Prediction of long-term stability of high-concentration formulations to support rapid development of antibodies against SARS-CoV-2.

Long-term stability of antibody therapeutics is required to ensure their safety and efficacy when administered to patients. However, obtaining shelf life supporting, long-term stability data are often a limiting factor for new drug candidates starting clinical trials. Predictive stability, which uses short-term accelerated stability data and kinetic modeling to forecast long-term storage stability, has the potential to provide justification to support establishing shelf life, although its application for biologics has only recently gained traction.

Practical advice in the development of a lyophilized protein drug product.

The development of lyophilized protein drug products is a critical and complex task in the pharmaceutical industry, requiring a comprehensive understanding of the myriad of factors affecting product quality, stability, and the efficiency and robustness of the lyophilization process. This review offers practical advice on the critical aspects of lyophilized protein drug product development. Practical considerations across both the early and late stages of development are discussed, underscoring the necessity of a strategic approach from initial development through to commercialization.

Investigating the impact of static destabilization mechanism on fat crystallization dynamics, emulsion rheology, and whipping properties of whipping cream.

In this work, the effect of storage time on the fat crystallization, rheological and whipping characteristics of emulsions was studied and the static destabilization mechanism during storage was explored. As the storage time prolonged, peak melting temperature and onset of melting temperature increased while both the crystallization temperature and crystallization rate increased. Crystal birefringence was more pronounced at the oil/water interface accompanied by the desorption of interfacial proteins from fat droplets.

Characterization of Microbial Growth Potential in Antibody Drug IV Admixtures by Microbial Challenge.

Monoclonal antibody (mAb) drug products (DP) for IV administration are commonly diluted in a diluent such 0.9% sodium chloride (saline) or 5% dextrose (D5W) injection yielding IV admixtures before infusion or injection. During dose preparation, storage, and administration, the sterility of IV admixtures must be maintained to ensure patient safety.

An Intercompany Perspective on Compatibility and In-use Stability Studies to Enable Administration Of Biopharmaceutical Drug Products.

In-use stability and compatibility studies are often used in biotherapeutic development to assess stability and compatibility of biologic drugs with diluents and/or administration components at relevant conditions for the target route of administration (commonly intravenous, subcutaneous or intramuscular), to assure that patient safety and product efficacy are maintained during clinical use. To gain an understanding of current industry approaches for in-use stability and compatibility studies, the Formulation Workstream of the BioPhorum Development Group (BPDG), an industry-wide consortium, conducted an inter-company collaboration exercise, which included five bench-marking surveys around in-use stability and compatibility studies of biologic drugs. The results of this industry collaboration provide insights into the practicalities of these studies and how they are being used to support administration of biologics from early clinical programs to marketed products.

Characterization of Proteinaceous Particles in Monoclonal Antibody Drug Products Using Mass Spectrometry.

In recent years, monoclonal antibodies (mAb) have become one of the most important classes of therapeutic proteins. Among many of the quality attributes monitored and controlled throughout therapeutic antibody development, particulate matter is one of the critical quality attributes (CQAs) for drug products. Visible and subvisible particulates in drug products may pose safety and immunogenicity risks to patients and therefore are tightly controlled and regulated.

An Industry Perspective on Compatibility Assessment of Closed System Drug-Transfer Devices for Biologics.

The Formulation Workstream of the BioPhorum Development Group (BPDG), an industry-wide consortium, has identified the increased use of closed system drug-transfer devices (CSTDs) with biologics, without an associated compatibility assessment, to be of significant concern. The use of CSTDs has increased significantly in recent years due to the recommendations by NIOSH and USP that they be used during preparation and administration of hazardous drugs. While CSTDs are valuable in the healthcare setting to reduce occupational exposure to hazardous compounds, these devices may present particular risks that must be adequately assessed prior to use to ensure their compatibility with specific types of drug products, such as biologic drugs, which may be sensitive.

Alginate-zinc (II) phthalocyanine conjugates: Synthesis, characterization and tumor-associated macrophages-targeted photodynamic therapy.

Tumor-associated macrophages (TAMs)-targeted photodynamic therapy (PDT) has dual-selectivity and hence is promising in cancer treatment. Since the scavenger receptor-A (SR-A) on TAMs can recognize polyanions, two molecular-weight sodium alginates (SA1, 41.2 kDa; SA2, 1231.

A non-aggregated silicon(IV) phthalocyanine-lactose conjugate for photodynamic therapy.

To develop a highly efficient photosensitizer for photodynamic therapy (PDT), we have designed and synthesized a phthalocyanine-lactose conjugate (Pc-Lac) through axial modification of silicon(IV) phthalocyanine with lactose moieties. With the lactose substituents, Pc-Lac is highly hydrophilic and non-aggregated with efficient reactive oxygen species (ROS) generation in aqueous media. With these desirable properties, Pc-Lac shows high photocytotoxicity and cellular uptake toward HepG2 cells.

Size-Tunable Targeting-Triggered Nanophotosensitizers Based on Self-Assembly of a Phthalocyanine-Biotin Conjugate for Photodynamic Therapy.

Self-assembled phototheranostic nanomaterials used for photodynamic therapy (PDT) have attracted increasing attention owing to their several advantages. Herein, we developed a novel strategy for size-tunable self-assembled nanophotosensitizers for PDT through a simple method. A series of switchable self-assembled nanophotosensitizers (, , , and ) of different particle sizes were readily prepared based on an amphiphilic silicon(IV) phthalocyanine (SiPc)-biotin conjugate by regulating the amount of the Cremophor EL surfactant used.

Highly efficient miniaturized coprecipitation screening (MiCoS) for amorphous solid dispersion formulation development.

Microprecipitated bulk powder (MBP) is a novel solid dispersion technology to manufacture amorphous formulations of poorly soluble compounds that cannot be processed by spray drying or melt extrusion. An efficient high-throughput screening method has been developed to aid the selection of polymer type, drug loading and antisolvent to solvent ratio for MBP formulation development. With a 96-well platform, the miniaturized coprecipitation screening (MiCoS) includes mixing of drug and polymer in dimethylacetamide, controlled precipitation to generate MBP, filtration/washing, drying and high throughput characterization.

Evaluation of chemical labeling strategies for monitoring HCV RNA using vibrational microscopy.

Raman and coherent anti-Stokes Raman scattering (CARS) microscopies have the potential to aid in detailed longitudinal studies of RNA localization. Here, we evaluate the use of carbon-deuterium and benzonitrile functional group labels as contrast agents for vibrational imaging of hepatitis C virus (HCV) replicon RNA. Dynamic light scattering and atomic force microscopy were used to evaluate the structural consequences of altering HCV subgenomic replicon RNA.

Synthesis and characterization of CN-modified protein analogues as potential vibrational contrast agents.

A recombinant VH single-domain antibody recognizing staphylococcal protein A was functionalized on reactive lysine residues with N-hydroxysuccimidyl-activated 4-cyanobenzoate. Surface plasmon resonance analysis of antibody-antigen binding revealed that modified and unmodified antibodies bound protein A with similar affinities. Raman imaging of the modified antibodies indicated that the benzonitrile group provides vibrational contrast enhancement in a region of the electromagnetic spectrum that is transparent to cellular materials.

Accelerating unimolecular decarboxylation by preassociated acid catalysis in thiamin-derived intermediates: implicating Brønsted acids as carbanion traps in enzymes.

Mandelylthiamin (MT) is formally the conjugate of thiamin and benzoylformate. It is the simplified analogue of the first covalent intermediate in benzoylformate decarboxylase. Although MT is the functional equivalent of the enzymic intermediate, it is 106-fold less reactive in decarboxylation.

Making thiamin work faster: acid-promoted separation of carbon dioxide.

The conjugate of thiamin and benzoylformate, mandelylthiamin (MTh), undergoes decarboxylation about 106 times slower than the analogous enzymic intermediate. It has now been discovered that the decarboxylation of MTh is accelerated by the acid component of pyridine and 4-picoline buffers. There is no role for a proton donor to stabilize the transition state for decarboxylation: catalysis must be achieved by the acid's trapping the product carbanion, preventing recarboxylation.

Fragmentation of the conjugate base of 2-(1-hydroxybenzyl)thiamin: does benzoylformate decarboxylase prevent orbital overlap to avoid it?

The base-catalyzed addition of thiamin to benzaldehyde produces 2-(1-hydroxybenzyl)thiamin (HBnT), but in neutral solution HBnT undergoes base-catalyzed irreversible fragmentation into pyrimidine and thiazole derivatives. The fragmentation (rather than elimination) occurs in proportion to the extent that N1' is protonated or alkylated. Generating the conjugate base of HBnT by decarboxylation surprisingly leads to fragmentation independent of the state of N1'.

Reactivity of intermediates in benzoylformate decarboxylase: avoiding the path to destruction.

Benzoylformate decarboxylase forms a covalent intermediate from thiamin diphosphate (TDP) and benzoylformate, alpha-mandelylTDP. This loses carbon dioxide to form a carbanion (enamine). Protonation of the carbanion and elimination of benzaldehyde regenerate enzyme-bound TDP.