12-14 March 2024
It has been a hot inspection summer. FDA Warning Letters and EU Non-Compliance Reports seem to increase at the moment. It is worrying that the GMP non-compliance issues apparently get more serious than in the past. But what is the reason?
Many deviations found refer to data integrity. Here two different areas are covered. First: inadequate computer systems and maintenance. For example, electronic records that were not archived correctly and data that was deleted - either by mistake or due to inadequate systems. The second area is the more worrying part. Staff in production and QC have very little or no knowledge of what is expected. They are simply not trained in GMP. Going through these many findings on Data Integrity one can loose faith. This is not a new topic. It is simply a lack of knowledge in Good Documentation Practice. Principles like no data should be deleted or modified without an explanation and visually retaining the original data. In addition every activity needs to be documented in a timely manner etc. This is no "rocket science"! In the past we saw Warning Letters which went into the details of validation procedures or analytical activities. But now the non compliance is so basic that every person who received an initial GMP training should know about how to avoid it.
In parallel to the above described "trend of non-GMP compliance" we see another trend. That is the trend to put more and more pressure on the cost of manufacturing. Every country has to deal with increasing costs for their health care system. This has resulted in increasing pressure for medicinal products (lower prices). To save costs also manufacturing has come under pressure. First, APIs moved to low cost countries, especially to Asia. Then generic manufacturing of medicinal products also moved for the same reason. The remaining sites in Europe and the US also came under pressure to reduce costs. In the past a medicinal product was manufactured in many countries by different manufacturing sites. Today, for cost optimization the number of sites has been reduced. Sometimes only one or two sites exist, and an API is possibly only available from a single source in Asia. If inspectors find GMP problems at the remaining site(s), it will immediately lead to drug shortages because there is not enough capacity left at other sites to step in. This has become the main reason for drug shortages in the US and EU.
In Spain inspectors just recently detected a site which was expected to manufacture according to EU GMP. However, they were unable to, simply because they didn't have enough staff. The inspectors of the Alcor plant in the city of Guadalajara found "that the company does not have suitable facilities, personnel and materials resources to ensure proper compliance with GMP. A total number of 29 deficiencies were identified. Eight of them were classified as major."
And the company was not able to solve the issues detected during the inspection. In the Inspection Report it was stated: "the company proposed a corrective action plan on 8 and 29 July 2016. After its evaluation, on 2 August 2016 the inspectorate concludes there are many outstanding issues and that Alcor S.L. does not comply with EU GMP requirements. In general the proposed corrective actions were insufficient, diffuse and do not provide a description about the extent of the measures, so to ensure the correction of the major deficiencies. In particular, those related to the lack of personnel remain unsolved, and the accumulation of tasks and responsibilities in some personnel is a risk to quality. It does not ensure the proper conduct of the activities required for EU GMP compliance."
A very similar issue can be identified in multiple Warning Letters issued by the FDA this year. Many of them contain Data Integrity matters. In addition to a lack of adequate IT systems and IT procedures (e.g. on how to archive data electronically) many issues relate to basic Good Documentation Practice principles. Companies did not invest in staff and in the initial and ongoing training of staff. A number of Warning Letters therefore included a kind of standard "Data Integrity Remediation" requirement - and comprised among others:
"Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company's data."
If we bring the two trends together, we can see evidence that pressure to reduce production costs will inevitably lead to activities to reduce facilities and staff. The remaining staff might not be able to perform all tasks and receives less GMP training to save costs. A good inspector can see this trend very easily. Taking a look at the training records and the open issues in the corrective action plan is often enough to discover the problem.
What could be the way out of this? One scenario might be to assess the GMP problems with regard to their root cause. A company with a good compliance history that has a GMP compliance issue should be treated differently to a company that violates basic GMP problems - like lack of Good Documentation Practice. If a company falsifies data, deletes records by intention (not by mistake), this company should face more serious consequences than a company with a good compliance history and with a good quality culture. Quality Metrics like those proposed by the FDA could become a tool to make the difference visible. There is no easy solution. But we need to work on this to safeguard patient safety.