One of the most common tasks ahead is variation submission, and one of the major changes in RA work concerns variation classification. The previous way of classifying variations cannot be used with the new Regulation; what was once classified as an IAin variation may now require assessment or vice versa. Time and effort are needed for classification of Variations Requiring Assessment (VRA) and Variations Not Requiring Assessment (VNRA). Several experts may be needed for classification, and the conditions and documentation requirements must be checked carefully. The competent authority can also be consulted at this phase if advice or confirmation for classification is needed.
Once the variation classification is clear, the schedule for the variation and implementation can be planned. The schedule also depends on the type of process and possible product information changes. Some examples of schedules and implementation are given below:
|Implementation See more information under “Implementation rules”||within 30 days before submission||only after authority approval|
|Submission||UPD||VNeeS via the CESP/EMA portal|
|Validation||no validation phase||15 days validation phase|
|Schedule||30 days||VRA-R: 30 or 60 days* VRA-S: 60 days VRA-E: 90 days see further CP-specific rules**|
|Decision||will be informed in the UPD by Day 30 after submission||According to schedule For MRP/DCP: national approval within 1 month after EoP / when applicable, depending on national practices. For CP: Commission decision within 1–2 months after the CVMP’s opinion***|
* depending on the need for supplementary information
** VRA-R: weekly submission schedule; VRA-S/VRA-E: monthly submission schedule; advance notice is needed for VRA-S and VRA-E: 2 months and 4 months before planned submission, respectively.
*** Commission approval is expected within 1 month after adoption of the CVMP’s opinion. Linguistic review is often required for PI changes, and Commission approval in these cases takes about 2 months.
Although VNRAs are considered as “do and tell” variations, some exemptions and implementation interpretations apply. Generally, implementation is the date when the company makes the change in its own Quality System. On some occasions, this can also be a future date. For more information for CP products, see question 1 on implementation for VNRA changes, and for NP/MRP/DCP, see BPG – VNRA.
VRAs can be implemented only after authority approval. It is important to remember that this does not mean right after the CVMP’s opinion or EoP.
- For CP products, the VRA can be implemented only after the Commission Decision has been issued and according to the time limit for the implementation set by the Commission.
- For MRP/DCP, the RMS gives a common earliest implementation date, which is 1–2 months after EoP.
- For NP, this varies according to national guidance.
For best possible variation management, the MAH should also consider the possibility of grouping variations. With the new VRA and VNRA classification in place, there are some limitations. VRAs can be grouped together with other VRAs in one application. In this case, the variation timetable is accordant with the longest of the included variations. However, VNRAs and VRAs cannot be grouped together. The VNRA submissions via the UPD were aiming to reduce administrative burden, but VNRAs have been found to be a bit challenging when it comes to grouping. With linked or consequential VNRA and VRA variations, consider the following approaches:
- Submitting the consequential VNRAs as VRAs under the appropriate z-variation classification code in a grouping with the other VRA(s).
- Submitting the consequential VNRAs once the VRAs are approved (CP).
- Submitting the consequential VNRAs before implementation (MRP/DCP).
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