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Bye Bye – Bioequivalence testing? Long live drug dissolution testing! —– #2 (gift from heaven)

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, or capsules, with often unknown and proprietary composition 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 in principle product specific guidance concept is an invalid concept. Drug dissolution testing is a scale used to measure dissolution characteristics of a product. By definition it (scale) has to be independent to the tested items. Point being that the guidance documents cannot be restricted one or two drug products. These have to be applicable 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 one time decision, as many believe, may it be taken under an emergency situation. It would not be possible to withdraw such a decision once taken i.e. if dissolution test alone can provide 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 labelled inferior. However, with the requirement of dissolution testing only, everyone can manufacture and promote (for local and/or international markets) their quality products with confidence.

Keep these thoughts in mind and proceed accordingly.

Bye Bye – Bioequivalence testing? Long live drug dissolution testing!

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). There is really no need of conducting bioequivalence (BE) assessments. These (BE) assessments procedures have never been validated of the intended purpose. In fact BE are 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).

Is Coronavirus really causing abnormally higher number of deaths?

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

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

Response to a recent query: Manufacturing of hydroxychloroquine and seeking help from the authorities

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

“Regarding 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.


Scientifically speaking water is an appropriate 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 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, precisely to address this issue. Perhaps consider using this suggested spindle and simpler dissolution method not only for this product but also avoiding future issues with the use of USP apparatuses. There is a stronger argument available in using an alternate dissolution tester than changing dissolution medium i.e. the USP apparatuses are non-GMP compliant (link, link).

I hope you will find 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.

My recently published book chapter (details below) …

… provides in depth discussion on establishing and monitoring quality of pharmaceutical products in particular tablet and capsule. I hope you will find the chapter useful.

Chapter title: “Quality” of pharmaceutical products for human use – underlying concepts and required practices, published in

Drug Delivery Trends: Expectations And Realities Of Multifunctional Drug Delivery Systems Volume 3 Edited by Ranjita Shegokar, PhD., Available from Amazon (March 18, 2020), link.

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