Use of Stability Modeling to Support Accelerated Vaccine Development and Supply

Abstract

Stability assessment of pharmaceuticals in specific storage and shipment conditions is a key requirement to ensure that safe and efficacious products are administered to patients. This is particularly relevant for vaccines, with numerous vaccines strictly requiring cold storage to remain stable. When stability evaluation is exclusively based on real-time data, it may represent a bottleneck for rapid and effective vaccine access. Stability modeling for vaccines represents a key resource to predict stability based on accelerated stability studies; nevertheless, this approach is not fully exploited for these kinds of products. This is likely because of the complexity and diversity of vaccines, as well as the limited availability of dedicated guidelines or illustrative case studies. This article reports a cross-company perspective on stability modeling for vaccines. Several examples, based on the direct experience of the contributors, demonstrate that modeling approaches can be highly valuable to predict vaccines’ shelf life and behavior during shipment or manipulation. It is demonstrated that modeling methodologies need to be tailored to the nature of the vaccine, the available prior knowledge, and the monitored attributes. Considering that the well-established strategies reported in ICH or WHO guidelines are not always broadly applicable to vaccines, this article represents an important source of information for vaccine researchers and manufacturers, setting the grounds for further discussion within the vaccine industry and with regulators.

Long-Term Stability Prediction for Developability Assessment of Biopharmaceutics Using Advanced Kinetic Modeling

“…Such non-linear degradation over time, as detected for HMWP formation of SAR441255, is also often observed for several (e.g., aggregation related) quality attributes of vaccines and therapeutic antibodies [25,[34][35][36][37]49,[51][52][53][54], underlining the benefit of screening various kinetic models for biopharmaceutics. With appropriate kinetic models that accurately describe the degradation progress as a function of time and temperature, various applications emerge, such as estimation of shelf life [34][35][36][37][38], accurate degradation-based predictions for products during various types of temperature excursions [35,38,49], ranking of formulations [37,39,49], batch-to-batch comparisons and real-time shelf-life monitoring of products during shipments [39,40,49].…”

“…The AKTS-Thermokinetics software (version 5.3, AKTS AG, Advanced Kinetics and Technology Solutions, Siders, Switzerland), combining advanced kinetics and statistical analyses of the accelerated stability datasets obtained from 5 • C to 40 • C over a period of three months, was used to identify kinetic models which best describe the rates of purity loss and HMWP increase for each peptide formulation. Except for the use of replicates, our procedure used "good modeling practices" recently recommended for accelerated stability predictions of bioproducts [39,49,50]. Briefly, the software screened and compared the variety of kinetic models, including one-step and two-step models (Equation ( 1)), describing the reaction progresses (i.e., purity loss and HMWP formation) independent of the complexity of their molecular mechanisms as a function of time and temperature in a manner as previously described [34,35,51].…”

Formulation development of a stable influenza recombinant neuraminidase vaccine candidate

“…The design of studies ensured the “good modeling practices” recommended for accelerated stability predictions of bioproducts was followed. 25 After the model that best fits the collected data was identified by, bootstrapping analysis (resampling of data 100 times) was used to calculate the 95 th percentile prediction intervals (PI) for the selected model. Long-term predictions of loss of antigenicity by ELISA and % closed tetramer by SEC as a function of time and temperature were determined using the selected model and corresponding PIs.…”

CMC Strategies and Advanced Technologies for Vaccine Development to Boost Acceleration and Pandemic Preparedness

“…To make the application of accelerated stability modeling successful, the establishment of the experimental plan is of critical importance: the accelerated temperatures should be adequately selected allowing to exhibit a degradation over a short period while remaining representative of such degradation at long-term conditions; the frequency of time points as well as the number of analytical replicates at each condition should be established based on prior knowledge (regarding, e.g., preliminary information about the degradation pathway and its kinetic particularly in the context of a vaccine platform, This example, among others [14,59], demonstrates how advanced stability modeling combined with statistical approaches to consider model uncertainties can be of precious help to predict the stability of a product at long-term conditions based on data generated over a restricted period. Therefore, this approach becomes a critical asset to support the acceleration of vaccine development and supply, especially in the case of pandemic emergencies and unmet medical needs.…”

“…To achieve this ambition, coordinated dialogue across different manufacturers is key to generating a common and objective set of proposals and points of attention to be shared with regulatory agencies in different world areas. Several proposals have been published by industry groups to address technical and regulatory challenges, including risk-based process validation, comparability, and stability strategies, post-approval changes, national control laboratories testing, and regulatory harmonization [ 7 , 8 , 9 , 14 ]. The tackling of new variants, which is still a potential concern for COVID-19, deserves particular attention.…”