The process validation section has been doubled from 2 to 4 pages, with extra sections about verification of transportation, validation of packaging, qualification of utilities and validation of test methods.
Besides a traditional approach, now a continuous verification approach is also allowed. Regardless of the approach chosen, of course consistent product quality and a robust process must be assured. Bracketing is explicitly mentioned: it is allowed, provided that the necessary justification and the necessary process knowledge can be demonstrated. The underlying process knowledge for design space justification (if used) and mathematical models (if used) must be demonstrated. In other words, the use of a Quality by Design approach is clearly mentioned, and is therefore allowed.
It is clearly stated that retrospective validation is no longer allowed. The relevant section has been removed.
Concurrent validation is, in exceptional circumstances, still allowed. This decision must be clearly justified and documented in the validation master plan. The role of the QP for certification of batches within the concurrent validation is explicitly described.
For process validation, the new annex now foresees 3 options: the traditional manner (the only one that used to be allowed), a continuous process verification (the quality by design approach) or a hybrid approach, in which empirical and historical batch data have led to sound product and process knowledge. The hybrid approach may also be used in the event of changes or in the ongoing process verification, even if the initial validation was carried out in the traditional manner.
Regardless of which of the three options is used, ongoing process verification during lifecycle is requested afterwards. Besides constant monitoring of the process, it is also described how the process verification itself must be monitored and adapted at regular intervals.
Verification of transportation
Due to the different variable factors, this is seen as challenging. However, it is necessary to define transport routes clearly, taking account of seasonable variables. All critical external factors must be monitored. For those variables for which this is not possible, a risk assessment is required.
Validation of packaging
Since equipment variation can have a significant impact on the integrity and functionality of the packaging, the equipment for primary and secondary packaging must be qualified. The qualification for the primary packaging element must be carried out at the minimum and maximum ranges for the critical process parameters.
Qualification of utilities
The quality of steam, water, air and other gases used must be guaranteed. For this purpose, the plant must be qualified, taking account of seasonal variables and intended use. In the event that direct product contact is possible, a risk assessment must be carried out.
Validation of test methods
All test methods used for qualification, validation or cleaning validation must themselves be validated. (for this point, see section 6 from Eudralex Volume 4). In case of microbial testing, the method evaluation must show that the product or cleaning agents used (in the case of surface testing in clean rooms) have no influence on the recovery of micro-organisms.