FDA Warning Letter: GMP Deficiencies at US Pharma Manufacturer, e.g. in Water System

Recommendation

17-19 September 2024

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The FDA has recently issued another Warning Letter to an US pharmaceutical manufacturer describing serious GMP deficiencies. This concerns among others the water system, the QC laboratory and quality assurance.

Microbial count exceedances in pharmaceutical water system

According to the FDA, the manufacturer is not in a position to produce pharmaceutical water that meets at least the USP Purified Water requirements (aqua purificata). The high and multiple microbial count exceedances at various instances in the water system used for the production of oral liquid drugs are extremely problematic.

The FDA considers a biofilm infestation of the water system to be probable on the basis of the level of the microbial count findings. Potentially pathogenic bacteria were found in the system as well as at various points-of-use. The FDA expects a CAPA plan including a complete remediation of the water system, validation of the redesigned system and a plan to keep the system under control.

Inadequate method validation

In the area of quality control, the FDA criticizes the inadequate method validation. For example, the recovery of a pathogenic microorganism, which was found in the water system, was not validated. In addition, the manufactured products are not tested for impurities in accordance with USP.

Furthermore, several HPLC analyses of the finished drug were aborted in the QC laboratory and the data were destroyed. There is no SOP on how to deal with such data and how access control is regulated.

Deficiencies in quality assurance

Quality assurance is also affected by deficiencies. For example, an unnamed substance was added during the manufacture of a batch, without modification of the manufacturing documentation, stability studies or approval by the QA. The FDA thus questions the company's change control procedure as well as the Annual Product Review System.

Another case also concerns QA oversight about the manufacturing process. For example, when the content of a product was too high, the pharmaceutical company corrected this by longer mixing times or adding water, for example, without validating this process. This means that neither the initial mixing process nor the dilution process are validated.

In another case, the manufacturer had received a complaint from the market about the smell of a product. The FDA considers the processing of the CAPA to be insufficient. The company had indicated an improperly cured product container as the cause, but judged the product to be safe. However, the company does not have any data as to whether this is the case over the entire shelf life.

The FDA strongly recommends that the company engage a GMP consultant to address the numerous GMP deficiencies.

To get more details please also see the FDA Warning Letter to RIJ Pharmaceuticals.