Quality equals safety/efficacy of the pharmaceutical products

[This post results from a query to one of my posts on LinkedIn Network (link), I think visitors of 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 with this confusion; even the regulatory authorities are confused with it, in fact 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 and 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. 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 objective is to produce PRODUCTs of the drugs which must contain the required dose and they must also be capable of providing (often described with terminologies of releasing/delivering/bioavailability) expected amount of the drug in the human body whichever route of drug administration is suggested (often time it is oral, but could be others IV, dermal, sublingual etc.). There would not be any concern or focus here for the safety and efficacy of the drug, along with other non-actives or excipients, which have been already established. In the generics cases, these are assessed often by bioavailability or bioequivalence assessments which is also usually one time shot and often at the pre-production stage. The point being that at the production stage there is hardly any (clinical) safety and efficacy assessment.

On the other hand, at the production stage safety and efficacy refer only to the ability of the product to release drug/dose as expected and this becomes quality metric for the product. If a product does not deliver/release the drug/dose as expected it would not be of quality which mean (equal to) it would not be efficacious and/or safe. This is where equality comes from (you may consider it as mathematical relationship if you like which may not be incorrect either), however, we are dealing with yes/no, pass/fail, or equal/not-equal situation.

So, in short, at the production stage of the PRODUCTs, quality is equal to safety and efficacy.

Compliance/guidance-based regulatory system and products safety and efficacy assessment

Safety and efficacy of the pharmaceutical products (e.g. tablet/capsule) can only be established by determining quality of the products. If 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 quality, safety and efficacy cannot be achieved by compliance as well. Use caution in promoting or accepting such claims. Quality of the products, and by extension their safety and efficacy, has to be defined and determined independently.

Please seek definition of the quality of the pharmaceutical products in terms of a quantifiable parameter to substantiate claims of safety and efficacy. For further details the following links would be useful (123) .

Validation – what it really means!

It is really hard to believe or accept how people have been blind-sided with “validation” (re-validation, continued validation etc.) requirement. The simple fact is that to run validation for any process one requires a reference product or parameter to show that process is validated (or capable of providing an expected outcome or product). If one does not have a reference product with known parameter and its value, then it is impossible to validate anything. Please, people this is logic and science 101.

If anyone is requiring or conducting validation without a reference (as in the case of current practices of manufacturing of quality pharmaceutical products in particular tablet/capsule), then validation of such manufacturing processes must be considered as “abracadabra” practices commonly accepted as meeting the “compliance”, “harmonized standard” etc. and do not link to quality aspect of the process or product.

I hope authorities, including pharmacopeias, will work in addressing these bizarre trends of validation approaches/concepts currently in practice and/or required, which have no scientific and/or logical basis.

Please, define a quality product and then provide a reference product which would allow the manufacturers to meet or exceed the standards of quality.

Revision of the USP General Chapter <1058> – a credibility issue!

Whenever one would like to evaluate a pharmaceutical product such as tablet/capsule, a commonly accepted approach is to seek a test described in the USP. The reason being that the tests described in the USP are being promoted and considered as references for products testing. The USP often provides seminars and hands-on training describing these tests (e.g. drug dissolution) and their validations. The regulatory authorities world-wide enforce the standards described in the USP monographs (see e.g. US FDA dissolution methods database, https://tinyurl.com/y78ovyez) considering that the methods and associated instruments described in the USP are adequately and independently qualified and validated.

With the revision of the USP General Chapter <1058>, however, this situation appears to have changed (https://tinyurl.com/y9wdfl58). In the revised Chapter it is described that the users are responsible for the qualification, and by extension validation of the instruments. This may not be a true representation of the practice. If this would have been the case then instruments would have to come with the users’ reference as to who performed the qualification (as well as how), and on what basis the instruments have been included in the USP. In reality, vendors and users promote manufacturing and the use of these instruments, respectively, by making claims that instruments manufactured or used are as per “USP specifications”, not those of their own qualification or validation standards. Obviously, this revision of the USP chapter is unusual and in error and might impact negatively on USP’s credibility as a standard setting organization for quality assessment of pharmaceutical products.

If the issue is with a certain specific type of instruments such as drug dissolution, which are known to be non-qualified and non-validated, then a more appropriate approach would be to remove such instruments from the USP rather than creating doubts about the qualification/validation of all instruments and associated methods described in the USP.

It is my view that the revision of the Chapter is not in line with the USP objectives and practices, and the decision may have been taken in haste, therefore, requiring reconsideration.


Another link/article on the same topic – A must read! Drug dissolution testers: “A modern-day mystery” – Are people being fooled by promoters of (paddle/basket) dissolution testers? It appears so! (Link).

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