POTENTIAL REGULATORY SITUATIONS

Below are few scenarios that demonstrate how complaints and OOS reporting can be handled.

Scenario 1. The license holder receives a complaint from a hospital indicating that a lyophilized product will not completely dissolve. The license holder manufactures and tests the product. It completes its investigation and closes it within 30 days as defined in the SOP. In this scenario, there is little risk of regulatory audit action should the complaint be reviewed during an inspection.

Scenario 3. The license holder receives a complaint from a customer indicating that a lyophilized product will not completely dissolve. The Quality Agreement indicates that the contract manufacturer has 30 days to complete a complaint investigation but restricts the contract manufacturer from closing the investigation until the license holder gives approval. The complaint is passed on to the contract manufacturer for investigation within 5 days of receipt. The contract manufacture provider investigates the complaint and the results of the investigation are provided to the license holder within 20 days from receipt. The license holder reviews the investigation and closes the investigation in its system but does not notify the contract manufacturer to close its investigation. In this scenario, the typical timelines for handling complaints and completing the investigation as defined in the Quality Agreement and SOP have been met.

In this scenario, there is a slight risk of regulatory audit action at the contract-manufacturing site because its complaint displays as "open." The contract manufacturer needs to show due diligence that it has requested a statement from the license holder to close the complaint should this complaint be reviewed during an inspection.

Scenario 4. The license holder receives a complaint from a hospital indicating a patient experienced a serious adverse event (SAE). The Quality Agreement indicates that the contract manufacturer has 30 days to complete a complaint investigation but restricts the contract manufacturer from closing the investigation until the license holder gives approval. The contract manufacturer has an SOP in place that defines the process for handling complaint investigation for SAEs. The complaint is passed on to the contract manufacturer for investigation within 24 hours. The contract manufacturer investigates the complaint and the results of the investigation are provided to the license holder within 24 hours. The license holder accepts the investigation of the contract manufacturer and completes its own investigation within 24 hours. The result of the investigation is satisfactory and no field action is needed.

In this scenario, the typical timelines are not appropriate. There is a risk that the contract manufacturer could be cited for a regulatory violation because its complaint remains "open." In this case, it is fortunate that the contract manufacturing organization has an SOP that defines its heightened reporting requirements for handling complaints associated with SAEs. The contract manufacturer needs to show due diligence that it has requested a statement from the license holder to close the complaint should this complaint be reviewed during an inspection. Both parties need to revise the Quality Agreement to define responsibility and timelines associated with investigations associated with SAEs.

Scenario 5. The license holder is informed of an OOS result from the contract-testing laboratory responsible for final product testing. The OOS was for a moisture failure on stability. The license holder has independent Quality Agreements with the contract testing organization and the contract manufacturing organization. The OOS is confirmed by the contract-testing laboratory. The separate Quality Agreements, in this case, may not have been reviewed to ensure consistency regarding timelines, notifications to regulatory agencies and partners, and authorizations to close. These inconsistencies may lead to increased regulatory scrutiny and possible actions if deemed sufficiently serious.

CONCLUSION

The above scenarios illustrate how important it is for all parties involved in product manufacturing to understand the regulatory requirements and build requirements into SOPs and agreements so that unnecessary regulatory actions during inspections can be averted. In today's environment, all parties must take responsibility for product quality and regulatory compliance through clear delineation and communication of responsibilities.

Susan J. Schniepp is vice-president of quality at OSO Biopharmaceuticals, susan.schniepp@osobio.com