linking in the gelatin. Forced cross-linking is used during method development to select the appropriate conditions for the product being evaluated.

Q Where can the preparation of dissolution media be found in USP - NF?
A The most common solutions that can be used as dissolution media can be found in the Buffer Solutions, Test Solutions, and Volumetric Solutions sections in USP - NF. Other more specific dissolution media can be found in the individual USP monographs. The complete list of all dissolution, disintegration, and drug release methods in USP - NF, with all the test conditions including medium composition, can be found at https://www.usp.org/resources/dissolution-methods-database.

Q In USP general chapter <1092> The Dissolution Procedure: Development and Validation, under Linearity, it says that, in the preparation of the standard solutions, if more than 5% of organic solvent is used, it should be validated. What kind of validation is needed? Is it not enough to demonstrate linearity?
A The parameters to be evaluated when using more than 5% of organic solvent to prepare the standard solutions will depend on the quantitative analytical technique that is being used. The presence of organic solvent may affect the results in different ways if the quantitative procedure is ultraviolet/visible spectroscopy, HPLC, fluorescence, etc. Linearity alone may not be enough. In addition, accuracy and specificity may need to be evaluated depending on the analytical technique.

Q Under Medium USP general chapter <711> Dissolution states, “A suitable dissolution medium is used. Use the solvent specified in the individual monograph. The volume refers to measurements made between 20 °C and 25 °C.” If the deaeration procedure described in this chapter is used, should the medium be cooled down before proceeding with filling the vessels?
A No, the dissolution medium should not be cooled down after the deaeration procedure. It needs to be transferred to the dissolution equipment as soon as possible and, because it is at a temperature higher than 20 °C - 25 °C, its transference should be done by weight and not by volume. The deaerated medium needs be equilibrated to the appropriate temperature in the dissolution equipment. You can see more details at https://www.usp.org/sites/default/files/usp/document/our-work/reference-standards/dissolution-toolkit-version2.pdf.

Q Is it acceptable to use comparative dissolution profiles for different dosage forms? As an example, can the dissolution profile of a tablet be compared with a profile obtained from a capsule, or the same for capsules and suspensions?
A It depends on how the information obtained is going to be used. If this comparison is for product registration, it needs to be discussed with the regulatory agency where the product is going to be marketed. If it is simply for internal informational purposes, this type of comparison may have some value in understanding the manufacturing process or formulation behavior.

Q Can the dissolution apparatus be qualified by performing only mechanical calibration? The USP general chapter <711> Dissolution, under Apparatus Suitability, states that “the suitability for the individual apparatus is demonstrated by the Performance Verification Test,” but it does not state the frequency of this qualification.
A Information about apparatus calibration can be found in 21 CFR 211.160(b)(4). This document does not specify the frequency of apparatus calibration. USP general chapter <711> Dissolution speaks to the suitability of the apparatus used for dissolution testing according to USP monographs. USP finds the use of the performance verification test to be a necessary demonstration of the performance of the test assembly. For the purposes of <711>, conformance with the dimensional and operational specifications, however enhanced, is not sufficient. More information can be found at https://www.usp.org/sites/default/files/usp/document/our-work/referencestandards/dissolution-toolkit-version2.pdf.

Q Every 6 months we do an enhanced mechanical check of our USP apparatus 1 and 2. We received an inspection by a regulatory agency and the inspector insisted that a test with prednisone tablets is still essential. Does USP accept an enhanced mechanical check instead of the PVT?
A USP takes the position that mechanical qualification of USP Apparatus 1 and 2 is only one part of qualification of the apparatus. The USP performance verification test (PVT) provides evidence that the dissolution equipment can produce a dissolution sample that is sufficiently similar to results from the laboratories that participate in the collaborative study that is conducted to determine the ranges on the USP Prednisone Tablet Reference Standard certificate. Mechanical calibration with a successful PVT is the best demonstration that the equipment is suitable for dissolution testing.

Q Can we use the average of the dissolution results as a replacement for assay testing? If we are going to reduce testing, between dissolution and assay, which is the most critical and needs to be conducted to check the quality of the finished product?
A Dissolution and assay testing measure different characteristics of the dosage form, and the results obtained with these two tests are neither equivalent nor interchangeable. In these two tests, the sample is treated in very different manners. Both dissolution and assay testing are very critical for the quality evaluation of the product and both need to be conducted. One possible option to reduce testing is to use the average result in the Uniformity of Dose as the assay result. For USP, this approach is allowable if the analytical procedure for content uniformity is the same as for the assay. Even then, replacement must be verified in a case-by-case approach.