Accelerating the speed of innovative anti-tumor drugs to first-in-human trials incorporating key de-risk strategies.

Pharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool can be used to produce materials for the toxicology (Tox) study, reducing time to the clinic by 4-5 months. During the coronavirus disease 2019 (COVID-19) pandemic, the anti-COVID drugs timeline from DNA transfection to the clinical stage was decreased to 6 months using a stable pool to generate a clinical drug substrate (DS) with limited stability, virus clearance, and Tox study package. However, a lean chemistry, manufacturing, and controls (CMC) package raises safety and comparability risks and may leave extra work in the late-stage development and commercialization phase. In addition, whether these accelerated COVID-19 drug development strategies can be applied to non-COVID projects and established as a standard practice in biologics development is uncertain. Here, we present a case study of a novel anti-tumor drug in which application of "fast-to-FIH" approaches in combination with BeiGene's de-risk strategy achieved successful delivery of a complete CMC package within 10 months. A comprehensive comparability study demonstrated that the DS generated from a stable pool and a single-cell-derived master cell bank were highly comparable with regards to process performance, product quality, and potency. This accomplishment can be a blueprint for non-COVID drug programs that approach the pace of drug development during the pandemic, with no adverse impact on the safety, quality, and late-stage development of biologics.

An Evaluation of the Glass Vial Hydrolytic Resistance Method.

The European Pharmacopoeia (Ph. Eur.) hydrolytic resistance method for glass vials is routinely used to screen pharmaceutical glass vial supply. In an effort to better understand and control the factors affecting method precision and robustness, several potential sources of variability in the Ph. Eur. alkalinity method have been studied for 3 cc glass vials. Method parameters including vial rinsing, vial covering, autoclave cycle execution, sample hold times, and titration procedure were evaluated in this study. The results of this study indicate the method parameters which require stringent control in order to achieve acceptable method precision and robustness.LAY ABSTRACT: The European Pharmacopoeia (Ph. Eur.) hydrolytic resistance method for glass vials is routinely used to screen biopharmaceutical glass vial supply. The method was studied to assess contributions to its variability and to potentially improve its reliability. The results of this study indicate which method parameters require stringent control in order to generate reliable data using the Ph. Eur. hydrolytic resistance method.

Probing Shear Thinning Behaviors of IgG Molecules at the Air-Water Interface via Rheological Methods.

Shear thinning behavior, often observed in shear viscosity tests of IgG therapeutic molecules, could lead to significant disparities in the projections for the viscosity profile of a molecule. Despite its importance, molecular determinants of sheer thinning in protein suspensions are largely unknown. To better understand the factors influencing sheer thinning, viscosity profiles of IgG1 and IgG2 molecules were monitored over a wide range of bulk concentrations (0.007-70 mg/mL). The degree of shear-thinning of 70 and 0.007 mg/mL samples was minimal in comparison to the 0.7 mg/mL solution for both IgG molecules. These observations suggest that bulk concentration alone does not determine the degree of sheer thinning, and additional factors play a role. Additional data reveals, within a threshold range of concentrations, that a strong correlation exists between the degree of shear thinning and the surface area to volume (SA:V) ratio of an IgG sample exposed to the interface. The influence of the interface, however, diminishes when the bulk concentration falls outside this concentration window. Also revealed by interfacial oscillatory rheological testing, both IgG molecules showed solid-like behavior (G'i) at the air-water interface at 0.7 mg/mL, whereas liquid-like behavior (G″i) was dominant at 0.007 and 70 mg/mL concentrations. These observations imply that the lack of solid-like behavior was due to the absence of a network structure. Likewise the addition of polysorbate 20 (PS20) to the 0.7 mg/mL solutions decreased the degree of shear thinning by disrupting the network structure at the interface. Taken together, the results presented here suggest that, although shear thinning behavior is a manifestation of an interfacial, rather than a bulk, phenomenon, the extent of it depends on how susceptible the surface molecules are to the air-water interface, where the surface molecular structures are influenced by the bulk properties.

Determining the delamination propensity of pharmaceutical glass vials using a direct stress method.

An accelerated lamellae formation (ALF) methodology has been developed to determine the delamination propensity and susceptibility of pharmaceutical glass vials. The ALF process consists of a vial wash and depyrogenation mimic procedure followed by stressing glass vials with 20 mM glycine pH 10.0 solution at 50 °C for 24 h and analyzing the resulting solutions by visual inspection for glass lamellae. ALF results demonstrate that while vial delamination propensity generally correlates with glass hydrolytic resistance, ALF is a more direct test of glass delamination propensity and is not affected by post-production vial washing that can affect results obtained using hydrolytic resistance tests. ALF can potentially be used by pharmaceutical companies to evaluate and screen incoming vial lots to minimize the risk of delamination during the shelf life of parenteral therapeutics, and by glass vial manufacturers to monitor and improve their vial manufacturing processes. LAY ABSTRACT: Glass flakes can sometimes appear in liquid pharmaceutical drugs contained in glass vials. These glass flakes are a result of several factors related to the glass vial production process, glass vial sterilization procedures, and the formulation of the liquid pharmaceutical drug. Vial testing is routinely done in order to select glass vials that are less likely to form glass flakes. The factors leading to the formation of glass flakes were studied and applied to a method designed to directly screen vials for their propensity to form glass flakes. The washing of vials followed immediately by sterilization at high temperatures was determined to be a critical factor in the formation of glass flakes. As a result, a laboratory mimic of this procedure was incorporated into the newly developed method for screening vials. This mimic procedure as well as robust accelerated incubation conditions and a sensitive visual inspection procedure are key aspects of this vial screening method.