Author: Dr. Saeed Qureshi, Ph.D.

The stated and promoted mandate of regulatory authorities, including pharmacopeias, is to ascertain that consumers and patients receive safe, efficacious, quality pharmaceutical products such as tablets and capsules. It is important to note that at the commercial manufacturing stage, the safety and efficacy of the products are not usually monitored, only the quality which acts as a surrogate for the safety and efficacy. Therefore, authorities can only claim that they are establishing or monitoring the quality of the products, and by extension products would be considered safe and efficacious. From the industry perspective (both brand-name and generic), it is, in fact, a relatively simple and standard exercise of manufacturing fine chemicals and their composites. This follows the same or similar scientific/manufacturing principles and practices for manufacturing any other chemical or its products.

Considering the strong hold of the authorities, manufacturers and distributors can only sell or import/export products that would meet the regulatory/pharmacopeial requirements and/or standards, i.e., they have to be in compliance. In this regard, it should be important and critical to note that “quality of the products” or “product quality” is an undefined term or parameter, and thus cannot be determined or established. Therefore, claims made by the authorities and/or pharmacopeias for establishing quality are not correct or truthful.

The main reason for this false claim or practice is that the authorities consider and promote compliance as quality, which is incorrect. At present, compliance is not linked to the quality of the products (as it is undefined) but to numerous self-created arbitrary, flashy, and catchy phrases (considered as requirements/standards/practices). They are data Integrity (DI), risk based-assessments, Real World Evidence (RWE), Quality by Design (QbD), Process Analytical Technologies (PAT), regulatory perspectives, precision medicines, patient-centric, and many others. However, the fact remains that none of these requirements and practices has any link to the quality of the products (logically or scientifically) as “quality” is an undefined parameter – but confusing and frustrating vocabulary and mumbo-jumbo for regulatory purposes.

This arbitrariness in setting standards and requirements has choked manufacturing and severely restricted access to actual quality products for patients at affordable prices. One of the main reasons for this manifestation is the implementation of arbitrary standards/requirements through facility inspections by “experts” internal or external to the authorities through so-called GMP practices and/or the implementation of other guidelines. Many of these “experts” may, in reality, be characterized as “snake oil salesmen or women” applying “laws” by choosing or picking some “exploitable,” mostly superficial deficiencies (“observations”), to bad mouth the industry and its staff. On the other hand, the industry and the staff watch and bear this absurdity and humiliation with horror without any options of being heard or reacting. The industry has no choice but to bow down to survive – hence the fraud continues with a vengeance and “gained admiration/credibility” of the “experts.”

In short, it is not possible for public to have quality drug products until authorities start setting logical and science-based standards and specifications. As a start, the “quality” of products needs to be defined clearly with a measurable parameter using valid scientific principles. The irony is that if relevant science and its principles are to be followed, these issues can easily be addressed. This not only would result in reducing the regulatory burden but also provide freedom to the industry for manufacturing quality products as well as open the doors for innovations for affordability and accessibility. I describe such concerns and potential solutions in extensive details through my blog (link) and would be happy to explain these in person as well if it helps. Some suggested blog articles:
(1) Promoting quality standards for drug products: Scientifically speaking, please be systematic and logical! (link)
(2) Possible interpretation of the FDA response to my Citizen Petition – a positive and encouraging development (link).
(3) Pharmaceutical product manufacturing as per current regulatory requirements! (link).
(4) Consumers and patients must wait, and suffer, for the availability of quality pharmaceutical products such as tablet/capsule as well as their genuine and affordable prices. The reason may surprise you! (link).
(5) Comparing Quality Standards – Pharmaceutical vs Consumer Products (link).

In a recently published article (link), titled “FDA Q&A: Generic Versions of Narrow Therapeutic Index Drugs National Survey of Pharmacists’ Substitution Beliefs and Practices” by a Senior Science Advisor, responding to a question regarding concerns expressed in a recently published book, the author of the article claims that “…Americans can be confident in the quality of the products the FDA approves.”

It is to be noted that the claim made by the FDA cannot be considered truthful and/or scientifically valid. The reason is that the quality of the products, in particular tablets and capsules, has not been defined and thus cannot be measured or established. Furthermore, meeting compliance requirements as a substitute of “quality”, which in most cases are arbitrary, lacks validation of the suggested methods and/or procedures (both in vitro and in vivo) for their relevancy and accuracy for their intended purpose or claims (link). Therefore, it is requested that the FDA reconsider its

Response to a recent query

I am sorry I cannot be of help because, in my view, based on 30 years of research experience, as stated frequently, currently recommended and used dissolution testers  (USP Paddle/Basket) are non-validated testers. Hence, they cannot provide any product’s relevant dissolution methods and/or results. Furthermore, developing a discriminating dissolution test, often promoted and suggested as a regulatory/pharmacopeial requirement, is a scientifically flawed or invalid concept. A properly developed dissolution test by default becomes a discriminating test; however, as one cannot develop a relevant and/or appropriate dissolution test at present, thus one cannot develop a discriminating test.

On the other hand, if you like to work with some modified version of a dissolution tester, developed in-house or as I have suggested (with a crescent-shape spindle),. Then, there is a possibility of conducting an appropriate and relevant dissolution test, which will act as a discriminating test too. I will be happy to discuss this approach in further detail if you like to explore this further.

In the meantime, the following blog article may help explore the topic further (link).

They promote and impose fake science, irrelevant and invalid scientific methods, false data/statistical analyses, and foolish manufacturing/inspection practices. This is also creating unscrupulous “experts” and “expertise” in the area, multiplying the damage to the industry, consumers, and patients due to the limited availability of pharmaceutical products and significantly higher costs.

Stuck and suffocated!

Some relevant links: (1, 2, 3, 4, 5)

Below are some posts about the Similarity Factor (F2), which is suggested for assessing the quality of pharmaceutical products using drug dissolution testing.

(1)    F2 – Similarity Factor (Link)

(2)    F2 – Similarity Factor (A Deficiency). (Link)

(3)    F2 (similarity factor) or a 2F (faulty facts) factor (Link)

(4)    F2 – Similarity Factor (Link)

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

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

If one asks a physician and/or pharmacist whether a prescribed product is of quality, the response would be – sure. But why would it be of quality? Again, the response would be because it is approved by regulatory authorities such as FDA, Health Canada, and other national agencies as they assess and establish the “quality.”

Now ask the authorities the same question! Their response would be sure – we use up-to-date knowledge and the most elaborate manufacturing facilities assessment approaches for such assessments. But the question is, what are “such assessments”? Would you be able to equate or differentiate the quality of two given “blinded products” from different manufacturers or generic vs. brand names? Again, their answer would likely be – well, it is not that simple!

The reason being no one knows what a quality product is! It has never been defined and hence cannot be determined and/or established. Period!

This is clearly a violation of commonly accepted manufacturing practices (such as US FDA – GMP/GLP requirements) which dictates that tests and testers employed must be validated and qualified for their intended use. The use of non-GMP compliant apparatuses provides incorrect or false (quality) assessment of pharmaceutical products in particular tablet and capsule – for both innovator and generic products. Will it not be correct to say that the public and the manufacturers are receiving false information and assurance about the product quality?

Why are the pharmacopeias, in particular USP, not seeking and/or accepting new ideas and scientific research for addressing the issue? No one at present is determining, or can determine, the drug dissolution characteristics of any product using pharmacopeial dissolution testers.

Please share your thoughts and discuss approaches to address the situation so that the development and manufacturing of pharmaceutical products (such as tablets/capsules) could become simpler and more efficient.

Some relevant links for further details  (1,  2, 3, 4)

[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]

Bob:

I hear and feel your frustration. What you have described is reality and quite a common one. Why is it so? The reason (Charles mentioned it somewhere as well) is that authorities make claims of being science-based when they should be considered as regulatory authorities USING science and its principles. Let me explain that they (authorities, including pharmacopeias) 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 that everyone must 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, even a very basic one. In fact, practically, they can never have the necessary resources and expertise – but they make the related laws and enforce them. The law requires setting standards/specifications; however, some (for their own gain) have twisted it to provide guidelines/advice on how the industry should behave and be working. They are guiding the industry on how to develop and validate methods, which methods to use, and what approach to take (management, record keeping (“data Integrity”), QbD, PAT, statistical methods and modeling, 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 addressing the issue is to have more guidelines and/or pass the blame to the industry and, if possible, punish it, sometimes fairly harshly. Unfortunately, most likely the country (or countries) will lose national/local industry and the underlying science, if they have not already, to developing countries that are fairly ahead in the “game.”

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

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

Best.

In case anyone is looking for sophisticated “statistical” jugglery, F2 provides an excellent example of thoroughly confusing people and science. Everyone must use it (compliance requirement), as suggested in the regulatory (FDA) guidance documents. This parameter has not been described in statistics and is irrelevant to assessing the 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. Calculation-wise, it is simpler than calculating typical standard deviation, like a skill-test arithmetic exercise often provided at the back of lottery tickets or some 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 disconnect between science and its practice at the regulatory level, which requires attention.

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

On April 1, 2019, the FDA responded on an interim basis, stating that the 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).

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

The Petition has two parts; Part 1 (Rationale) – requires 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 the 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, making 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 the FDA had to do was provide 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 it would have taken the Agency couple of days (maximum) to run an experiment to establish the dissolution characteristics of the product. As the testers are not qualified or validated, obviously, testing of a (blinded) sample is not possible. Thus, the Petition could not be dismissed.

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

If my interpretation is correct, it becomes important to promptly inform the scientific and manufacturing communities 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 no one is determining, or can determine, valid or useful dissolution results of any product (1, 2).

I look forward to promptly resolving the issue by removing the non-validated/non-qualified (thus non-GMP) dissolution testers and tests and the associated guidance documents from the regulatory system. It will lead to simpler, efficient, and science-based approaches to assessing and monitoring the quality of pharmaceutical products.