Author: Dr. Saeed Qureshi, Ph.D.

During the last few days, to all those who wished me well, on LinkedIn and in person, for completion of my 30 years of service with Health Canada and retirement, and now initiating a new professional journey. I greatly appreciate your good wishes and the support you provided during the past few years. I am fully committed to continue providing such contributions in the future. I look forward to working with you to provide scientific ideas and solutions to problems and help bring quality products into the market faster and in a cost-effective manner.

To enhance more open scientific interactions, I am initiating a LinkedIn group (rDissolution) complementary to my blog (www.drug-dissolution-testing.com), as often people request a more open medium of interaction for my articles and blog postings which is not available on the blog itself. Please, join the forum (rDissolution) for more active discussions to learn and contribute.

I look forward to an exciting future, and if I could be of any assistance, please do not hesitate to contact me at principal@pharmacomechanics.com or moderator@drug-dissolution-testing.com.

As of May 29^th, 2015, after 30 years of service as a research scientist at Health Canada, I will be retiring. I look forward to a new phase in my career with great excitement. If I could be of any assistance, please do not hesitate to contact me by email: moderator@drug-dissolution-testing.com; Tel: +1 613-797-98155 (cell)

Sincerely
Saeed A. Qureshi, Ph.D.

… 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) simultaneously.

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 to their nature, but results on average will be the same and technique independent.

The same tablet/capsule can’t 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, this means that these measures 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 values. 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 the 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 that 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 break down 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 the quality or reproducibility of the tablets. The quality and reproducibility of calibration/PVT are established using the paddle/basket apparatuses themselves. Therefore, the 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 of the analytical (quantitation) technique and may send the samples to another analyst/analytical laboratory physically located hundreds of miles away to determine drug levels from dissolution testing using techniques of their choice. Read the rest of this entry �

A discriminatory test reflects that it can differentiate a bad batch/product from a good one. The question is, how should one define bad vs. good? In general a good product, in the context of dissolution testing, is a product that should be capable of releasing a drug from the product in the GI tract in an expected and reproducible manner. It is important to note that a drug release, or dissolution test is linked to product behavior in the GI tract. On the other hand, it is a well-known fact that currently suggested dissolution methods/testers have no link to the product behavior in the GI tract (link). In fact, it is almost impossible to obtain reliable and physiologically relevant dissolution results using currently suggested apparatuses, particularly paddle/basket apparatuses, because of the flaws of the testers (link). Therefore, it is almost impossible to have discriminatory dissolution methods to differentiate a bad product from a good product by extension.

The irrelevancy of current practices of developing discriminatory tests, methods or testers may also be explained in another way with the following analogy. For example, one may ask if anyone has seen a discriminatory thermometer, laboratory balance, pH meter, spectrophotometer, chromatograph etc. The answer is, not really; because all one does, by using a tester/method, is to measure the parameter’s value. The test/method is used only to determine value/result, and the scientist/analyst uses this value for the interpretation of the characteristics of the product. For example, one never says, requires or develops a discriminatory thermometer when one monitors the temperature. One uses the thermometer to measure the value (temperature) of the corresponding parameter (body temperature). The thermometer never tells if a person has a fever or not. It only tells the temperature, but a physician interprets it as a fever or any other deviation. So, why does one have discriminatory dissolution methods or testers? It is simply to market the made-up science and flawed testers. Developing a discriminatory test/method, as practiced or required, has no meaning and serves no useful purpose. One requires a dissolution tester or method to measure the dissolution characteristics of a product reflecting it’s in vivo dissolution characteristics. Once one has such a method, it automatically becomes a discriminatory test. One does not require any extra effort or steps to make it a discriminatory test. The dissolution results thus obtained using such a method/tester would reflect dissolution characteristics of a product, and then the analyst/formulator is to decide whether the product is of acceptable quality/characteristics or not. Read the rest of this entry �

The title of the post is a bit catchy but is factually 100% correct, i.e., no one is using dissolution testing for product development, as explained below:

Suppose a formulator would like to develop a product having a certain dissolution characteristic/profile. The product is to be developed for human use; therefore, the target dissolution characteristic/profile should also be relevant to humans. With this objective in mind, the formulator proceeds to develop a product by mixing some ingredients/excipients and compressing it into tablets, referred to as product “A.” However, the formulator realizes that perhaps all he/she must do is compress the pure drug (powder) into tablets, which might give the desired dissolution characteristic. So, he/she compresses the drug powder into tablets as well, referred to as product “B.” Now the formulator would like to determine/compare dissolution characteristics of these tablets, i.e., if they are able to provide the desirable characteristics or require some adjustments. For this purpose, the formulator requires a dissolution test/method (apparatus and associated experimental conditions). Unfortunately, currently, no such test/method exists. Therefore, a formulator cannot determine the dissolution characteristics of the products and thus cannot develop a product having a desired characteristic. Read the rest of this entry �

This chapter appears quite popular and is often cited for help and information concerning dissolution methods development and validation. However, if one evaluates it, even superficially, one should immediately realize that the chapter is based on invalid assumptions and false science. For example:

The chapter is meant to be helpful and useful in developing and validating a dissolution method. However, the problem is that a fundamental requirement is that one requires a reference product with known dissolution characteristics established independently for such a purpose. In this case, one requires a reference product, which should be approved for human use as the method is to be used for such a purpose, with known dissolution characteristics. The (dissolution) method development means that using valid scientific principles and testers, the developed and validated method would be able to provide an expected answer for the reference product. This developed and validated method will then be used for evaluating the test products. As, at present, a reference product with known dissolution characteristics is not available, therefore, it is not possible to develop and validate a dissolution method. It is simply a scientific impossibility.

Furthermore, the valid scientific principles and testers mean that developed and validated methods must be based on experimental conditions relevant to the applications of the method. In this case, the relevancy aspect comes from the physiological environment of the GI tract in particular intestinal. The only purpose of the test/method is to evaluate dissolution characteristics of a drug product in the GI tract. It is important to note that even for QC purposes, the method measures the dissolution characteristics for the GI tract. That is why most, if not all, pharmacopeial tests are conducted using physiologically relevant conditions as well. Therefore, the choice of experimental conditions must be physiologically relevant.

A fundamental requirement, in this regard, is that whatever experimental conditions one chooses to represent the GI tract environment, these should remain consistent from product to product or should be product independent, as does the GI tract environment. This is the second flaw (invalid science) of this chapter that it suggests and emphasizes selecting the test product-dependent experimental conditions. It will be impossible to determine a test product’s true and accurate dissolution characteristics using experimental conditions specific to the product itself. Furthermore, as the experimental conditions change from product to product, which is unlike the GI tract environment, therefore, such tests would be considered invalid for any purpose. No matter how one presents the argument, it will be an irrelevant evaluation method and test for product-dependent experimental conditions.

It is, therefore, critical to understand that the chapter cannot provide help or accurate information for developing or validating a scientifically valid dissolution method.

It is often suggested that to obtain appropriate dissolution characteristics of a product one may use or select an apparatus depending on the product attributes and/or desired release characteristics such as discriminating profiles, reproducibility, bio-relevancy, etc. Such reasoning dictates that the analyst/formulator should have an idea about the expected outcome of the results, whether based on an educated guess or from prior experimentation. Thus, by selecting a particular apparatus and/or its associated experimental conditions, one is trying to achieve the results reflecting one’s expectation.

For example, when one conducts an experiment using the paddle apparatus and finds dissolution results of a tablet product, and their variability, higher than expected while observing that some, or all, tablets are floating within the vessel during testing. Such behavior or experiment is commonly considered flawed or inappropriate. A common practice to rectify this “problem” is to either use the basket apparatus or a sinker to restrict this floating behavior assuming that this may be causing higher results and variability. This means that the analyst/formulator already has a preconceived idea/expectation about the results and variability of the product, and is trying to obtain those results by adjusting the means, in this case by using a different apparatus or a sinker. Obviously, the analyst is not determining dissolution characteristics of the product but achieving intended results by adjusting tester and/or associated experimental conditions. Read the rest of this entry �

Similar C-t (plasma drug concentration-time) profiles or BA/BE (bioavailability/bioequivalence) shows that the products (tablets/capsules) provide similar dissolution characteristics (all other things being equal). Therefore, for all practical purposes, the C-t profiles or BA/BE studies are the measures of in vivo dissolution characteristics of the products. Thus, by definition, assessment of in vivo dissolution becomes a product assessment/development tool while the same assessment tool becomes a quality control/assurance tool as well. It is scientifically and logically incorrect to separate or differentiate dissolution tests based on their use, i.e. as a product assessment/development tool and a “quality” control/assurance tool. The dissolution test remains exactly the same in both cases.

The same BA/BE test can be, and are, used during the product development stage as well as for comparing the performance of different batches of the same product. The BA/BE test does not change with the stages of product development and manufacturing.

Considering ethical reasons (testing in humans), cost and time, BA/BE tests can neither be conducted nor conducted routinely, but only for confirmatory purposes. However, for all other purposes, such assessments (during the product development stage and as a quality control tool during manufacturing of products) dissolution characteristics of a product are evaluated by in vitro dissolution tests. For all practical purposes, current drug dissolution tests are indeed used as a substitute of BA/BE, including for QC purposes such as pharmacopeial tests. Therefore, by definition, dissolution tests conducted as recommended are indeed bio-waivers. One does not require any further or special step to transfer a dissolution test to a bio-waiver status or vice versa. Stating otherwise would not change the reality or the fact.

If a dissolution test does not provide an in vivo relevant outcome, then the issue is with the dissolution test, and such a test should not be used any further until corrected. Requiring the use of dissolution tests that do not provide bio-relevant results for any purpose, cannot be justified on any basis, scientific or logical. It simply confuses reality, science, and people, and furthermore hinders efficient product development and manufacturing.