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“When Will They Ever Learn”… about GMP Compliance?

In keeping with their recent policy, FDA recently published a summary of Form 483 observations for 2010. Around the same time, the British MHRA published the results of their inspections for the period April 2011 – March 2012. The juxtaposition of these two summaries provides us with an ideal opportunity to compare the two agencies views on GMP compliance to determine whether there have been any real change in non-compliance issues identified by each. For a broader data base, we also looked at the EMA’s Summary of Findings for the period 1995-2005 and their Annual Report for 2011 as well as warning letters issued by FDA over the last 12 months.

In 2010, most FDA 483 observations to drug companies focused on written procedures (SOPs) which were either not written or not properly followed. The EMA’s 1995-2005 list had “Documentation – quality system elements/procedures” as the #1 deficiency and “Design & Maintenance of Facilities” as #2. By 2011-12, however, the emphasis had changed with the top five categories of non-compliance now listed by MHRA all being quality-related. “Failure to investigate discrepancies, deviations and OOS observations adequately” topped the list, followed by Change Control, CAPA, Complaints/ Product Recalls and Quality Management.

Together these five categories represented over half (347; 52%) of the 670 critical or major observations made by the agency during 303 inspections. “Failure to Investigate Discrepancies…etc.” was also the #1 topic in FDA warning letters issued between September 2011 and August 2012. “Inadequate aseptic procedures” was #2 on FDA’s list, reflecting their concentration on this high-risk area of manufacturing. Although the EMA did not give any details of its inspectional findings, the 2011 Annual Report stated that reported quality defects rose 38% over the previous year. It is possible that this increase was due to more inspections being performed. There were 375 inspections in the last year versus 245 in the previous period, a 53% increase. The greatest increase in inspections came for API manufacturing and “for cause” inspections.

The increase in inspections of API manufacturers is of particular note. FDA issued 8 warning letters to API manufacturers in the first 9 months of fiscal year 2102. Only one of these letters went to a US company with three going to API manufactures in Mexico, two to German manufacturers, of which one referred to sites in France and Italy, and one each to Polish and Spanish manufacturers. The main problem at these API manufacturers seems to be in the QC laboratories, but problems with cross-contamination, including inadequate cleaning and lack of physical separation or dedicated areas/equipment were also high on the observation list.

The ICH Q7 Guidance on GMP for APIs was issued about 12 years ago and the Q10 Guidance on Quality System Management was issued in 2005. How long will it take companies to fully implement these guidances and learn from the mistakes of others? It is not just the small manufacturers that are being cited for quality failures. One of the world’s two largest vaccine manufacturers received a warning letter dated July 12, 2012, for “cGMP Deviations” at two of its plants. The letter cited inadequate QC methods, failure of environmental testing and inadequate aseptic procedures, to name the first few observations. If a company that big still has quality management problems, no wonder the list of “inspectional observations” continues to grow in number and seriousness. Once again, the increasing number of observations relating to cGMP compliance reminds us that “those who cannot remember the past are condemned to repeat it.” When will they ever learn?


Blog article by: Alex Kanarek and Howard Levine