… provides in-depth discussion on establishing and monitoring the quality of pharmaceutical products in particular tablets and capsules. I hope you will find the chapter useful.
Chapter title: “Quality” of pharmaceutical products for human use – underlying concepts and required practices, published in
Drug Delivery Trends: Expectations And Realities Of Multifunctional Drug Delivery Systems Volume 3 Edited by Ranjita Shegokar, PhD., Available from Amazon (March 18, 2020), link.
Reasons:
(1) They do not define the quality of the products. Hence it cannot be measured and/or established (link).
(2) Suggested methods and procedures lack scientific relevancy and validity (link)
(3) GMP practices, including inspections, are about the operation of manufacturing, not per se reflection of product quality (link).
A discriminatory test, in general, is a test or procedure which would measure a given parameter and would be able to differentiate/discriminate between tested objects where the differences exist. A common and simple example of such a procedure or routine is monitoring body temperature using a thermometer. A thermometer is usually placed in the mouth, and after a bit of waiting, the thermometer provides a body temperature reading. Thermometers are pre-standardized/calibrated against reference standards (temperatures). There is no thermometer or monitoring procedure developments, no discriminatory test/procedure development, no “life-cycle” variations in procedures, and no subject-dependent (gender, age, race, body weight/type) procedures. Note that a thermometer does not even tell if the person has a fever. It will only tell body temperature, which is interpreted as whether the person has a fever. Point being a pre-standardized/calibrated thermometer by default becomes a discriminatory test or tester. This is how life/science works.
Similarly, a pre-standardized/calibrated dissolution test/tester must provide a product’s drug dissolution/release characteristic (tablet/capsule). Placing a product into a vessel equipped with a stirrer with pre-set rpm containing pre-defined solvent, its volume, and temperature is the dissolution test/tester. Determining drug release after a pre-defined time would provide the answer, i.e., drug dissolution characteristics of the product. Period! There should be no need for dissolution methods development of any type at the product/formulation development and/or evaluation stages.
Why do we have or need dissolution method development practices, including discriminatory methods – pure ignorance and incompetency of the subject? This is simply nonsense and fake-science! Be clear that no one is currently determining the dissolution characteristics of any product, hence the quality for which this test is conducted and promoted.
Seek sensible and scientifically valid solutions! (1, 2, 3, 4)
The quality of a drug product, such as a tablet and capsule, may be defined as the product’s ability to release the drug in humans in the expected amount and consistently. In technical terms, it is known as the drug release characteristics of the product. This characteristic is established at the manufacturing stage by conducting an in vitro test known as a drug dissolution/release test. The test is commonly conducted as recommended by regulatory agencies (such as FDA) and pharmacopeias (such as USP) using paddle and basket apparatuses. The quality assessment of most of the solid dosage forms, if not all, in particular, tablet and capsule products, is determined using this test.
The testers for this test, however, have never been validated for the intended purpose. Therefore, conclusions drawn from this test, hence the quality of the products, would be invalid and false. Use caution in accepting and/or making claims about the quality of products! (link)
Seek help for conducting a scientifically valid drug dissolution test and establishing the quality of the drug products.
Drug dissolution testers, particularly the most commonly recommended ones (paddle and basket), are based on a closed system/environment, i.e., without a drain. Therefore, it is not possible to have or create a sink condition. Yet, authorities and pharmacopeias require it while “experts” create it. How? Magic!
In addition, one does not require a sink condition for in vitro drug dissolution testing. 900 ml of water with or without a small amount of solubilizer sufficient to (freely) dissolve the expected amount of drug present in the product – is all one needs. For further details, please follow the link to simplify your life and avoid wasting time and resources (link).
One cannot avoid being part of it. It is the regulatory agencies’ (e.g., FDA) and pharmacopeias’ (such as USP) practices and requirements to use the non-validated/non-qualified (hence non-GMP) testers and tests causing the fraud. Any claim concerning the quality of the products, in particular tablets and capsules for brand-name and generic products, must be false.
Blaming and punishing the industry for product quality and manufacturing are not relevant or valid and would not help. Instead, the authorities and pharmacopeias need education, advice, and help in defining quality and setting its standards and specifications (1, 2).
I will be happy to explain the issues with quality assessments in detail and can provide solutions to address them (link).
“Understanding How the Public Perceives and Values Pharmaceutical Quality” link
During today’s presentation ( @ 1:58), responding to a question from the floor concerning drug dissolution methods at the FDA, Dr. Cindy Buhse stated that they use USP methods. Unfortunately, Dr. Buhse does not realize that USP methods are based on non-validated/non-qualified (hence non-GMP compliant) dissolution testers. These are the most commonly recommended, i.e., paddle and basket apparatuses. Including a test or tester in the USP does not make it valid or qualified. Validation requires scientific/experimental evidence showing that the testers are good/fit for the intended purpose, which these testers lack.
Scientific studies have clearly shown that these testers do not, and cannot, provide relevant and valid results. It would, therefore, be requested that all the results obtained using these testers should be considered null and void and be removed from product quality evaluations. Furthermore, it should be noted that Citizen Petition is under consideration at the FDA requesting the withdrawal of these testers and corresponding tests from regulatory use (link).
These are often visitors to manufacturing facilities under the titles of investigators, inspectors, auditors, consultants, experts, compliance officers, etc. (internal or external to the regulatory agencies). Logically and scientifically speaking, they provide no useful or valuable purpose for developing, manufacturing, and assessing pharmaceutical products such as tablets and capsules. They cause hindrances, interruptions, and exuberant costs to industry and by extension to consumers/patients. Their observations and conclusions are based on subjective and narrative discussion, not scientific, measurable, or quantifiable assessments. Their reports are often filled with fancy catch phrases or acronyms such as cGMP, validations, CSV, data integrity (DI), record-trailing, inappropriate SOPs, improper documentation, root cause analysis, and CAPA. These phrases are, in general, book/record keeping (admin/clerical) exercises mostly unrelated to the quality of the products and/or the manufacturing quality. Note that any deficiency or observation, unsupported with corresponding direct and/or validated evidence of the quality of products or their manufacturing (which often is the case), must be rejected as superficial or irrelevant. The industry should protect its employees’ expertise, academic credentials, and manufacturing competence from these “visitors,” who often lack the needed expertise. Seek help protecting your expertise and manufacturing quality products with scientific evidence, knowledge, and support. The following links to articles describing the basis of irrelevancy of often reported deficiencies.
(1) Biggest violators of GMP (link)
(2) Can Regulatory And Pharmacopeial Compliance Practices Establish Quality? (link)
(3) Consumers and patients must wait and suffer for the availability of quality pharmaceutical products such as tablets/capsules and their genuine and affordable prices. The reason may surprise you! (link)
(4) Making unsubstantiated and/or false claims by the regulatory authorities, including FDA, regarding the quality of pharmaceutical products (link)
(5) Pharmaceutical product manufacturing as per current regulatory requirements! (link)
(6) Promoting quality standards for drug products: Scientifically speaking, please be systematic and logical! (link)
(7) Quality assessment of pharmaceutical products – regulatory/pharmacopeial standards and methods require urgent attention! (link)
(8) Regulatory/pharmacopeial assessments of the quality of the pharmaceutical products – in the grip of falsehood and fraud! (link)
(9) Time to rescind the regulatory requirements of bioequivalence evaluations and the current pharmacopeial drug dissolution practices as these do not provide quality assessment of pharmaceutical products (link)
(10) Why are regulatory authorities, including pharmacopeias, allowing and promoting (through guidance documents and seminars/conferences) the use and sale of non-GMP-compliant drug dissolution testers? (link)
Often I visit the PubMed site (link) to search for recent articles with the search phrase “drug dissolution.” A chart on the top right corner of the search outcome shows the number of articles published yearly for the search phrase. I have reproduced (below) this chart from 1970 to 2019. As seen from the chart, there is a dramatic decrease in the number of publications during 2019. This might not be a scientific or statistical conclusion; however, the decrease (about 27%) is significant.
There is a strong possibility that scientists have lost credibility and faith in the relevancy of drug dissolution testing. I was highlighting for the past years through my citizen petition to the FDA in 2018 (link). In the future, people should take note of this observation and use caution in conducting dissolution tests using USP testers and methods.
