PharmTech: Will real-time release testing replace the final release procedure?
Häusler:
The main benefit of RTR testing when combined with quality by design and process analytical technology (PAT) tools is increased
quality assurance for patients. In addition, such a strategy can lower manufacturing costs through improved yields, less waste,
faster cycle times, and fewer deviations and rejects.
Process understanding and the definition of a robust control strategy are key aspects of RTR. The interaction of material
parameters and attributes, as well as the dynamics of processes, must be taken into account, and are one important part of
submission dossiers for marketing authorisations. As such, when implementing RTR systems it is essential to use PAT to efficiently
monitor and record all quality-relevant parameters. In this area, there have been a number of improvements, including advances
in NIR- and Raman microscopy, fluorescence microscopy, image analysis and laser-based methods. Using chemometics and multivariate
analysis, it is now also possible to monitor production processes in real-time. However, a move towards RTR is not only about
using advanced analytical and physical measurement techniques, but also involves performing statistical calculations on the
resulting data masses. Importantly, regulatory authorities worldwide have to accept the move from final product testing to
RTR applications. RTR has to be accepted by all regulatory authorities because the current varied acceptance can be a major
issue. The equivalence between RTR-testing and pharmacopoeial testing must also be explained.
If one wishes to implement new tests and procedures, then it is important to adapt the whole quality assurance system. This
approach is mandatory for compliance. The new quality system must also be aligned with ICH Q10.
These steps constitute the transition from rigid to risk-based cGMP, and a mindset change from reactive to proactive quality
thinking, which could be quite a challenge. In particular, there will be a huge impact on qualified persons or other persons
responsible for product release. Specifications will need to be elaborated carefully, and the definition of deviations that
require investigation and the process to declare analytical results as outliers or invalid data must be described in SOPs.
RTR will be implemented over time as industry understanding increases and regulatory expectations are clarified. There is
a long road ahead, but as the saying goes: a journey of a thousand miles begins with a single step.
Heribert Häusler is head of quality systems excellence at Boehringer Ingelheim GmbH (Ingelheim), haeusler@ing.boehringer-ingelheim.com
.
References
1. EMA, Note for Guidance on Parametric Release (March 2001).
2. EMA, Guideline on Real Time Release Testing (February 2010).
3. 21 CFR Part 11 Title 21 (April 2010).
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