Before using any tester, it is commonly understood and often in fact is a requirement to establish that the tester is capable of measuring the expected parameter or characteristics. For our purpose, prior to its use, the apparatus or tester must be shown that it is capable of providing appropriate dissolution characteristics (i.e. percent drug dissolution at times) of a pharmaceutical product. There are different ways of saying the same thing, for example:
The tester is capable of measuring the dissolution characteristics with the required precision; the tester is fit for its intended purpose; or the tester is qualified and validated for its intended purpose.
A usual practice for establishing the “fit-for-purpose” or performance of a tester would be to determine dissolution characteristics, with its associated precision, of a reference product. If the tester provides the dissolution value, with required precision, then the tester will be considered as qualified and validated.
One of the critical requirements for the reference product would be that it must be directly linked to products the tester will be used for. This reference product must be a drug product (tablet/capsule) for human use with a known dissolution value, because this is what the tester is going to be used for i.e. evaluation of products for human use. If one does not have such a (reference) product, one cannot establish performance of the tester and thus it cannot be used to determine dissolution characteristics for a product hence its quality.
At present, as there is no reference product available with known dissolution characteristics, one cannot check/establish the performance of any of the dissolution testers. The testers should not be considered as qualified and validated dissolution testers, hence, results obtained using these testers/apparatuses should not be considered valid for the assessment of any product, new or old.
The USP promotes its prednisone tablets as performance verification tablets (PVT) for two apparatuses, paddle/basket. As described above, in the true sense of the requirements these tablets cannot be considered PVT because these neither represent a product for human use nor have known dissolution characteristics. The dissolution values reported for the USP PVT are arbitrary because the same product cannot have two or more sets of values for the same parameter. It is like saying one can have multiple solubility values of a compound depending on how it is measured (e.g., using beaker with a laboratory stirrer, an Erlenmeyer flask with magnetic stirrer, or using a top loading shaker etc.). Obviously, it will not be accurate because the solubility of a compound is the property of the compound and should be independent of the method used to measure it.
On the other hand, there are no PVT/tablets available for other commonly suggested apparatuses (USP 3 and USP 4). Therefore, in reality, there is no mechanism available to establish the validity of claims for these to be considered as (qualified and validated) dissolution testers.
With an apparent twist in defining and practice of PVT, USP promotes the use of these tablets for monitoring appropriateness of de-aeration of dissolution media, establishing a vibration free environment of a dissolution tester and its surroundings and/or overall establishing “fitness” of the testers/analysts. Unfortunately, these are not legitimate claims and may be considered as scientifically invalid or useless as explained below with an analogy.
In seeking the source of lack of stability of results from a laboratory balance, one might consider that the instability issue may be due to instability of the laboratory environment such as room temperature and/air flow within a laboratory. To monitor the stability (or lack) of laboratory environment, the laboratory balance itself be used as a monitor, by weighing a Styrofoam-based piece (say a tablet). Note, by its very nature Styrofoam material, due to its lightness, will add to the variability. The question would be; why is the performance of a balance to be monitored using Styrofoam tablet, and not using the reference weight itself? What is the link between the Styrofoam tablet, room temperature and air flow? If the issue is instability of room temperature and/or air flow then these should be measured using their own respective meters or instruments, how does the balance become the monitor of these variables?
This is precisely the situation with PVT for paddle and basket, in that they are being suggested for monitoring stability or “fitness” of the dissolution media and/or vibration-free laboratory environment. This is simply not a logical or scientific practice. The reality is that at present these are made-up reasons for calibration or performance verifications which have no relation to assessing or validating a dissolution apparatus/tester. The fact is that these testers are neither stable nor relevant for drug dissolution testing and unfortunately attention has been diverted promoting useless practices rather than fixing the problem.
In short, as of now currently used dissolution testers are not qualified and validated dissolution testers. Their qualification and validation can only be performed with the use of a reference product with known dissolution characteristics, which is not available at present.
In the interim, one may qualify and validate the testers based on using a relative dissolution testing approach. Relative dissolution testing refers to the evaluation of two products (approved for human use), one IR and the other ER, having the same drug using exactly the same experimental conditions. The tester and experimental conditions which provide the dissolution characteristics reflective of the bio behavior (bioavailability/bioequivalence) of the drug in humans would be considered an appropriate tester and should be used for the evaluation of the test products using the same experimental conditions. For further detail and explanation, the following links may be of help:
(1) Apparatus Calibration or Performance Verification: Misleading Conclusions and False Comfort (link)
(2) MQ (Mechanical Qualification) vs PVT (Performance Verification Testing) which one to choose and why? (link)
(3) Two-Tier System for Setting Tolerances – (PVT vs Products) (link)
(4) PVT (Performance Verification Test) – Difficulties and a suggestion to address those (link)
(5) The issue of validation/qualification of dissolution apparatuses (link)
