Regulatory compliance is more appropriate description than QC/QA

It is important to note that at present pharmaceutical laboratories are operating under non-GLP/GMP conditions, in particular for the assessment of 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 as QC/QA laboratories to provide relevant and accurate quality characteristics of the products. For further details, please follow the links (1, 2, 3).

Need for a quantifiable quality parameter for pharmaceutical (tablet/capsule) products

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 tablet/capsule. However, there is hardly any scientific principle involved in most of the current “compliance” requirements in the area. 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 the area of establishing quality of the manufactured products, such as tablet/capsule of both generic and branded products, nowhere it is defined what would be considered as a “quality product” and how the quality should be measured or established. However, all the pharmacopeial and regulatory requirements (national or international) make claims of achieving it. Is it not interesting that quality of a product is not defined or known, but claimed to be achieved, how?

Quality assessment of pharmaceutical products – regulatory/pharmacopeial standards and methods require urgent attention!

A patient needs a drug but prescribed or purchases a drug product (such as tablet or capsule) with an implied assurance that 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 being if the quality is acceptable then safety and efficacy will be acceptable as well because drug levels in the body and safety and efficacy are directly linked.

The tests most often conducted to establish quality of products at the manufacturing stage are the chemical tests, commonly known as in vitro tests. The most common in vitro test which is conducted to establish drug release or quality of the tablet/capsule products is known as a drug dissolution test. This is the only test which forms the basis of 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. There are numerous guidance documents available from the regulatory authorities, including US FDA, which describe the requirements of the dissolution testing procedures forming the basis of drug product approvals.

The important, and perhaps a very disturbing, fact to note here is that the dissolution testers, along with associated methods, as 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 extensive set of requirements and standards through elaborated set of “compliance” guideline such as ICH or US FDA guidance documents for establishing quality of the products. This guidance-based compliance system is directly or indirectly dependent on the drug dissolution test at least for tablet/capsule products. Therefore current guidance-based system is not only providing false assurance about the quality of the products but also causing severe hindrance for the industry to produce quality products appropriately and efficiently. In addition, this guidance based system adds 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 which 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 take a note of this critical deficiency which exists in the drug product approval requirements caused by requiring non-GMP drug dissolution testers. This deficiency needs to be addressed quickly so that quality of the manufactured products could be established and monitored accurately and efficiently.

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) .

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