[Editor's Note: The following has been excerpted from PDA Technical Report No. 39 (Revised 2021): Guidance for Temperature-Controlled Medicinal Products — Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment.]
5.5 Management of Nonconformances
From a temperature perspective, distribution must be designed to keep the product within the defined limits described by the manufacturers, applicable regulations, or visible on the outer packaging. The distribution process is a complex and dynamic process, where product is exposed to the external environment, less controllable than e.g., a typical drug manufacturing process, not managed directly by the product manufacturer and exposed to various entities in the supply chain. Due to the inherent variability of the external environment, nonconformances should be expected and documented according to the level of impact on the product.
Written procedures should be in place so that nonconformances are defined, their impact on product quality is assessed, and their root cause investigated, determined and, as applicable, eliminated (see Section 5.5.1).
5.5.1 Categorization of Nonconformances
Nonconformances can be categorized by their type (e.g., temperature excursions outside the defined limits described by the manufacturer or visible on the outer packaging, logistic process deviation, equipment breakdown, theft/loss, anomalous trends, noncompliance with a good-practices requirement), as well as their criticality (e.g., no impact or potential or determined minor or major impact on product quality or patient safety). The categorization applied by each company must be described in a written procedure.
5.5.2 Impact Assessment
An impact assessment must be performed following written procedures. The impact assessment must also consider and define the boundaries of the nonconformance in terms of which products may have been affected and which are out of scope.
The level of impact determines the level of investigation and correction needed. A prompt correction of the nonconformance to limit its immediate impact is required, and all actions undertaken in that respect must be properly documented.
All products impacted (or potentially impacted) must be individually assessed. An investigation should be conducted involving the appropriate subject matter experts (SME) for the product(s) to determine the impact on product quality. Stability data might be used to assess temperature excursions. Nevertheless, the cumulative impact of any possible previous excursion must be assessed. All investigations including temperature excursions should be properly documented and approved by the Quality Unit.
When product quality, compliance, or patient safety is not impacted, it is considered acceptable to close the nonconformance with minimal or no root cause investigation (as applicable and described by the procedure). The impact assessment must be formalized and approved as required by the local procedure.
5.5.3 Corrective and Preventive Actions (CAPA)
If a root cause of a nonconformance is determined, a CAPA should be considered and implemented in order to remove the root cause of the nonconformance. A corrective action is taken to prevent recurrence, whereas a preventive action is taken to prevent occurrence. Depending on the CAPA, the implementation of the CAPA should be monitored for its timeliness and effectiveness. The thoroughness of a CAPA must be commensurate with the risk posed by the nonconformance.
A CAPA is used to address quality and compliance issues and should result in process improvements and process understanding. It should be used in conjunction with the root cause analysis. To facilitate the trend analysis, a root cause should be identified according to the elements, for example, the route where the nonconformance occurred, root cause location (where it happened), and root cause owner (who or what is at the origin). The level of effort, formality, and documentation of the actions should be commensurate with the level of impact of the issue on product quality.
The development, implementation, and verification of the CAPA’s effectiveness will often require collaboration with the LSP(s) and/or packaging/container manufacturers.
5.5.4 Product Control and Disposition Decision
Should an absence of impact for products in the boundaries of the nonconformance be determined, the product can be distributed after that no-impact determination has been confirmed, according to product specifications and local procedures.
Should an impact be determined, product(s) must be held and can be distributed only after a correction of the impact, if possible, has been successfully executed and product quality impact no longer exists.
When correction of the impact is not possible, impacted product(s) must not be released.
5.5.5 Approval and Closure
The responsibilities for approving nonconformances and their investigations must be described in a local procedure. The Quality Unit is typically responsible for approving all nonconformances as described.
The person responsible for the approval and closure of a nonconformance must have access to all information and investigation elements as required to perform the closure. When more information or investigations are needed to enable the approval and closure of a nonconformance, these must be requested from and provided by the investigation team.
The approval can be granted only after all investigative elements are available and formalized and all applicable CAPAs have been satisfactorily identified and approved.
[The complete PDA Technical Report No. 39 (Revised 2021): Guidance for Temperature-Controlled Medicinal Products--Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment is available at the PDA Bookstore and the Technical Report Portal for members.]