Freeze-drying; Lyophilization; Moisture sorption; Monoclonal antibody; Near-infrared spectroscopy; Partial least squares; Principal component analysis; Protein formulation; Quality by design; Factorial design
Abstract :
[en] Moisture content (MC) is a critical quality attribute of lyophilized biopharmaceuticals and can be
determined by near-infrared (NIR) spectroscopy as nondestructive alternative to Karl-Fischer
titration. In this study, we create NIR models to determine MC in monoclonal antibody
lyophilisates by use of statistical design of experiments (DoE) and multivariate data analysis
(MVDA). We varied the composition of the formulation as well as lyophilization parameters
covering a large range of representative conditions, which is commonly referred to as ‘robustness
testing’ according to quality-by-design concepts. We applied principles of chemometrics with
partial least squares and principal component analyses (PCA). The NIR model excluded samples
with complete collapse and MC > 6%. The two main components in the PCA were MC (91%)
and protein:sugar ratio (6%). The third component amounted to only 3% and remained
unspecified but may include variations in process parameters and cake structure. In contrast to
traditional approaches for NIR model creation, the DoE-based model can be used to monitor MC
during drug product development work including scale-up, and transfer without the need to
update the NIR model if protein:sugar ratio and MC stays within the tested limits and cake
structure remains macroscopically intact. The use of the DoE approach and MVDA ensures
product consistency and improves understanding of the manufacturing process.
Research center :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège
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