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Questions and Answers February 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 What is the appropriate way of presenting the acceptance criteria for dissolution testing, Dissolution NLT 75% (Q) or Dissolution (Q=75%) NLT 80%?
A The acceptance criteria will be Dissolution NLT 75% (Q), and all results should be evaluated using the appropriate acceptance table.

Q Is it acceptable to establish different dissolution specifications for batch release and stability studies for the same product?
A No. The acceptance criteria for dissolution is the same for the entire life cycle of the product including stability studies. The dissolution acceptance criteria are established using all dissolution profiles generated during product development, including the dissolution profiles obtained with samples under stability studies. The acceptance criteria, in most cases, represents the discriminative capability of the test.

Q During development of a new product in gelatin capsules, we observed that the dissolution results were slowing. We suspect crosslinking of the gelatin capsules. Therefore, we will add papain to the dissolution medium. Do we need to determine the enzyme activity of this enzyme independently in our lab or can we use the value of enzyme activity stated in the certificate of analysis?
A The easiest way of evaluating the presence of crosslinking in gelatin capsules is by visual observation. The capsules swell, become deformed, but do not open. To add the enzyme to the dissolution medium, you must have evidence of the presence of crosslinking of the gelatin capsules. If the product is failing dissolution testing by other reasons, adding enzyme to the dissolution medium is not going to solve the problem. The papain used in dissolution testing must comply with the USP monograph for papain. You need to verify if the activity of the papain you bought was determined using the procedure specified in the USP monograph. It is up to your lab to decide how to qualify any reagents used in your lab.

Q We run stability programs where we test the products in gelatin capsules at 0 month (release), 1 month, 2 months, 6 months, etc. Typically, we do not see crosslinking until 2 months. Should we use the enzyme from 0 months onwards even though we don’t see the presence of crosslinking until 2 months, or should we use the enzyme only when there is presence of crosslinking in the gelatin at 2 months?
A You can only add the enzyme to the dissolution medium if there is evidence of the presence of crosslinking in the gelatin. During stability studies, once you have evidence of crosslinking you can add the enzyme to the dissolution medium onwards. In your example, if there is evidence of crosslinking at 2 months, you are going to add the enzyme to the dissolution medium for samples at this time and for all subsequent times. Once the crosslinking procedure starts, it does not stop even if the crosslinking cause is removed.

Q Is it necessary to validate the dissolution procedure for products in gelatin capsules when enzymes are added to the dissolution medium, even if crosslinking is being observed only at later timepoints in stability studies?
A Every time you develop a dissolution method for a product that is filled in gelatin capsules you need to consider that crosslinking will occur. Therefore, the development and validation of any dissolution method for gelatin capsules is done with and without the enzyme. You need to have all the steps evaluated during the method development: type of enzyme to be used, how to determine its activity, how you are going to filter the samples, specificity, etc. The final version of the dissolution method for gelatin capsules needs to have the procedures with and without the enzyme well described and the analysts need to be well trained, particularly on how to detect the presence of crosslinking.
To develop and validate the procedure using the enzyme you need to force the presence of crosslinking in your samples. Crosslinking can be promoted by: exposing the capsules to formaldehyde vapor, exposing the capsules to high humidity and high temperature, or filling the capsules with an excipient spiked with known amounts of formaldehyde. More information can be found in the USP general chapters <711> Dissolution and <1094> Capsules - Dissolution Testing and Related Quality Attributes, and in the paper by Marques.
Marques MRC. Enzymes in the dissolution testing of gelatin capsules. AAPS PharmSciTech, 2014, DOI: 10.1208/s12249-014-0162-3.

Q During the dissolution testing of a particular dosage form, degradation of the drug substance was observed resulting in around 5% of a known degradation product. Can we report the sum of the remaining main component and the degradation product as the amount of drug released in the dissolution testing?
A First, verify if you can minimize the degradation by any appropriate means. If that has been done, you can express the dissolution results as a sum of the main compound and its degradation product, but you need to monitor both of them during the entire method/product development, including the samples under stability studies, to verify that the rate of degradation is more or less the same during the entire test.

Q What performance verification procedure should be used for a tester with automated sampling? USP states that “If automated equipment is used for sampling or the apparatus is otherwise modified, verification that the modified apparatus will produce results equivalent to those obtained with the standard apparatus described in this general chapter is necessary.” Does the performance verification need to be done with the USP Prednisone Tablets RS? Can a finished product be used? How can we determine that both sampling procedures are equivalent?
A Manual and automated systems should give similar results. Statistical tools are available to show equivalence of the procedures. See USP general chapter <1010> Analytical Data - Interpretation and Treatment. For the qualification of the equipment you are going to use the USP Prednisone Tablets RS. You need to validate each dissolution method with automated sampling, and you need to describe in the final version of the dissolution procedure, if needed, any cleaning, washing, rising procedures to avoid cross-contamination of the samples.

Q We are running an immediate-release tablet dissolution test with an acceptance criteria of NLT 80%(Q) in 30 min. We are obtaining results of some individual units below 50%. Looking at these values, the product will not meet the Stage 3 (S3) level on acceptance table 1 in USP <711> Dissolution. Is it mandatory to complete the testing until S3 even if it is seen in stage 1 (S1) that the sample will not meet S3 criteria?
A No, it is not mandatory to go to all the three stages if you have evidence that at S1 the sample is not going to meet the other stages criteria. The recommendation is that, before you make the decision of stopping the test, you discuss the results within your organization because it may be the case that you need to have more results to make a decision on the batch/sample disposition.

Q The USP general chapter <711> Dissolution only mentions the maximum amount of enzyme that needs to be added to the dissolution medium. The minimum amount is not mentioned. Is there such a requirement for the minimum amount of enzyme?
A No, there is no requirement for the minimum amount. The highest amount allowed as stated in <711> has been demonstrated to be suitable for use.