Author Archive

Citizen Petition (FDA) – Requesting withdrawal of drug dissolution apparatuses from FDA regulatory requirements

Today, I have submitted a Citizen Petition on the FDA site on the above mentioned subject (Tracking Number 1k2-94p3-9n4b). The content of the petition may be found here. I will keep you updated with the progress).

A revised Citizen Petition ((with procedural/format adjustment)) has been registered with the FDA (FDA-2018-P-3742) and can be found here ( (October 3, 2018)

F2 (similarity factor): An arithmetic skill-test – not a widget for quality assessment of pharmaceuticals

While surfing the internet, I found a prize Claim Form from Tim Hortons (Coffee Shop), which requires the winners to complete a skill test, a simple arithmetic exercise, to claim the prize (link). The exercise goes like this: multiply 2×4, add 8, subtract 4, add 6 and then show the correct answer. The exercise is unrelated to the quality or value of the prize, but a requirement for receiving the prize.

It reminds me of F2 (similarity factor) requirement, which is a very similar arithmetic exercise as well, with added parameters of taking logarithm and square root of numbers to come up with an answer to receive the “prize” of “regulatory compliance”, i.e. regulatory approval of your product (usually tablet/capsule) as bioequivalent with or without a human bioequivalence study. The point being, the skill test, in this case “similarity factor” unrelated to the product quality (scientifically, statistically or otherwise) and/or lack relevance to human bioequivalence study, but is required to meet a compliance requirement (link).

BTW, if you would be using a scientific calculator or computer spreadsheet for the calculations, then you might also be required “validation” of the calculator and spreadsheet software, and its use, to confirm if they or you are performing proper calculations for which one might require help of a CSV (Computer Software Validation) expert or consultant.

Just a thought in case you are considering using F2 (similarity factor) for your studies or product evaluation for regulatory compliance – otherwise you do not have to worry about this factor as this is pretty much useless exercise unrelated to quality aspect of the pharmaceutical products.

Data integrity/management violations or accommodating flawed regulatory requirements for compliance?

It has almost become fashionable to talk out loud about data mismanagement and integrity issues in the pharmaceutical industry highlighting lack of trust in the industry’s competency and honesty by the regulators and associates, which is really unfortunate. Please, do not be this distrustful! Many times many influential people in regulatory agencies come from the industry and vice versa. People cannot be dishonest only on one side. I doubt that the pharmaceutical industry has a higher ratio of bad behavior to good behavior when compared to any other industry – perhaps less.

In my opinion and experience, people in the pharmaceutical industry are doing their best to accommodate flawed (non-scientific and illogical) regulatory requirements. It is the regulatory authorities which have to correct their assessment methods and approaches including inspections.

For example, considering the case of generic product assessments, both in vivo (bioequivalence) and in vitro drug release/dissolution, are based on scientifically invalid methods and/or testers which cannot provide accurate and reproducible results as well as quality products. This would simply be impossible. To bring the data/results within acceptable range to meet compliance requirements, not the quality which is undefined as of yet by the authorities, the industry has to “play” with numbers and techniques such as repeats and discarding test results. This appears “data fudging” (or “dishonesty”), most often to those who have limited expertise and experience working in the laboratory environments. Please avoid such blames under the practices of computer software validation, data integrity, data security, missing data trails, etc. These are neither helping nor addressing the underlying issues.

The only possible solution to address this lack of trust situation is that the regulatory authorities, including pharmacopeias, have to clearly define quality of the products with an objective measurable parameter. Let the industry meet these standards using scientifically valid and qualified methods not working with the flawed science imposed by the authorities.

The following are some relevant links provide further details in this regards:

Quality of pharmaceutical products: “Regulatory Science” – its illusions, obstacles and a potential solution.

“Regulatory Science” is a term often used to describe practices of national, sometime international, bodies to establish and monitor quality of pharmaceutical products such as tablet and capsule, which would include safety and efficacy aspects as well. A clear description of the term “Regulatory Science” appears to be lacking. In practice it may be considered as a practice of setting standards (specifications) and protocols for describing and establishing quality of products available on the market for human use. The underlying concepts for setting standards/specifications and protocols usually come from the fundamental principles and laws of sciences, engineering and mathematics such as biology, chemistry, manufacturing and statistics. “Regulatory Science” uses these scientific principles to set specifications and protocols, rather than generating new scientific knowledge which is generated under the auspices of a specific scientific and/or engineering discipline. Therefore, regulatory bodies hardly ever generate new scientific knowledge but use it to generate specifications and standard procedures for implementation for the public good. The authorities also get the mandate to enforce the developed and suggested specifications and protocols – as these are intended to be followed. This mandate of enforcement results in the term “compliance” i.e. industry must adhere (“compliant”) to the standards and protocols for their manufactured products to be approved for marketing. Read the rest of this entry »

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.

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