Author: Dr. Saeed Qureshi, Ph.D.

There is no doubt that drug dissolution evaluation is a very important and critical step for developing and assessing products and will remain so in the future. However, dissolution testing itself will change significantly and dramatically.

The simplification will be reflected by the availability of a very small number of methods, if not only one or two, even for QC purposes. It is important to note that the currently described methods in the hundreds, if not in thousands, will be discontinued as they will not be considered dissolution methods. In fact, these will be considered sets of experimental conditions to show presumed or pre-set dissolution results that will be of limited use. For an appropriate dissolution characterization of a product, the test must be product-independent, which is currently not the case.

The test procedures and apparatuses mostly used, particularly paddle and basket, are not validated and qualified for their intended use. Surprisingly, these apparatuses have been in use for such a long time. However, this practice cannot continue further in a modern and highly regulated and standardized industry such as pharmaceutical, particularly for QC purposes.

It is to be noted that these apparatuses (paddle/basket) cannot be qualified and validated: (1) these apparatuses are inherently flawed because of the poor hydrodynamics within the dissolution vessels hence cannot provide the required repeatability and reproducibility for testing; (2) the stirring/mixing environment within the vessels is such that they cannot simulate the required GI tract physiology appropriately. Thus they will never provide physiologically relevant results. Therefore, the use of these apparatuses will be discontinued.

In addition, it should be noted that as the results and conclusions drawn from many years of work are based on the use of these flawed apparatuses, all the observations and claims will require reconsideration.

Consider the above-described facts, it should be prudent to start preparing for this eventuality of discontinuation of paddle/basket apparatuses.

However, the good news is that the dissolution characteristics, including predicting the plasma drug levels, can easily be determined using a modified approach of Assay and CU determination. For further discussion in this regard, please see the selected links below:

https://bioanalyticx.com/a-simple-and-unique-approach-for-developing-and-evaluating-products/
https://bioanalyticx.com/assay-and-content-uniformity-cu-based-on-dissolution-testing-poster-presentation/
https://bioanalyticx.com/currently-suggested-dissolution-testers-methods-may-not-be-capable-of-determining-dissolution-characteristics-of-drug-products/
https://bioanalyticx.com/apparatus-calibration-or-performance-verification-misleading-conclusions-and-false-comfort/

The present-day confusion regarding IVIVC comes from a poor understanding of the concept and its presentation in the literature. The commonly presented description of the IVIVC concept in literature is the development of the relationships, or lines, between in vitro (dissolution profiles) and in vivo (dissolution or plasma profiles) results, as described earlier (see link).  The confusion comes from both aspects, i.e., theoretical, associated mathematical procedures, and experimental.  Please click here for the complete article

The development of IVIVC is often described as follows: In vitro in vivo correlation (IVIVC) is an important concept and a tool in the development and evaluation of pharmaceutical dosage forms, especially modified release dosage forms. The objective of developing an IVIVC is to establish a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. Please click here for the complete article

There is a common belief within the dissolution community that the stirring within a dissolution vessel should be very gentle, but the product should also not be in contact with the rotating spindle/paddle. Touching or moving the product by the spindle is considered a harsh and undesirable testing environment that may result in loss of the discriminatory ability of the dissolution test. On the other hand, no standards or requirements describe such gentleness or softness of the stirring, other than the belief that the softer the environment/stirring is, the better it will be. Such a belief has resulted in the practice of the other extreme i.e., the commonly recommended stirring (e.g., 50 rpm) in fact provides no, or extremely limited, stirring, which in reality makes the current practices of dissolution testing meaningless. please click here for the complete article

It is a fact that the currently used dissolution testers, in particular the paddle and basket, are not qualified and validated apparatuses, thus cannot be used for an appropriate and accurate evaluation of dissolution characteristics of the products. To address these deficiencies, a new spindle, known as the crescent shape spindle, has been suggested as a substitute for the paddle and basket in the vessel-based apparatuses. This substitution addresses the flaws of the paddle and basket apparatuses, as described below, and provides a number of additional advantages for easier, scientifically valid and superior product evaluation. For example: please click here for the complete article

Considering the flaws of poor hydrodynamics of the most commonly used apparatuses, paddle and basket, it is very well established that these apparatuses are not qualified and validated to provide relevant and reproducible dissolution results. Therefore, it is natural that people are seeking alternatives. The vessel-based apparatuses using the crescent shape spindle provides such an alternative. The next obvious question would be, are such apparatuses qualified to be used as dissolution testers? Also, have these been standardized? The answer to both questions is yes, as explained below. please click here for complete article

The purpose of a dissolution tester is to test a tablet/capsule product for its potential dissolution characteristics in the human GI tract. In general, it is now well recognized that the currently used dissolution testers, in particular paddle and basket, do not provide such dissolution characteristics. In fact, they cannot provide dissolution characteristics because of the flaws of poor product/medium interaction within the apparatuses. Therefore, these apparatuses cannot be qualified and/or validated as dissolution testers and thus cannot be used to develop and evaluate the products.

The practices of the past many years have been to keep using these apparatuses for product development and evaluation (isn’t this bizarre?) with a change/twist in the objective of dissolution testing by calling it a quality control test. However, how does one link the dissolution test to the quality of the product when it requires its link to the dissolution characteristics in vivo, i.e., human GI tract? Oops, there is no link here, as stated in the paragraph above.

The objective of the testing should be twisted again. This time it would be called testers/testing for batch-to-batch consistency check. As the link or relevance of the test to its original and actual objective has been severed, but the same testing is still required to be done. Therefore, certain practices (“rituals”) have to be suggested to come up with some standards, any standard, that everyone has to follow. Presently, this standard is called Q-Value (to make it sound professional!), which is 80/30, i.e., 80% of the drug should dissolve within 30 minutes. Where did this number, 80/30, come from? One is not expected to ask or know! One just has to accept it. However, one can negotiate this number, based on one’s negotiating skills, to get another number for one’s product say, 70/45 or 75/20 or any other.

Now there is a problem: it is often difficult to meet this standard (80/30 or a different one) because the tester itself is highly variable in nature. One cannot obtain repeatable and reproducible results within the expected norms.

So, what should one do now? Let us introduce a Performance Verification Test (PVT) to test the tester. What is a PVT?  It is a dissolution test, using in-house developed tablets, which everyone is expected to conduct to get one’s own product approved. How does this PVT help in improving the tester? No one knows. It is assumed that the PVT establishes: the validity of a vibration-free environment in and around the tester, the de-aeration content of the medium, the perfectness of the vessel dimensions, and its alignment. Oops, what happened to the evaluation of the performance of the tester? Does it improve the repeatability and reproducibility of the testers? Of course not, because the issue of repeatability and reproducibility relates to spindle/vessel combination remains the same, so remains the problem.

So, what should be done now? Let us get rid of this PVT. It causes too much hassle and frustration. Let us have something else and call it the Enhanced Mechanical Qualification (EMQ or simply MQ). What is the MQ? It is a set of (same old) physical specifications but with somewhat tighter tolerances. Now everyone is required to get certified that the tolerances are within the expectations. How does MQ establish or improve the performance of the tester? It does not. It is assumed that if one has certificates and good record keeping, the performance of the testers will be considered (assumed) improved or OK. But the lack of performance, or flaws, was not because of the broader tolerances. It is because the combination of spindle/vessel. As the spindle/vessel combination remains the same, so does the problem. However, one will not see the problems anymore, as there is no performance test associated with MQ. Therefore, the idea is if one does not see the problem, it is safe to assume that the problem does not exist. So, how could the MQ help? It does not.

 What should be done now? Develop a performance qualifier for the PVT and/or MQ.  What is a performance qualifier? It is a piece of equipment that perhaps costs many thousands of dollars, which will help show that the apparatus is within required specifications. The question is, why would the specifications change when the manufacturers provide all the certifications. Remember, you are not supposed to ask questions! Will this performance qualifier help? Of course not, because it was never a specification issue, tight or broad, so how it can be addressed or solved. It does not.

Specifications were correct all along. These are the same apparatuses/testers with practically the same specifications and tolerances, but maybe with some tweaking for personal gratification, otherwise nothing has changed.

We started with the use of these apparatuses as dissolution testers but generated a whole new industry of the performance verification/validation and qualification, which is based on made-up requirements of MQ and PVT for monitoring irrelevant and useless parameters.

Let us hope that this practice stops here. If you ask my opinion, then I will say that brakes have already been applied to use paddle and basket apparatuses. It is just taking time to formalize and generalize it. People have already started evaluating other alternatives because current apparatuses are not qualified and validated for the intended purpose and thus, the results obtained from them cannot be trusted.

These apparatuses:

1. Lack of scientific merit and support. Experimental studies have shown that they will provide highly variable and unpredictable results because of poor product/medium interaction.

2. Cannot be qualified/validated using commonly used industry-wide practices of qualifications for analytical instruments. In particular, they do not meet the requirements of design qualification (not fit for intended use) and operation qualification (cannot be qualified using a reference product).

3. Require meeting undefined and unqualified requirements such as de-aeration of the medium and control of vibration in and around the equipment.

4. Require drug and/or product-dependent experimental conditions. Therefore, it will not be possible to know whether dissolution characteristics reflect the products or the experimental conditions used.

5. Do not differentiate between IR and ER products. The analyst must first know what type of release/dissolution to expect from the product and then use the design of the experimental conditions to provide the presumed released/dissolution characteristics.

6. Are routinely used for evaluating drug products for human use (e.g., pharmacopeial testing). However, they have never been validated to demonstrate that they can provide bio- or physiologically relevant results.

7. Are often used for quality control and to check lot-to-lot consistency purposes. However, a link of these apparatuses, and associated experimental conditions, to the quality of a product, and consistency thereof, is unknown or undefined. The only criterion used for this purpose is that the dissolution results must meet some arbitrary standards/tolerances. If the criterion is not met, it is assumed that the products may be of substandard attributes.

8. Are expected to provide discriminatory tests which should be capable of showing formulation/manufacturing differences among products and/or batches. On the other hand, it is a well-known fact that these apparatuses frequently provide discriminatory results lacking any physiological significance or consequence.

9. Do not simulate in vivo or physiological environment (stirring and mixing) thus, one cannot develop bio-relevant tests.

10.   Require tolerances be set lower than potency and content uniformity values. Thus, results will reflect the inaccurate and inappropriate quality of perfectly acceptable products.

Considering the above-mentioned deficiencies, results obtained using these apparatuses can easily be questioned/challenged for their validity and relevance.

It is a fact and often a regulatory requirement that one has to demonstrate that an apparatus is capable of providing the intended and expected outcome. A simple and common example of this requirement is the calibration of a laboratory weighing scale or balance. Initially, when a balance is purchased, and then occasionally after that, it must be calibrated against reference weights to show that the balance can provide accurate weights of the references. If the balance does not perform as expected, then it has to be adjusted accordingly. please click here for the complete article

It is often asked which approach one should choose and why, i.e., is there a reason for the preference for one over the other?

Such a question has two components; (1) scientific or logical (2) required standards. Generally, the required standards component is based on the first one, i.e., science and logic. Unfortunately, in the case of the current practices of dissolution testing, scientific principles are entirely absent from the standardization. That is why there is so much difficulty, along with the associated frustrations.

I provide suggestions based on underlying scientific principles, which often do not fit well with the current practices because, as I stated above, the current practices lack scientific reasoning and logic. People say that both MQ and PVT are good and valid, which is correct, and an analyst can choose either. However, the next question is, which one is better and why. That is where the difficulty is. If one likes to know which one is better, then one has to know the reason behind conducting these tests, which will help decide and rationalize the preferred one.

So, the question is, why these MQ and PVT are done? The answer is to establish that the apparatuses fit their intended purpose, i.e., apparatuses can be used to evaluate the dissolution characteristics of a product for human use. The next question is, or at least should be, that if one meets the requirements of MQ/PVT, will the apparatuses be considered fit for evaluating the product for human use. The answer is no because both MQ/PVT lack the critical link between apparatuses and the evaluation of dissolution characteristics of a drug product (please use the link to read the article for further discussion). Therefore, in general, MQ and PVT are not useful practices and requirements and are unnecessary burdens on the pharmaceutical industry.

If the testing (MQ/PVT) lacks any real benefit, but has to be performed to meet the requirement, I would prefer the MQ. The MQ takes the responsibility away from the analysts and transfers it to the vendors of the dissolution testers. They can provide certification that the testers meet the specifications, which they usually provide when one purchases an apparatus and may provide later as well. In addition, the beauty of MQ is that no one can question that an apparatus does not work/perform as expected because there is no way to prove that it does not work, as the performance of the apparatuses is not associated with the MQ requirements. So, my dear analysts, go with the MQ and say goodbye to the PVT and its so-called “best practices”.