The analysis of the Warning Letters of FY (Fiscal Year) 2014 has revealed an unexpected result: again, paragraph 211.113 "Control of microbiological contamination" was at the top of the most observed deficiencies - the section from the Code of Federal Regulations (CFR) which was absent from the top 10 of the ranking list of the most frequent GMP deviations the year before. Although this paragraph appeared as the second and respectively the third most frequent quote in the Warning Letters of the fiscal years 2011 and 2012, a closer look at the addressees of the total 33 Warning Letters from FY 2014 shows yet that - unlike the Warning Letters of the past years - over half of them were addressed to so-called "compounding facilities" and "compounding pharmacies". "Compounders" are establishments which manufacture patient-specific preparations according to a prescription issued by a doctor. Compounders are mostly large pharmacies or establishments emerged from pharmacies and manufacture also sterile dosage forms among other things. "Compounding pharmacies" are in the focus of FDA's inspection programme since many patients have been harmed (in some cases death) because of serious deficiencies in the sterile production of these facilities. Whereas in FY 2013 only 5 out of 42 Warning Letters (12%) were sent to "compounders", the number of Warning Letters in FY 2014 increased to 20 out of 33 (61%).
In these establishments, the GMP deviations are practically everywhere all the same: beside insufficient control of microbiological contamination (211.113) deficiencies in design and construction of premises were observed. This means that the requirements from 211.42 "Design and Construction Features" were disregarded. The context is simple: in premises which fulfil in no way the requirements for a modern, GMP-compliant sterile production, adequate control of contamination is difficult to realise. It is therefore hardly surprising that deficient behaviour of the staff during production (211.28 "Personnel responsibilities") appeared in almost all the Warning Letters issued to the "compounders" as severe criticism. FDA investigators also criticised nearly as often the insufficient performance of stability testing and the absence of a stability review program.
The hit list containing the top five GMP deviations (incl. Warning Letters to the "compounding facilities") is now as follows:
1. 211.113 "Control of microbiological contamination"
2. 211.42 "Design and construction features"
3. 211.28 "Personnel responsibilities"; 211.166 "Stability Testing"
4. 211.167 "Special testing requirements"
5. 211.165 "Testing and realease for distribution"
If one doesn't consider the Warning Letters issued to these specific US American establishments manufacturing patient-specific drugs, a completely different statistic arises (based on 13 Warning Letters only). The ranking list consists of only 4 positions (the CRF paragraphs indicated under position 4 have been respectively quoted once).
1. 211.25 "Personnel qualifications"; 211.68 "Automatic, mechanical, and electronic equipment"; 211.100 "Written procedures, deviations"; 211.113 "Control of microbiological contamination"; 211.160: "General
requirements" (Laboratory Controls); 211.192 "Production record review"
2. 211.42 "Design and construction features"; 211.84 "Testing and approval or rejection of components, drug product containers, and closures"; 211.166 "Stability Testing"
3. 211.56 "Sanitation"; 211.67 "Equipment cleaning and maintenance"; 211.94 "Drug product containers and closures"; 211.110 "Sampling and testing of in-process materials and drug products"; 211.125 "Labeling
issuance"; 211.180 "General requirements" (Records and Reports); 211.188 "Batch production and control records"
4. 211.22 "Responsibilities of quality control unit"; 211.28 "Personnel responsibilities"; 211.87 "Retesting of approved components, drug product containers, and closures"; 211.111 "Time limitations on production";
211.137 "Expiration dating"; 211.142 "Warehousing procedures"; 211.170 "Reserve samples"; 211.182 "Equipment cleaning and use log"; 211.194 "Laboratory records"; 211.198 "Complaint files".
The topics "Microbiological control" and "Design and Construction Features" are still frequently quoted but they appear along with quotations to quite a number of other CFR paragraphs. Among the addressees of the Warning Letters, there are 6 manufacturers of parenteral drugs, the other ones are producers of solid and liquid dosage forms (partly also OTC). The companies are located in the following countries: USA (5), India (4), China (1), Mexico (1), Australia (1) and Germany (1).
The analysis of the Warning Letters clearly demonstrates the risk-oriented approach which the FDA uses for the inspections. According to this approach, companies running a sterile production have top priority and this particularly applies to such establishments like "compounding pharmacies" which have inadequate resources for this kind of production - with regard to well-trained personnel and premises.