USP considers adherence to measurable dimensional and operational parameters to be a critical component of apparatus suitability. However, without a challenge to the apparatus demonstrating the ability to produce dissolution results from a standard material, mechanical qualification alone does not provide sufficient evidence that the apparatus is performing satisfactorily. Furthermore, the USP PVT relies on more than the reference standard material itself. The ranges for the geometric mean (GM) and the coefficient of variation (%CV) are an integral component of the PVT and are obtained from a multinational collaborative study conducted for each new lot of reference standard tablets. Those two statistics, GM and %CV, help the laboratory using the reference standard determine if their results are accurate within the context of ISO 5725-6, Accuracy (Trueness and Precision) of Measurement Methods and Results—Use in Practice of Accuracy Values. Accuracy is comprised of trueness and precision, which are embodied in the geometric mean and %CV, respectively. A discussion of these concepts can be found in an article by Walter Hauck, et al. in Pharmacopeial Forum 33(3), “Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing.”
Mechanical qualification is a procedure to control the limits for individual operational parameters of dissolution test assembly (i.e. rotation speed, temperature, etc.). The PVT using the Prednisone Tablets reference standard (RS) is a holistic test that demonstrates the operation of the entire assembly setup as it produces dissolution samples from a standardized material. Simply put, failing the PVT means that the results are different from those obtained by the labs in the collaborative study. Failing results can indicate the faulty operation of the dissolution assembly, deviation from the correct procedure, or an error due to the analyst conducting the test.
Although the formula and the process are well controlled, each lot of tablets is unique. Consequently, the PVT limits for the geometric mean and %CV must be evaluated for each lot. As a global standard, these limits must accommodate reasonable lab-to-lab variability. To minimize that variability, USP requires that internationally participating labs follow a rigorous protocol that includes documentation of the use of mechanical calibration standards. By participating in the collaborative study, a laboratory ensures that their equipment and facility is included in the determination of ranges and can compare their results with the other participants.
Experience with PVT collaborative studies for Prednisone Tablets RS has shown that the data are better analyzed in the log scale to improve the normality assumption. The acceptance limits are calculated as the arithmetic mean and standard deviation in the log scale. Therefore, the arithmetic mean and standard deviation are converted into a geometric mean and %CV, respectively. Then these statistics are converted back to the percent-dissolved scale to make them more easily interpreted. See the 2008 Stimuli Article for details.
The design of the PVT allows the use of either a Single-Stage or a Two-Stage testing approach. The choice of Single- or Two-Stage testing is significant. Valid use of this approach to the PVT requires that the laboratory make the choice of Single-Stage testing or Two-Stage testing as a standard procedure. Documentation of that choice will support the validity of the PVT by the individual laboratory.
In the Single-Stage test, two consecutive runs are to be performed on the dissolution assembly, and all data generated are collected. Then the overall geometric mean and the %CV of the variances of both runs are evaluated and compared with the applicable acceptance limits. Both values have to meet the applicable acceptance criteria to pass the PVT. If either the geometric mean or %CV is not within the respective acceptance range, the PVT failed and the assembly is not suitable for routine usage.
In the Two-Stage test, a singlet of data (one run) is collected from the test assembly, and the geometric mean and %CV are compared with the applicable acceptance limits. If the geometric mean and the %CV are within the ranges given, the criteria are met, and the test is concluded. If either the geometric mean or %CV is not within the respective acceptance range, a second set of data should be collected. Then the geometric mean and %CV for the combined data are calculated and compared with respective acceptance ranges for the second stage. Both values have to meet the applicable acceptance criteria to pass the PVT. If either the geometric mean or %CV is not within the respective acceptance range, the PVT failed, and the assembly is not suitable for routine usage. The acceptance criteria are more stringent for the first stage than for the second stage of the Two-Stage Test. This difference reflects the risk of falsely accepting the performance of an assembly based on the smaller first-stage data set.
In the case of an assembly with 12 or 14 positions, a single run (with all positions tested) is required for the PVT.
Per General Notices Section 7.20, numbers/intermediate results should not be rounded until the final calculations for the reportable value have been completed. Intermediate calculations may be rounded for reporting purposes, but the original (not rounded) value should be used for any additional required calculations. In particular, the percent dissolved values should be retained to at least three decimal places prior to calculation of the geometric mean and %CV.
If nothing but the stirring elements is changed when switching from Apparatus 1 to Apparatus 2, then the PVT for Apparatus 1 is considered to be successful. In this case, the assembly can be used for Apparatus 1 but not for Apparatus 2. The cause of failure for Apparatus 2 should be investigated and any adjustments made. If the cause is the paddle stirring elements and no other changes are made, the PVT has to be repeated for Apparatus 2 only. If any changes are made other than the replacement of the paddle stirring elements, the PVT should be repeated for both Apparatus 1 and Apparatus 2.
In the collaborative study to establish the ranges for the PVT reference material, no automated systems are allowed to be used. This approach is to reduce the contribution of the individual components of the automated system to the variability of the results. However, ensuring that automation does not significantly affect the validity of the dissolution results falls within the responsibility of the individual user. With an automated dissolution system that has been verified to produce equivalent results to those from manually sampled prednisone tablet solutions, the inclusion of the automated system during the PVT should not be a cause for failure. Demonstrating that automation does not influence the results is the responsibility of the individual user.
The acceptance ranges for the Prednisone tablets RS have been established using 1-L vessels. Therefore, the acceptance ranges apply only for dissolution assemblies configured with the 1-L vessels.
This approach is not acceptable because the acceptance ranges are lot-specific, and the results cannot be combined.
Any intrinsic variability of the tablets is captured by the PVT limits for the geometric mean as well as the %CV. If the limits were simply based on the performance of the tablets in our labs, they would be tighter. However, the USP PVT is a world standard, so the limits also reflect the lab-to-lab reproducibility based on results from an international collaborative study.
USP Prednisone Tablets RS should be stored in a dry place at a controlled room temperature not exceeding 25°C. Refer to General Chapter <659> for the definition of dry place and controlled room temperature.
For the USP Prednisone Tablets RS, a period of validity is assigned and is stated on the Certificate. The lot should not be used after its assigned valid use date.
USP will consider volunteer laboratories. Candidate laboratories will need to meet QA qualification. Interested laboratories should contact rstech@usp.org.
Additional Questions?
Please contact Reference Standard Technical Services with any USP Reference Standard-related questions.
Email: rstech@usp.org