Question and Answer Section - May 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 The certificate that accompanies the USP Prednisone Tablets RS says that if the equipment has fewer than 12 positions, Step 1 should be repeated with an additional set of tablets. If a dissolution apparatus with six or eight vessels are being evaluated, should the test be carried out with two sets of tablets?
A For test assemblies with not more than eight vessel positions, the Performance Verification Test (PVT) using USP Prednisone Tablets RS, lot Q0, can be performed as either a two-stage or a single-stage procedure. The choice of performing the single- or two-stage procedure must be made in advance of the test and will be based on the experience that the laboratory has gained on the quality of performance of the test assembly. Both procedures can use as many as 2X tablets, where X is the number of positions. For a six-position test assembly, 2X would be 12 tablets tested. The two-stage procedure allows a stop at 1X if the criteria are met. For the six-position assembly, that would be after only six tablets are tested (one tablet in each vessel). For the two-stage procedure, if the criteria after Stage 1 are not met, six additional tablets are tested. The single-stage procedure goes immediately to 2X or 12.

Q We are testing an immediate-release product with two components. At the S1 testing level, only one component satisfies the criteria. Should S2 testing be conducted for both components? What about S3? Is there any difference if both components are tested by the same procedure?
A If both components are tested by one dissolution procedure, then the procedure is repeated with the number of additional units required for the next stage (e.g., 6 for S2 and 12 for S3). You would follow the test procedure at each successive stage. For the later stages, you would only need to report the percent dissolved for the component of interest at that stage. If a different dissolution procedure is used for each component, then the testing is independent. However, the final results are linked in that the product is evaluated on the basis of all requirements.

Q I have an extended-release product that does not meet the requirements for the L1 stage of testing at only one time point. Must I repeat the test, level L2, only for the failing time point?
A For an extended-release product, each level of testing includes all time points.

Q What is the USP recommendation for the dissolution testing of implantable pellets? We have two pellet products with an expiration of approximately 4—6 months. Any insight you could provide on recommended buffers and referenced calculations would be appreciated.
A Currently, USP has one pellets monograph, Estradiol Pellets, but it does not contain a dissolution or drug release test. Quality control of drug release from implantable products designed to release over a long period of time relative to tablets or capsules presents an issue in method development. Any in vitro test would have to challenge the product in an accessible time frame, and the test conditions would have to be discriminative. The FDA has a dissolution database that may be consulted to determine if other similar products have registered a test method ( http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm).

Q We have performed the dissolution profiling of one lot of tablets from a U.S. innovator and have found that the results are borderline when compared with the USP limits. How can this product still be on the market?
A A product will be expected to meet USP standards during its shelf life on the market. However, storage and handling variables may affect the performance and quality of the product and may only represent the performance of the sample at hand. That is the reason that the labeling will advise storage conditions. From the USP General Notices, “statements about whether the compendial standard is met apply only to the units tested.” Furthermore, regulatory agencies have mechanisms through which they monitor the marketplace and work with manufacturers to ensure the quality of drug products.

Q The USP dissolution test in the potassium chloride extended-release tablets monograph said to dilute the 2-h sample so that it contains 60 μg/mL of potassium chloride. What is the actual concentration in the dissolution medium after 2 h?
A The analytical procedure requires that the sample and standard concentrations are comparable, and in the procedure that you cite, the dissolution sample is diluted to 60 μg/mL of potassium chloride prior to further manipulations. Because the concentration of the sample is the variable of interest in the performance test for the dosage form, it will not be known prior to analysis. The appropriate dilution will have to be determined by trial and error starting with what is known, label claim, and medium volume. However, as the analyst gains experience with the product performance, the appropriate dilution can be anticipated. It should be understood that the performance of the unknown sample cannot be known by USP even though the tolerances have been set.

Q During a recent dissolution run, our lab lost power. The autosampler had a UPS that allowed it to continue sampling but the paddles stopped turning. At some point, power was restored and the paddles started turning again. Can we use the results for the samples taken while the paddles were not turning? Is there a maximum time that power disruption to the baths is allowed for the tests to be valid?
A The description of Apparatus 1 and 2 as well as the procedure indicates that the apparatus is operated at the specified rate within a range of 4%. If the rotation stops, the test does not conform to the expectations.

The underpinning of the dissolution test is that solubility, medium, formulation and manufacturing variables, and agitation will affect the observed dissolution rate. With a specified dissolution test system (medium, drug solubility, and agitation), the performance of the sample should be the main variable under investigation. Where the agitation is discontinuous, the effect on the observed dissolution rate becomes an overarching concern. The samples taken while the paddles were not powered, and even those taken after power was restored, are of little value.