Quality of pharmaceutical products: Lack of scientific expertise and understanding at the authorities, including pharmacopoeia, levels requires attention!

[I posted the following comments on one of the LinkedIn discussions (link); I think visitors of this website would also find it a useful read]


I hear and feel your frustration. What you have described is reality, and quite common one. Why is so? The reason being, (Charles mentioned it somewhere as well) that authorities make claims of being science based when in fact they should be considered as regulatory authorities USING science and its principles. Let me explain this that they (authorities including pharmacopoeias) should not be doing science but USING science developed elsewhere only to set and enforce standards/specifications. However, authorities suggest, develop and enforce (through guidelines) analytical methods/procedures which everyone has to follow.

Working within a regulatory agency (Health Canada) for 30 years, and having relatively close interactions with counterparts in the FDA and the USP, I can say that they do not have the resources and expertise to understand or conduct the needed science, not even very basic one. In fact, practically they can never have the needed resources and expertise – but they make the related laws and enforce them. The law requires setting standards/specifications; however, somehow some (for their own gain) have twisted it to provide guidelines/advices as how the industry should behave and be working. They are guiding industry how to develop and validate methods, which methods to use, what approach to take (management, record keeping (“data Integrity”), QbD, PAT, statistical methods and modelling, manufacturing “continuous” vs “batch-wise” etc.). They have dug a big and deep hole for the Agency and the Agency does not know how to get out of it – as they do not have the needed scientific expertise. Their approach to address the issue is to have more guidelines and/or pass the blame to the industry and if possible punish it, sometime fairly harshly. Unfortunately, most likely country (or countries) will lose national/local industry and the underlying science, if have not already, to developing countries which are fairly ahead in the “game”.

To address the problem, in my view, authorities (and pharmacopoeias) have to go back to their main mandate or objective i.e. to become standards setting and enforcing organisations. For example, if they like that public should get quality products (in your case analytical methods) then they must define and provide standards/specifications for such which are missing at present. Therefore, Agency is not fulfilling its given mandate that needs to be addressed.

BTW if you have not noticed, my Citizen Petition (link) is precisely concerning and highlighting these flaws or weaknesses of the science, at the Agency level, in the area of analytical method development. The Agency suggests a number of guidelines for conducting drug dissolution test (which could be considered as one of the simplest analytical tests/techniques). Amazingly the recommended apparatuses have never been validated for their intended use, showing lack of understanding of scientific expertise at the authorities/pharmacopoeias. I am quite optimistic that my Citizen Petition will be accepted which will open the door for addressing the issues/frustrations, you and many other describe. Perhaps you would like to take this route as well to convey your specific issues to the Agency.


Similarity Factor (F2) – false and illusionary “statistics”!

In case, anyone is looking for sophisticated “statistical” jugglery, F2 provides an excellent example of thoroughly confusing people and science. Everyone has to use it (compliance requirement), as it is suggested in the regulatory (FDA) guidance documents. This parameter has not been described in statistics and absolutely has no relevance to the assessment of quality of manufactured products (tablet/capsule). It has been developed using drug dissolution data, and then applied to such data, which are invalid and irrelevant to start with. Calculation wise, it is simpler than calculating typical standard deviation more like a skill-test arithmetic exercise often provided at the back of lottery tickets or some sort of promotion or advertisement (link). Now consider this, a 2-day workshop/conference (yes two full days) is organized at the university level to explain and teach about it to make it look like science or statistics!!! (link or here). There certainly is a serious disconnect here between science and its practice at the regulatory level which requires attention.

Possible interpretation of the FDA response to my Citizen Petition – a positive and encouraging development

I submitted a Citizen Petition to the FDA, on October 1, 2018, requesting withdrawal of its guidance documents and related recommendations concerning assessments of drug dissolution characteristics of pharmaceutical products such as tablet and capsule (link).

The FDA responded, on April 1, 2019 on an interim basis, stating that FDA has been unable to reach a decision on the petition because it raises complex issues requiring extensive review and analysis by Agency officials (see here) or @ the FDA site (link).

My view is that a decision has already been made in support of the Petition (i.e. withdrawal of the guidance documents); however, FDA requires time for its implementation. My reasoning is as follow:

The Petition in fact has two parts; Part 1 (Rationale) – requiring the use of currently recommended dissolution testers (USP Paddle/Basket) which have never been validated and/or qualified for the intended purposes i.e. relevance to assessment of products dissolution in humans. Further, if a (blinded) product sample is given to an analyst, he/she would not be able to determine its dissolution characteristics, which makes the test scientifically invalid and practically useless. Part 2 – (Guidance withdrawal) considering the lack of validity of the apparatuses and testing as described in Part 1, the guidance documents become null and void as these depend on the use of non-validated apparatuses, hence their withdrawal was requested.

To dismiss the Petition, all FDA had to do was to provide: an evidence (link, reference and/or laboratory document) demonstrating that apparatuses are validated/qualified for the intended use. This should have required practically no time. Secondly, if an example was not available already for the analysis of a blinded sample, then all it would have taken the Agency couple of days (maximum) to run an experiment to establish dissolution characteristics of the product. As the testers are not qualified or validated, obviously, testing of a (blinded) sample is not possible. Thus, Petition could not be dismissed.

Therefore, in my view, FDA is considering withdrawing the guidance documents. This should not require extended time period as well. However, considering complexity of the issue (as noted in the response as well) such as meeting procedural formalities, along with associated adjustments, may require extra time which is understandable. This may easily take many months.

If my interpretation is correct, then it becomes important to inform the scientific and manufacturing communities promptly about the situation so that they should be cautious and avoid using the non-validated dissolution testers and methods. In addition, it will provide an opportunity to explore other options for addressing the issues, perhaps submitting ideas to the authorities as well for moving forward – noting that at present no one is determining, or can determine, valid or useful dissolution results of any product (1, 2).

I look forward to a prompt resolution of the issue by removing the non-validated/non-qualified (thus non-GMP) dissolution testers and tests, along with the associated guidance documents, from the regulatory system leading to simpler, efficient and science-based approaches for the assessment and monitoring quality of the pharmaceutical products.

Strange regulatory and pharmacopeial requirement for establishing quality of pharmaceutical products!

Requiring the use of drug dissolution testers, which do not (and cannot) determine dissolution characteristics of any product (tablet and capsule in particular). Amazing fact is that these are the only ones mostly recommended and accepted by the authorities, even sometimes as substitute for clinical (bioequivalence) assessments. Why? How does it make sense – scientific or otherwise?

Some links for further details:
(1) Note that no one can determine, or has determined, dissolution characteristics of any product using the currently suggested apparatuses and/or methods. It has all been an illusion! (link)
(2) Bio-waivers! (link)
(3) Pharmacopeial Dissolution Testers (link)

Authorities are on the defensive! This may provide an opportunity for a change for the better as well as to be heard regarding assessing the quality of pharmaceutical products.

A couple of days ago I read two recent articles, one from the US FDA [1] and the other from the USP [2], defending and rationalizing regulatory and pharmacopeial practices and standards for assessing the pharmaceutical products. These reports appear to be in response to the concerns often expressed regarding deficiencies in regulatory product evaluations. This article provides an alternate view of the issues and suggests a solution for the authorities’ consideration. Read the rest of this entry

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