Author: Dr. Saeed Qureshi, Ph.D.

First, it is important to know what the “ills” are. These (“ills”) are not usually specific but described by some (inspectors/investigators) from regulatory authorities, in particular, FDA, with observations and statements following facility inspections.

These facility inspections are conducted under the requirements of Good Manufacturing Practices or GMP, which are usually part of the country’s laws and regulations, giving the practices “authenticity” and enforcement ability. The GMP requirements and implementation are based on the fundamental assumption that GMP requirements are enforced so that the end products from manufacturing are of quality. For example, per FDA, “FDA ensures the quality of drug products by carefully monitoring drug manufacturers’ compliance with its Current Good Manufacturing Practice (CGMP) regulations” [Link].

 A quick literature survey provides examples of some descriptions of observed deficiencies (often also known as “observations”) of compliance requirements. These deficiencies could fall into one of the nine categories such as organization and personnel; buildings and facilities; equipment; control of components and drug product containers and closures; production and process controls; packaging and labeling control; holding and distribution; laboratory controls; records and reports [Link].

These deficiencies or observations are usually descriptive or narrative, not objectively measurable or quantifiable. Therefore, these can be considered subjective, based on the individual investigator’s personal judgment or inclination, as noted by the FDA, e.g., “During an inspection, ORA investigators may observe conditions they deem to be objectionable.

These observations are listed on an FDA Form 483 when, in an investigator’s judgment, the observed conditions or practices indicate that an FDA-regulated product may be in violation of FDA’s requirements [Link].

Once such observations become public, people (often experts/consultants external as well as internal to agencies) blow these out of proportion arguably for their own personal and business advantages and benefits [e.g., see here]. These (“observations”) then promoted as “ills” of the manufacturing and the industry.

 In short, the opinions expressed, formally or informally, by the investigators/inspectors mostly about the operation are considered as “ills” of the industry and manufacturing.

It is important to note that, as per GMP requirements described above, inspections must establish or relate to the ability to manufacture quality products. However, as stated above, most noted deficiencies are related to manufacturing and its operation – not the product quality. For example, the outcome of an inspection or warning letter is usually concluded as follows: “Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 USC 351(a)(2)(B)” [link, link].

The question is: where is the evidence of manufacturing of substandard quality (or adulterated) products?

The product’s quality can only be established by testing it, which is mostly neither part of the inspections nor “observations” claims. It is like saying that as the staff was not found adequately cleaned and dressed (in the investigator’s view), staff would be considered to lack intelligence and competence for the job.

For the validity of such a statement or conclusion, it must be based on evaluating and establishing their competence and intelligence and must be established independently. However, experts/consultants would conclude and promote inspections/observations as product deficiencies or inability to manufacture “quality” products – these are simply false assumptions and conclusions because observations are not linked or validated against the deficiencies of the product quality.

Therefore, blaming the manufacturing or industry for poor manufacturing quality products would generally be inaccurate. Instead, it is the practice of the current investigations or inspections which needs to be reassessed. To make “observations” or inspections, logical and scientifically valid agencies should define the quality of the products with a measurable parameter.

Samples should be collected at appropriate checkpoints and evaluated against (strictest) pre-set standards and specifications for the quality of products. On the other hand, manufacturers and affiliated contract facilities should seek help in addressing and defending the current irrelevant conclusions drawn from the facilities’ assessments and removing the weaknesses of the regulatory (GMP) requirements and practices worldwide.

The main intention of GMP implementation is to ensure that manufacturing facilities can manufacture quality products. Unfortunately, there exists some confusion, mainly in the minds of inspectors, and corresponding experts and consultants, that the purpose of GMP is to enforce the implementation of standards/specifications (or “compliance”) as per the regulations, not the assessment or evaluation of product “quality.” This, however, is an incorrect interpretation of the law and regulations. Below are citations from some of the major regulatory authorities defining the GMP, which includes inference to “quality.” Therefore, GMP requirements and practices relate to or require establishing the “quality” of the manufactured products.

On the other hand, it is also a fact that, at present, a scientific and/or enforceable definition/description/criteria for establishing and assessing the “quality” of pharmaceutical products, in particular tablets and capsules, is unavailable. Therefore, the requirements and practice of GMP are weak and unenforceable.

In general, scientifically and logically, most outcomes of a facility inspection (e.g., FDA 483s) should be considered irrelevant and invalid in establishing good manufacturing practices and reflecting on the quality of the manufactured products. Regulatory authorities worldwide, including from developed economies, should take note of this serious weakness of the current inspection practices (or law enforcement), which may not pass the test of the laws.

(1) FDA ensures the quality of drug products by carefully monitoring drug manufacturers’ compliance with its Current Good Manufacturing Practice (CGMP) regulations. (Link)

(2) Any manufacturer of medicines intended for the EU market, no matter where in the world it is located, must comply with GMP. GMP requires that medicines: are of consistent high quality; … (Link)

(3) Good Manufacturing Practices (GMP) are the part of quality assurance that ensures that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization. (Link).

(4) Good manufacturing practice (GMP) is a system for ensuring that products are consistently produced and controlled according to quality standards. (Link)

(5) The Good Manufacturing Practice (GMP) guidelines are a set of regulations that ensure that food, drugs, medical devices, and cosmetics are produced at a high quality. (Link)

(6) Good Manufacturing Practice (GMP) is a system for ensuring that products are consistently produced and controlled according to quality standards. (Link)

In response to a recent query, I provided the following opinion, which others may also find helpful.

Your query has two parts: (1) scientific; and (2) regulatory. I will try to provide you with my opinion on both and hope it will work for you.

Scientifically speaking:

(1)    There is no need to develop a discriminatory dissolution test. A valid dissolution test/method becomes a discriminatory test by default which must exist a priori to product development. This is a fundamental scientific principle.

(2)    One cannot develop a dissolution or discriminatory dissolution test while developing the product. It does not matter if the product is of immediate release type or anything else.

(3)    An official discriminatory dissolution medium does not exist. A dissolution medium represents the GI tract environment, which remains constant for all products (immediate and slow release), i.e., product independent. Therefore, dissolution media cannot differ for different drugs and their products. Requiring such would be illogical and unscientific.

(4)    A requirement of product-specific dissolution tests should be considered unscientific. The method has to be product independent; otherwise, anyone can “develop” a method showing their product as per their liking.

Regulatory (“compliance”) aspect:

(1)    As noted above, there is no logical/scientific reason to ask for a discriminatory test or its development.

(2)    I realize that “experts,” including from within regulatory agencies, are implementing unlawful requirements as lawful/legal. Governments, e.g., US  FDA, have started acting against such practices [1].

(3)    The only suggestion I have, is to request your respective authority to provide an example of an officially recognized “discriminatory dissolution medium/method” which you can reproduce for your work/product. That is a medium/method shown to discriminate between “good” and “bad” products, clearly describing the “good” and “bad” products for human use.

You may find several articles/blogs on this site (https://bioanalyticx.com/) in support of the above. I hope this will help.

The recent presidential executive order [1] aims to clarify the practice of developing guidance documents and their implementation. Current guidance documents, such as drug dissolution testing and bioequivalence, may be scrutinized as back-door law-making practices.

The law and regulations (such as cGMP) require that the recommended scientific methods be relevant, qualified, and validated for establishing and monitoring the quality of the drug products. However, FDA guidance documents ignore these requirements and enforce regulatory requirements by using irrelevant, non-qualified/non-validated testers and methods [2,3].

They remain chemicals!

Establishing and monitoring the quality of these products, such as tablets/capsules, follow fundamental principles of chemical sciences. Unfortunately, these principles are ignored and violated under non-scientific practices such as regulatory guidance/requirements or pharmacopoeial standards. Hence, the fact remains that no one is monitoring, or can monitor, the quality of these products, no matter how or who presents/promotes them – claims would be false.

The manufactures do not have the freedom to manufacture quality products because they have to comply with irrelevant and non-GMP regulatory requirements and standards.

On the other hand, if the “quality” of the products is defined with a measurable parameter that is surprisingly simple and straight forward, it will become much simpler and more efficient to establish, monitor, and manufacture quality pharmaceutical/medicinal products.

The following links (1, 2. 3. 4) provide relevant references for further details.

It has become a common practice that people get offended by my postings and comments, e.g., on LinkedIn Forums. This leads to receiving offensive responses on the Forums, blocking me from some discussions. On the other hand, I hardly ever receive any such comments or reactions privately but support and admiration of my contributions described in peer-reviewed journal publications, presentations, seminars, direct advice, and consultations, as well as on my blog postings.

I believe my postings are not offensive, nor am I a crackhead with subnormal intelligence to get such impolite responses. However, it is because my postings do not fit with the current practices, challenges, and strongly held dogma (in the name of science). I consider this is normal whenever the status quo is questioned, which my posts are about.

My main concern and view is that the assessment of the quality of products and the claims made, including by regulatory authorities and pharmacopeias, are scientifically untruthful and invalid. Without going deeper into technical details (which are described in my publications and/or on the blog), it can be stated that as the quality of the products has never been defined in measurable terms, it cannot be established and claimed. So, all the claims made in this respect are scientifically false and invalid.

People, in particular from the compliance side, believe that if analysts, facilities, operations, management and/or specifications comply with the guidance and/or SOPs, then products obtained from such facilities would be of quality. However, this is where the problem is, i.e., compliance DOES NOT make the products of quality.

For a product to be of quality, it must be shown that it is fit for the intended purpose, which is currently missing. Hence, the quality cannot be established and monitored. No matter how many facility inspections are done (with or without “observations/483s”), from quality product manufacturing aspects, the practice is a waste of time and resources, i.e., one cannot establish the actual quality of the products.

Compliance people who are accustomed to following compliance specifications believe that everything is fine if one meets the specifications. However, they do not realize that the specifications or SOPs they monitor so religiously are, in fact, baseless and, in most cases, foolish. They get offended and feel insulted when this flaw is pointed out to them. The reason is that they have been trained (“brain-washed”) to listen and believe in self-promotion and rightfulness. Anything else has to be considered illogical and must be rejected. Instead of listening to the concern carefully, understanding the problem, or studying the underlying scientific issues, they blame and start “shooting the messenger.” They are not hurting me but themselves by exposing their ignorance and incompetency of the subject.

The question is why non-science-based and irrelevant specifications and SOPs are there to start with, and which inspectors are bound to follow? Again, the lack of science-based expertise at the agencies’ level! It goes back to the same deficiency argument that if one does not know a quality product, then how they have been developing specifications, SOPs, guidance, and advisory practices. What is so difficult to understand about this lack of thinking or competency here? This violates the fundamental principle of science, i.e., providing answers or solutions without clearly defining or describing the objective (“quality”) and its measurable parameter.

However, without defining the quality of the products, agencies keep introducing specifications after specifications, SOPs after SOPs, guidance after guidance, and observations after observations, with claims that these are based on up-to-date/currently available scientific thinking and knowledge (the result of self-promotion).

The fact remains that all the current guidance document, advice, etc., at present, at least for tablet/capsule products, has no link to the quality assessment of the products – because it is undefined. Therefore, all the suggested guidances, SOP, and specifications, and their implementations, at the drug application reviewing and facilities inspection stages are scientifically irrelevant and useless.

In addition, the practice opens the door for new specifications and irrelevant requirements because nothing is required or needed to show relevance. Everything becomes good, necessary, and admirable. The more convoluted and complex it is, the better it will be. No questioning and challenging is allowed but wholehearted acceptance and following.

Any unusual thought has to be rejected as crazy and jargon. This lack of product quality definition and development of an arbitrary guidance-based system has wrecked the whole system. So much so that non-validated / non-qualified testers are forced to be used. A cardinal sin if the industry would follow such a practice). If the industry or any other organization had conducted such a practice, it would have been banned from doing business, leading to bankruptcy and persecution of its keep players. Theranos is one current example of going through this process.

On the other hand, the same regulatory authorities, which punish others for such a crime, actively encourage the industry to sell non-validated testers and methods and seek advice and suggestions for developing guidance documents for the industry to follow.

 I hope people will understand my view and reason for my writings, i.e., bringing science for the product evaluation. A critical first step in this regard will be defining the quality of the products with measurable parameters and THEN setting the corresponding specifications for compliance.

n the end, I request that you please do not make claims that you (or anyone else) are monitoring or helping in monitoring the quality of the pharmaceutical products – you are not! Such a view is often promoted by the “consultants/experts,” which not only give legitimacy to irrelevant and non-scientific practices but also deter authorities from understanding the issue and addressing the deficiencies.

This causes me to write and respond at every opportunity to keep highlighting the problems. So I hope people will see my point from this perspective.

Please consider reading the following blogs for further details:

(1) Regulatory/pharmacopeial assessments of quality of the pharmaceutical products – in the grip of falsehood and fraud! (Link)

 (2) Please God protect us from the ignorants – the regulatory/pharmacopeial authorities! (Link)

(3) Comparing Quality Standards – Pharmaceutical vs Consumer Products (Link)

(4) Quality of pharmaceutical products – a quiz! (Link)

(5) And more @ https://bioanalyticx.com/.

Testing into compliance is a USP/FDA requirement for drug dissolution testing, the only test available and recommended to indicate the quality of the products in a particular tablet/capsule.

The reason for the 3- (or 4-) stage testing into compliance (USP/FDA Tolerance) is because of regulatory requirements of using flawed (also non-validated/non-GMP) dissolution testers and methods which are known to provide irrelevant and unpredictable results. Scientifically speaking, there is no reason to use the currently recommended testers, in particular USP Basket/Paddle, to evaluate the products. Blame the USP/FDA for requiring this testing into compliance practice, not the analysts and/or the companies.

“Quality by International-Culture,” “Designer’s Quality,” “Barrels of Lies,” “Risk/Braggart Analyses,” “Chains of Supply-Lines,” “Quality by Who,” “Quality by Scripts,” “Non-stop Manufacturing,” “Chomping the Provider,” “Bullying the Peasants,” “Pharmaceutically Assumed Technology,” “Curing the Unknown,” “Promoting Deception,” “Spreading Fear,” “Conceit of Acronyms,” “Drumming (fake) Science,” “Observing for Nothing,” “Fun with Data Recording,” “Rotten Desserts with Statistical Toppings” and others (see here and here).

In reality, these are drug products containing medicines or drugs. It is just like candy is not sugar but contains sugar, i.e., candy is a sugar product. The quality of drugs or medicines and their products are two completely different and separate characteristics. However, authorities in ignorance mistakenly describe these as the same. No one, including authorities and pharmacopeias, can determine or establish the quality of such products because the “quality” of such is undefined. Therefore, claims most often made following facility GMP inspections (positive or negative) or regulatory reviews reflecting the quality and by extension, safety and efficacy of the products are simply false. Pay attention to such false claims.

To learn more about the differences between drugs and drug products and how to determine the quality of the drug products, consider attending the upcoming seminar (link)

Regulatory authorities, including pharmacopeias, stated and promoted mandate is to ascertain that consumers and patients receive safe, efficacious, and 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 products’ quality; 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. They follow the same or similar scientific/manufacturing principles and practices as for manufacturing of 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 comply. In this regard, it should be critical to note that “quality of the products” or “product quality” is an undefined term or parameter, 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). However, it is linked to numerous self-created arbitrary, flashy, and catchy phrases (considered as requirements/standards/practices) such as 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 of standards and requirements has choked manufacturing and severely limited access to high-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. But, on the other hand, the industry watches this absurdity and humiliation with horror. It does not have any option of being heard that what is required from them is neither relevant nor scientific. 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, the public can’t 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 would not only result in reducing the regulatory burden but also provide freedom to the industry for manufacturing quality products and open the doors for innovations for affordability and accessibility. I describe such concerns and potential solutions extensively through my blog (link). I would be happy to explain these in person (mailto:principal@pharmacomechanics.com) 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).