Author: Dr. Saeed Qureshi, Ph.D.

Quality has to be defined and measured independently. Currently, as a definition of the quality of a (pharmaceutical) product, such as a tablet/capsule, is unavailable; thus, it cannot be measured and/or established (link).

Consider attending the upcoming seminar to learn how the quality of a pharmaceutical product can easily be defined and then how it can be measured efficiently and scientifically (link).

Necessary knowledge of physiology, pharmacokinetics, pharmaceutics, or modeling/simulation can be easily acquired or learned. In addition, scientifically valid dissolution results can be easily obtained and transferred to plasma drug levels without involving the in vitro-in vivo correlation (IVIVC) step.

Focusing on defining quality and then establishing it by measuring its parameter will lead to simple, efficient and cost effective product development and manufacturing practices, significantly reducing regulatory burden.

Recently USP revised the above-mentioned chapter (https://tinyurl.com/y9wdfl58) to clarify AIQ terminologies, including the definition of Design Qualification [DQ]. There is nothing new in the description that should not have been clearly understood by both – the users and manufacturers of the apparatuses including their service providers. However, confusion exists in the minds of analysts and manufacturers who consider testing and re-testing the fixed parameters as the qualification, calibration and/or performance verification steps. The chapter clearly describes that such fixed parameters never need to be retested or re-established. Regarding drug dissolution apparatuses, the so-called mechanical calibration and/or meeting of the specifications as described in the USP dissolution chapters <711> and <724> would fall in the fixed parameters category, therefore, would never require testing or re-testing. 

On the other hand, in the revised chapter, the phrase “intended purpose” has repeatedly been used, which is important to note. For example, it is stated that “AIQ is the collection of documented evidence that an instrument performs suitably for its intended purpose (emphasis is mine).” A dissolution apparatus’s intended purpose is to provide a product’s dissolution characteristics under standardized experimental conditions. For this purpose, one requires a reference product with known dissolution characteristics established independently from a dissolution tester itself so that the tester can show its suitability for providing appropriate dissolution results. The reference product, with known dissolution characteristics, must be approved as the testers are used for testing products for human use. As no such reference product is available, one cannot qualify a dissolution tester. If one cannot qualify as a dissolution tester, then the USP General Chapters and the monographs referred to such testers lose their validity and scientific credibility. Therefore, enforcement of pharmacopeial monographs for quality assessment of the products loses their purpose and usefulness.

Furthermore, as per the chapter, the requirement that “Users are ultimately responsible for specifying their needs and ensuring that a selected instrument meets them” appears confusing and contradictory to the commonly understood roles of the pharmacopeias. Pharmacopeias generally set standards/specifications for instruments and guide their use so that users follow a common and standard protocol. However, this chapter appears to imply that pharmacopeias have no or limited role in this regard, but the users and manufacturers should decide between themselves as to what the intended use of the apparatuses is and what specifications are to be developed. It does not make sense that the pharmacopeia would not play any role in setting standards/specifications for instruments and their operation. An indirect implication of this suggestion would be that, as of now, any tester with associated specifications of users’ choice could be used. This clearly opens up the possibility of acceptance of non-compendial testers of users’ choice, at least for drug dissolution testing purposes.

Drug dissolution tests are included in the pharmacopeias to establish the quality of the manufactured pharmaceutical products, particularly tablets and capsules. Pharmacopeial standards/specifications play an important role in this regard by setting the standards/specifications. Therefore, there is an urgent need for an alternate qualified tester to fill this gap created by the revision of the USP Chapter. In this regard, three items need to be addressed: (1) suggestion of a modified dissolution tester(s); (2) selection of a set of standardized experimental conditions; and (3) availability of a reference product, or its alternate, with known dissolution characteristics.

I have provided suggestions that would help fulfill these requirements. These can be found at the links provided below. In addition, I provide detailed and thorough in-person seminars and customized on-site training to help understand the science of drug dissolution testing and address its associated problems for product evaluations. One may consider attending the seminars, such as an upcoming one in Boston, MA (Link), or request an on-site training at principal@pharmacomechanics.com.

Relevant links:

(1) Suggested tester and standard set of experimental conditions (link)./*/

(2) Reference product or its alternate (link)

Recently USP revised General Chapter <1058> [Analytical Instrument Qualification (AIQ) – 1, 2].  Generally, it is recognized that instruments described in the pharmacopeias (e.g., USP) are suitable and qualified for their intended purpose, so laboratories/industries may use these confidently as per recommended specifications. In addition, instrument manufacturers provide such instruments meeting or exceeding the recommended pharmacopeial specifications. However, this situation has changed with the revised Chapter <1058>.

The USP does not seem to provide such assurance of qualification or suitability of the instruments for their intended purposes. Instead, USP describes that it is the responsibility of the users and the instrument manufacturers to provide evidence for the AIQ.

In interpreting this revision, the chapter clearly describes that instruments meeting the USP specifications do not necessarily mean or assume to be qualified for the intended purpose. In fact, this has been the case all along for drug dissolution instruments, i.e., they are not qualified/validated for the intended purpose, and USP only acknowledges this inadequacy now. But, on the other hand, users of these instruments are expected to establish and/or demonstrate that they are qualified and suitable for their intended use. This is interesting! If USP cannot qualify/validate its recommended testers, how could the users? They can’t!

In addition to laboratories and industry as instrument users, regulatory authorities are heavily dependent on the use of the dissolution instruments for developing and promoting their guidance documents (e.g., see US FDA Dissolution Methods Database – link). Unfortunately, the regulatory authorities assume that these instruments are qualified as they are part of the pharmacopeias such as USP, which is not a valid assumption. Therefore, now the regulatory authorities have to provide supporting evidence of qualification and validation of such instruments for the current and future guidance, which they can’t, as noted above. Therefore, the implementation of this change of policy from USP would not be trivial for the authorities but a messy, excessively time-consuming, and costly exercise. Furthermore, it is unlikely to be a successful exercise using currently recommended USP dissolution instruments. These apparatuses are non-qualified and known to have serious reproducibility and relevancy issues (link), presumably the reason USP withdrew its support for such instruments.

It may be much easier and cost and time effective if the authorities consider using a different or new tester based on the crescent-shape spindle (link), which has been suggested as an alternative to Paddle/Basket apparatuses. Crescent-shaped spindles can easily be used with the current vessel-based apparatuses (link). In addition, it would provide scientifically valid dissolution testing and, as a universal tester, remove the requirements of any product-dependent method developments – an extremely cost-saving step.

The purpose of the evaluation of generic products, such as tablets and capsules, is to establish that the two or more products containing the same drug provide the same/similar plasma profiles of the drug -independent of their formulation and manufacturing attributes. Thus, evaluation or testing must be product-independent. If requirements and standards are based on product-specific attributes, then these would not be applicable to other products, including generics, as they could have different attributes (formulation/manufacturing). In addition, product-specific testing and standards are similar in concept to labeling an item’s weight (drug, excipient, etc.) with a weighing-scale associated with it – which obviously would be unacceptable.

The concept of product-independent product evaluation would be scientifically valid and facilitate simpler and expeditious product evaluation and approval.

Therefore, the concept of product-dependent assessment of products requires reconsideration. I hope this suggestion will be given favorable consideration.

In my view, the collapse of the regulatory pharmaceutical science as we know it is coming because it is reaching the limits of promoting fake science, regulatory bullying, and disregarding consumer/patient needs and affordability.

To begin with, it is not even possible to know what one means by regulatory pharmaceutical science or regulatory science. It may be considered a hodgepodge collection of documents and checklists, often termed Regulatory Guidance/Guidelines or pharmacopeial monographs, which like-minded groups of people compile them. The main promoted objective of such exercises is to provide “care or help” to customers/patients by establishing the “quality” of pharmaceutical products, such as tablets/capsules, which should be available at reasonable prices. The irony is that no definition or criterion is provided for evaluating the quality of products. The regulatory authorities and pharmaceutical community never defined what a quality pharmaceutical product is. Compliance with guidance reflects quality without an established link between the two (compliance and quality). Thus, everything related becomes illusionary and scientifically invalid, requiring extraordinary efforts, mostly bullying, to promote and maintain the pretense of patients’ safety and product quality

There is, thus, an urgent need for reassessing current regulatory practices so that the manufacturing of pharmaceutical products and their assessments start to make sense and consumers/patients have access to affordable quality pharmaceutical products. Some ideas and suggestions, as links to some articles, are provided in this regard.

Issues:

(1)    Defining roles and practices of pharmaceutical regulatory authorities (Link)

(2)    In-compliance with regulatory standards and requirements do not necessarily mean that a pharmaceutical product (tablet/capsule) or process is of quality! (Link )

(3)    In all seriousness – this is really an “abracadabra” exercise! (Link).

(4)    Quality assessment and prevailing illusions! (Link)

(5)    KABOOM! Pharmaceutical Product Quality Issue (Link)

(6)    Something to think about! (Link).

(7)    Bio-waivers! (Link)

(8)    Inspections and quality of pharmaceutical products and/or manufacturing processes – dilemma! (Link)

(9)    Fashionable Nonsense (Link)

(10)Non-GMP compliant dissolution testers but no warning letters! (Link)

(11)A Quality Product – Please Define! (Link).

(12)Let me be bold and direct! (Link)

(13)Assessing quality of pharmaceutical products! (Link).

(14)Scientific and GMP violation! (Link)

(15) Guidance Documents – Deficiency (Link )

(16)f2 – Similarity Factor (Link)

(17)If one likes that a manufactured drug product should be of quality, then one needs to define (tell) what a quality product is? (Link).

Suggested Solutions:

(1)    Quality of Pharmaceutical Products (Link)

(2)    The missing quality definition or metric (Link)

(3)    Product Quality Metric (do not confuse it with drug/medicine quality) (Link

(4)    Universal Dissolution Test/Tester (Link)

(5)    Universal Dissolution Test/Tester – Second Part (Link)

(6)    Promoting quality standards for drug products: Scientifically speaking, please be systematic and logical! (Link)

(7)    Establishing safety, efficacy and quality of drugs and drug-products (tablet/capsule) – serious confusion! (Link)

There is no doubt that regulatory authorities worldwide are facing numerous challenges in establishing efficient availability of quality pharmaceutical products, in particular tablets and capsules. It appears that a lack of clarity of objective/mandate may be the main cause of the problem and, by extension, the reason there are difficulties in addressing these. The following suggestions maybe considered in addressing the current challenges.

  1. If the objective is to facilitate bringing quality products to patients, which indeed is the objective. In that case, authorities should establish a definition of “quality products,” providing a reference quality product with associated measurable quality parameters. No one can manufacture and/or evaluate a quality product without a definition. A suggested definition in this respect is provided here.
  2. On the other hand, if the objective is monitoring the manufacturing quality, which appears to be the main emphasis of current regulatory practices (cGMP etc.). Then, authorities should not be in this business because this is neither their mandate nor they possess competency/expertise in the area. Moreover, they have never developed or manufactured products or run or maintained cGMP manufacturing facilities for commercial purposes. It would, therefore, be impossible to evaluate or guide the industry adequately to establish or run efficient manufacturing facilities.

It is hoped that these suggestions will be given favorable consideration.