The trending preferential parenteral route of administration of monoclonal antibodies is via subcutaneous autoinjectors with increased patient autonomy, compliance and reduction in healthcare trips and costs. A notable source of device failure is from highly viscous protein solutions, requiring increased force for full injection. A multitude of studies have focused on alterations in formulation composition and there are increased emerging trends in device engineering solutions. However, an earlier and alternative cost and time-effective strategy is introducing single point mutations in the variable domains of mAbs. This project focuses on the latter, with unique aims to holistically characterize biophysical profiles of candidate mutants as well as their viscosity.

Advanced AI/ML models can be applied to protein science, specifically in high-concentration antibody formulation. In silico methods improve the selection process and design steps in protein development. This presentation summarizes strategies being developed and implemented for structural assessment of biotherapeutic proteins in combination with designing high-throughput formulation using modeling and simulation.

One trend in biologicals is the shift to self-administration, associated with convenient home dosing, but also restricted injection volumes that necessitate high strength formulations for subcutaneous injection. We have automated and miniaturised the preparation and characterisation of up to 96 antibodies at formulation strength, enabling the determination of critical molecular properties, such as viscosity and solubility, at an earlier stage in the discovery process and thus improving candidate quality.

• Developability assessment in discovery phase
  
• Miniaturisation and automation
• Predicting stability
  

In this talk, I will discuss phase-appropriate and state-of-the-art approaches for developing high-dose subcutaneous drug products.

The talk would summarize the variables that determine the upper threshold for aqueous mAb formulations as well as known mitigation strategies.  I would then potentially go into new modalities that would allow us (in theory) to exceed the limits of aqueous formulations.

The present research provides a comparative evaluation of scalable manufacturing strategies to develop low viscosity (150mg/mL) formulation for lyophilized biosimilar IgG1; suitable for single, subcutaneous injection ~600mg/3.0mL, per dose.IgG1 was concentrated to ~200mg/mL and provides a comparative evaluation of manufacturing strategies and their impact on the chemical and structural stability of IgG1. Techniques used for the concentration of IgG1 are tangential flow filtration (TFF), spray drying (SPD), and spray freeze drying (SFD).

Drug products undergo handling by patients and healthcare professionals, including reconstitution of lyophilized products, transfer to syringes, and dilution into IV bags for administration. In-use compatibility studies are performed to show that stability and concentration are maintained, ensuring patient safety and accurate dosing. However, regulatory expectations are not well-defined, leading to uncertainty in study parameters. Recent cross-product data and a multi-company collaboration offer guidance for streamlined experimental design.

The use of CSTDs with biologics have been on the rise without an associated compatibility assessment. This is of significant concern as the impact of CSTD exposure on biologic drug products has not been well understood. The talk will focus on evaluating the compatibility of monoclonal antibodies with various CSTDs and strategies to mitigate risks when using CSTDs for delivering biologics.

Despite the benefits that Prefilled Syringes (PFS) can provide to patients, the silicone oil pre-coated on the glass barrel may migrate into the drug product and impact drug product quality. Due to current supply chain shortages and procurement preference for commercial product, the PFS source may have to change in the middle of development and a need of establishing source duality is also required by health authorities. The presentation focuses on risk assessment of silicone oil migration to enable a thorough and optimal selection of primary container closure and de-risk the impact of silicone oil on drug product quality.

As healthcare systems increasingly rely on medical care administered at home, the focus on ease of administration, safety, compliance and sustainability is driving the development of combination products for home use. This presentation will discuss approaches to addressing three key challenges: i) drug-device compatibility, ii) reliability and robustness of performance and iii) usability issues in the context of high concentration mAb formulations.

Recombinant adeno-associated virus (AAV) has emerged as a promising gene delivery vector for the treatment of various diseases. There are marked differences in buffer selection for formulation development with AAVs and protein therapeutics, which must be considered in the context of product manufacturing, long-term storage, in-use administration, and shipping/handling. This entails screening for buffer pH, ionic strength, and the impact of added surfactants on stability/degradation trends of drug product.

Liposome and LNP formulations have evolved as highly potent drug delivery systems. Recent literature gives valuable insights in developing and manufacturing these formulations, with focus mainly set on delivering different liposome and LNP compositions/sizes. This presentation will give some insight into thermodynamic equilibrium considerations, such as long-term (size) stability of liposomes and LNPs at various temperature, as well as equilibrium radius considerations in manufacturing liposomes and LNPs.

Lipid nanoparticle (LNP) technology, as currently one of the most promising and emerging technologies, shows the ability to deliver nucleic acid therapeutics for non-viral gene therapy (NVGT). Compared to intramuscular vaccine delivery, intravenous (i.v.) delivery of a LNP formulation for gene therapy shows unique challenges. An LNP formulation for gene therapy via i.v. may require different lipid and formulation design. Here, we will discuss the considerations and challenges in early LNP development and impact on tissue targeting for NVGT.

In the development of LNP-based drug product, the choice of manufacturing technology is one of the key factors for success. The choice of technology can have a significant impact on the biophysical properties, structural characteristics, colloidal stability, and efficacy of the LNP. This study describes the impact of different manufacturing parameters and the scale-up consideration to enable successful LNP drug product manufacturing.

RNA activation in acquired and genetic diseases Small activating RNAs (saRNA) are double- stranded 21 nucleotide RNA that can target promoters or enhancers leading to mRNA upregulation. MTL-CEBPA is an investigative drug that resulted from the conjugation of saRNA CEBPA with NOV 340 lipsomes that targets tumour associated macrophages in order to alter favourably the tumour microenvironment. MTL-CEBPA has been administered safely in over 140 patients with advanced cancer and improved clinical outcome in a sub-set of patients when co-administered with TKI or check point inhibitor. 

In this talk, we discuss de-risking mRNA adduct formation in lipid nanoparticle formulation intended for glycogen storage disease type-1a using analytical tools.