… a product can have only one value for a parameter at any given time. It is not possible that the same product can have multiple values or characteristics of a parameter (drug release or dissolution) at the same time.

This is just like a tablet or capsule can only have a single weight at any given time, no matter which type of balance one would use to measure it. Or just like a dissolution bath can have one temperature at any given time no matter which type of thermometer one could use to measure it. Similarly, just like the content of a tablet/capsule (amount of drug) can have one value at any given time, no matter which type of analytical technique one would use to measure it. Of course, different techniques/methods may provide different precisions due their nature, but results on average will be the same and technique independent.

It is not possible for the same tablet/capsule to have different weights at the same time. It is not possible that a dissolution bath can have different temperatures at the same time. It is not possible that a tablet/capsule can have different contents (amount of drug) at any given time.

If different balances, thermometers or analytical techniques provide different results, then this means that these are not measuring the values of the intended parameters but something else. Such techniques or testers are considered unreliable and, as a common practice, are not used any further.

On the other hand, in drug dissolution testing practice it is commonly accepted that each and every product can, and should, provide tester-dependent different dissolution value. A notable example in this regard is dissolution values for the USP prednisone PV Tablets, where paddle and basket provide two different drug dissolution values.

All four of the most commonly recommended dissolution testers are expected to provide different dissolution results for the same product. The analyst or formulator is free to choose, and rationalize, the one which suits his or her purpose, however, he or she will never be able to know the actual dissolution characteristics of a, or any, product. Presently, the drug release/dissolution characteristics are not product dependent, but tester dependent. Obviously, one cannot establish quality or bio-relevancy of any product as the results are not linked to the product but the tester.

It is such an unfortunate and bizarre practice and logic, not sure how this has been accepted and practiced for so long in the industry and regulatory environments. This is a serious anomaly which certainly requires urgent attention for correction.

Problems of failures of calibration/ Performance Verification Testing (PVT) are not new. These have been with us since their introduction in the USP. Presently, the issue is not of the failures of calibration/PVT, which is very well established, but how it should be addressed.

To address the issue, let us breakdown the testing, calibration/PVT or drug dissolution testing in general, in different components.

(1)    Calibration/PVT Tablets
(2)    Dissolution testing procedure and/or analyst training/experience
(3)    Apparatuses (paddle/basket)

(1)    Calibration/PVT Tablets: At present there is no independent mechanism available or used to establish quality or reproducibility of the tablets. The quality and reproducibility of calibration/PVT are established using the paddle/basket apparatuses themselves. Therefore, quality and reproducibility of the tablets, hence failures, are dependent on the characteristics of the apparatuses used. Using statistical analyses, studies from the USP clearly demonstrated that PVT tablets do not significantly contribute to the failures (1, 2).

(2) Dissolution testing procedure and/or analyst training/experience: In this regard, one should note that dissolution testing means dropping a tablet/capsule into the vessel containing a medium maintained at 37ºC and starting the stirrer (spindle) at a pre-set rpm, followed by withdrawing a sample from the vessel. It is extremely important to note that an associated or required analytical technique such as spectrophotometry or chromatography is not part of the dissolution testing or testers. An analyst can conduct a dissolution test independent to the analytical (quantitation) technique and may send the samples to another analyst/analytical laboratory physically located hundreds of miles away to determine drug levels in the samples from dissolution testing using techniques of their choice. Continue reading →