GxP-Blog

All pharmaceutical manufacturers know that the requirements for the safety and quality of medicinal products are constantly increasing and must be implemented, while taking into account the continuous adjustments and additions to the regulatory and legal requirements. Pharmaceutical manufacturers are inspected by the competent authorities at more or less regular intervals before obtaining manufacturing approval and during the routine production phase. In the EU, this is done by the competent local or national supervisory authorities. If the manufacturer markets its products abroad, additional inspections may be made by the competent foreign authorities. For European manufacturers who market their products in the USA, inspections by the U.S. FDA have been dreaded in recent decades. The reasons for this are a different orientation, different thematic priorities and, in some cases, different intensity and depth of U.S. FDA inspections compared to inspections by European authorities. As a result, drug manufacturers have often sought external advice for the preparation and follow-up of regulatory inspections. Last but not least, the main objective has been to obtain or renew the manufacturing permit.

A number of factors have contributed to a significant reduction in the number of inspections by foreign authorities, such as U.S. FDA inspections, at European drug manufacturers, including:

• A sharp increase in the number of drug manufacturers,
• An increase in the scope of the requirements to be checked and the associated increased requirements for the inspectors, and
• Limited budgets available for conducting inspections.

These factors have led to a realignment of regulatory inspection objectives. By adapting and supplementing the regulations, manufacturers have been and continue to be required to carry out more and more self-monitoring. Your quality system must have sufficient self-monitoring to ensure the quality of the medicinal products. Regulatory inspections are increasingly focused on ensuring that this self-monitoring is working within the pharmaceutical quality system.

In addition, so-called Mutual Recognition Agreements (MRAs) have been concluded between many countries and regions that mutually recognize the official inspections or inspection results. This has been made possible not least by extensive harmonization of regulatory requirements.

The coronavirus pandemic has also contributed to the postponement of inspections by foreign authorities, inspections carried out in “remote mode” or the acceptance of inspections by local authorities as sufficient in the context of the MRAs. The MRAs lead to a stronger emphasis on inspections by local authorities in part because the standard of inspections based on the MRAs is raised to a common and expected higher level across countries. The backlog of postponed inspections by foreign authorities will intensify this trend in the future.

An audit of Quality Oversight has been a focal point in the inspections of the American authority for years. What importance does Quality Oversight have in the inspections of the European authorities and don't the manufacturers in the EU have to prepare for the issue of Quality Oversight due to the low and decreasing number of inspections by the U.S. FDA?

When we look at the typical official observations and/or defects found regarding “Oversight of the Quality Unit”, we quickly see that the European authorities during their inspections also take into account and focus on the associated systems and processes. Such typical defects include:

• Accumulation of non-compliance with written production and quality control procedures,
• Loss of document control, including through the use of non-controlled or non-approved documents,
• Lack of or inadequate processing of complaints, in particular critical complaints in connection with a lack of cause analysis,
• Accumulation of out-of-specification (OOS) results in the release analysis of medicinal products, in particular in the case of recurring OOS cases and lack of elimination of the cause(s),
• Accumulation of open deviations, in particular in the event that critical deviations have not been opened or closed for years and the derived corrective and preventive measures have not been implemented and their effectiveness has not been checked,
• Accumulation of incomplete change control procedures,
• Loss of an oversight of quality management of the qualification and validation status of the rooms, systems, devices, manufacturing processes and test methods,
• Lack of or rudimentary risk management. Lack of specifications in which cases a risk-based procedure must be implemented,
• Lack of oversight of the qualification status of personnel, including a training system,
• Lack of oversight of the suitability of the raw materials and materials used for production and quality testing,
• Lack of oversight of the qualification status of the suppliers.

In the cases mentioned, it is not uncommon for a complete loss of control to occur. The loss of control over a system or process and the expense of regaining control ties up the resources of quality assurance to such an extent that the monitoring of further systems and processes is often at risk or fails. The workload to be worked on for quality assurance accumulates over a long period of time and in some cases for years to such an extent that it is difficult or impossible to process with the existing human resources. Ultimately, quality assurance is so overburdened that it is not up to the task of monitoring the areas of production and quality control or implementing its own processes.

Our observations show that in cases of a lack of Quality Oversight, the cause is a lack of human resources for quality assurance, the processing of QA-related processes within quality assurance and/or production and quality control. This shortcoming has partly grown “historically” because just the fact of the increase in regulatory and legal requirements has not been met by the provision of adequate resources. In other cases, it was also not taken into account that the company had achieved significant growth without involving quality assurance.  

The differences in Quality Oversight between the FD&C Act and the EU GMP Directive lie in the interpretation of the question of which requirements of the regulations Quality Oversight should be implemented. Practical experience shows that this question is actually irrelevant, as the shortcomings described above are assessed essentially equally by the U.S. FDA and the EU authorities. This means that European manufacturers cannot feel “safer” despite the decreasing number of inspections by the U.S. FDA. This is in particular not the case in view of the MRAs mentioned and the historical development of the inspection objectives. On the contrary, an increase in the verification of the manufacturer’s self-monitoring within the framework of official inspections can be expected.

But how should manufacturers respond to this development?

A proactive approach is always preferable to a reactive approach. An essential measure is to ensure that the critical processes, including the quality assurance processes, are functioning in advance of the official inspections. Because in these processes, each authority will audit your pharmaceutical quality system, regardless of whether a quality unit or qualified person is jointly responsible for monitoring and ensuring the functioning of these processes with the areas of quality control, manufacturing and quality assurance in the pharmaceutical quality system.

Our Pharma Compliance Team will support you with gap analyses and mock inspections that will put your Quality Oversight to the test. The defects listed above must be avoided. For this purpose, processes must be developed, checked and adapted in a practical manner, along with the goal of implementing them with the planned resources.

These include in particular the systems and processes:

• Manufacturing, quality control and quality assurance
• Document management or document control
• Complaint and claims management
• Out-of-Specification (OOS) procedure
• Deviation management
• Change management
• Qualification and validation of premises, equipment, devices, manufacturing processes and test methods
• Risk management
• Training system and trainings
• Supplier qualification

Our Pharma Compliance Team will be happy to help you with these necessary tasks.