Considering the weakness (non-specificity) of BE assessments, it is suggested that in vitro drug dissolution/release testing would provide a better alternative to establishing the quality of pharmaceutical products such as tablets and capsules. It is argued that using in vitro dissolution tests should be the method of choice for developing and monitoring improved or better quality generic products because BE assessment focuses only on equivalence and not on improving the product quality. Other significant advantages of using an appropriate in vitro dissolution test in place of BE assessment are described.
For a further detailed explanation, please follow the link.
A human bioequivalence study is conducted to establish that two or more products can provide the same/similar blood/plasma drug levels. The underlying assumption is that if the products provide the same plasma drug levels, then their therapeutic effects would be the same as well, thus would allow interchangeability of the products such as the generics.
Therefore, for all practical purposes, the bioequivalence assessment may be considered a typical analytical chemistry test where the assessment is based on determining plasma levels. For an appropriate and accurate analytical test, the test must follow some fundamental principles of analytical tests, such as specificity and validation (accuracy, precision, and reproducibility). A test cannot be validated if it is not specific.
In this regard, a bioequivalence test is a non-specific test as plasma drug levels include (confounded) variabilities from stomach emptying/motility and liver metabolism of the drug – independent of the product characteristics. Therefore, caution is warranted in establishing the quality of the test products based on the bio-equivalence test.
For a further detailed explanation, please follow the link.
Consideration should be given to simplicity and appropriate regulatory involvement as current practices and requirements certainly appear anti-innovation and make products less accessible and expensive. Please follow the links for further discussion on the topic (1, 2, 3).
It is important to note that, at present, the availability of pharmaceutical products such as tablets and capsules is heavily regulated and more accurately controlled by regulatory authorities worldwide. As a result, manufacturers and suppliers must follow extensive suites of protocols (national and/or international) to get their products approved for marketing. These protocols are often described by different names, such as regulations, guidelines, standards, etc. The manufacturers must comply with these protocols, literally to the letter, which are mostly arbitrary in nature. Thus, in practical terms, contrary to popular belief, there is limited or no room for deviation, simplification and/or innovation from these protocols, at least from the manufacturers’ side. These protocols may be considered formats for data/results presentations for product development or manufacturing, which are promoted as regulatory science. However, unfortunately, these are administrative and procedural requirements, not the science’s practice and/or requirement. The underlying “science” remains based on traditional practices and assumptions, more accurately, may be considered as rituals. Therefore, with the passage of time, the burden of adhering to these regulatory formats (“guidelines”) has become increasingly frustrating, time-consuming, and financially challenging for both authorities and manufacturers without any added value to the product quality and/or benefit to the users.
In addressing these challenges, manufacturer-bashing approaches (implied or explicit) are common and fashionable, often criticizing the lack of their integrity and competencies. This approach certainly appears to be a deviation away from the regulatory mandate or requirements, which is establishing and monitoring the quality of the products and not assessing and criticizing manufacturing ability or capacity. Regulators and their associates should be able to establish if the manufactured products, at the consuming stage, are of the required quality and, by extension, safe and efficacious. However, they can’t at present – thus deviation from their mandated objective!
There are two reasons for this regulatory shortcoming: (1) Regulatory authorities have never defined required quality, and its associated parameter, for product assessments. In fact, it could be argued that it is unknown to them. (2) Authorities require and enforce many flawed product testing requirements for compliance without their validations and relevance. As these requirements lack scientific credibility and validity, anybody, not just the manufacturers, would have difficulty meeting or meeting the current regulatory requirements and expectations. Please consider viewing the links below for a more technical description of this aspect. Therefore, there is a clear need for re-evaluating the practice of setting regulatory standards and requirements, starting with defining a quality product and then using scientifically/GMP-valid instruments and procedures. Otherwise, it is impossible for the manufacturers to produce quality products and for the regulators to develop and implement appropriate guidelines and standards for product evaluation.
Some suggestions are provided to address these issues, and authorities sincerely hope to consider these thoughts./*/ For further reading (1, 2, 3, 4, 5)
A discussion is provided showing the weakness of BE assessments for comparing or establishing the quality of products such as tablets/capsules. It is argued that in vitro drug dissolution/release testing would provide a better alternative for the assessment of the quality of such pharmaceutical products. Please click here for complete article.
People try to understand the logic and scientific principles behind the (pharmacopeial and regulatory) “compliance” requirements for meeting the quality aspect of the pharmaceutical products such as tablets/capsules. However, there is hardly any scientific principle involved in most of the area’s current “compliance” requirements. Most compliance requirements are based on subjective (individual or collective) opinions and guesses, often presented through publications or regulatory guidance documents to gain or establish their authenticity. For example, in establishing the quality of the manufactured products, such as tablets/capsules of both generic and branded products, nowhere is defined what would be considered a “quality product” and how the quality should be measured or established. However, all the pharmacopeial and regulatory requirements (national or international) claim to achieve it. Is it not interesting that the quality of a product is not defined or known but claimed to be achieved? How?
It is important to note that pharmaceutical laboratories are currently operating under non-GLP/GMP conditions, particularly for assessing solid oral dosage forms such as tablet and capsule products. This is surprising that such negligence has been going on unchecked. This deficiency needs to be corrected so that facilities can be considered QC/QA laboratories to provide the products’ relevant and accurate quality characteristics. For further details, please follow the links (1, 2, 3).
A patient needs a drug but is prescribed or purchases a drug product (such as a tablet or capsule) with an implied assurance that the product will release the drug in the body as expected to provide its therapeutic effect. This characteristic of drug release/delivery in the body from the product defines the quality of the product.
At the manufacturing stage, one hardly ever conducts clinical tests to establish the safety and efficacy of the products but only the “quality” tests. The reason is that if the quality is acceptable, then safety and efficacy will also be acceptable because drug levels in the body and safety and efficacy are directly linked.
The tests most often conducted to establish the quality of products at the manufacturing stage are the chemical tests, commonly known as in vitro tests. The most common in vitro test conducted to establish drug release or quality of the tablet/capsule products, is known as a drug dissolution test. This is the only test that forms the basis of the quality assessment of tablet/capsule products. Regulatory authorities, including pharmacopeias, worldwide recommend and enforce proper use of this test to establish the quality of the products. Numerous guidance documents are available from the regulatory authorities, including the US FDA, which describe the requirements of the dissolution testing procedures forming the basis of drug product approvals.
The important and perhaps very disturbing fact to note here is that the dissolution testers and associated methods recommended by the authorities have never been validated for their intended use or relevance. In fact, many scientific studies (e.g., link) have clearly shown that the tests do not and cannot provide relevant results, i.e., the testers cannot provide accurate results/data regarding the products’ (tablet/capsule) quality. Therefore, any claims made regarding the quality of the approved products by anyone, including authorities, lack accuracy, and scientific authenticity.
The regulatory authorities enforce an extensive set of requirements and standards through an elaborated set of “compliance” guidelines such as ICH or US FDA guidance documents for establishing the quality of the products. However, this guidance-based compliance system is directly or indirectly dependent on the drug dissolution test at least for tablet/capsule products. Therefore the current guidance-based system is not only providing false assurance about the quality of the products but also causing severe hindrances for the industry to produce quality products appropriately and efficiently. In addition, this guidance-based system adds an enormous administrative burden for both authorities and manufacturers – unfortunately, of no or limited benefit to either party. Furthermore, as the recommended testers are non-qualified/non-validated, which makes them non-GMP compliant, thus authorities could easily be found in violation of GMP practices – potentially a serious and disturbing claim. Therefore, this deficiency should be addressed on an urgent basis with the highest priority.
It is important to note that scientific studies have clearly shown that currently recommended apparatuses have a design problem that could be corrected by simple modification. Suggestions have been made in the literature in this respect addressing the issues. Further information in this regard may be obtained from here.
In short, authorities should note this critical deficiency in the drug product approval requirements caused by requiring non-GMP drug dissolution testers. This deficiency needs to be addressed quickly so that the quality of the manufactured products can be established and monitored accurately and efficiently.
[This post results from a query to one of my posts on LinkedIn Network (link), I think visitors to my website would also find it a useful read]
I believe your view/confusion is valid and understandable, considering the current state of drug product evaluation practices. Note that this confusion occurs from considering or mixing drugs and drug products as the same. You are not alone in this confusion; even the regulatory authorities are confused with it, indirectly extending it. For example, for generic product evaluations, US FDA requires ANDA (abbreviated new DRUG application, in Canada ANDS), which is an incorrect terminology; in reality, these are new PRODUCT applications (link). Your confusion also appears to be arising from the same mix-up i.e., not differentiating the drugs from drug products.
My post is regarding PRODUCTs, where one hardly ever conducts clinical tests/studies, especially at the commercial production stage. However, safety and efficacy studies/evaluations of DRUGS are done in the beginning, sometimes decades ago (e.g., consider the examples of aspirin, acetaminophen, ibuprofen, and others, perhaps most drugs). From these clinical studies, dose levels are set based on their safety and efficacy profiles.
At the production stage, these drugs as PRODUCTS are manufactured worldwide without any further clinical evaluation. At the production/manufacturing stage, the objective is to produce PRODUCTs of the drugs that must contain the required dose. They must also be capable of providing (often described with terminologies of releasing/delivering/bioavailability) the expected amount of the drug in the human body. There is no concern about the safety and efficacy of the drug and the non-actives or excipients, which have already been established. The generic products are often assessed by bioavailability or bioequivalence assessments which are also usually one time shot and often at the pre-production stage. The point is that there is hardly any (clinical) safety and efficacy assessment at the production stage.
On the other hand, at the production stage, safety and efficacy refer only to the ability of the product to release the drug/dose as expected, and this becomes a quality metric for the product. If a product does not deliver/release the drug/dose as expected, it will not be of a quality which mean (equal to) it will not be efficacious and/or safe. This is where equality comes from (you may consider it as a mathematical relationship if you like, which may not be incorrect either). However, we are dealing with yes/no, pass/fail, or equal/not-equal situations.
So, in short, at the production stage of the PRODUCTs, quality is equal to safety and efficacy.
The safety and efficacy of pharmaceutical products (e.g., tablets/capsules) can only be established by determining the quality of the products. If the quality of the products cannot be established, as currently is the case, then claims of safety and efficacy cannot be made either. In addition, as compliance does not necessarily equate to quality, safety and efficacy cannot be achieved by compliance as well. Use caution in promoting or accepting such claims. The products’ quality, safety, and efficacy must be defined and determined independently.
Please seek a definition of the quality of pharmaceutical products in terms of a quantifiable parameter. The following links would be useful (1, 2, 3).
