Issue:May 2021

EXECUTIVE INTERVIEW - Micropore: Innovation in Drug Delivery

Traditional batch processing is frequently regarded as forgiving of mistakes because they can generally be resolved through post processing. On the other hand, continuous processing has many advantages of stability, repeatability and reproducibility, but is more difficult to establish at the outset because it needs the greater rigour and process understanding epitomised in the principles of Quality by Design. For these reasons, pharma regulators have been driving manufacturers towards the continuous processing. As part of the industry’s response to this drive, Micropore Technologies is pioneering the continuous formulation and manufacturing of drug products across a wide variety of administration routes. Headquartered in the biopharma cluster of Teesside, UK, Micropore Technologies serves the pharma and biopharma sectors. Dai Hayward, CEO at Micropore, recently spoke with Drug Development & Delivery about the company’s expertise and underpinning technology in the development of safe, efficient, and scalable continuous manufacturing of drug delivery solutions.

Q: Micropore’s core technology, continuous membrane emulsification, has been around for some years. Why has it only now become of interest?

A: You’re correct about membrane emulsification being around for some time – it was identified in Japan in the mid-1980s. Despite its promise of being a gentle process for the manufacture of monodisperse formulations, it struggled to break out of the lab because the technology could not be scaled. That was until 2017 when we launched the Micropore AXF-1, which enabled scale-up to 100 kg/hour. This was followed by the Micropore AXF-7, for use in large-scale applications, which is capable of about 1,000 kg/hour, thereby demonstrating that scaling to a robust manufacturing solution is no longer an issue. We have also harnessed the technology recently to improve the API crystallisation process.

The developments in the technology have resulted in Micropore being awarded several peer-reviewed globally recognized awards over the past few years. In Micropore’s hands, membrane emulsification has finally come of age

Q: What makes Micropore’s technology viable as a solution for pharma and biopharma today?

 A: Today, Micropore has expertise in all the major administration routes of drug products, especially those that are more complex in nature. We are working with pharma and biopharma in both early stage drug product development as well as clinical trials to enable our customers to bring their products efficiently and economically to market.

Micropore’s suite of capabilities runs from early lab formulation development to full GMP capability, starting at a few grams per hour all the way to multiple kilograms per hour.

As a result of our scale-up activities, and somewhat ironically, our pharma and biopharma customers have asked for the scale to be reduced to be able efficiently to cope with GMP operation at the scale in which a few milligrams of product is all that is available for formulation development. We have responded by developing a small version of the AXF-1 to meet this brief while still ensuring scalability for later manufacturing volumes.

We take great pride in being part of the trend toward advanced formulations to enhance large molecule stability or enable new routes of delivery. Colloidal dosage forms, in which Micropore’s expertise is increasingly being called upon, like nanoparticles, liposomes and microemulsions, offer many new opportunities for delivery of protein drugs across challenging biological barriers, such as the blood-brain barrier and ocular routes.

Q: I understand Micropore has identified a topically interesting application for its technology?

 A: Because of the need for a rapid response to the coronavirus pandemic, the world is in the midst of a paradigm shift in the treatment of diseases through novel developments in vaccine and gene therapies. The overnight success, following decades of development of “synthetic biology” is enabling easily made, precisely programmed, mRNA vaccines to be developed for a number of infectious diseases as well as cancer immunotherapies. The need for a universal modular delivery mechanism has been fulfilled by the development of lipid nanoparticle systems. This plug and play approach of mRNA and lipid nanoparticle will also enable manufacturers to reprogram new versions of approved vaccines in a matter of weeks, allowing almost real-time responses to the emergence of new virus variants.

Our most topical application is our ability to manufacture lipid nanoparticles at the desired size of 80-100 nm at scale. Recently, we’ve been working with Prof Yvonne Perrie at Strathclyde University to demonstrate the viability of our room-temperature continuous process. We’ve demonstrated the capacity at over 1 kg/hour and we’ve not really begun to push the boundaries yet. For both our previous work and this more recent development, we’re very confident in being able to achieve 10s if not 100s of kg/hour before the end of 2021.

Needless to say, given the potential for lipid nanoparticles and liposomes unleashed through current coronavirus vaccine programs, we’re very excited about contributing to the dawning of this new age through our “Better Medicines” initiative. We expect to publish the full results from Strathclyde University later this year.

Q: Can you discuss some of the other benefits Micropore’s technology offers pharma and biopharma?

A: As I mentioned, our previous work has focused on the manufacture of long-acting, controlled-release microspheres for injectable drug products. One of our licensees, G2GBIO Inc of South Korea, is using the technology to manufacture 1,000 vials per hour of an Alzheimer’s therapy, and about 30,000 vials for animal-neutering drugs per hour.

The ability to produce monodisperse materials, of the desired size, means there are no under- or over-sized microspheres to remove in post processing steps such as sieving. This has the effect of ensuring all product manufactured falls within specification and does not produce material that needs to be removed. Micropore has customers that regularly report the need to remove at least 30% of their product. We have many examples of much higher wastage and – because this is generated at almost the final manufacturing step, this material is unrecoverable and is therefore expensive waste. This confers significant operational cost savings as well as offering patient benefits through the use of narrow-gauge needles.

Another notable feature of our technology is its gentle nature. This means we can retain protein integrity at over 90% compared with high-energy processes in which retention is often reduced to about 50%. Clearly, this also brings major economic benefits to the drug manufacturer, in addition to those I’ve just described, when a smaller dose can be administered that is almost completely therapeutically effective.

Benefits of ease of scale-up using the Micropore approach includes continuous process with very little hold-up, which means small development batches and larger production can be done with the same device.

Q: Micropore works with other companies to innovate drug delivery formulations. How do those relationships work?

 A: Micropore’s relationships are firmly centered on our customers’ needs. Many clients come to us for development of their drug product from initial idea to final formulation, while others reach out at a particular point in the development cycle. Our customers rely on the broad range of time-efficient problem-solving expertise and strict confidentiality to protect our relationships.

We often start working with a customer as they begin to develop their early ideas about formulation of their drug product. In partnership, we will develop an optimal formulation for the desired drug delivery route. Micropore works up to the GMP boundary beyond which, for strategic reasons we do not wish to go, we will work with the customer to ensure a smooth technology transfer to their chosen GMP partner – whether that be in-house or, more usually, to a chosen CDMO.

Q: How many companies around the world are actually using Micropore’s technology right now? And how is Micropore structured as a business to provide technical support globally?

 A: While still relatively small, Micropore has always been global in outlook. Over 80% of our revenues come from customers outside our home country of the UK. Our customers span the globe from South America to Australasia and are numbered in the hundreds – and this is growing monthly as customers explore for themselves the benefits we bring them. We have invested in establishing subsidiaries in the US and India to ensure a responsive local presence for our customers in these markets. Other subsidiaries are planned. We have also recently appointed a distributor in Japan.

Q: Earlier, you mentioned that you’ve harnessed your technology for API crystallisation. Would you like to tell us more about this?

 A: I have a long personal history in speciality chemical manufacture for API and intermediates. One of the most challenging parts of the process is the ability to produce drug substance crystals of the correct size and morphology. Traditional crystallization processes suffer from uneven mixing, heat transfer, seeding, etc. This results in significant post-processing to achieve the correct size and size distribution – all the while running the risk of degrading the form of the product through high-energy processes, such as jet milling. We have begun building on the conceptual work of our founder, Prof Richard Holdich, at Loughborough University to develop a continuous crystallisation process that delivers the desired size and form of API crystal without the need for downstream processing, thereby saving both time and money while avoiding the degradation risks inherent in these processes.

We are currently working to expand the range of APIs to include many more. This initiative offers an improved process at the time that many countries have substantial initiatives to return API manufacture to their shores, thereby co-ordinating well with any re-registration process.

Q: I see that Micropore has published a statement about its contribution to the UN Sustainable Development goals. Why have you done this?

 A: As a past Chairman of the UK’s Responsible Care Board, I have long been committed to our industry being part of the solution to climate change through the development of sustainable business practises. Although we are small, we have the strategic goal of delivering improvements across many of the UN’s goals through our customers; whether that be directly, through process improvements, reducing energy use by around 80%, to delivery of zero waste processes or indirectly, through product improvements, such as removal of microbeads from cosmetics to self-healing concrete to lengthen building life. The pharma and biopharma benefits described elsewhere are an integral part of this commitment.

Embedded into our statement is our code of ethics, which was developed by the entire Micropore team and is integral to our approach to all our stakeholders; employees, customers, suppliers, investors, schools, and the local community. It is our goal to “move the dial” in the way we do business to leave the world a better place.

Q: What are the next critical steps for the business to take?

A: As a revenue-generating company with a proven technology and established market position, Micropore is growing rapidly across its chosen market sectors and geographies, but funding is our limiting resource. We are impatient to grow further and faster to bring the demonstrable benefits I’ve described to the widest possible markets as quickly as possible. For this, we are seeking a corporate investor to join in our growth plans with existing investors. This will allow a rapid reinforcement and expansion of existing capabilities to capitalize on the opportunities in front of us. And, by way of a teaser, we have other ideas about how to deploy the scalable precision of our engineering into new applications.