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

It is a well-established understanding that the drug/pharmaceutical industry is a highly regulated industry. The purpose of the elaborate regulations and their implementation is that the products manufactured should be of the highest quality standards possible.  There are numerous sources of such regulations, most often country- or territory-specific such as US, Japan, European etc., or some others harmonized such as from ICH. However, in general the most commonly referred, or quoted, are those from the US FDA, US Pharmacopeia, EMA and ICH.

Regulatory authorities such as US FDA, Health Canada, EMA and many others enforce such regulations and standards to ascertain that manufacturers and manufactured products are in-compliance with regulations leading to manufacturing of quality products. It is very important to note that a fundamental underlying assumption here is that if a product or process is in-compliance then the product or process will be of quality. In general such an underlying assumption is correct; however, for the pharmaceutical industry this underlying assumption does not appear to be valid.

In general, regulations and standards are based on, or derived from, scientific research following underlying scientific principles and theories. A common terminology which is used to describe these underlying scientific principles and theories is “validation” i.e. the process, or processes, has been validated to provide quality products. Each and every step (small or large) is considered or broken further into smaller steps to have their own validation so that the end result (or product) should be of quality. For example, analytical techniques (such as chromatographic instruments and methods) may not be directly considered as a manufacturing step but are critical in monitoring the outcome of manufacturing, thus require validation of their own.

From the scientific and regulatory compliance perspectives, validation of manufacturing processes, along with associated steps or components, is therefore perhaps the most important and critical step and/or requirement. It is further important and critical to note that regulatory compliance requirements are, or at least should be, dependent on the well-established validation steps. It is not practical or useful to develop and/or implement compliance requirements and/or standards without having validation steps first.

So what does a validation step/process mean? In simple terms, it means that if a claim is made, then it must be substantiated based on scientific (mostly experimental) evidence. For example, if it is claimed that a product is of quality then it becomes mandatory first to state what quality means and then how this defined quality is established using scientific methods. The regulatory mandate is to evaluate if the quality is defined accurately and then the methods and processes used are capable of measuring quality of the products. In general, regulatory standards and requirements focus primarily on the outcome of manufacturing and may not be manufacturing itself which for all practical purposes is secondary in the assessment of the outcome (products).

From a regulatory perspective one has to deal with two aspects; (1) what is a “quality” product or what is “quality” of a product, and (2) how is it measured or established experimentally (scientifically). Unfortunately, however, it is a disturbing fact that quality of a pharmaceutical product has never been defined, in particular, for regulatory assessment purposes. Therefore, it is not possible, at present, to know or establish whether a, or any, given product is of quality even if it is approved by the regulatory authorities. This situation needs to be addressed and corrected on an urgent basis.

On the other hand, regulatory authorities do suggest and enforce some traditional practices and standards, assuming that if manufacturers are in-compliance of such then the products would be considered of acceptable quality. Here again, there is a serious deficiency in suggesting compliance requirements. Often methods and techniques suggested, at least some, have never been validated for the claims made for them. For example, a technique known as drug dissolution testing often mandatory for the evaluation of quality of products, in particular oral such as tablet and capsule, has never been shown capable of providing any relevant characteristics of a product. There are so many stringent requirements for the required testers and testing methods without any scientific basis or reasoning. These are often extremely frustrating and resource consuming exercises for the manufacturers and the regulatory authorities to meet compliance requirements for this test which has no link or contribution towards the quality assessment of the products. Recommendations and requirements for the use of non-validated and non-qualified testers and tests are serious violations of GMP requirements.  Regulatory authorities should reconsider the current requirements of such testing on an urgent basis.

In short, as the quality of pharmaceutical products is an undefined parameter (metric), at present, it is not possible that manufactured products can be assessed for quality. On the other hand, current regulatory requirements which manufacturers are to follow to be in-compliance for products approval are based on techniques and assumptions which lack scientific merit and/or validation of testers and methods, thus would give false hope or comfort about the quality of products.

The good news is that both of the above mentioned issues can be addressed with relative ease if a more logical and scientific approach/thinking would be pursued. Based on my working experience in a regulatory environment for an extended period (30 years), I have extensively written about these issues and suggested possible solutions for addressing these issues by publishing in the scientific literature as well as through this blog (www.drug-dissolution-testing.com) which can be used as a starting point in understanding the issues as well upcoming with possible solutions. Perhaps, the following articles would be useful as a start.

(1)    Promoting quality standards for drug products: Scientifically speaking, please be systematic and logical! (http://www.drug-dissolution-testing.com/?p=2359).

(2)    Establishing safety, efficacy and quality of drugs and drug-products (tablet/capsule) – serious confusion! (http://www.drug-dissolution-testing.com/?p=2351)

(3)     The science of drug dissolution testing: Testers or apparatuses, experimental conditions and interpretation of results – A systematic approach for learning (http://www.drug-dissolution-testing.com/?p=1668)

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