Between 70 and 80% of new chemical entities (NCEs) suffer from poor water solubility[1], which can lead to poor bioavailability and have implications for a drug product’s therapeutic effect. Poor bioavailability may mean higher amounts of the API are required in a finished drug formulation or even multiple doses, potentially resulting in adverse side effects for the patient. In some cases, poor bioavailability can also hinder innovation, limiting the developability of otherwise promising APIs.

However, poor solubility needn’t be a barrier to development. The right contract development and manufacturing organization (CDMO) can help enhance the solubility of APIs through particle engineering using technologies such as nanomilling.

Nanomilling APIs enhances solubility by comminution – physically breaking down their crystalline structure by converting large, coarse particles into smaller, fine particles. The most common technique for nanomilling is high-energy media milling, where 0.2–1 µm beads, made from ceramics or highly crosslinked polystyrene, grind the API to the reduce their particle size.

To ensure you have the best CDMO support for the needs of your project, it is important to consider infrastructure, capability, and technical expertise. Here are some key qualities pharma companies should identify when selecting a nanomilling partner:

Comprehensive and verifiable experience

The complexities and intricacies involved in nanomilling mean that it is often as much an art as it is a science. It takes years of experience to fully understand and appreciate the technology. Having the latest equipment is not enough to deliver the desired precise results at the highest standards. A high level of expertise in performing nanomilling is necessary as well.

For this reason, it is essential to ask your potential CDMO partner about their experience offering nanomilling to their customers. If possible, explore their case studies and technical collateral and ask about the results they have delivered. These pieces of information will give you better insight into their expertise and capabilities and provide you with the confidence of knowing they have successfully handled projects like yours before.

Sterile milling and processing capabilities

Many modern drug development and manufacturing projects rely on sterile processing. This is particularly true for parenteral and ocular drug products as these bypass the body’s natural defences, leading to risk of infection if microbial contaminants are not removed.

An alternative to requiring a fully aseptic process is terminal sterilization. This commonly involves autoclaving, gamma irradiation, or e-beam irradiation. However, at commercial scale these processes can be difficult to accomplish and may result in unacceptable chemical or physical degradation of the API.

Therefore, when formulating parenteral or ocular drugs with poorly soluble APIs, it is important that CDMOs offer access to sterile processing systems throughout the development and manufacturing process. This includes sterile nanomilling.

However, few CDMOs have the capability to perform sterile nanomilling, and sterile nanoparticulate suspensions are often hard to achieve. If sterile nanomilling is required, it is important to find a CDMO partner that has the necessary capabilities and experience. With its proprietary SteriMill™ nanomilling technology, Particle Sciences is well placed to support companies requiring aseptic processing.

Expertise in nanosuspension formulation

Throughout the nanomilling process, the API is typically suspended in a solution containing water and stabilizers to prevent reaggregation of particles. This intermediate of nanoparticles in suspension is known as a nanosuspension.

Poorly formulated nanosuspensions are at risk of aggregation, Ostwald ripening, fast sedimentation of particles, and cake formation during milling or storage. These can not only lead to various issues throughout downstream processing, but they can also hinder product performance.

When formulating nanosuspensions, it is essential that nanomilling partners are aware of the many factors that must be taken into consideration, such as:

• physicochemical properties of the APIs and stabilizers
• concentration of APIs and stabilizers
• regulatory status of stabilizers for the intended route of administration

Having an in-depth understanding of nanosuspension formulation can help in successful implementation of this enabling drug delivery technology.

Proficient in analytical characterization of nanosuspensions

As mandated by regulators, there must be tight control over parameters including particle or droplet size, viscoelastic properties, and the correlation of these properties to efficacy throughout the production of nanosuspension. Monitoring and characterization of nanosuspensions is also important for determining physical stability.

As a result, it is important to ensure your nanomilling partner can offer an array of analytical services. They should be able to establish the zeta potential, which is especially vital when ionic surfactants are used in formulation. Aggregation should be determined by optical microscopy and solid-state characterization should be used to analyze whether a change in morphology has occurred. It is also important to be able to assess API particle size distribution to further understand processability and performance.

On top of this, nanomilling partners should be transparent with the data collected throughout analysis and provide clear and open communication. Transparency can help ensure process traceability and product quality.

Nanomilling feasibility insights

It costs a considerable amount of time and money to undertake a nanomilling project and, as with other solubilization approaches, success is not a given.

Some APIs are not amenable to nanomilling. In these cases, it is important to work with a CDMO partner that is open and honest about the risks and can give an indication of probability of success from the outset.

Particle Sciences’s nanomilling feasibility program provides early-stage support in a relatively quick, cost-effective package. It enables companies to make balanced and informed decisions on whether to embark on the project or explore other options. This process can save valuable time, resources, and money; and if the development program proves successful, Particle Sciences is positioned to provide ongoing optimization, scale-up, and manufacturing.

Technology transfer knowledge

Technology transfer is complex. This is especially true for nanomilling projects. Complications during transfer from bench-scale R&D work to GMP manufacturing at clinical and commercial scale can lead to delays or even failures, resulting in valuable capital investment being wasted.

With this in mind, it is critical to work with a CDMO partner with experience in technology transfers and has specialist teams devoted to performing the process smoothly. It must offer flexibility when scaling projects to quickly provide solutions to any unforeseen challenges. It must also be able to effectively determine the appropriate processing parameters regardless of the batch size. Additionally, it is important that the CDMO establishes a highly reproducible, optimized process, minimizing the risk of batch-to-batch variations.

A future with your nanomilling partner

It is likely that more and more NCEs will require solubility enhancement as a key part of the formulation development process in order to maximize drug bioavailability. Due to the complex nature of solubility enhancement, expert help and infrastructure will always be required to ensure optimum chances of success, so having the right CDMO partner in place is crucial.

It is important to understand that not all CDMO partners are created equal. Ideally, your CDMO partner should have knowledge of, and access to, a range of solubility enhancement techniques. In our experience at Particle Sciences, we’ve found nanomilling to be a particularly efficient, reproducible process that is very scalable and commercially validated.

We have the latest technology, available capacity, and teams with expertise in solving solubility challenges. Contact us today to find out more about our nanomilling capabilities.

Authors: Robert Lee