Biomolecule Processing

Biological drugs have seen significant clinical and commercial success due to their high specificity and binding affinity, making these targeted therapies one of the fastest growing areas of the pharmaceutical industry. However, biomolecules are often sensitive to heat, requiring refrigeration which limits widespread availability and use outside of a hospital setting. Furthermore, biomolecules can be sensitive to degradation when exposed external stresses which are common to pharmaceutical development processes, such as temperature changes (heating and cooling), pH, shear forces, mechanical agitation and light.

Crystec’s mSAS® (modified Supercritical Anti-Solvent) technology allows biomolecules to be processed in a relatively benign environment. Operating close to ambient temperature and eliminating exposure to surface tension and shear forces, mSAS® provides an attractive alternative to conventional technologies and offers the potential for improved retained activity, stability, and reconstitution. With the ability to buffer against transient acidity, incorporate additional agents (for stability or function) and titrate water into the composition of the particles where appropriate, further opportunities exist to retain structural and chemical integrity, promoting potency and stability, even at room temperature.

Due to the low permeability and sensitivity to enzymatic degradation of these often large, polar molecules in the intestine, oral delivery can be challenging, and many biological agents can only be delivered by injection, which often requires treatment to occur in clinical settings, and creates a burden on healthcare workers and patients. However, inhalation offers an attractive, non-invasive route of administration for both local and systemic delivery of biologics. In order to achieve this, manufacturing processes to produce dry, inhalable sized particles need to be identified which can harness the full therapeutic potential of a biologic, without sacrificing its potency. mSAS® offers the ability to engineer particles for inhaled delivery, by generating non-agglomerated, free flowing powders with a targeted particle size, which readily aerosolise. As a result, mSAS® particles can be efficiently deposited in the lung, delivering high therapeutic doses to the target site, even from simple inhaler devices. This efficiency of lung delivery can also result in lower dose requirements, reducing the cost burden of notoriously expensive biological agents. For systemic therapies, where large amounts of the drug have typically been required to achieve the necessary therapeutic levels, mSAS® provides opportunities to achieve impressive levels of lung deposition, even without the use of a carrier (e.g. lactose), further increasing the dose that can be achieved through inhalation.

Conversely, many biologics are administered at very low doses. This can introduce a challenge in solid dosage forms, where the active must be blended with a bulking agent for the purposes of accurate dosing, which can result in process complexity and blend uniformity issues. By co-precipitating a regulatory approved bulking agent with the biologically active ingredient to generate mSAS® particles with a precise and uniform ratio of components, doses can be readily and reliably weighed into capsules for subsequent patient administration using a suitable inhaler device. A similar approach was taken in the case study below.

Crystec mSAS® Case Study

The aim of this study was to rapidly develop a dry powder inhaled (DPI) formulation of an existing IV therapeutic. Due to the clinical urgency of the study, where direct pulmonary delivery was required for local effect, a pre-formulated IV solution was processed by mSAS® directly to generate inhalable particles containing the equivalent composition of active and excipients.

Product Analysis and Performance

From a pre-formulated solution containing approximately 2% active to excipients, dry uniform particles with an inhalable particle size (D90 = 3.32 µm) and aerodynamic particle shape were generated. Powders were evaluated by enzymatic breakdown analysis to demonstrate that > 85% activity was reproducibly achieved post-processing.

The powder was then filled directly into capsules and in vitro NGI (Next Generation Impactor) analysis was conducted using a simple off-the-shelf DPI device. These data confirmed a Fine Particle Fraction (FPF) of 75%, indicating an impressive level of lung deposition can be achieved.

Scanning Electron Microscope image of mSAS® product

Sympatec laser particle size analysis (PSA) data

NGI data for mSAS® composite particles showing deposition of constituents across stages representing the mouth and throat (left) through to the upper and lower airways (right)