Warning Letter: Serious Defects in Zoning, Cleaning and Disinfection and Monitoring

At the end of January, the FDA inspected the company AllerQuest LLC, which operates the aseptic production of pharmaceuticals, including injectables, in its premises. The inspection revealed a number of deficiencies that queried the assurance of sufficient quality and sterility.

Room and equipment design and zoning

For example, the premises used did not meet the requirements defined in 21 CFR 211.42© for separate and defined zones for aseptic production areas. Zone A (ISO5) of the ampule filling area was, for instance, directly accessible through a double door from the uncontrolled area, whereby this door had large gaps which the manufacturer had tried to seal with adhesive tape. The aseptic processing line design was also inadequate. The production line had limited protection and there was a high risk of contamination from manual intervention and envorinmental air.

Since the company's response on 22 March announced the commitment of external advice, unfortunately insufficient supporting documentation was provided to evaluate the effectiveness of the corrective and preventive action (CAPA). While the company pointed out that all batches of its drug had passed the sterility tests for release, the FDA points out that a final product test alone is not sufficient to determine the sterility of all units, as contaminants are not distributed homogeneously.

FDA requests answer

That is why the FDA demands the following as from AllerQuest:

• Preliminary plans for the manufacture and distribution of your sterile pharmaceuticals, while the defects in plant and equipment design and all other defects are corrected.
• Detailed identification of all contamination hazards related to your aseptic processes, equipment and facilities and the provision of an independent risk assessment (including cleanroom behavior, design and layout, personnel and material flow).
• A detailed CAPA plan with deadlines taking into account the risk assessment.
  - Detailed, supportive documentation of your CAPA, e.g. with plans for the remediation of plants and for the separation of the critical area ISO 5 from unclassified areas.
  - Description of all filling operations (ampoule and vial filling) Description of equipment switching practices between ampoule filling machine and vial filling machine in the ISO 5 curtain area.

Avoidance of contamination and cross-contamination and confusion

In addition, shortcomings in the area of environmental monitoring and personnel monitoring were also identified which were not sufficiently defined and implemented. Even in the event of deviations, no corresponding effective measures were taken, e.g.

• In case of contamination with Bacillus sp., a spore-forming agent, no corresponding spore-effective disinfectants were used to remove the contamination.
• In the case of exceeding the action limit during monitoring, no sufficient cause analyses were carried out, not even when a sample was contaminated with fungi.
• Other measures, such as regular glove monitoring, were completely lacking and were replaced by an annual qualification.

Further information on this and other deficiencies identified can be found directly in the Warning Letter on cGMP deficiencies according to 21 CFR, parts 210 and 211.