In the area of simulation and modeling, including developers of commercial software, note that I may not be able to argue with you regarding your methodologies of data analysis, modeling and/or simulation aspects as this is not my area of expertise. However, I know with certainty that you would require valid and accurate data for your analysis purposes. The difficulty is that you would not have access to such valid and accurate data, at least for evaluating tablet or capsule products for predicting plasma drug levels or profiles. The in vitro drug dissolution results represent or simulate in vivo dissolution and, by extension, plasma drug levels or profiles.
You would require such data to validate your simulation or modeling outcome at least for the product development and manufacturing stages. Unfortunately, no one, at present, is generating or can generate valid in vitro dissolution data. Thus, your efforts of conducting simulation/modeling are regrettably of no use and would not help the industry, regulatory authorities, or anyone else. Please, do not make claims about the successes and usefulness of such exercises.
One of the main reasons for not being able to obtain valid in vitro dissolution or drug release data is that the recommended and required (e.g., from USP and FDA) dissolution testers for such purposes have never been shown to provide valid and accurate dissolution results. These testers have never been validated for their intended use or purpose. Vendors/manufacturers make extraordinary efforts and take pride in providing “compliant” testers, i.e., meeting or exceeding “physical or fixed” specifications according to the pharmacopeial (such as USP) requirements; however, they are unable to validate the testers as dissolution testers. For example, no present vendor can provide valid in vitro dissolution results if given a blinded sample of a tablet/capsule product. Therefore, in this respect, claims made by the vendors are also not accurate that they are selling or manufacturing dissolution testers. At best, the only claim they can, or should, make is that they are selling simple stirrers. Perhaps more disturbing is that these stirrers, when used as required for dissolution evaluations, cannot provide valid and accurate dissolution results, which are documented extensively in the literature because of their design and operation limitations and flaws.
In short, please use and promote the simulation and modeling techniques with care and certainly use extra caution in making claims about future expectations and successes.
[I posted the following comments on a discussion on the AAPS Community Forum. I think visitors to this website would also find it a helpful read].
Thanks for your comments in response to my post. I am unsure how I should respond because your comments focus more on philosophy than subject matter.
Indeed I worked with Health Canada as a research scientist to support and criticize the assignments’ underlying scientific aspects. Most of my laboratory work has been published, and views have been known publically as well – as you noted. I have never undermined any ones’, including authorities’, hard work or practices.
However, through my laboratory work and related applied experience, I did find some very disturbing misunderstandings about the use of science for the quality assessment of pharmaceutical products. Drug dissolution testing is one part of it; the second, more noticeable, is the claims of establishing the quality of the manufactured products, particularly tablets and capsules. These misunderstandings should be highlighted and addressed, in my opinion, not be ignored and concealed; otherwise, everyone involved in it will lose their credibility, in particular scientific, for a long time to come.
Your statement, “We, working in the industry, have worked very hard trying to make it work.” I am sorry, what does it mean? Can you determine the dissolution characteristics of a given blinded product sample? Have you used a validated dissolution tester for dissolution testing? How? How could you or anyone else develop a valid dissolution method without the availability of a validated dissolution tester? Can you define and establish a product’s quality using the drug dissolution method? How? Please, note that the quality of the products is not yet defined with a measurable parameter. Then how could a dissolution test be used as a quality control tool? These are some unanswered questions about using flawed science and its practice in manufacturing and regulatory assessments. These questions are not directed toward you as a person but at the industry and regulatory authorities in general. I do not know how to direct my concerns only to the regulatory authorities. I do not think that AAPS Community Forum is only for the industry. I observed it is equally read and participated in by the regulatory scientists. A discussion was just started on this community forum by a scientist from FDA (e.g., see under METHODS IN IMAGING DATA ANALYSIS).
So please join hands with me and inform the regulatory authorities that there are severe problems in regulatory requirements rather than a suggestion of avoiding discussions of these issues. This would not be public service or service to patients but something else!
You noted from my post, “A dissolution method should not be used for product development until and unless it has been clearly shown ………….” This is not my view or my suggested requirement – this is a general principle of science and regulatory (i.e., cGMP) requirement. If anyone is not following or meeting this requirement, then the results obtained would not, at least should not, be accepted under (cGMP regulation. As an example, I quote the following three FDA regulations for your information [21 CFR 111.320, 21 CFR 820.72, 21 CFR 211.194 (a) (2)]. Please correct me if I am wrong on this.
In the end, please consider using this forum to inform the authorities that fundamental scientific principles, as well as cGMP requirements, are being violated, which need to be addressed so that the industry could be able to function appropriately and the public should receive accurate and honest information about the quality of the manufactured pharmaceutical products.
I will be happy to help anyone explain the issues and suggest possible solutions to such if you suggest or provide leads in this regard. I look forward to future fruitful discussions on the subject with you.
Today, I submitted a Citizen Petition on the FDA site on the subject mentioned above (Tracking Number 1k2-94p3-9n4b). The content of the petition may be found here. I will keep you updated on the progress).
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.
Consideration should be given to simplicity and appropriate regulatory involvement as current practices and requirements certainly appear anti-innovation and make products less accessible and expensive. Please follow the links for further discussion on the topic (1, 2, 3).
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)
