July 10 FDA Warning Letter Review

This past week two warning letters to 503B outsourcing facilities were posted to the FDA website.

In one of the warning letters, the outsourcing facility compounded drugs using raw material not on the 503B bulks list, failed to include all drugs compounded in the prior 6-months, and failed to report an adverse event within the required time period.

The second warning letter identified more typical observations including:

  • Aseptic filling within a [redacted – I am assuming hood] in an unclassified environment where the [redacted – I am assuming hood] was operating at a negative pressure to the surrounding environment. 
  • Use of non-sterile cleaning pads inside the ISO 5 processing area.  This firm used pre-wetted sterile wipes in a resealable pouch stored within the ISO 5 area for an unspecified time.  The firm apparently had no testing/documentation that the wipes would remain sterile when used/stored in this manner.
  • Failure to perform airflow visualization studies under dynamic conditions.  Additionally, following construction in the production room the certification report did not include viable air monitoring.
  • And lastly, the firm performed media fills but not under the most challenging or stressful conditions.  

The latter warning letter illustrates some fairly common observations within 503B’s.  It is up to the firm to determine what is required to meet cGMPs and then to perform testing to demonstrate that the firm (facility, equipment, people, materials) can meet those expectations.  This may include hold times for sterile wipes, or depyrogenated glassware, or sterilization.  This may require the firm to evaluate which operations performed in the ISO 5 production area is most challenging (and of course to document this risk approach) and use media fills to demonstrate the firm can successfully operate under these conditions. This also requires the firm to perform critical airflow visualization under dynamic conditions – in a previous warning letter/Form 483 the FDA identified a firm had an operator moving their arms around “to simulate” dynamic operations within the ISO 5 space – clearly this doesn’t pass the test.  

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