A technology that sprung up at the University of Helsinki in 2012 is now fully functioning and making a difference to the big picture. Nanonisation is a term used to describe the process of reducing a substance to particles of nanometre-scale without changing its chemical properties, and it is now commercially available.
Companies that provide these novel API particle-size reduction services are cropping up as adding this technology to manufacturing processes can provide significant returns.
But what is the point of taking particles down to this scale? Nanoform, a company creating the technology, provides a breakdown to understand the mechanism and infrastructure behind this new process.
What is the point
Nanonisation is useful in addressing the problem of bioavailability. This presents great market opportunity as the company states that 75% of new drugs are poorly soluble.
“Nanonising greatly increases the surface area of drug particles. This translates to faster dissolution rates and increased bioavailability in the body," says Niklas Sandler, the Chief Technical Officer at Nanoform.
Nanonising greatly increases the surface area of drug particles translating to faster dissolution rates and increased bioavailability
Insufficient bioavailability is often a problem during drug discovery. Adding a step to increase it during the manufacturing process can turn a failed drug into a success.
But there is more to the process than just shrinking. To get the best performance out of the substance the size of the molecules must be consistent.
Sandler explains: “We can control our process very accurately to produce uniformly sized particles every time and can control the particle size of the particles that are formed. Uniformity of drug particle size is critical for enhancing dissolution, absorption and the onset of clinical effect.”
Once the effectiveness of the process was established, Nanoform moved from the university to commercialise it in Finland in 2015. The company's operations are now centralised in Helsinki.
While carrying out commercialisation, the company was environmentally focused with its Controlled Expansion of Supercritical Solutions (CESS) process. A distinguishing feature in the nanonisation landscape.
Sandler describes how this works: “Our CESS process is a bottom-up green technology that only uses CO2 as a solvent. It is also excipient free. We can produce nanoparticles that are crystalline or amorphous and are able to tailor the particle size depending on the needs of the client.”
The bottom-up green technology only uses CO2 as a solvent
The CESS process has been well applied to small molecules, but the company is gradually working towards technology for biologicals.
BCS classes II and IV of drugs are a particular focus of the technology, though solutions are available to every class, Sandler says. This is owing to the problems with solubility seen in classes II and IV. This causes subsequent low bioavailability.
Nanoform has worked on approximately 30 compounds to date (nanomedicines), and in June 2019 received a Seal of Excellence from the European Commission for its “Nanomedicines of Tomorrow” project. The award certifies that the proposal is of high quality with an exceptional degree of innovation and impact.
Nanoform has appointed a new CCO, Chief of Business Operations, CTO, AI expert and new Vice Chairman, all since October 2018. These are significant roles to fill and Sandler reveals that this is because there is a greatly increased interest from customers to fuel these.
“It is clear that we have made huge progress in the development of the technology, along with its reproducibility, throughput and scalability. We are now in a position to further invest in the development of CESS, our facilities and the fast growth of the company,” Sandler says.
The Nanoform team employing the CESS process for nanonising drug molecules
Turning failure to success
For the technology to work the environment needs to control and optimise pressure, temperature, flow rates, level of supersaturation, depressurisation, nucleation and particle formation.
When creating the technology, scalability, optimal particle formation and throughput were the main hurdles the company faced. Once these had been addressed the progression to large-scale manufacturing was swift.
Although the process is elegant, there is still a level of individualisation for scale that is required when processing an API.
“The assessment for any given API varies as the manufacturing scales can be very different depending on the required API demand for a drug product. We need to assess the line configuration, which may depend on the demands of the particle collection vessels and the amount of CO2 needed,” says Sandler.
Line configuration may depend on the demands of the particle collection vessels and the amount of CO2 needed
To achieve the end result, the Finnish company takes its client through three steps:
- Initial evaluation – An initial evaluation is performed to understand compound characteristics. Extensive conversations with partners enable the definition of what is aimed to be achieved and the challenges involved.
- Proof of concept and process – A proof of concept study is initiated to determine the feasibility of nanonising the material. A proof of process study is then performed to find the optimal process parameters for consistent, reproducible results.
- Scalability assessment and manufacture – A demonstration batch is produced at a larger scale before being moved into GMP facilities for clinical production.
Further investment of a US$11.3 million private placement was given to Nanoform by Ilmarinen Mutual Pension Insurance Company and Mandatum Life Insurance Company (Sampo Group), amongst others. The funding will be used to further develop Nanoform’s technology and strategically expand its ability to handle highly potent APIs.
Building a future
Nanoform is currently building a D-class API manufacturing cleanroom, not just to achieve the conditions and scale needed but also to increase API handling capacity. This is the first facility for the company, and it requires these stringent conditions as the nanonisation process is carried out within a high-class isolator to protect operators and the drug substance.“We aim to have the GMP facility operational by the end of 2019. The containment level is up to Safebridge Cat 3a for non-GMP and GMP. The plan is to build Cat 4 or sterile in the second phase of GMP expansion,” Sandler predicts.
The nanonisation process is carried out within a high-class isolator to protect operators and the drug substance
The 600 sqm manufacturing plant is the first for the company, and will be located at Cultivator II in Viikki Life Science Park, Finland. For this GMP facility construction project, Nanoform has worked with multiple partners.
The facility is now also on track to be licensed by the Finnish Medicines Agency by the end of this year. When the first phase of construction is complete Nanoform will have the capacity to handle potent APIs and provide nanonised materials for clinical trials. Once the second phase is complete, which is expected by mid-2020, Nanoform's GMP capacity will be doubled and strengthened with the addition of high potency capabilities.
Nanotechnology is a growing sector, this is illustrated by the success of companies like Nanoform providing the services. Integrating these futuristic processes into current manufacturing capabilities is one way to improve both a drug and a business model.