Formulation development of adeno-associated virus drug products is challenged by high molecule complexity, complicated degradation pathways, complex delivery routes, and scarce material for studies. This talk will describe some of Spark Therapeutic’s approaches to leverage automated, small-scale, and high-throughput screening techniques to address these challenges. Examples will include a case study of formulation optimization for an engineered AAV serotype.

Emerging bio(pharmaceutical) technologies (e.g., additive manufacturing, electrospinning, and micro/nanofluidics) are aiming to prepare systems that can be used for personalised medicine, be adapted to patient’s needs, and teach old drugs new tricks. For example, proteins can be encapsulated into lipid or polymeric (e.g., PLGA) particles formulated by microfluidics, biologic molecules can be encapsulated in nanofibers by electrospinning for drug delivery and/or tissue engineering applications, and additive manufacturing (e.g., 3D printing & bioprinting) provides the ability on preparing biodegradable systems (e.g., drug delivery systems or medical implants).

In this presentation, Rob will discuss the key challenges associated with the design and development of novel biologics formulations for low content, highly potent, Botulinum Neurotoxin products. The presentation will span a range of subject areas including the challenges of low concentrations for analytical capabilities and the control of content in development, manufacturing, and clinical processes.

Developability screenings in conjunction with establishing technology platforms allowed for a significant reduction in development timelines for monoclonal antibodies without increasing the development risk. However, the need for the convenient delivery of high doses of antibodies, in combination with new molecular formats and the further acceleration of development timelines leads to increasing development risk. Therefore, new tools and development concepts are presented that would enable to cope with these challenges.

Rapid development of new therapeutic modalities requires delivery methods to be adapted or fully re-designed to ensure both efficacy and patient convenience. In addition, the user convenience of many existing products can be significantly improved by modifications in their formulation and delivery method. The talk, which will include several case studies, will outline the critical role of creative formulation in addressing the delivery challenges of both existing and emerging therapies.

Novel biotherapeutics and vaccines for cancer treatment can require new approaches to formulation and selection of delivery methods and devices. This presentation reviews strategies being used by Scancell to address these challenges.

Developability assessments have grown more challenging with the proliferation of novel modalities and constructs. This presentation will explore strategies for approaching developability evaluations for new programs that do not fit with platformed approaches and consider how these studies impact the formulation steps that follow.

Sub-visible particle testing is mandatory for any bio-pharmaceutical preparation because particles are critical for patient safety. Until today the robust and mature light obscuration technology only provides counting and sizing information and destroys the sample during testing. Today we can transform it into a non-destructive, accurate technology that stays compliant to the regulations and soon will be able to discriminate particle types. Higher computational power, smart automation and a spark of innovation does the trick.

Development of protein/peptide-based drugs includes several disciplines from initial target exploration to final submission for regulatory approval. Identification of the lead drug compound has conventionally focused on optimization of in vitro/in vivo parameters such as receptor binding/selectivity, PK/PD, toxicity, etc., whereas parameters including biophysics/stability of importance for the final drug performance have been given less attention. A case exemplifying in-parallel optimization of in vitro and biophysics/stability properties is presented.

Commercial Biotherapeutics Stabilized with Trehalose and Sucrose

Key Issues in Biopharma Formulation Development

Essential components of a “Platform Biopharma Formulation”

Examples for utilizations and functionalities of Sucrose and Trehalose in Covid 19 related formulations/vaccines and techniques

Understanding important physicochemical properties of Trehalose and Sucrose

Purity, Quality, Consistency in Pfanstiehl’s Trehalose and Sucrose

Advantages of Trehalose over Sucrose

Analysis of high concentration protein formulations poses some challenges. Molecular crowding and dipolar interactions lead to self-association with increased viscosity and changes in fluid dynamics. Sub-visible particles (SVPs) pose a major challenge in the development of high concentration protein formulations. Distinction between proteinaceous and other SVPs is vital in monitoring form stability. The current LO method has limitations to detect translucent particles. Thus, an unambiguous method to characterize SVPs is needed. This talk will discuss some of the techniques to characterize and distinguish SVPs in protein formulations by MFI/FlowCam/SLIM with the MIA and Lumetics.

With emerging non-mabs like Fc silencing formats, bispecific mabs, therapeutics proteins, and newer modalities such as gene therapies and AAV’s, designing stable liquid formulation is more challenging. Co-development of the clinical service formulation enables an in-depth understanding of the degradation pathways and the possibility of a stable liquid formulation. With the use of forced degradation studies and high throughput biophysical predictive tools, key developability questions can be addressed.

Adenovirus vectors offer a versatile vaccine platform. The Oxford Jenner Institute ChAdOx platform is licensed for Ebola and the Oxford-AstraZeneca COVID-19 vaccine which has been administered to >500m people. Distribution and storage at 2-8 °C is possible for months, but storage at higher temperatures would enable easier access to communities and people in regions without cold-chains. Here we present the formulation and process development for stable freeze-dried ChAdOx vaccines.

Viscosity is one major challenge in formulating highly-concentrated antibody drug products suitable for subcutaneous injection. Even during filtration steps in downstream processing, attractive interactions and resulting high viscosity in these formulations bear challenges to material and schedules.

We have developed the Viscosity Reduction Platform consisting of viscosity-modifying excipient combinations that provide a tailored approach to address these issues in both manufacturing steps.

Protein instability in liquid formulations, especially aggregation is a cause of the molecular interactions in solution. Besides several analytical techniques that allow for their characterization, these interactions can be modeled (and in some cases even predicted) using coarse-grained modeling approaches. This allows results in a first estimate on aggregation propensity induced by the respective excipients, enables a first choice synergetic excipients, and an initial formulation window for further evaluation.

Biologics are complex molecules and good formulation conditions are difficult to find. There is a need for public data where stress experiments are compared with characterization. In the PIPPI consortium, high-throughput characterization was performed on 16 different proteins in different buffers. As expected, good formulation conditions were highly protein depended and more data are needed to enable a valid prediction tool. Additionally, some methods showed good correlation with long-term stress studies.