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 do I have to test both paddle and basket if I only use the paddle in my testing?
A
The PVT is performed for each apparatus (basket or paddle) that will be used in the test assembly. The PVT is for each apparatus separately. If the test assembly uses both paddles and baskets and one apparatus fails, adjust- ments should be made to bring the apparatus into conformance. Adjusting the test assembly will affect the performance of each apparatus, and thus the complete PVT will begin again. Where only one apparatus is used in the assembly, then only the PVT for that apparatus is performed.
Q
Why are the PVT results converted to the natural logarithm? What is the difference in calculating the single-stage and the two-stage %CV and geometric mean?
A
The interpretation of the test includes the determina- tion of both the %CV and the geometric mean and comparison to the appropriate criteria. Both the %CV and the geometric mean must conform. The calculation of the geometric mean and %CV is easier to do after converting the results to the natural log scale.The choice of single- or two-stage test must be made in advance of performing the test. In the single-stage test, two runs are performed for 6-, 7-, or 8-position test assemblies. The results for the two runs are pooled, and the geometric mean and %CV calculated as in the certificate. For the two-stage test, the results for a single run are converted to the geometric mean and %CV and compared with the criteria. If the criteria are not met, an additional run is performed, the results pooled with the original results, and the combined geometric mean and %CV are calculated. The calculation of the %CV and geometric mean is the same for the single-stage test and the second stage of the two-stage procedure.
Q
I would like some background on how the acceptance tables in the USP General Chapter <711> Dissolution were established.
A
The three-tier criteria for dissolution were set early in the history of the development of the USP General Chapter <711> Dissolution. Before that, the original test was interpreted based on the number of results that were not less than the tolerance level. Even that test was performed in two stages of six samples each. If one or two of the first set of six results was above the tolerance, another set of six results was obtained and no more than
two of the twelve results could be greater than the tolerance. Subsequently, the acceptance table was introduced with the more familiar Q-value and three stages with a total of 24 units tested. The three-stage procedure, with the opportunity to stop at any stage for which the results conformed, became the standard for immediate-release solid oral dosage forms. Three-stage testing has also served as a model for performance testing of other dosage forms such as extended-release and delayed-release solid oral products and transdermal systems. The paper "Transdermal Drug Delivery Systems— Report of the PMA Committee," published in Pharm. Forum 1986, 12 (5), 1798—1807, presents the thinking of the Pharmaceutical Manufacturers Association (pre-PhRMA) on quality and performance testing for transdermal systems. The acceptance table suggested in that paper became the current table in <724> Drug Release.
Q
We are developing a unique combination medical device/drug product that is not specified in either the USP General Chapter <711> Dissolution or in <724> Drug Release. Can we use the acceptance tables in these general chapters for our product?
A
We do not have any information that these acceptance tables are appropriate for the product that you are developing. However, you can use them as a starting point to evaluate the drug-release behavior of your product. The acceptance tables have been of use for a large number of USP articles. If these tables are not suitable, you can develop acceptance criteria specific for your product. USP has several examples of monographs with specific acceptance tables, such as Mesalamine Delayed-Release Tablets; Nicotine Transdermal System, drug release test 3; Nitrofurantoin Capsules, dissolution test 2. The most complex example is the monograph for Extended Phenytoin Sodium Capsules, in which each dissolution test has its own acceptance table according to the dose. For setting dissolution and drug-release specifications,
it is useful to review the FDA Guidance for Industry
Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations, under the section Setting Dissolution Specifications. Although oriented toward oral products, the guidance speaks to general evidence-based principles that can be employed to set performance specifications. Another useful paper is "Background of the USP Policy on Modified-release Dosage Forms," published in Pharm. Forum 1984, 10 (2), 4103—4105.
Q
USP dissolution test criteria usually do not have an upper limit for immediate-release products. The permissible API content, typically 90—110%, should limit the upper amount that can be released. What is your opinion of a dissolution result of 113%?
A
Each test in a specification provides a part of the overall assessment of quality. For dissolution testing of immedi- ate-release solid oral products, the typical criteria are simply the amount dissolved at a specified time under controlled conditions. Other tests in the specification would typically provide evidence that the content of the units is within an acceptable range. Where a dissolution result is outside the range for individual unit content, several possible causes might be acting. First, the accuracy and specificity of the dissolution test procedure might be in doubt, or some component of the sample may interfere with the test procedure. Second, a single value of 113% does not provide evidence that the result of the assay would be out of range or that the content uniformity test would fail. Typically, assay values are results from the
analysis of a composite, and some variability is allowed in the content uniformity test.
Q
The disintegration test for plain, coated tablets says to apply the test for uncoated tablets. If I am working with a product that is not in USP or is in USP but the monograph does not have a disintegration test, what criteria do I use to determine if a disintegration test should be used?
A
In general, the disintegration test has been replaced by the dissolution test in USP monographs. Disintegration is typically a part of the overall dissolution process for many immediate-release tablets and capsules. Disintegration testing is often viewed as redundant from that perspective. Occasionally, the disintegration test will provide a distinct value, as is the case for orally disintegrat- ing tablets. You may want to review the FDA Guidance, Orally Disintegrating Tablets, at
UCM070578.pdf