Author: Dr. Saeed Qureshi, Ph.D.

As a fundamental scientific principle, it should be obvious that one should NOT develop or use product-dependent methods or parameters to characterize the product itself. However, this is precisely the practice in the pharmaceutical area for product development and/or its evaluation, i.e., everyone seeks/develops and uses a product-dependent dissolution method.

This is clearly an example of a mindset that is incorrect and scientifically invalid. It appears that the practice of pharmacopeial testing has created this mindset. Most pharmacopeial tests (e.g., USP) are drug and/or product-dependent. However, these should be considered scientifically invalid or useless. If a dissolution test is product-dependent, then it will not be possible to establish whether observed dissolution characteristics are because of the product or due to the experimental conditions used. Therefore, it should be noted that one cannot rely on product-dependent (e.g., pharmacopeial) methods to establish dissolution characteristics of a product, thus its quality.

To evaluate the quality of a drug product, the dissolution method must be product-independent. Therefore, developing product-dependent dissolution methods for any purpose, i.e., QC, discriminatory, bio-relevant, IVIVC, bio-waiver, QbD etc should be considered a mistake and complete waste of time and resources.

At present, a vessel-based dissolution tester with crescent shape spindles (link) has been suggested for product independent dissolution testing. Thus, it provides unbiased and scientifically valid dissolution testing but also helps in saving large resources.

Commonly described dissolution methods are product-dependent. Therefore, it is not possible to know whether the observed dissolution characteristics are a reflection of the product (formulation and/or manufacturing) attributes or because of the experimental conditions (apparatus, rpm, medium, etc.) employed.

For an appropriate and accurate assessment of dissolution characteristics of a product, the dissolution method must be product-independent. The use of crescent shape spindle has been suggested based on this principle, thus providing true product dissolution characteristics. Please see the following links for further discussion:https://bioanalyticx.com/simpler-and-more-appropriate-dissolution-testing/
(2) http://www.drug-dissolution-testing.com/blog/files/Flyer.pdf
(3) https://bioanalyticx.com/product-dependent-dissolution-testing-a-scientifically-invalid-practice/
(4)

The Crescent-Shaped Spindle

A drug dissolution test is an analytical test of such significance that it is hard to imagine that any oral drug product such as tablet and capsule would be developed and manufactured without its use. The majority of the tests are conducted using testers, commonly known as paddle and basket apparatuses. It is a well-accepted and implied understanding that not using one of these apparatuses will require a long and unkind explanation for deviating from the “norms,” resulting in potentially extensive and costly delays in bringing the products to the market. Therefore, Please click here for the complete article

A suggested definition of “quality” for QbD purposes is described. It is hoped that the article will help highlight the underlying scientific issues and deficiencies that will prevent achieving the intended objectives of the suggested “QbD-based ANDA example documents.” It is argued that the documents are based on invalid analytical (dissolution) methodologies, which also makes the suggestions/recommendations invalid. Suggestions for improvement are provided. Please click here for the complete article

A method based on the convolution technique has been described earlier to predict plasma drug concentration-time (C-t) profiles. This article describes further refinement of the method for a more realistic representation of a human bioavailability study outcome by including variabilities in stomach emptying time and bioavailability factor (F). The advantages of such refinement are discussed, including setting physiologically relevant specifications for dissolution testing. Please click here for the complete article

PS: Please note that an error in the text was detected on page 2, column 2, and paragraph 2, which has been corrected. The revision reads as follows: “For this particular example, it is assumed that the filter will release (not adsorb) on average 44%±10(±SD) of the drug, representing average F (bioavailability) and variation in the F for diltiazem.”  My apologies for the oversight and any inconvenience it may have caused. Saeed (July 27, 2012).

This article summarizes the principles of drug dissolution testing, emphasizing the underlying scientific assumptions that are often not clearly described or understood. It should be noted that the dissolution technique itself is extremely simple to use. However, current practices of selecting experimental conditions and the interpretation of dissolution results are seriously misunderstood and require attention. To address these deficiencies, analysts should seek essential training in the areas of relevant physiology and pharmacokinetics. In the absence of such required training and knowledge of the subjects, it is highly unlikely that an analytical laboratory can generate relevant and accurate dissolution data, thus failing to meet the products development and evaluation objectives. Links to some articles on the subjects are provided, which may help the analysts in improving their overall skills in these areas. Please click here for the complete article

This article summarizes the principles of drug dissolution testing, emphasizing the underlying scientific assumptions that are often not clearly described or understood. It should be noted that the technique itself is extremely simple to use. However, current practices of selecting experimental conditions and the interpretation of dissolution results are seriously misunderstood and require attention. To address these deficiencies, analysts should seek essential training in the areas of relevant physiology and pharmacokinetics. In the absence of such required training and knowledge of the subjects, it is highly unlikely that an analytical laboratory can generate relevant and accurate dissolution data, thus failing to meet the products development and evaluation objectives. Links to some articles on the subjects are provided which may help the analysts in improving their overall skills in these areas. Please click here for complete article

Recently a question was asked as to whether my suggested approach of IVIVP for predicting plasma drug levels, based on convolution technique, is applicable for evaluating the stability samples. The answer is yes, an explanation follows:

It appears that this question originates from the current thinking and belief that dissolution methods depend on the nature and source of a product. For example it is quite common that different products such as IR and ER are often analyzed using different dissolution methods. Similarly, often dissolution methods for QC purposes and product development are different. Unfortunately, this current thinking, i.e., product-dependent dissolution testing is not correct.

Appropriate prediction of plasma drug levels requires that dissolution results should be obtained using physiologically relevant experimental conditions. As the physiological (GI tract) condition or environment is independent of the nature or source of the product, one requires the use of product-independent dissolution testing.

The artifact of the poor stirring and mixing within dissolution vessels dictates that the tests using paddle and basket apparatuses should be conducted using product-dependent experiment conditions. Therefore, results obtained using these apparatuses cannot be considered physiologically relevant. The predicting of plasma drug levels to evaluate products using these apparatuses becomes a futile exercise.

To overcome this deficiency, a new stirrer has also been proposed, known as a crescent shape spindle. This spindle provides an efficient and reproducible stirring environment, thus have the ability of providing a single and product-independent dissolution testing environment. The suggested dissolution testing experimental conditions are 900 mL of distilled water maintained at 37 °C using the crescent shape spindle set at 25 rpm. A small amount of solubiliser (e.g. SLS) may be required for drugs with low solubility in water.

As the experimental conditions are set, the tester becomes a tester in the true sense of the word, meaning that the analyst can just drop the product (tablet/capsule) into the vessel and measure the dissolution. The source of the product (stability, QC, product development, or from a stability study) is immaterial. In fact, a dissolution tester must possess such quality and have the ability to be used to determine dissolution characteristics of a product because the analyst likes to evaluate the impact of variation in products based on dissolution results. If a dissolution test is dependent on the product or its source, then one cannot observe or compare the effect of variations of the products on dissolution, which would defeat the purpose of the dissolution testing.  

The tester with a crescent shape spindle should be considered exactly like a spectrophotometer for dissolution testing purposes. In the case of a spectrophotometer, which measures the absorption value, the solution can be from any of the sources such as tablets/capsules (QC, stability, product development). Analysts measure the absorbance and calculate the concentration of the solution and relate it to the product. Similarly, a dissolution tester with the crescent shape spindle provides the solution formation rate or dissolution. Again, the product (table/capsules) can be from any source QC, stability, or product development. The dissolution tester is and should be blinded to the source. An analyst takes out dissolution samples, measures the solutions’ concentration, and reports the results as percent drug released with time or further converts these results into plasma drug levels using the suggested convolution (mathematical manipulation/calculation) approach. The results are then related back to the product to establish consistency and change in its quality. It is to be noted that both the tester, including the experimental condition and the calculation of plasma levels, are independent of type and source of products. It is, indeed, a truly simple yet extremely powerful approach for measuring dissolution and then predicting plasma drug levels leading to products development and evaluation.

A more detailed description and discussion on the crescent shape spindle, suggestion and use of a single set of experimental conditions, and convolution approach may be found in scientific literature and/or on the website (www.drug-dissolution-testing.com). If you have a question or would like further information in this regard, you may obtain it by writing to moderator@drug-dissolution-testing.com

As a part of an ongoing discussion on the LinkedIn Network group (Quality-by-Design), I posted the following response. For the interest of people who do not participate in the LinkedIn Network or the particular group, I am also posting the response on the blog. I hope that you will find the post useful.

Bill:

With all due respect and with all my humbleness, I say that your post in response to my question about a fairy tale itself is a fairy tale. Do this or do that and fire some people, who file papers/data which were created by others, you know who, but keeping the lobbyists should hardly be considered as defining and describing the problem and let alone solving it.

Let me go one step further. In my view, a bigger and juicier fairy tale is QbD itself. It is an adult version of children’s fairy tales. Only it costs a lot more than children’s versions. Let me explain:

In our area (related to drug product quality), the quality of products, in particular oral products such as tablets and capsules, is determined by plasma levels of the drug. However, in most cases, the quality after initial stages of product development is established based on in vitro methods. The leading test in this regard is a drug dissolution test. People, who are not familiar with this subject, can take my words for it (considering my 25+ years of experience in all aspect of such testing) that it is the most simple test one can have in the entire science area perhaps after the procedure for taking body temperature. The idea behind this test is that if the drug dissolves (which we measure by this test), the drug will be absorbed in the body and will provide its intended efficacious effect. It is part of all GMP requirements and all national and international guidances and standards.

Now, is it too much to ask that anyone please show me that if the test, as it is performed, is indeed repeatable/reproducible and relevant to plasma drug levels? The answer is: There is absolutely no evidence available. In fact, there are tens, if not hundreds, of examples that exist to show that the test is not valid and it cannot predict the plasma drug levels with any accuracy. The FDA’s experimental studies confirmed this lack of an in vitro-in vivo link, formally known as in vitro-in vivo correlation (IVIVC). However, guidance has been developed, with the expectation that everyone should follow them to develop such IVIVC and predict plasma levels. Now the question is, how come we have the guidances and requirements of something when experimentally it has been shown that the test is neither valid nor relevant. Is it not a fairy tale?  I think it is.

I often refer to our over indulgence with statistics, statistical modeling, or computing because, I believe, people think that if we have enough data and powerful statistical software packages, we may be able to show IVIVC.  For at least 10 years, people and guidance have suggested and demanded such practices to show IVIVC.  Furthermore, believe it or not, people make claims of successes by using complex and propriety software (black boxes) which I am almost 100% sure that they do not understand. Remember, it is scientifically and mathematically impossible to achieve such IVIVCs and use these (Inna please, note your belief of checking/verifying the underlying science). If you would like to know more about the bizarre practices of drug dissolution testing, IVIVC, or often commonly made claims (fairy tales) please visit the website (www.drug-dissolution-testing.com).

Recently, the FDA has released a QbD-based document for establishing the quality of products based on the very concept, you guessed it, IVIVC.  They assume that if the title contains the word QbD in it, then the technique might work. I say; good luck. For my comments on the document, please see the link). I know of at least two upcoming conferences in the next few months on the very subject of developing IVIVC (storytelling), based on the same old concepts, instrumentation and procedures. What should we call these conferences? I will leave it up to you!

So, to conclude, believe it or not, we are telling adult versions of the fairy tales under the name of QbD. The mystery in our story comes from the statistical and computing parts. The story become interesting, mystical and sellable.