The EU recently issued the comprehensive GMP Annex 1 for the manufacture of sterile drug products. This guidance is broad and thorough covering all aspects of sterile product manufacture.

Under the Quality Control section, (10.5) the following is referenced:

The sterility test applied to the finished product should only be regarded as the last in a series of critical control measures by which sterility is assured. It cannot be used to assure sterility of a product that does not meet its design, procedural or validation parameters. The test should be validated for the product concerned.

For commercial production, the Quality Control release testing should be looked upon as a confirmation of the ongoing effectiveness of the established systems, processes, and procedures that are associated with the manufacture of that product. This will include those product-specific validated processes (including sampling and test procedures) but also the non-product-specific processes such as the WFI, Equipment Controls, Training, EM program, etc. Therefore, when during release testing, an unexpected result is obtained (such as an OOS), it is imperative that an investigation ensues to determine the cause for that result and that considers all those systems, processes, and procedures involved in manufacture of the product.

Under Section 3 of the Annex 1 guidance (Pharmaceutical Quality System) the following is stated:

All non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures should be adequately investigated before certification/release of the batch. The investigation should determine the potential impact upon process and product quality and whether any other processes or batches are potentially impacted. The reason for including or excluding a product or batch from the scope of the investigation should be clearly justified and recorded.

The investigation must be thorough and consider all the factors that could ultimately impact that release test result and rule out potential contributory factors. It is recommended that, within the site’s investigation procedures, there is guidance on those factors that should be evaluated as part of the root cause analysis, that considers the type of product that is being manufactured / tested (e.g., OSD vs sterile injectable).

Annex 1 further states under Section 3:

Root cause analysis of procedural, process or equipment failure is performed in such a way that the risk to product is correctly identified and understood so that suitable corrective and preventive actions (CAPA) are implemented.

 A critical element of the investigation is to determine the corrective action (CA) that is to be taken to remediate the root cause, along with the criteria to demonstrate the effectiveness. Such an assessment must obviously address the subject of the investigation but also consider any needed actions at the Quality System level. The investigation must also determine the potential impact to other batches considering those that have not been exposed to that CA. The measure of impact should not be based solely upon the QC release data but should also consider other signals for impact, such as in-process data, EM, incoming release data, post-marketing indicators, stability, process capability trending, etc. (dependent upon investigation subject/type), again with documented rationale within the investigation. Again, it is recommended that the site’s investigation procedures include guidance for how impact could be potentially assessed depending upon the type of incident and the product that is impacted. The Quality Unit review/approval of an investigation (as part of quality investigational oversight) should be wary where an investigation has no defined CA, as there should be robust documented justification which includes consideration of the risk of repeat incidents.

If you have any questions relating to your site’s investigation program and enhancing investigation oversight, please contact us at