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

Considering the non-specificity, because of confounded variabilities from the physiological system, drug release assessment of pharmaceutical products (tablet/capsule) for which this test is conducted, the bioequivalence test becomes a scientifically and statistically in-valid practice. See here for further discussion on the topic (1,2).

An in vitro drug release test, commonly known as drug dissolution test, which by its nature avoids the above mentioned non-specificity, provides a better alternative for assessing drug release characteristics of the products thus their quality. Pharmacopeias worldwide recommend this test. Unfortunately the recommended testers suffer a serious design problem thus providing irrelevant and unpredictable results not reflecting product quality or lack of it (3,4). In short, the drug dissolution tests as currently recommended are based on non-qualified and/or non-validated testers, hence results from the testing cannot be relied upon. Therefore, their use is to be discontinued as well.

As a solution, a simple revised dissolution testing approach has been suggested which would provide superior drug release evaluation thus quality of the products for human use (5, 6). In addition, as it is an in vitro technique, the test can be conducted without the use of human subjects avoiding unnecessary risk to participating healthy volunteers and/or patients. The suggested approach not only provides scientifically valid method for assessing quality of the pharmaceutical products but also would give much needed flexibility to pharmaceutical industry for innovation to bring out products faster, and with a reduced price, into the market.

Quality generic products without bioequivalence (BE) assessment – a simple and practical approach!

Considering the weakness (non-specificity) of BE assessments it is suggested that in vitro drug dissolution/release testing would provide a better alternative to establish quality of pharmaceutical products such as tablet and capsule. It is argued that the use of in vitro dissolution test should be the method of choice for developing and monitoring improved or better quality generic products because BE assessment focuses only on equivalence and not on the improvement of the product quality. Other significant advantages of using an appropriate in vitro dissolution test in lieu of BE assessment are described..
For further detailed explanation please follow the link.

Pharmaceutical products quality and bioequivalence assessments – what a waste and needless use of human subjects!

A bioequivalence study is conducted in humans to establish that two or more products are capable of providing same/similar blood/plasma drug levels. Underlying assumption is that if the products provide same plasma drug levels then their therapeutic effects would be the same as well, thus would allow interchangeability of the products such as the generics.

Therefore, for all practical purposes the bioequivalence assessment may be considered as a typical analytical chemistry test where the assessment is based on determining plasma levels. For conducting an appropriate and accurate analytical test, the test must follow some fundamental principles of analytical tests such as specificity and its validation (accuracy, precision and reproducibility). A test cannot be validated if it is not specific.

In this regard, a bioequivalence test is a non-specific test as plasma drug levels include (confounded) variabilities from stomach emptying/motility and liver metabolism of the drug – independent of the product characteristics. Therefore, caution is warranted in establishing quality of the test products based on the bio-equivalence test.

For further detailed explanation please follow the link.

Pharmaceutical product manufacturing as per current regulatory requirements!

Consideration should be given for simplicity and appropriate regulatory involvement as current practices and requirements certainly appear anti-innovation as well as making products less accessible and expensive to buy. For further discussion on the topic please follow the links (1, 2, 3).

Consumers and patients must wait, and suffer, for the availability of quality pharmaceutical products such as tablet/capsule as well as their genuine and affordable prices. The reason may surprise you!

It is important to note that at present availability of the pharmaceutical products such as tablet and capsule is heavily regulated, more accurately controlled, by the regulatory authorities worldwide. Manufacturers and suppliers have to follow extensive suites of protocols (national and/or international) to get their products approved for marketing. These protocols are often described by different names such as regulations, guidelines, standards etc. The manufacturers have to be in compliance with these protocols literally to the letter, which are mostly arbitrary in nature. Thus, in practical terms contrary to popular belief, there is limited or no room for deviation, simplification and/or innovation from these protocols at least from the manufacturers’ side.
In simple terms, these protocols may be considered as formats for data/results presentations, may these be for the product development or manufacturing – promoted as regulatory science. However, unfortunately, these are administrative and procedural requirements, not the practice and/or requirement of the science. The underlying “science” remains based on traditional practices and assumptions, more accurately may be considered as rituals. Therefore, with the passage of time and the introduction of extensive sets of standards and requirements, the burden of adhering to these regulatory formats (“guidelines”) has become increasingly frustrating, time consuming and financially challenging for the both, authorities and the manufacturers, without any added value to the product quality and/or benefit to the users.
In addressing these challenges, manufacturer bashing approaches (implied or explicit) are common and fashionable, often criticizing lack of their integrity and competencies. This approach certainly appears to be a deviation away from the regulatory mandate or requirements which is establishing and monitoring quality of the products and not that of assessing and criticizing manufacturing ability or capacity. Regulators’ and their associates should be able to establish if the manufactured products, at the consuming stage, are of the required quality, and by extension, safe and efficacious. However, they can’t at present – thus deviation from their mandated objective!
There are two reasons for this regulatory shortcoming: (1) Regulatory authorities have never defined required quality, and its associated parameter, for the product assessments. In fact, it could be argued that it is unknown to them. (2) Authorities require and enforce a large array of flawed product testing requirements for compliance purposes without their validations and relevance. As these requirements lack scientific credibility and validity, anybody, not just the manufacturers, would have difficulty in meeting or will be unable to meet the current regulatory requirements and expectations. For a more technical description of this aspect please consider viewing the links provided below.
Therefore, there is a clear need for re-evaluating the practice of setting regulatory standards and requirements starting with the definition of a quality product followed by the use of scientifically/GMP valid instruments and procedures. Otherwise, it is impossible for the manufacturers to produce quality products, and for the regulators developing and implementing appropriate guidelines and standards for product evaluation.

Some suggestions are provided to address these issues, and it is sincerely hoped that authorities will give consideration to these thoughts.

For further reading:
(1) http://www.drug-dissolution-testing.com/?p=3022
(2) http://www.drug-dissolution-testing.com/?p=3007
(3) http://www.drug-dissolution-testing.com/?p=2956
(4) http://www.drug-dissolution-testing.com/?p=3037
(5) http://www.drug-dissolution-testing.com/?p=2922

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