Specification-driven acceptance criteria for validation of biopharmaceutical processes.

Intermediate acceptance criteria are the foundation for developing control strategies in process validation stage 1 in the pharmaceutical industry. At drug substance or product level such intermediate acceptance criteria for quality are available and referred to as specification limits. However, it often remains a challenge to define acceptance criteria for intermediate process steps. Available guidelines underpin the importance of intermediate acceptance criteria, because they are an integral part for setting up a control strategy for the manufacturing process. The guidelines recommend to base the definition of acceptance criteria on the entirety of process knowledge. Nevertheless, the guidelines remain unclear on how to derive such limits. Within this contribution we aim to present a sound data science methodology for the definition of intermediate acceptance criteria by putting the guidelines recommendations into practice (ICH Q6B, 1999). By using an integrated process model approach, we leverage manufacturing data and experimental data from small scale to derive intermediate acceptance criteria. The novelty of this approach is that the acceptance criteria are based on pre-defined out-of-specification probabilities, while also considering manufacturing variability in process parameters. In a case study we compare this methodology to a conventional +/- 3 standard deviations (3SD) approach and demonstrate that the presented methodology is superior to conventional approaches and provides a solid line of reasoning for justifying them in audits and regulatory submission.

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Copyright © 2022 Marschall, Taylor, Zahel, Kunzelmann, Wiedenmann, Presser, Studts and Herwig.

Déclaration de conflit d'intérêts

Authors MK, AW, BP, and JS were employed by Boehringer Ingelheim Pharma GmbH. Authors LM, CT, and TZ were employed by Koerber Pharma Software. This work was funded by Boehringer Ingelheim Pharma GmbH in the course of a project with Koerber Pharma Software. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.