Author: Dr. Saeed Qureshi, Ph.D.

While surfing the internet, I found a prize Claim Form from Tim Hortons (Coffee Shop). It 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. It is a very similar arithmetic exercise as well, with added parameters of taking the 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 is the skill test, in this case, the “similarity factor” unrelated to the product quality (scientifically, statistically, or otherwise) and/or lacks relevance to the human bioequivalence study but is required to meet a compliance requirement (link).

By the way, suppose you would use a scientific calculator or computer spreadsheet for the calculations. In that case, you might also be required “validation” the calculator and spreadsheet software to confirm that they or you are performing proper calculations, for which one might require the help of a CSV (Computer Software Validation) expert or consultant.

The F2 (similarity factor) is an invention of the FDA for regulatory compliance. Otherwise, one does not have to worry about this factor as this is a useless exercise unrelated to the quality of the pharmaceutical products.

“Regulatory Science” is a term often used to describe practices of national, sometimes international, bodies to establish and monitor quality of pharmaceutical products such as tablet and capsule, which would include safety and efficacy aspects. However, a clear description of “Regulatory Science” appears to be lacking. It may be considered a practice of setting standards (specifications) and protocols for describing and establishing the quality of products available 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 developed 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 are mandated to enforce the developed and suggested specifications and protocols – as they are intended to be followed. This mandate of enforcement results in the term “compliance,” i.e., the industry must adhere (“compliant”) to the standards and protocols for their manufactured products to be approved for marketing.

The authorities’ role may be explained with an analogy of a distribution company (e.g., Amazon, eBay, Costco) which acts as a go-between between a manufacturer and its consumers. These distributors hardly ever manufacture or develop any of the listed products they sell; however, they ensure the quality of the products and their appropriate delivery to the consumers or customers meeting well-described quality standards/specifications. The distributors’ role is limited only to providing or transferring quality products from manufacturers to consumers, nothing more. If a product has a fault or issue of quality/compliance discovered through the distributor’s internal audit or by a third party. In that case, the particular supplier or manufacturer of the item is informed. The manufacturer has to deal with the issue. The distributor does not start addressing the issue or advising the manufacturer on fixing the manufacturing problem as they would lack the needed expertise. If the manufacturer cannot resolve the issue, the product must be taken off the market.

The regulatory authorities’ mandate is that of a go-between, like a distributor described above, to ensure that the manufactured products available on the market are quality. For this, authorities have to define a “quality product” and then set its “quality attributes,” along with measurable specifications, in collaboration with the manufacturers. Unfortunately, the authorities do not provide a definition/criteria for the “quality product” but expect that the manufacturers must offer quality products – obviously, they can’t! Therefore, by default, manufacturers become guilty of not providing quality products, and thus they need to be “corrected or fixed.”

With this presumed lack of trust or capability of the manufacturers came the regulatory guidance and inspection-based system to guide and/or advise the manufacturers on how to manufacture quality products. Therefore, the mandated responsibilities of the authorities have completely deviated (metamorphosed) from establishing and monitoring quality of the products to the quality of the manufacturing. Considering the lack of competencies of the authorities in manufacturing, as they never manufacture or develop any product like the above-mentioned distributors, understandably, they would be unable to advise the industry appropriately and correctly, especially in the absence of a definition of quality products and their attributes. Rather than providing appropriate definitions and standards for quality products that which industry should follow, authorities frequently start a new fad of “science-based guidance” documentation such as SUPAC, IVIVC, QbD, ICH, cGMP, PAT, inspections, etc., commonly even violating well-established scientific principles, for enforcing a new set of requirements for manufacturing. This practice has resulted in perpetual cycles of more guidance documents, reorganizations, rebranding, and policing activities turning the authorities from facilitators to bullies blaming and/or punishing the industry for not following quality standards and practices. The industry can’t follow arbitrary protocols and/or employ non-validated tests and procedures, as recommended and required by the authorities, to provide a scientifically valid outcome and, by extension, quality products. This has put an enormous administrative and financial burden on the industry and society in general – without improvement in manufacturing or availability of quality products and/or addition of any other value.

Therefore, to resolve this issue, the regulatory authorities worldwide should reconsider focusing their role as the standards-setting organizations for the products and not providing guidance to the industry on how to manufacture products and market these to the public.

Some relevant links which would be helpful to read in this regard (1, 2, 3, 4)

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 a drug dissolution test, which by its nature avoids the above-mentioned non-specificity, provides a better alternative for assessing the drug release characteristics of the products and 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, the 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 a scientifically valid method for assessing the quality of pharmaceutical products but also would give much-needed flexibility to the pharmaceutical industry for innovation to bring out products faster and with a reduced price into the market.

Considering the weakness (non-specificity) of BE assessments, it is suggested that in vitro drug dissolution/release testing would provide a better alternative to establishing the quality of pharmaceutical products such as tablets and capsules. It is argued that using in vitro dissolution tests 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 improving the product quality. Other significant advantages of using an appropriate in vitro dissolution test in place of BE assessment are described.

For a further detailed explanation, please follow the link.

A human bioequivalence study is conducted to establish that two or more products can provide the same/similar blood/plasma drug levels. The underlying assumption is that if the products provide the 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 a typical analytical chemistry test where the assessment is based on determining plasma levels. For an appropriate and accurate analytical test, the test must follow some fundamental principles of analytical tests, such as specificity and 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 the quality of the test products based on the bio-equivalence test.

For a further detailed explanation, please follow the link.

It is important to note that, at present, the availability of pharmaceutical products such as tablets and capsules is heavily regulated and more accurately controlled by regulatory authorities worldwide. As a result, manufacturers and suppliers must 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 must comply 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.
These protocols may be considered formats for data/results presentations for product development or manufacturing, which are promoted as regulatory science. However, unfortunately, these are administrative and procedural requirements, not the science’s practice and/or requirement. The underlying “science” remains based on traditional practices and assumptions, more accurately, may be considered as rituals. Therefore, with the passage of time, the burden of adhering to these regulatory formats (“guidelines”) has become increasingly frustrating, time-consuming, and financially challenging for both authorities and 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 the 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 the quality of the products and not 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 product assessments. In fact, it could be argued that it is unknown to them. (2) Authorities require and enforce many flawed product testing requirements for compliance without their validations and relevance. As these requirements lack scientific credibility and validity, anybody, not just the manufacturers, would have difficulty meeting or meeting the current regulatory requirements and expectations. Please consider viewing the links below for a more technical description of this aspect.
Therefore, there is a clear need for re-evaluating the practice of setting regulatory standards and requirements, starting with defining a quality product and then using scientifically/GMP-valid instruments and procedures. Otherwise, it is impossible for the manufacturers to produce quality products and for the regulators to develop and implement appropriate guidelines and standards for product evaluation.

Some suggestions are provided to address these issues, and authorities sincerely hope to consider these thoughts./*/ For further reading (1, 2, 3, 4, 5)

A discussion is provided showing the weakness of BE assessments for comparing or establishing the quality of products such as tablets/capsules. It is argued that in vitro drug dissolution/release testing would provide a better alternative for the assessment of the quality of such pharmaceutical products. Please click here for complete article.

People try to understand the logic and scientific principles behind the (pharmacopeial and regulatory) “compliance” requirements for meeting the quality aspect of the pharmaceutical products such as tablets/capsules. However, there is hardly any scientific principle involved in most of the area’s current “compliance” requirements. Most compliance requirements are based on subjective (individual or collective) opinions and guesses, often presented through publications or regulatory guidance documents to gain or establish their authenticity. For example, in establishing the quality of the manufactured products, such as tablets/capsules of both generic and branded products, nowhere is defined what would be considered a “quality product” and how the quality should be measured or established. However, all the pharmacopeial and regulatory requirements (national or international) claim to achieve it. Is it not interesting that the quality of a product is not defined or known but claimed to be achieved? How?