18-20 April 2023
The US Food and Drugs Administration (FDA) has issued a Warning Letter to a British API manufacturer. They criticized cross contamination by penicillin products, deviations regarding pharmaceutical water and foreign particles in the product. The inspection already took place in July, 2015. The current Warning Letter was issued on 30 June, 2016.
Key Points of this Warning Letter:
A: Cross Contamination by Penicillin
The frequently found cross contamination of non-penicillin drugs by penicillin is severe. Furthermore, the testing method is not validated for detecting the different types of penicillin manufactured. The cleaning method was not validated for all penicillin products either. The FDA offers two options in their Warning Letter: Dedication of the facility to penicillin-only production or decontamination of the facility of any beta-lactam residues in order to resume production of solely non-penicillin drugs. As it is very difficult to completely decontaminate a facility according to the FDA, they expect a comprehensive decontamination plan for that case. Until then, no non-penicillin drugs may be introduced into the U.S.
B: Microbial Contamination in Pharmaceutical Water
breaches of the alert level or action level colony forming units for microbial contamination were found in water used for production. Among others, Burkholderia cepacia was found, a waterborne organism known to contribute to biofilm formation in water systems. 16 of the 25 investigations were classified as sampling errors. However, no root cause was determined in the remaining nine investigations. In addition, the inspectors found that the water system loops were not sanitized as required in the internal SOPs. They also found product batches with bacterial counts (bioburden) exceeding the specification, also by bacteria identified in the water system. These batches were not released. However, the FDA assumes that microbial contamination rarely occurs uniformly and that therefore, batches that had passed the microbiological test may pose a risk as well.
C. Foreign Particles in the Product
In an API batch, green fibers (scouring pad), red flakes (paint) and black (glass) particles were identified. The manufacturer concluded that these were acceptable intrinsic contaminates. Again, there was no root-cause evaluation and no a risk analysis to evaluate the impact of the contaminants on other drugs manufactured in the same facility.