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This is the third and last in a series of interviews with a collection of subject matter experts (SMEs) operating throughout Lonza. We have, over the last six months, covered a range of topics that the company covers, and heard from some of the foremost experts in the world of pharma - this final collection of questions and answers is no different.
Jai: “Successful implementation of jet milling requires a robust Quality by Design (QbD) approach that ensures the critical quality attributes of the micronised particles are maintained throughout the process development”. What is the QbD approach that Lonza utilise?
Salvatore Mercuri, Head of New Product Introduction & MSAT: The best approach is to acquire as much information as possible during the development phase to reduce the risk associated with the subsequent scale-up and validation phase. Interaction with the customer is crucial during the initial phase, as they own most of the information related to the solid state and stability of the API (if they are an API manufacturer) or the final CQAs (Critical Quality Attributes) for the formulation phase (if they are responsible for the drug product).
With this preliminary information, an appropriate DoE methodology is applied to define the correlation between the CPPs (predefined considering the risk assessment and preliminary micronisation runs) and the CQAs and to define an initial PAR (Proven Acceptable Range). After this preliminary phase, some post-DoE analyses, such as Monte Carlo simulation, are conducted to predict how known variabilities encountered during the scale-up phase may affect the PAR.
All the data generated so far will be used to update the risk assessment and to define the scale-up and design space (DS) verification strategy; at least three experimental points are used. At this stage, at least one engineering batch is used to assess process reliability (intensive sampling) and inter-batch variability if multiple batches are used. Finally, process validation is performed (PAR is verified) and continuous monitoring and improvement are carried out using the appropriate control charts and PQR. This approach will ensure that by controlling the CPPs the process will be stable, predictable, and capable.
Jai: Insolubility is, as Lonza has repeatedly stated, a large issue. What approaches do Lonza use to address challenges of insolubility?
Corey Bloom, Lead Principal Investigator: There are several formulation technologies that can be used to address poor solubility. The most appropriate approach depends on the specifics of the molecule, the dose, and the target product profile. Examples include salt or cocrystal formation, amorphous dispersions prepared using spray drying or hot melt extrusion, and micronisation by jet milling, among others.
Jai: Can you detail the process and benefits of spray-dried dispersion technologies and how this technology can impact solubility?
Hannah Worrest, Group Lead, Bioavailability Enhancement Engineering: The process of spray drying is in common usage and involves solubilising an API along with a polymer in an organic solvent, disrupting the API’s crystalline structure. By rapidly drying the solution via spray drying, the API can be trapped in a stable, higher-energy amorphous form that is more soluble than the crystalline form. The enhanced bioavailability that results can be the difference between success and failure for a new drug product.
Here at Lonza in Bend, we have implemented further improvements to the spray-drying process and associated technology. One example is our use of novel solvents, including acetic acid and ammonia, to enhance the solubility of APIs in various solvent systems. This increase in organic solubility creates the opportunity to evaluate bioavailability enhancement for brick dust compounds, opening the market to more potential treatments.
We have also developed internal modelling tools to optimise the process and increase throughput. These include thermodynamic and particle size modelling, which helps us design a right-first-time, high-throughput process. In conjunction with our chemistry analysis, these models allow us to balance the risks posed by physical and chemical stability in spray dried dispersions with creating an optimised process.
The models reduce the amount of process optimisation and scale-up activities required, with the need for additional experimentation often eliminated as risks will have been modelled and understood beforehand. Importantly, this means less material is required for the work.
Finally, enhancing solubility and optimising manufacturing processes are a significant contributor to the overall sustainability of the process. Designing an optimised, high-throughput process decreases our operating times and requirements for processing aids and, with greater drug solubility, less solvent will be required. For those solvents that we do use, we have been working hard to expand our capabilities for solvent capture and recycling.
Jai: Can you describe what brick dust compounds are and their utility?
Michael Morgen, Head of Advanced Drug Delivery Technologies: In the pharmaceutical industry, ‘brick dust’ refers to APIs that have poor solubility in water, and in many common processing solvents. This typically results from the compounds having very high melting points, as is often the case for planar molecules that stack well. These types of API structures are particularly common for oncology drugs developed in the past 10-15 years, but they are also seen in other therapeutic areas. The strong crystal forces in these compounds make it difficult to dissolve such compounds in many solvents, and this is a particular challenge for drug development. Solubilisation is necessary for oral absorption, and often also for effective parenteral delivery, and innovative approaches are often required to improve solubility if they are to be formulated as effective drug products.
There appears to be a larger fraction of orally administered small molecules that have poor oral absorption due to low aqueous solubility. How do Lonza approach a problem such as this and what solutions have been presented?
Corey Bloom, Lead Principal Investigator: A paper evaluation of the specific problem statement is an important first step, along with measuring important parameters including solubility in biorelevant aqueous media, plus biomodelling simulations to guide formulation selection.
Selection of the preferred solid form of API is important. In some cases, a salt form with increased solubility and acceptable stability can be identified. Salt forms can also be used in tandem with concentration enhancing polymers or other excipients in the dosage form to provide improved bioavailability.
At specific dose-to-solubility ratios, a small fraction of low solubility molecules can achieve acceptable oral bioavailability by increasing the dissolution rate relative to bulk crystalline API. Micronisation or wet bead milling of bulk crystalline API can be employed, and the resulting micro- or nanocrystals can be incorporated into standard tablet or capsule formulations.
Many low solubility compounds at higher dose-to-solubility ratios require increased solubility relative to the most stable crystalline form. Amorphous solid dispersions (ASDs) are a common and very effective approach to deliver these compounds. Spray dried dispersions (SDDs) can employ a wide range of performance enhancing polymers and are widely applicable. In addition, depending on the molecular properties, these molecules can also be delivered using hot melt extrusion (HME) technology. Both ASDs can be incorporated into tablets or capsules for oral solid dosage forms.