Simulation and modelling practices for establishing quality of pharmaceutical products – valid intentions but invalid outcomes

Dear experts:

In the area of simulation and modelling, including developers of commercial software for such, note that I may not be able to argue with you regarding your methodologies of data analysis, modelling 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 the evaluation of tablet or capsule products for the prediction of plasma drug levels or profiles. That is, in vitro drug dissolution results which represent or simulate in vivo dissolution and by extension plasma drug levels or profiles. You would require such data to validate your simulation or modelling 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/modelling are regrettably of no use and would not help the industry, regulatory authorities or anyone else. Please, do not make claims of 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 i.e. 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, unable to validate the testers as dissolution testers. For example, no vendor, at present, can provide you 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 the fact that these stirrers when used as required for dissolution evaluations, because of their design and operation limitations and flaws, cannot provide valid and accurate dissolution results which is documented extensively in the literature.

In short, please use and promote the simulation and modelling techniques with care and certainly use extra caution in making claims for such about the future expectations and successes.

Regulatory requirements for establishing quality of pharmaceutical products – serious scientific and cGMP deficiencies and flaws!

[I posted the following comments on a discussion on the AAPS Community Forum; I think visitors of this website would also find it a useful read].

Thanks for your comments in response to my post. I am not sure how should I respond because focus of your comments is more of philosophical than subject matter.
Indeed I worked with Health Canada as a research scientist to provide support and critic on the underlying scientific aspects of the assignments. 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 quality assessment of the pharmaceutical products. The drug dissolution testing is one part of it and the second more noticeable is the claims of establishing quality of the manufactured products in particular tablet and capsule. These misunderstandings should be highlighted and addressed, in my opinion, not that be ignored and concealed otherwise everyone involved in it will lose their credibility, in particular scientific, for a long time to come.
Your statement that “We, working in the industry, have worked very hard trying to make it work.”, I am sorry what does it mean? Can you determine 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? Are you able to define and establish quality of a product using drug dissolution method, how? Please, note that quality of the products is not even defined yet with a measurable parameter, then how could a dissolution test be used as a quality control tool? These are some of the unanswered questions about the use of flawed science and its practice in manufacturing and regulatory assessments. These questions are not directed towards you as a person but to the industry and regulatory authorities in general. I do not know how I can specifically 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 by the regulatory scientists as well. 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 serious problems in regulatory requirements rather than suggestion of avoiding discussions of these issues. This would not be public service or service to patients but something else!
Regarding the scientific aspect 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 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 informing the authorities that fundamental scientific principles, as well as cGMP requirements, are being violated which need to be addressed so that industry could be able to function appropriately and public should receive accurate and honest information about the quality of the manufactured pharmaceutical products.
I will be happy to provide help to anyone in explaining the issues and suggesting 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.

With best regards.

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)


Response from the FDA, as of April 1, 2019, “FDA has been unable to reach a decision on your petition because it raises complex issues requiring extensive review and analysis by Agency officials”. A copy of the letter is available from the FDA site (

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:

Crescent-Shaped Spindle

Now Available
Click here