Apparatus Calibration or Performance Verification: Misleading Conclusions and False Comfort

In a recent issue of Dissolution Technologies, in an article titled “Overview of Dissolution Instrument Qualification, Including Common Pitfalls” the authors started the article with a statement (or quote) of the claim that “For almost fifty years, the pharmaceutical community has been relying on dissolution data as an indication of drug product performance. Effective qualification of the dissolution apparatus is critical to the value and integrity of these data”.

The above mentioned statements can be misleading and may provide false and erroneous comfort for a drug product performance using instrument qualifications (IQ) as its basis, as explained below:

IQ based on Enhanced Mechanical Calibration (EMC): Meeting the EMC means that the instrument is within the expected and required specifications. However, it does not mean that the instrument is capable of determining dissolution characteristics reflecting the appropriate performance of a product. To fulfill such a requirement the instrument must be capable of producing the expected dissolution results of an approved drug product linked to the product’s performance.

The situation may be explained with an analogy that an analyst requires a laboratory thermometer to monitor the temperature of a dissolution water bath. The supplier provides the thermometer to the analyst with a detailed list of specifications for: lengths and diameters of the outer tube and inner capillary, heat conducting bulb, the quality of glass used and marking on it, and the amount of mercury present in the capillary with a detailed theory of the heat expansion coefficient etc. The question is will this thermometer perform as expected and monitor the temperature of the bath accurately? No, there is no data available on the performance of the thermometer. For the performance evaluation, the supplier needs to provide evidence to show that when the thermometer is placed in freezing water, the mercury will show a reading of 0 °C and while in boiling water the mercury will expand to the 100° C mark. This would reflect that indeed the thermometer performed as expected and is good for use.

Similarly, a dissolution instrument should also demonstrate that if a test (performance or calibration) is performed using a drug product for human use, the instrument is capable of providing the expected dissolution results.   

IQ based on Performance Verification Test/Tablets (PVT): In this case, in addition to establishing the instrument specifications as with EMC, dissolution tests are conducted using USP calibrator tablets (not a pharmaceutical product) to achieve certain expected results. This type of testing (calibration) will show the capability of the tester to evaluate dissolution characteristics, however, its capability of showing the performance of a product for human use is still lacking.  In reality, the dissolution results thus obtained would be similar to those obtained using a kitchen blender set at slow rotation speeds. The link to reflect the performance of a drug product in humans is lacking in both cases.

On the other hand, continuing with the thermometer analogy, in this case (i.e. PVT) the supplier, in addition to the specifications as described above, provides a pouch filled with a unknown or mysterious liquid, which causes the mercury in the thermometer to expand to somewhere in the middle of the thermometer. The expansion is expected to vary from user to user. Should this be considered as a performance evaluation test? Not really, because one does not know that indeed, the mercury should expand to the middle. The performance test becomes arbitrary and of limited use. The question is why the supplier of the thermometer is making so much effort in developing the specifications and an arbitrary performance test (pouch). Why doesn’t the supplier of the thermometer provide evidence of the performance with the use of freezing and boiling water?

The same situation is with the suppliers of the dissolution testers and provider of the calibrator tablets, why are they making so much effort in developing tablets and setting arbitrary specifications and performance evaluation criteria for these? Why can’t they use a tablet or capsule product approved for human use and demonstrate that the apparatuses are capable of providing the expected dissolution behavior of the product. The simple and short answer is that the presently used apparatuses are not capable of providing appropriate dissolution results for a product.

Therefore, using such an instrument, along with stated performance testing, will provide false comfort which can result in misleading conclusions about the performance of the pharmaceutical products.

Note: This post has been shared with the authors of the article. They have provided the following response. Their contribution is greatly appreciated. Saeed

 We appreciate the thoughtfulness of Dr. Qureshi’s response to our article. Striving for clinically relevant specifications is paramount for our drug products. Therefore sufficiently challenged methods that give information on the critical quality attributes that contribute to the release mechanism are the key. We disagree that dissolution is not a useful test, and that if we are going to use dissolution as a test then it is important that the apparatus is appropriately qualified.

Vivian Gray, V. A. Gray Consulting, vagray@rcn.com
Greg Martin, Complectors Consulting, greg.martin@complectors.com

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