Characterization of key manufacturing uncertainties in next generation therapeutics and vaccines across scales

Abstract

Viral vectors are advanced therapy products used as genetic information carriers in vaccine and cell therapy development and manufacturing. Despite the first product receiving market authorization in 2012, viral vector manufacturing has still not reached the level of maturity of biologics and is still highly susceptible to process uncertainties, such as viral titers and chromatography yields. This was exacerbated by the COVID-19 pandemic when viral vector manufacturers were challenged to respond to the global demand in a timely manner. A key reason for this was the lack of a systematic framework and approach to support capacity planning under uncertainty. To address this, we present a methodology for: (i) identification of process cost and volume bottlenecks, (ii) quantification of process uncertainties and their impact on target key performance indicators, and (iii) quantitative analysis of scale-dependent uncertainties. We use global sensitivity analysis as the backbone to evaluate three industrially relevant vector platforms: adeno-associated, lentiviral, and adenoviral vectors. For the first time, we quantify how operating parameters can affect process performance and, critically, the trade-offs among them.Results indicate a strong, direct proportional correlation between volumetric scales and propagation of uncertainties, while we identify viral titer as the most critical scale-up bottleneck across the three platforms. The framework can de-risk investment decisions, primarily related to scale-up and provides a basis for proactive decision-making in manufacturing and distribution of advanced therapeutics.

Uncertainty quantification for gene delivery methods: A roadmap for pDNA manufacturing from phase I clinical trials to commercialization

“…The production of pDNA benefits from economies of scale, however, to a smaller extent than lentiviral vector production. [ 90 ] Manufacturing a batch size of M = 22.8 mg, IQR = 22.8–34.9 mg pDNA for 200 patients in a phase I/II clinical trial leads to production costs of M = 37.95$·dose −1 , IQR = 30.60–47.24$·dose −1 . On the other hand, when pDNA is manufactured for commercial use in batch sizes of M = 5.05 g, IQR = 4.13–6.16 g for a market of 40,000 patients, the production cost declines to M = 0.32$·dose − 1 , IQR = 0.27–0.39$·dose −1 .…”

“…These circumstances emphasize the need for a proactive approach to capacity planning under uncertainty for raw material suppliers. [ 90 ]…”

“…The lentiviral vector production process follows the steps of cell cultivation, vector concentration, purification, formulation and fill & finish as shown in Figure 3, and it is based on the model presented in Sarkis et al ( 2023). [90] 2.…”

“…The production of pDNA benefits from economies of scale, however, to a smaller extent than lentiviral vector production. [90] Manufactur- Sarkis et al (2023) [90] quantified the benefit of economies of scale in lentiviral vector production, revealing that small-scale manufacturing translates into a 100-fold increase in cost per dose. This highlights the significance of maximizing the volumetric scale in lentiviral vector manufacturing, as it substantially reduces costs.…”

Editorial

“…The fourth paper [ 4 ] turns to one of the core application domains of the journal, manufacturing for healthcare. The paper addresses the topic of viral vector manufacturing systems, which are a key component enabling the delivery of genetic payloads for vaccines and other advanced therapies.…”