Addressing “ills” of pharmaceutical products manufacturing

First, it is important to know what the “ills” are. These (“ills”) are not usually specific but described by some (inspectors/investigators) from regulatory authorities in particular FDA with observations and statements following facility inspections. These facility inspections are conducted under the requirements of Good Manufacturing Practices or GMP which are usually part of country’s laws and regulations giving the practices “authenticity” and enforcement ability. The basis of GMP requirements and implementation is on the fundamental assumption that GMP requirements are enforced so that the end products from manufacturing are of quality, e.g. as per FDA “FDA ensures the quality of drug products by carefully monitoring drug manufacturers’ compliance with its Current Good Manufacturing Practice (CGMP) regulations”[1].

A quick survey of literature provides examples of some descriptions of observed deficiencies (often also knows as “observations”) of compliance requirements which could fall in one of the nine categories such as: organization and personnel; buildings and facilities; equipment; control of components and drug product containers and closures; production and process controls; packaging and labeling control; holding and distribution; laboratory controls; records and reports [2]. These deficiencies or observations are usually descriptive or narrative in nature, not objectively measurable or quantifiable. Therefore, these can be considered as subjective in nature, based on individual investigator’s personal judgement or inclination as noted by FDA as well e.g. “During an inspection, ORA investigators may observe conditions they deem to be objectionable. These observations, are listed on an FDA Form 483 when, in an investigator’s judgment, the observed conditions or practices indicate that an FDA-regulated product may be in violation of FDA’s requirements [3]. Once such observations become public, people (often experts/consultants external as well as internal to agencies) blow these out of proportion arguably for their own personal and business advantages and benefits [e.g. see here 4]. These (“observations”) then become and/or promoted as “ills” of the manufacturing and/or the industry.

In short, the opinions expressed, formally or informally, by the investigators/inspectors mostly about operation are considered as “ills” of the industry and manufacturing.

It is important to note that, as per GMP requirements described above, inspections must establish or relate to the ability of the manufacturing of quality of products. However, as noted above as well, most of noted deficiencies are related to manufacturing and its operation not about quality of the products. For example, outcome of an inspection or warning letter is usually concluded as follows “Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B)” [5,6]. Question is where is the evidence of manufacturing of substandard quality (or adulterated) product? The products quality can only be established by testing a product itself, which is mostly neither part of the inspections nor “observations” claims. It is like saying that as staff was not found properly cleaned and dressed (in the investigator’s view) hence staff would be considered lacking intelligence and/or competence for the job. For the validity of such a statement or conclusion, it must be based on evaluating and establishing their competence and intelligence and must be established independently.

However, experts/consultants would conclude and promote inspections/observations as product deficiencies or inability to manufacture “quality” products – these are simply false assumptions and conclusions, because observations are not linked or validated against the deficiencies of the product quality. Therefore, putting blame on the manufacturing or industry for poor manufacturing of quality products would in general be inaccurate. It is the practice of the current investigations or inspections which needs to be reassessed.

To make “observation” or inspections logical and scientifically valid agencies should define quality of the products with a measurable parameter. Samples should be collected at appropriate check points and evaluated against (strictest) pre-set standards and specifications for the quality of products.

On the other hand, manufacturers and their affiliated contract facilities should seek help in addressing and defending the current irrelevant conclusions drawn from the facilities assessments and removing the weaknesses of the regulatory (GMP) requirements and practices on a worldwide basis.

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