Author: Dr. Saeed Qureshi, Ph.D.

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.

It is requiring drug dissolution testers, which do not (and cannot) determine dissolution characteristics of any product (tablet and capsule in particular). The amazing fact is that these are the only ones mostly recommended and accepted by the authorities, even sometimes as a 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)

A couple of days ago, I read two recent articles, one from the US FDA [1] and the other from the USP, defending and rationalizing regulatory and pharmacopeial practices and standards for assessing pharmaceutical products. These reports appear to respond 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. For the complete article, please follow the link (http://www.drug-dissolution-testing.com/?p=3198).

In the report from the US FDA, the emphasis is on justifying the current regulatory practices for adequately evaluating manufacturers or product manufacturing. It is claimed that the US FDA uses rigorous risk-based approaches in monitoring the plants (i.e., inspections) and evaluating pre-manufacturing submissions (i.e., NDA, ANDA). However, such claims may not be new, and the concerns persist, perhaps with increasing frequency and intensity. These concerns are due to mixing and confusing the two, i.e., manufacturing (or its quality) and the quality of the manufactured products. Authorities miss the difference and consider them the same thing. This misunderstanding confuses and is the root cause of the issues and concerns.

Public or patients need or require quality products, while the regulatory authorities have to ensure such. Unfortunately, there is no commonly accepted or official definition of a quality product; thus neither patient would get quality products, nor authorities can provide assurance. Authorities assume that if manufacturers meet the suggested regulatory processes and/or specifications (i.e., in compliance), then somehow the products manufactured would become of quality. On the other hand, if deviations from the processes and/or specifications are observed or perceived (which are often subjective), then the manufacturers would be labeled as non-compliant, and by extension, product quality is considered to be as substandard (or “adulterated”). Under the current regulatory system/requirements, it is really impossible to establish the quality of the products and their link to manufacturing.

It is important to note that, at present, product quality and manufacturing are based on in vivo (bioequivalence) and in vitro (drug dissolution) assessments. These techniques, as recommended by the authorities, are in fact scientifically in-valid and non-GMP compliant [3, 4]. It is, therefore, essential to recognize that regulatory assessments provide no scientifically valid support for establishing or monitoring the product quality, or lack of it, pre- or post-approval. Unfortunately, the manufacturers have been to bear the faults when guidance documents, standards, and specifications require attention and reconsideration.

The USP article rationalizes the approach of conducting performance of the dissolution testers used and required for establishing the quality of the products. This performance test is based on an arbitrarily selected product (which has no link to human use as a product) to establish validation of testers for the products for human use. In reality, claims made by the USP are scientifically invalid and simply false. USP promotes the use of these testers and tests for establishing the quality of products for human use, while these have never been tested or validated using any drug product for human use. If a company had made such a claim, it would have been disqualified and put out of business immediately (e.g., Theranos case [5]). However, USP and the US FDA promote these testers/tests for the quality assessment of the products. These apparatuses have clearly been shown to provide highly variable, unpredictable, and irrelevant dissolution results [6]. So much so that no one can determine appropriate and accurate dissolution characteristics of any product using USP apparatuses [7]. Therefore, authorities have to reconsider the use and requirements of the tests and testers.

To address the concerns and adequately assess product quality, authorities must define “product quality” with a measurable parameter and implement its use with scientifically qualified and validated tests and testers. Some suggestions in this regard are provided here [8] 

[1] Statement from FDA Commissioner Scott Gottlieb, M.D., and Director of FDA’s Center for Drug Evaluation and Research Janet Woodcock, M.D., on the FDA’s continuing efforts to maintain its strong oversight of generic drug quality issues domestically and abroad (Link).

[2] The Critical Role of the USP Performance Verification Test in Dissolution Testing and Qualification of the Paddle Apparatus (Link]

[3] Time to rescind the regulatory requirements of bioequivalence evaluations and the current pharmacopeial drug dissolution practices as these do not provide quality assessment of pharmaceutical products (http://www.drug-dissolution-testing.com/?p=3065)

[4] “Regulatory (pharmaceutical) science” – lacks logic as well as science! (Link)

[5] Theranos (Link)

[6] Variability and unpredictability, everywhere! (Link)

[7] 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! (http://www.drug-dissolution-testing.com/?p=1957]

[8] Seeking Metrics to Define Drug Quality (Link)

[9] Product Quality Metric (do not confuse it with drug/medicine quality) (Link).

[10] Universal Dissolution Test/Tester (Link)

In general, to apply a risk-based approach to establish the quality of anything, one would require a defined and measurable outcome/parameter. Once such an outcome/parameter is known or established, then it is used to reflect the chances of achieving success or failure in manufacturing or producing quality products. If the defined outcome/parameter is not available, then it would not be possible to use a risk-based approach. The manufacturing of quality pharmaceutical products falls in this category, i.e., there is no define parameter/outcome available for a “quality product,” thus risk-based assessment approach in pharmaceutical manufacturing is not possible at present.
To apply a risk-based approach, one would require to define the quality pharmaceutical products with a measurable parameter. So, please seek a definition of a “quality pharmaceutical product” along with its measurable parameters using qualified and validated scientific methods. As an example, please see here (Link).

Hopefully, the year in which “quality pharmaceutical products” will be defined along with their measurable standards/specifications so that manufacturers worldwide can manufacture such products efficiently and economically. Please follow the link for more details (1, 2).

In the life cycle of drug product development, several types of biorelevant dissolution data are generated (single stage, 2-stage, ASD, etc.) to aid formulation development. These dissolution data are also used in PBPK models.

What type of in vitro biorelevant dissolution methods do you use as input in PBPK modeling?

Can there be a general decision tree on the use of types of biorelevant dissolution data in PBPK models for applications in formulation selection?

That is a very good question!
In this respect, one should ensure that the apparatus/method used for dissolution testing should be validated first. It is important to note that, at present, none of the apparatuses/methods have been validated. For validation purposes, the apparatuses/methods are to be validated independently using a reference product with known dissolution characteristics, which should be applied to the test products. Scientifically validation cannot be achieved using products under development (Link).