Author: Dr. Saeed Qureshi, Ph.D.

The quality of pharmaceutical products such as tablets/capsules may be defined as their ability to provide or release the drug present in the product in humans in an expected manner. It is important to note that a consumer or patient needs to take a drug product to have the drug (active ingredient) delivered to him/her in the right amount and in an expected manner. Therefore, a product provides only the means to deliver this drug.

For example, as shown above, a consumer requires juice, but the carton provides a means to deliver the juice to the consumer. If the juice comes out of the carton as expected, then the product becomes of quality. However, if the carton cannot pour out (deliver) the juice in the expected amount and in a consistent manner, even if the juice is present inside the carton, the product would not be considered of quality. The point is, even if the drug in a tablet/capsule is of the highest quality, but the product (tablet/capsule) is unable to release it, the product will be considered a poor quality product.

To assess the release characteristics of the drug products, thus quality, a pharmacopeial test known as drug dissolution test is conducted – a worldwide regulatory requirement for the approval and marketing of products.  The most commonly used standards or specifications for such purposes are pharmacopeial (e.g. USP), known as Q-based Acceptance Criteria. The Criteria may be summarized as if 24 units (capsules/tablets) are tested in a sequence of 6, 6, and 12 units, and the results are such that, on average units provide drug release of not less than 80% (Q-value of the product) of the labeled amount, while two units may release between 65% to 80% and one of the units may have a drug release of 55%. The product meeting these criteria will be considered approved or of quality. As the percentage of drug release is Q dependent, if the Q-value is lower for a product, the corresponding expected drug release would be lower.

To explain these complex approval criteria in simple terms, with the example of a 2L carton of juice, it would mean that juice cartons will be considered as a quality product if: they have a Q-value of (80%), out of 24 cartons, consumers should expect on average 1.6L (80% of 2L) of juice be poured out, and from two cartons it may be between 1.3 to 1.6L (65-80%) and for one carton 1.1L (or 55%). It should be obvious that if such standards/specifications are to be followed by carton manufacturers, which are equivalent to drug product manufacturers in this case, they would be out of business immediately for providing such extremely poor quality products. However, the pharmaceutical industry follows such standards, as a norm, with claims that they follow stringent quality standards. How does it make sense that a consumer/patient is expected to receive at random 55% to 80% of the labeled drug amount, and products are considered as of quality?

Therefore, it is humbly requested that regulatory authorities take note of such bizarre and poor criteria for establishing the quality of pharmaceutical products. Please pay attention!

Drug dissolution testing is a well-established analytical technique or test and is extensively employed for the development and assessment of pharmaceutical products, in particular, tablets and capsules. It would not be an exaggeration to say that it is the only test used to establish the quality of products. However, the tests and testers have never been qualified and validated for their intended purpose. Therefore, tests and testers cannot provide relevant and scientifically valid results regarding the quality of the tested products. This is simply common sense and scientific fact.

Some, however, still promote the current practices through training (conferences, seminars, and write-ups) as scientific and useful, which are not only causing delays and hindrances in addressing the issues at hand. This also creates false hope for analysts/scientists that this technique may provide useful and relevant results. Sometimes this training and advice are disguised with different fanciful names or topics such as clinical or bio-relevant, IVIVC, and bioavailability/bioequivalence assessment. Still, underneath it, all are flawed dissolution results. It is impossible to obtain reproducible and relevant dissolution results for any product using the currently suggested dissolution testers.

A simple and practical approach one could use to assess the credibility or authenticity of promoted claims and expertise is to request if the person (trainer or vendor’s representative) can determine dissolution characteristics of a given blinded sample of a product containing a highly soluble drug using an independently developed and validated method (see below). If yes, it could certainly be a good source for learning. Otherwise, one should use caution.

Please use caution and pay attention (link)

The main promoted claim from regulatory authorities such as the US FDA, Health Canada, and other national and international agencies concerning pharmaceutical products, such as tablets/capsules, is that they ensure that the public or patients receive quality medicinal or drug products. In this regard, it should go without saying that to establish the quality of products in a scientific manner, one would require to define the quality of a product in an objective manner with a measurable metric. However, at present, regulatory authorities worldwide do not provide such a definition or metric (link). Therefore, it is not possible to establish and/or assess the quality of the manufactured products.

Current practices of proclaimed monitoring and/or establishing the quality of products are based on traditional views and opinions compiled as Guidance documents and related compliance requirements. Although such documents and requirements are numerous of increasing complexities, their content remains subjective and arbitrary in nature, and in many cases, scientifically invalid and contradictory. This has given birth to fantastic illusionary practices of quality assessment named as pharmaceutical science, regulatory science, risk management (science), quality management (science), compliance, inspections, etc. However, the fact remains that no one is monitoring the quality of products, nor are they able to monitor it, as the “quality” is an unknown or undefined entity.  This is a fanciful example of an “illusionary science” promoted and practiced by most “experts” in the area, causing delays and hindrances in obtaining and manufacturing of products in a cost-effective and timely manner.

Such an impeding, confusing, and illusionary situation can be eliminated if one would define the quality of a pharmaceutical product, which is relatively easy to define as suggested here (link). Therefore, it is humbly requested that regulatory authorities take note of this request and consider including a definition of a quality product so that needed quality products could be manufactured in a timely and efficient manner.

Query:

Hello sir.. How r U? I want to know about Dissolution. If my product (Solid oral dosage form) is not available in any pharmacopoeia for dissolution then how can I select dissolution media, apparatus, RPM etc.??? how to develop dissolution method? its depend on solubility of drug or absorption of drug? Please sir help me about this topic. Thank you,

My response:

Thanks for asking the question and for your interest in my expertise. Considering what is available in the literature, including from US Pharmacopeia (e.g., General Chapters <711> and <1092>) and available guidance documents from FDA, Health Canada, and Europe, it is NOT possible to develop a dissolution method or select relevant experimental conditions to conduct a dissolution test. People do promote such practices. However, the fact remains that one cannot determine the dissolution characteristics of any product using the currently suggested apparatuses and methods. One of the main reasons for this effect is that currently suggested dissolution testers are not qualified/validated for dissolution testing purposes (e.g., see here). Therefore, any results obtained using such testers, in particular paddle/basket, would be null and void and GMP non-compliant.

On the other hand, considering the limitations of the current practices, I have proposed a slightly modified dissolution tester using a new stirring element known as the Crescent-shaped spindle, which provides a simpler and scientifically valid approach for conducting dissolution tests (1, 2). In this case, you would not need to develop a dissolution method at all, and dissolution tests can be conducted using a very simple set of experimental conditions. If you require more details about using the Crescent-shaped spindle, let me know, and I will be happy to help.

Best of luck!