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Once Again, Lack of SOP Compliance Tops List of 483 Observations

On January 15, FDA published its annual summary of inspectional observations for the period October 2102 – September 2013. Out of a total of 5,211 Form 483s issued, those resulting from the inspections of drug establishments were third in the ranking, with 690 reports and those of biologics, mainly blood establishments, sixth with 191. The majority (2,386) went to food establishments with medical devices being second on the list with 1,099.

Top of the FDA list, at 155 of the 690 citations (22%) was the observation that “The responsibilities and procedures applicable to the quality control unit are not in writing or not fully followed.” This finding emphasizes the importance that the regulatory agencies have always placed on the need for companies to have strong quality management systems. Considering that is has been about 50 years since FDA issued its first regulations governing Good Manufacturing Practice (GMP), it is surprising that the main topic of non-compliance listed in the 483s for drugs and biologics was the absence of written procedures, or a failure to follow Standard Operating Procedures (SOPs). In the summary of the citations issued to drug companies, 504, or 73% described instances of failure to comply with the requirements for SOPs. The creation and following of written procedures has always been a basic component of the GMP regulations and regulatory inspectors have always performed a review of these in order to understand a firm’s approach to production and control. The regulatory requirements for SOPs are simple and easy to follow. The fact that the observations cite problems with such basic SOPs as those governing cleaning methods suggests that many companies are not giving proper attention to developing and implementing SOPs and are also probably lax in their training programs for these SOPs. There is really no reason why this should be the case and we are baffled as to why inspectors continue to find firms lacking in this area and that SOPs are absent, poorly written, or not followed by those actually performing the procedures described.

The need for strong quality oversight of manufacturing and control operations is not going way and, if anything, will continue to be a focal point for regulatory inspectors. The current requirements for quality systems management and control are clearly defined in ICH Q10. A fundamental component of these quality systems should be appropriate risk assessments to define the potential risks to product quality inherent at each stage of product development and manufacture (see ICH Q9) and the creation of appropriate procedures to eliminate or significantly reduce these risks.

The European Medicines Agency has only recently started publishing the results of its inspections where companies have been found to be non-compliant so a comparison between EMA and FDA inspection results is difficult. A 2007 review of inspection findings by EMA from 1995 to 2005 found that “Concerns over documentation of quality systems and procedures head the list [of non-compliance findings] by a significant margin, representing 14.1% of the total number of deficiencies. However, if all deficiencies relating to documentation were grouped together, they would make up 24% of the total. This is a significantly high value, meaning that one out of every four deficiencies observed relates to a problem with documentation.” This suggests that the SOP problem noted by FDA is wide-spread and apparent to European inspectors as well.

The solution to this problem rests on the desks of every company’s senior management. Unless there is full commitment to quality from the top, it will be impossible for any company to establish a strong quality culture that will make compliance with simple things like following SOPs a routine thing and ensure GMP compliance throughout more complex quality and manufacturing operations. The GMP regulations require that each company have a Quality Unit, responsible directly to a Senior VP or the President. This Quality Unit should be capable of Quality Control and Quality Assurance by risk management, following the Q9 and Q10 guidances. Implicit in this is the capability to write clear, unequivocal operating procedures covering all critical manufacturing and control activities within the establishment. The staff responsible for these procedures must then be comprehensively trained in the written instructions and must demonstrate their ability to follow them. Finally, the QA unit must inspect and audit the operations on a regular basis and report to the responsible executive any deviations from the SOPs and the corrective activity which restores full compliance. It is then the responsibility of senior management to follow-up on the audit findings and implement appropriate corrective actions as quickly as possible.

As Dr. Kanarek stresses in greater detail in his upcoming article “SOPs Revisited – a 2014 Perspective,” failure to follow these simple rules will inevitably result in the inspectional observations and reports as discussed here. If these observations are not dealt with in a timely manner, Warning Letters and other more serious regulatory actions, including product recalls, refusal by regulatory authorities to approve a new drug, or even legal action, such as consent decrees, may result, leading to devastating effects on profitability or even viability of a company. We find it unconscionable that companies continue to drop the ball on simple things like writing and following SOPs. FDA and EMA are right to continue to focus on these areas; hopefully companies will finally take notice and get their acts together. As always, an ounce of prevention is worth a pound of cure.


Blog article by: Alex Kanarek and Howard Levine