Fire in Production! What are appropriate CAPAs?

An interesting case has occurred at the Marcus Research Laboratory, Saint Louis (USA). It is described in a Warning Letter from the FDA that was recently published.

What happened?

In March 2020, during the production of a povidone iodine active ingredient (PVP-I), a smoldering fire occurred in a reactor cabinet, which was extinguished by the staff with a fire extinguisher. Although the affected batches were exposed to temperature deviations due to the incident and there were production delays, the material was released for further processing after checking the available iodine. The quite critical deviation was not further investigated and no corresponding measures were taken.

An isolated case? Not at all!

In August 2020, there was smoke observed in a reactor cabinet. Production was stopped and the material was "held in unknown conditions". Again, after checking the available iodine, it was released for further processing.

How did the company (not) react?

In both cases, the company produced deviation reports, but released the drugs "based solely on composite results of percent available iodine". Influences of heat, fire, smoke or other contaminations, e.g. also by the use of the fire extinguisher, were not further evaluated. Deviating process steps that go beyond the normal, validated condition were also not taken into account. Also, no risk or impact assessment was carried out.

What does the FDA expect?

The FDA now expects a "comprehensive assessment and remediation plan" to ensure the "QU is given the authority and resources to effectively function". This assessment should include, but not be limited to:

• A statement that the procedures used by the company are sound and adequate.
• The provision of stability data for the batches concerned.
• Provisions for comprehensive quality oversight.
• A full and final review of each batch and associated information prior to quality release.
• A description of the role of top management and how it supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
• An action plan to address any risks to product quality or patient safety of the povidone iodine batches, including possible customer notifications and recalls.