Changes to Prequalified IVDs

During the life cycle of an in vitro diagnostic (IVD), changes to the product, its manufacturing process or location, or the quality management system (QMS) under which it is produced may become necessary for technical or economic reasons. Such changes (referred to as "variations" by some regulatory authorities) to a prequalified IVD may range from minor, with little potential to impact the quality, safety and/or performance of the IVD, to substantial, and likely to affect the quality, safety and/or performance of the IVD.

A critical part of a manufacturer’s QMS is a documented, controlled and approved process to design, review, verify, validate (if appropriate), approve and implement changes. Indeed, to meet WHO prequalification requirements, the manufacturer must have an established, maintained and implemented procedure for categorizing and documenting any changes to the product and/or the QMS. This procedure must be described in the product dossier submitted for prequalification and demonstrable during the inspection of the manufacturing site(s).

For any planned change, the manufacturer must determine its significance with respect to the function, performance, usability, safety and applicable WHO requirements for the prequalified
IVD and its intended use. Changes applied to an IVD must be made in conformance with the requirements for control of design change according to ISO 13485.

Determining the impact of a change

The requirement to report to WHO regarding a change depends on the impact of the change on the IVD’s quality, safety and/or performance. The impact of a change should be determined for all changes. The change to the IVD’s overall residual risk evaluation may have arisen from:

  • actions including field safety corrective actions (e.g. recalls or changes to labelling) taken in relation to concerns arising from post-market surveillance of complaints and adverse events
  • redevelopment including state of the art product improvements
  • changes to a manufacturing process, facility or equipment
  • changes to the design or composition of the prequalified IVD
  • changes to the organization of the manufacturer
  • changes to the intended use and /or test procedure
  • changes necessitating new clinical and/or analytical data that raise new issues of safety and performance.

Consideration should be given to the impact of the change on the overall residual risk:benefit evaluation of the IVD as per ISO 14971. This includes a determination of whether or not the change:

  • introduces new hazards that have not been previously addressed
  • adversely affects the risk associated with existing hazards
  • alters the details of any of the information submitted for prequalification (related to dossier, manufacturing site(s) inspection, or laboratory evaluation), such as the intended use and/or compliance with the Essential Principles of Safety and Performance of Medical Devices established by the former Global Harmonization Task Force
  • affects the continued compliance of the quality management system with the relevant standards.

If the change is considered to be substantial, it should be reported to WHO. The steps in the risk analysis rationale used for determining whether a change is reportable or not must be documented.

Reportable changes

All substantial changes are considered as reportable changes. A reportable change is one that is demonstrated, through risk analysis, to have a potential impact on the function, performance, usability, or safety of a prequalified IVD. In addition, some administrative changes must also be reported.

Reporting of reportable changes is mandatory for all prequalified IVDs. It is the manufacturer’s responsibility to notify WHO of changes, in order to keep the prequalification status of the product up to date. Failure to report changes in accordance with WHO prequalification requirements may result in the delisting of the product from the WHO List of Prequalified IVDs.

Changes requiring a new prequalification application

If WHO considers that the planned change(s) will result in a product or application information of substantial difference to that which was prequalified, WHO will notify the manufacturer that a new application for WHO prequalification is required. WHO will also notify the manufacturer on the impact of the planned change to the prequalification status of the product. 

Change assessment fee

The cost of the activities (documentation review, manufacturing site(s) inspection, and dissemination of change information)required to assess a change will be covered in part by the manufacturer. WHO charges a non-refundable fee of US$ 3,000 for a technical or abbreviated review. Review will not begin until payment has been verified. No fee is charged for administrative reviews. Payment of the change assessment fee does not guarantee that the change will be approved. WHO also reserves the right to reject the proposed change(s) at any stage if the manufacturer is unable or fails to provide the required information within a specified time period, or if the information supplied is insufficient for completion of the change assessment.

Non-reportable changes

Minor changes associated with a prequalified IVD are non-reportable and do not require the submission of a change report form to WHO. Nevertheless, these types of changes, and the manufacturer’s justification for not reporting them, must be documented and controlled in the manufacturer’s QMS.