Question and Answer Section - February 2012

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 Why are USP Salicylic Acid Tablets RS not used for the qualification of USP Apparatus 1 and 2?
A The explanation for the removal of the requirement to use salicylic acid tablets in the performance verification test (PVT) for USP Apparatus 1 and 2 is found in the briefing of the revision to the USP General Chapter <711> Dissolution published in Pharmacopeial Forum 34 (5) (available free of charge at www.uspnf.com):"A study published on page 1120 of PF 26 (4) [July—Aug 2000] indicated that the results of performance verification using Salicylic Acid Tablets offered no unique sensitivity beyond that available from other reference materials."The USP Biopharmaceutics Expert Committee subsequently initiated investigations including laboratory studies. The committee found that the use of salicylic acid tablets did not add value beyond what was given by USP Prednisone Tablets RS. As a result, the committee decided to remove the requirement for salicylic acid tablets testing from the apparatus suitability section of the general chapter.

Q In our last performance verification test (PVT) of dissolution equipment, all the physical parameters were within the USP ranges but the equipment failed the PVT with USP Prednisone Tablets for both USP Apparatus 1 and 2. Do you have any suggestions on what could be done?
A It is advisable to treat the Prednisone Tablets RS, Lot P1 as diagnostic aids. Especially in the case of the failure to meet the criteria for both the paddles and baskets, some issues exist. The geometric mean criterion should be an indicator of systematic issues common to the entire assembly, while the %CV will indicate variation within the assembly. Follow the information on the certificate supplied with the product. Vibration and vessel condition are variables associated with Apparatus 1 and 2 that are still not well understood. Studies are ongoing to evaluate the effects of these variables on dissolution results.

Q In the preparation of the dissolution medium for the PVT of USP Apparatus 1 and 2, we did not follow the deaeration procedure recommended by USP. Instead, we heated the medium at 42 °C, filtered through a vacuum filter (100 mBar), turned off the pump, and kept the medium stirring. The acceptance criteria for the PVT were met. What impact can the pressure have in the deaeration process of the medium? What type of pump is used at USP to deaerate media, and how is the pressure measured?
A It is not clear that the medium was stirred under vacuum after filtration. Ideally, you would keep the vacuum on while stirring. What was the pressure above the stirring medium? My guess is that if you allowed the medium to stir at atmospheric pressure instead of under vacuum, you only passed the PVT by luck. Our studies have shown that the condition of the medium unfortunately affects the results adversely.

In our laboratory, we have used a water aspirator to provide the vacuum for medium preparation.

Q We are performing the Performance Verification Test (PVT) for Dissolution using the USP Prednisone Tablets Lot P11300 and Lot Q0H398. We noticed that the packaging of the newer lot (Lot Q0H398) is a blister package, and the acceptance criteria for %CV are also wider than for the previous lot.

  1. Why did USP change to blister packaging? Is blister packaging better?
  2. Why did USP widen the specification of the new lot? How does USP determine the acceptance criteria for both the CV and GM of each lot?

A USP finds that the quality of the prednisone tablets is more consistent on opening by the user when the product is individually packaged. In the past, the history of the multiple-unit package was a concern. How often was the package opened? How was the container stored? As we know that the performance of the product is affected by exposure to humidity, we wanted to seal off the individual tablets from environmental humidity. The blister pack does this.

The ranges for criteria reflect the observations of data obtained in the collaborative study for this lot. Additionally, USP makes allowance for the predicted shift in performance over the life of the lot.We continue to consider the RS material, the PVT, and the criteria to provide valuable information on the performance of the individual dissolution test assembly using USP Apparatus 1 or USP Apparatus 2. Additional information can be found in "Establishing New Acceptance Limits for Dissolution Performance Verification of USPC Apparatus 1 and 2 Using USPC Prednisone Tablets Reference Standard" by A. J. DeStefano et al. in Pharmaceutical Research 28 (3), March 2011.

Q If a sample fails Stage 1 (S1) (one unit is 50%), is there still a need to proceed to Stage 2 (S2) and Stage 3 (S3) despite the fact that the sample is not going to meet the S2 and S3 requirements of Q — 15% (minimum 60%)?
A The way the text in the USP General Chapter <711> Dissolution, under Interpretation, Immediate-release Dosage Forms, is written, it is open to interpretation. It is advisable to run all the stages to better understand the sample being analyzed. It is very difficult to evaluate the problem with few results.

Q Is there a recommended limit for %RSD for dissolution results?
A There are no limits, but steps should be taken to monitor and evaluate the standard deviation. Variability in the results can come from many sources such as the sample, the dissolution test assembly, the operator, the procedure, and the environment. Attempts should be made to minimize variability that is not sample-related in the lab and during method development. The expected precision of the method and the product can be used to set control limits that serve to indicate problems with a product.

Q Are there any requirements for time interval between the testing of Stage 1, Stage 2, and Stage 3?
A No, there are no requirements for time, but the tests should be run as soon as possible, otherwise it will hold the batch release or it will delay any decisions regarding the batch destiny or investigations.

Q How are the results for Stages 1, 2, and 3 report- ed? I understand that the results at Stage 1 should not be averaged, and all the individual results must be reported. Will the same be applicable to Stages 2 and 3? What is the ideal way of reporting the results?
A The text in Acceptance Table 1 in the USP General Chapter <711> Dissolution, under Interpretation, Immediate-release Dosage Forms, in combination with the tolerances found in the monograph, provides the acceptance criteria for a product.The reportable values are compared with the acceptance criteria (see the General Notices, sections 7.10 Interpretation of Results and 7.20 Rounding Rules). For Stage 1 dissolution testing of immediate-release products, there would be six reportable values. For Stage 2, the reportable values would be the average of 12 results and any values less than Q - 15%.

Q Stage 3 calls for 12 tablets. Does it mean that only apparatus with 12-unit test assemblies can be used? Is it acceptable to use one six-vessel apparatus and repeat the test twice? How about using two six-vessel dissolution apparatus and testing them simultaneously?
A The USP General Chapter <711> Dissolution does not specify how the stages should be run. You need to verify what is feasible in your lab (i.e., what is the most appropriate procedure considering the conditions in your lab).

Q Is it acceptable that the dissolution results exceed the assay requirements, for example, the dissolution result is 112% and the assay requirements are 90—110%?
A There are no upper limits for dissolution results. The uniformity of dose should be taken into account. It is advisable in cases like this to investigate if the dissolution method was properly validated, mainly regarding specificity, accuracy, and the filter. These three parameters have a huge impact on the dissolution results.

Q What should be done if the performance verification test (PVT) result for a particular dissolution apparatus does not conform to the acceptance criteria?
A The USP Performance Verification Test (PVT) functions as a control on the performance of test assemblies with the basket or paddle installed. The criteria for USP Prednisone Tablets RS include the geometric mean of the data and the %CV. The geometric mean controls the relative position of the results when compared with the laboratories who participated in the collaborative study. The %CV controls the variability of the data against what was observed for the participants in the collaborative study. If the test assembly as a whole is functioning suitably to allow its use in the dissolution testing of unknown samples, then it should produce results for the USP RS tablets that conform with the ranges given. If the results do not conform, then some problem exists in the apparatus, environment, or procedure. You should evaluate the apparatus, environment, and procedure to determine the cause of nonconformance. If the test assembly does not produce conforming results, it is not suitable for dissolution testing. Once the cause of nonconformance is identified and adjusted, then the PVT can be performed again, and if conforming results are obtained, the assembly can be put back in service.