Steady Increase - All who follow industry trends will have noticed an increase in regulatory actions related to non-compliance issues. We can see this in the increased issuance of inspectional observations - or 483s - by the U.S. Food and Drug Administration (U.S. FDA) and by the withdrawal of certificates of suitability (CEP) certifications by the European Directorate for the Quality of Medicines and Healthcare (EDQM).

The first question to be addressed is whether this increase is due to a demand for a higher level of compliance as reflected by more demanding regulations, a more rigorous application of existing regulations or a lowering of standards within the companies?

An inspection of the nature of the non-compliance letters reveals that many of the issues raised are absolutely traditional, that is, issues that were prevalent in the 1990s and that had presumably become so well understood as to be virtually eradicated within the established industries. However, analysis of U.S. FDA data indicates that one of the major issues over the last two years has related to quality control units, with failure to review and resolve incidents adequately including: extending investigations to other lots affected; undocumented and/or unsubstantiated investigation conclusions; and lack of or inadequate corrective or preventive actions taken, including recalls.

Imprecise Wording

Two other major citation areas have been failure to adhere to production procedures and inadequate or failed validation of production procedures and analytical methods.

A significant increase was also noticed in training deficiencies, and here we can see a clue as to what is happening. The regulations state in 21 CFR 211.25(a): "Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with GMP requirements applicable to them."

Inspection of this simple regulation reveals three words that are somewhat imprecise: "qualified individuals", "continuing basis" and "sufficient frequency." The increase of actionable events is simply a reflection of the authority's interpretation of these terms.

For example, the head of a department may actually be a very poor trainer, or sufficient frequency may not be once every five years. A most astute phrase became popular with the FDA: "trained or really trained?"

Inaccurate Information And Heparin

Much of this more rigorous application of the existing regulations has been as a reaction to considerable criticism that has been levelled at the U.S. FDA. The U.S. Government Accountability Office (U.S. GAO) - the investigative branch of Congress - issued severe criticisms of the FDA, including comments that they have several separate data bases of manufacturing organizations, one listing 3,000 approved companies and another having approximately 6,800 establishments.

A not insignificant number have inaccurate information, including wrong names and addresses. This was highlighted by the Heparin crisis that started in 2008, where it was determined that Chinese companies that provided the starting materials used in its production had not been inspected, in part, due to confusion as to the exact names and addresses of the companies involved. Even after the crisis, which included US deaths and severe medical complications the FDA were not able to investigate some of the raw material suppliers.

The same GAO estimated that FDA may inspect about 8% of foreign establishments in a given year, and it would take the agency more than 13 years to inspect these overseas establishments once. The actions of the FDA were also called into question in that from 2002 through 2007, the agency issued warning letter following 15 overseas inspections in which serious deficiencies were identified. However follow ups were not timely and often relied on paper declarations rather than re-inspection.

At her appointment as commissioner of the FDA, Margaret Hamburg announced that the FDA would become far more aggressive by streamlining the issuance of warning letters and will follow up more quickly on assessment and follow up on corrective action after a warning letter is issued.

The Situation In Europe
The European situation is more difficult to monitor because there is no publically available data base. However, it can be seen that that since starting actual inspection of API manufacturers, the EDQM has revoked a significant number of certificates of suitability. In the second half of 2010, some 19 APIs had their certificates revoked or suspended because of either failed inspections or refusal to even allow inspection.

Thus we can see that there is a definite increase in the more rigid application of existing regulations, but this does not adequately explain the fundamental nature of the non-compliance issues.

Therefore we must ask if standards are getting lower. Certainly part of the explanation is that new companies are trying to get onto the European and U.S. markets without having done their homework. Statements such as "the investigator observed individuals in the clean area with open toe or open foot sandals, torn plastic booties, wearing no masks and wearing no gloves" or a sterile facility with " holes in the ceiling and visible light coming from the roof near the ventilation system, bubbling of the vinyl and disintegration of the wall under vinyl in the freeze dryer room, visible black mold on the wall, a poor drain system for the freeze dryer steam venting system, and a soft (spongy) wall" obviously reflect new management major lack of understanding of what is required in that they could even contemplate passing an inspection.