Author: Dr. Saeed Qureshi, Ph.D.

For example:

FDA claims that it establishes and monitors the quality of pharmaceutical products such as tablets and capsules. A lie – FDA neither defines the quality of the products nor its measurable parameter; hence it does not, or cannot, determine the quality of the products.

FDA claims that it establishes the safety and efficacy (as well as quality) of pharmaceutical products using valid clinical testing (e.g., bioequivalence assessment) and in vitro (drug dissolution) testing using USP apparatuses. Again, a lie – these tests and associated testers have never been validated for the intended purpose. In fact, these tests are scientifically invalid and irrelevant for their intended purpose.

USP claims that it provides reference standards for establishing the quality of the pharmaceutical products such as tablets and capsules. A lie – USP never provides reference standards for any product. It provides powder or liquid samples of pure chemical compounds, not the products which patients use. However, it falsely promotes reference standards of medicines.

USP claims that it provides a valid analytical test for assessing drug release characteristics of the products for establishing and monitoring the quality of the products. A lie – the test has never been validated for the intended purpose. The test cannot determine the drug dissolution/release characteristics of any product. It has been shown experimentally that the test provides irrelevant and highly unpredictable results/data with no relevance to product quality.

For more examples, please visit here and here. Manufacturers and patients should be cautious in accepting such claims from FDA and USP and other national and international authorities, which often follow FDA/USP claims and guidances.

Please consider accepting the Citizen Petition (under review with FDA for more than a year and a half, link) to address the underlying lies concerning products development, manufacturing, and their regulatory approval.

What should one expect, after FDA completely destroyed, and rightly so, the credibility and usefulness as well as need for bioequivalence assessment (aka clinical trials) by removing its requirement from ANDA approvals, at least for hydroxychloroquine (HCQ) and chloroquine (CQ) products to start with [1, 2]? It is to be noted that bioequivalence assessments have been shown to be scientifically invalid and irrelevant to establish the quality of the products based on their drug release assessment [3]. Such studies put large burden, financial and personnel, on the industry as well regulatory authorities for the development, manufacturing and approval of products and expose healthy human subjects, in particular young adults, to potent chemicals (a serious unethical practice).

Products can easily and accurately be assessed using drug dissolution testing. However, to implement its (drug dissolution testing) valid use, authorities, including FDA and USP, need to implement appropriate and scientifically valid dissolution testers and methods. Until then, authorities’ claims regarding monitoring and establishing products quality will remain false and invalid.

COVID-19 pandemic exposed the burdensome and unnecessary regulatory practices and requirements. It also provides an opportunity to simplify product development and manufacturing. Please consider the under-review Citizen Petition for removing the use of non-validated/non-qualified, hence non-GMP, USP drug dissolution testers/tests from regulatory requirements [4] and replace them with appropriate and scientifically valid tests and testers.

We, the authorities and experts, are extremely sorry to inform you that we made a colossal mistake in declaring the Coronavirus (COVID-19) pandemic. It is one of such rare situations where we found out at an extremely high cost (human and financial) that our scientific understanding of the subject was flawed and failed us. As a result, we honestly carried away with our projections and fear of a huge number of anticipated deaths by the potential spread of this variant flu, which clearly did not come out to be correct. We sincerely regret this unfortunate situation and ask for your forgiveness. Please accept our apologies. We hope the public will forgive us and start their usual daily life. In addition, we hope that the public will avoid the use and/or development of new medicines based on our falsely classified disease and pandemic, reducing any further damages that may occur.

Once again, we sincerely apologize and hope that we will be forgiven.

In general clinical trials are important and necessary. In any other area, one has to show that the “things” (in this case, medicines/treatments) work as expected – clinical trials serve such a purpose.

However, underlying scientific concepts and practices in the medicines area are extremely poor; hence “clinical trials” practices face credibility issues. For example, developing products (tablet/capsule) clinical trials (bioequivalence test – regulatory requirement) are conducted, lacking clinical relevance and usefulness. Therefore, it could be argued that such tests indeed expose subjects, often healthy human volunteers, needlessly to potent chemicals in the name of medicines development. (link)

Similarly, relating to the Coronavirus pandemic, there appears to be a rush towards the development of medicines/vaccines. It may be argued that as the underlying analytical science is not well-established to monitor the virus and/or its “disease,” it would be challenging to conduct appropriate and validated “clinical trials” (link)

In short, running clinical trials is a good idea. However, conducting appropriate and useful clinical trials remains challenging; that is where the confusion is.

1. Flu came and gone!
2. Why it was called a pandemic – not clear
3. Discredited the benchtop science – as disease state-monitored with charts and their shapes (humpy or dumpy) with protocol/testing developed on the fly
4. Discredited  the medicines approval system with the approval of medicines without requiring established protocols
5. Treatments could be suggested and implemented without having knowledge or expertise in the area of medicine.
6. Exposed the great weakness, perhaps more accurately ignorance, of “science” at the authorities!
7. Hope we learned something not to repeat in future

Further readings:

(1)Coronavirus pandemic: Public/patients deserve better! (link)
(2)Authorities (including FDA) and pharmacopeias (including USP) never establish the quality of products! (link)
(3) Is Coronavirus really causing an abnormally higher number of deaths? (link)

The unfortunate situation created by this Coronavirus pandemic is providing a serious opportunity for reassessing the current regulatory approaches in pharmaceutical products development and their manufacturing so that such irrelevant discussion can be avoided and patients can have access to modern and multiple options to treat ailments. Hopefully, in the future, patients will be treated with well-established products rather than products developed on the fly or with the use of disposable gowns, masks, washing hands and/or staying home policy which certainly is not the treatment. Patients expect and deserve something better from us as scientists, physicians, and regulators. Follow the link for the complete article (link)

Yesterday, I posted my view on the recent FDA guidance documents for chloroquine and hydroxychloroquine (link). I do not think people realize the long-term impact of this development where BE studies have been replaced/substituted with drug dissolution testing. Let me explain:

1. Saying that guidances are product specific is not correct because chloroquine and hydroxychloroquine are drugs not products. Products are tablets, capsules, often unknown and proprietary compositions of a drug, excipients, and manufacturing attributes (i.e. formulation and manufacturing attributes). Hence, guidances cannot be product-specific as assumed or suggested.
2. A drug dissolution test is conducted for products, not drugs. As product attributes are mostly unknown and propriety, as noted above, hence a dissolution test (or guidance) cannot be product specific but has to be independent “standard or universal.”
3. Furthermore, it is to be noted that the product-specific guidance concept is an invalid concept in principle. Drug dissolution testing is a scale used to measure the dissolution characteristics of a product. By definition, it (scale) has to be independent of the tested items. The point being that the guidance documents cannot be restricted to one or two drug products. These have to apply to ALL highly soluble drug products. It would not be possible for authorities, at least scientifically, to defend restricting to only one or two products. This decision could easily be challenged and won.
4. In addition, such a decision cannot be a one-time decision, as many believe, may it be taken under an emergency. It would not be possible to withdraw such a decision once taken i.e., if dissolution test alone can provide a quality assessment of the products, then why would BE studies be needed and required on what basis, especially when BE studies are known to be irrelevant (link).
5. This new development is a gift from heaven for the underdeveloped countries where because of lack of BE studies, products and their manufacturing have always been labeled inferior. However, with the dissolution testing only, manufacturers  can manufacture and promote (for local and/or international markets) their quality products with confidence.

Keep these thoughts in mind and proceed accordingly.

Recently FDA provided 1- and 2-pager guidance documents for chloroquine and hydroxychloroquine, respectively (link).

The most interesting part is that one can get product approval based on dissolution testing alone. This is what has recently been suggested in one of my recent published articles, i.e., products (“quality”) assessment can easily and accurately be established with drug dissolution testing alone (link). Therefore, there is really no need to conduct bioequivalence (BE) assessments. These (BE) assessment procedures have never been validated of the intended purpose. In fact, BE is scientifically invalid and can provide false conclusions and assurance about product quality. In addition, such testing exposes healthy human volunteers to highly potent chemicals under the disguise of medicine development.

On the other hand, switching to dissolution testing alone using currently recommended USP apparatuses is not valid either, at least scientifically. The recommended apparatuses are non-GMP compliant and can provide false and irrelevant results because of their intrinsic design and operation problems. Simpler and scientifically valid options are available and could be used (link).

Mortality in the United States, 2018 (as of January 2020, link).

“The age-adjusted death rate decreased by 1.1% from 731.9 deaths per 100,000 standard population in 2017 to 723.6 in 2018.” i.e., death rate is about 0.7236%

For the USA, having a population of 331 million (link), the normal/standard death (attrition) rate should be 199,593 deaths/month. Now compare this number with the reported number of deaths caused by the Coronavirus pandemic, which is 21,435 in about a month as of April 12, 2020 (link), which is far less than the normal/standard death (attrition) rate.

The death rate, therefore, does not appear to support the thesis that the pandemic is killing people in abnormally high numbers.

This morning I received the following query (my response is included below) about the manufacturing aspect of the above-mentioned drug product. It is hoped that authorities will take note and address the issue faced by the industry to manufacture this essential pharmaceutical product as per my year-and-a-half-old Citizen Petition (link).

Query:
“Regarding the dissolution of HYDROXYCHLOROQUINE SULPHATE TABLETS, the disso medium specified in IP & USP is water. The formulation sometimes fail to conform to IP and even USP parameters

I have tried replacing water with 0.1 M hydrochloric acid as dissolution medium and achieved a disso of above 90 %. I know the api is water soluble, but since this is an instant release formulation and the approximate pH of stomach is being maintained in disso medium, can we recommend change of disso medium from water to 0.1 M H Cl to IP & USP.

Response:

Scientifically speaking, water is a suitable dissolution medium, not the HCl (link).

In reality, your suggestion of changing the medium from water to HCl is for obtaining desired dissolution results, which is neither scientific nor logical.

In general, the issue you are describing is not of medium choice but the choice of the dissolution apparatus. USP apparatuses are known to provide slower and irrelevant results; most likely, you are observing this flaw. Such an issue can only be addressed by changing the tester, not the medium, rpm, etc. Considering USP apparatuses’ flaws and limitations, I have proposed a new stirrer to address this issue. Perhaps consider using this suggested spindle and simpler dissolution method not only for this product but also to avoid future issues with USP apparatuses. Additionally, there is a stronger argument for using an alternate dissolution tester than changing the dissolution medium, i.e., the USP apparatuses are non-GMP compliant (link, link).

I hope you will find the suggestion useful, and best of luck.

PS: Please request the authorities, in particular FDA and USP, to withdraw the requirement of using non-GMP (i.e., non-validated/non-qualified testers/methods) and allow the use of scientifically valid testers and methods to develop and manufacture urgently needed pharmaceutical products.