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Questions and Answers November 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 Can the chemical calibration of dissolution equipment be based on trend data?
A Conformance with the apparatus description and suitability are required at all times when performing a test with <711> Dissolution, apparatus 1 or 2. USP recommends that the Performance Verification Test (PVT) is performed no less than once every 6 months. Based on your analysis of risk, you may find that a shorter period is justified as necessary.

Q What is the recommend frequency to perform the Performance Verification Test (PVT) and mechanical qualification? Can we perform the two tests with different frequencies such as mechanical qualification every 6 months and PVT every 12 months?
A Conformance with the apparatus description and suitability are required at all times when performing a test with <711> Dissolution, apparatus 1 or 2. USP recommends that the Performance Verification Test (PVT) is performed no less than once every 6 months. To properly qualify the apparatus, the conformance with the apparatus description is checked at the same time. Based on your analysis of risk, you may find that a shorter period is justified as necessary.

Q In the proposal for the new USP general chapter <1711> Oral Solid Dosage Forms - Dissolution Testing, published in Pharmacopeial Forum 44(5) (available at www.usppf.com), under Granules or Pellets that Are Administered with Food or Beverages, it states that if the product has different doses according to body weight or age, then the amount of sample to be added to the dissolution equipment should correspond to the highest unit dose being administered. Since USP is talking about the highest dose, we interpret the unit dose as 1 capsule. Do we need to test the content of multiple capsules if the number of capsules being given to the patient is based on body weight or age?
A The text you are referring to applies to granules, pellets, powders, or tablets for suspensions. This text is not applicable to tablets or capsules that are ingested intact. If the dosage form is a tablet or a capsule that is ingested as an intact unit, then you should introduce just one unit to each vessel or cell. This is covered in USP general chapter <711> Dissolution. If the content of a capsule must be mixed/dispersed with any kind of beverage or soft food, then you should run the dissolution test with just the contents of the single capsule.

Q A USP monograph has the following instructions to run the dissolution test for gelatin capsules. “Perform the test using the conditions in Tier 1. In the presence of cross-linking, repeat the test with new capsules using the conditions in Tier 2 as follows. Drop a capsule in 450 mL of equilibrated Medium A, after 10 min, add 450 mL of pre-equilibrated Medium B. Continue the dissolution of an additional 20 min.” Is there any apparatus available to add the dissolution medium while stirring? We were unable to transfer the required amount of medium due to foam in the medium.
A There are no special apparatus to add the dissolution medium in the conditions described above. You can use any suitable glassware or syringe. The addition of the medium needs to be done in a controlled manner to not disturb the contents of the vessel. If the medium is foaming due to the presence of surfactants, an antifoam agent can be used. One possibility is octanol. A very small amount of antifoam, such as one drop in 10 L of medium, can be used. It is necessary to evaluate any possible interference by the antifoam agent in the quantitative procedure.

Q As per USP, we must test six tablets for dissolution or disintegration. Why only six and not more or not less?
A The number six is not a USP requirement; however, according to USP general chapters <711> and <724>, the acceptance tables are designed for three stages, starting with 6 and proceeding to a maximum of 24 units tested at the last stage.

Q What type of material can be used for the container to prepare large amounts of dissolution medium?
A The type of the material will depend on the medium composition and its compatibility with materials such stainless steel, glass, or plastic.

Q I would like to know what type of formulation can be classified under extended release? Can a USP monograph for an extended-release tablet be used to test enteric-coated tablets?
A Extended-release results from a deliberate formulation and makes the drug substance available for an extended period after administration. See the USP general chapter <1151> Pharmaceutical Dosage Forms. Neither FDA nor USP make any distinction about how the extended release is obtained. Enteric coating is not by itself considered to be extended release, it is delayed release, and the dissolution test for this type of formulation typically has a procedure with at least two stages, one acid and the other a buffer. See USP general chapter <711> Dissolution.

Q The USP general chapter <1092> The Dissolution procedure - Development and Validation states “There are many ways to challenge the sensitivity of the method. One option is to compare dissolution profiles of formulations that are intentionally manufactured with meaningful variations for the most relevant critical manufacturing variables, for example, ± 10%-20% change to the ranges of these variables.” Is this range just an example or is it a fixed value capping the change at 20%? To get a change in dissolution value with 20% change in critical variables may not be feasible for veterinary products.
A The range in <1092> is just an example. The product/process variables to be challenged are decided in a caseby-case approach. The components of the formulation and the entire manufacturing process need to be taken into consideration. The variables selected should be the ones that may have an impact in the in vivo performance of the product. The critical quality attributes of each product need to be identified. These attributes are the ones that, if they have a deviation, the in vivo response may be different. These attributes are different for each formulation. One example is the particle size range for poorly soluble drugs where micronization was used to increase the drug substance solubility.

Q We suspect to have cross-linking in the gelatin capsules we are testing for dissolution. Therefore, we will add papain to the dissolution medium. Do we need to determine the enzyme activity of this papain independently in our lab or can we use the value for the enzyme activity on the certificate of analysis of the enzyme? If we prove that we are having cross-linking by the use of enzyme, do we need to test each sample (for release and stability) using the normal medium first (without the enzyme) and then using the medium with enzyme added, or can we just add the enzyme to the medium for first attempt at dissolution? We run stability programs where we test the sample at 0 month (release), 1 month, 2 months, 6 months, etc. Typically, we do not see a cross-linking impact on dissolution until 2 months. Should we use the enzyme from 0 months onwards, or should we only use the enzyme when we begin to see the impact of crosslinking on dissolution at 2 months?
A The easiest way of evaluating the presence of crosslinking in gelatin capsules is by visual observation. The capsules swell but do not open. See pictures in the paper by Marques: "MRC - Enzymes in the dissolution testing of capsules," AAPS PharmSciTech 2014 DOI: 10.1208/s12249-014-0162-3. In order to add the enzyme, you must have evidence of the presence of cross-linking in the gelatin capsules. If the product is failing the dissolution test due to other reasons, adding the enzyme is not going to solve the issue. The enzyme used is selected taking into consideration the pH of the dissolution medium (See USP general chapter <711> Dissolution). The specification of the papain to be used in dissolution testing is in the USP monograph for papain. The measured enzyme activity depends on the method used. The activity of the papain used needs to be determined by the procedure described in the Papain monograph. You can only add the enzyme if there is evidence of the presence of cross-linking. Cross linking is an irreversible process. Therefore, once it is observed for a stability sample from a single lot, then you would expect cross-linking to be observed at later times. If you have evidence of presence of cross-linking with the 2-month samples, then you are going to add the enzyme into the medium for the 2 months samples and for all the other subsequent time points in the stability study of that lot.

Q Should the paddles be stationary when dropping a sample into the vessel?
A Yes, the paddles should not be in motion when a tablet or a capsule is introduced into the vessel to avoid having it damaged by hitting the paddle. See USP general chapter <711> Dissolution. If the dosage form is a suspension, the paddles need to be in motion during the introduction of the sample to provide a faster dispersion. See the proposal for the new USP general chapter <1711> Oral Solid Dosage Forms - Dissolution Testing, published in Pharmacopeial Forum 44(5) (available at www.usppf.com)

Q We are developing a dissolution test for a product that has a very low amount of drug substance. If we use 900 or 500 mL of medium, it is not possible to quantify the amount of drug released by HPLC. Which is the minimum volume of dissolution medium that can be used in a compendial dissolution test?
A The volume of dissolution medium is selected based on the solubility of the drug substance and on the discriminative power of the test and not on the quantitative procedure used to determine the amount of drug substance dissolved. The quantitative procedure needs to be linear and have a good accuracy and precision for the entire dissolution profile. Therefore, you need to do a search in the literature to find a quantitative method that can be used to quantify the amount of the drug substance dissolved over the entire dissolution profile.

Q We have a product in gelatin capsules in three different strengths. We are seeing cross-linking in the gelatin just for the highest strength at the second sampling point (2 months) in the stability study. Bearing in mind that there is no requirement for the use of enzyme for the two lower strengths and that there is no requirement of the use of enzyme for the release testing or for the first two sampling points in the stability study for the highest dose, do we need to revalidate the dissolution method specially for the highest dose using enzyme?
A Every time you develop a dissolution method for a product that is filled into gelatin capsule shells you always need to consider the possibility of cross-linking. Therefore, the development of any dissolution method for gelatin capsules is done with and without the enzyme. You need to have all the steps evaluated during method development (type of enzyme, how to determine its activity, how you are going to filter the samples, specificity, etc.). When you issue the final version of your dissolution method for gelatin capsules, this method needs to have the procedures with and without the enzyme well described and the analysts need to be well trained, mainly on how to detect the presence of crosslinking. See <1094> Capsules - Dissolution Testing and Related Quality Attributes and <1092> The Dissolution Procedure - Development and Validation.
To develop and validate the procedure using the enzyme you need to force the presence of cross-linking in your samples. You can do this by one of the following options: 1) exposing the gelatin capsules to formaldehyde vapor; 2) exposing the gelatin capsules to high humidity and high temperature; or 3) filling the gelatin capsules with an excipient spiked with known amounts of formaldehyde. The validation of the dissolution method is done in just one report including the method with and without the enzyme. You need to have well established (validated, written, and approved) dissolution method to be used in the absence or presence of cross-linking. So, if there is evidence of cross-linking, then the analyst knows which procedure must be followed.