European Pharmaceutical Manufacturer spoke to Dr. Margarethe Richter, pharma application specialist, Thermo Fisher Scientific and Dr. Anna Krause, PhD, co-founder, board member, and head of research and development at Pikralida about twin screw extruders and how they are revolutionising drug development for rare diseases.
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Dr. Margarethe Richter, pharma application specialist, Thermo Fisher Scientific:
How are technologies like twin-screw extrusion and continuous granulation changing the way pharma companies approach scale-up today?
Continuous processes help ensure that the material properties and product quality remain uniform when scaling-up from R&D to pilot production. Specifically, twin-screw extruders solve several scale-up challenges by enabling continuous processes. Unlike batch processes, twin-screw extruders solve several scale-up challenges by enabling pharmaceutical manufacturers to maintain the same temperature, pressure, shear rates, and other required process parameters across different scales.
Geometric similarity, which ensures that the geometric, kinematic, and dynamic similarities are maintained regardless of batch size, is one of these key advantages. This principle ensures that extruders are scalable by design, meaning that, when they share the same screw and barrel design ratios across different sizes, then the material experiences nearly identical conditions. Real-time monitoring also increases control over the extrusion process, allowing operators to catch issues immediately by continuously tracking torque, temperature, and pressure. When working with expensive active pharmaceutical ingredients (APIs) where waste must be minimal, identifying anything amiss allows operators to quickly respond to any deviations. This leads to improved product consistency and reduced batch-to-batch variability, both of which are crucial during scale-up.
With continuous processes, manufactures can run processes longer or add parallel lines – a flexible scaling approach. This “scale-out” approach often proves more cost-effective than traditional scale-up methods, as it removes the need for larger equipment purchases, and can lead to even more reliable manufacturing.
What are the biggest challenges biotechs face when moving from R&D to pilot-scale, and how does technology like Pharma 11 help overcome them?
The biggest scale-up challenge for hot melt extrusion (HME) is maintaining two critical factors: how long materials stay in the process (residence time distribution) and how much mechanical energy each kilogram receives. If either factor changes during the scale-up, then the final drug product changes too. The Thermo ScientificTM Pharma 11 Twin-screw Extruder solves this through geometric scaling. Its barrels and screws maintain the same proportions as larger production equipment from the same manufacturer. The system is small, processing as little as 20 grams per hour. This lets researchers work with expensive or rare APIs with very little waste. Additionally, the technology’s modular design allows for quick changes between HME, wet granulation, and other processes, making it ideal for biotechs exploring multiple formulations or even drug delivery methods.
In what ways does precision and repeatability impact drug development success rates, especially in fast-moving therapeutic areas?
Precision and repeatability can drive success within a very short amount of time, which is critical in fast-paced environments. By maintaining consistent dosage formats and minimising contamination, drug manufacturers can increase cost-effectiveness, optimise the use of raw materials, and enhance patient safety.
Consistent dosage formats mean patients get the exact amount they need, which matters especially for orphan diseases and specialised treatments where every milligram counts.
Repeatability in processes also minimises contamination risks by maintaining exact conditions, something especially critical when working with sensitive APIs. Replicating exact conditions prevents costly failures and helps protect patient safety.
Precision and repeatability also help optimise the use of scarce or expensive raw materials. New drug candidates may be poorly soluble or require expensive ingredients, so when working with APIs that can cost thousands per kilogram, manufacturers can’t afford variability that leads to rejected batches. Twin-screw extruders help by providing consistent mixing and processing that reduce material waste.
For fast-moving areas like gene therapy and personalised medicine, the advantages associated with precision and repeatability enable speed and scalability. Researchers can move from concept to clinical trials faster, iterate on formulations quickly, and scale successful candidates without starting over. This acceleration helps bring life-saving treatments to patients quicker than traditional methods allow.
Dr. Anna Krause, PhD, co-founder, board member, and Head of Research and Development at Pikralida:
Can you tell us about the specific challenges of developing treatments for rare and complex diseases, and how advanced manufacturing tech is helping address them?
At Pikralida, we work in two very different but equally demanding therapeutic areas. One is neuroprotection after stroke and traumatic brain injury – a large, global indication for which no effective neuroprotective therapies are currently available. The other is snakebite envenoming, which is classified as an orphan disease and remains one of the most neglected health challenges worldwide.
Both areas share a common challenge: treatment must work fast, in acute settings, often outside specialised hospital environments. That has major implications for formulation design, manufacturing strategy, and regulatory pathways.
What makes our work distinctive is that it builds on marimastat, a former clinical candidate that was never commercialised. We refer to this approach as drug rediscovery. In practice, drug rediscovery means working with molecules whose biology, mechanism of action, and human safety profile are already well understood, and re-developing them for new, clearly defined clinical uses.
Compared with discovering a completely new compound, this approach is typically faster, less risky, and significantly more cost-efficient. Much of the early uncertainty has already been removed, allowing us to focus resources on demonstrating clinical benefit rather than rebuilding fundamental knowledge from scratch.
In our case, earlier clinical programs showed that marimastat’s limitations were linked to long-term dosing, not to a lack of biological activity. By applying short-term, indication-specific use and modern formulation strategies, we can unlock therapeutic potential that was not feasible under the original development paradigm.
Because the original composition-of-matter patents have expired, our innovation is concentrated on how the molecule is manufactured, how it is formulated, and how it is
deployed clinically. This enables us to build new, defensible intellectual property while advancing therapies that can reach patients faster and at a lower development cost than traditional de novo drug discovery.
This work includes developing a new API manufacturing process, studying polymorphic forms, and filing patents covering specific pharmaceutical uses. In parallel, we are exploring multiple formulation strategies – oral, ophthalmic, intravenous, and topical – both to expand clinical applicability and to strengthen our IP position.
Advanced manufacturing technologies such as hot melt extrusion (HME) play a role in this strategy, as they allow us to design formulations that are difficult to replicate. At the same time, we remain pragmatic. In early proof-of-concept studies, we often deliberately keep formulations simple – for example, capsules or straightforward tablets. At that stage, flexibility matters more than sophistication. Dosing may still evolve, and technologies like HME are most effective once the clinical concept and dosing strategy are well defined.
How has working with twin-screw extrusion or similar tools changed your approach to formulation and development?
Having hands-on experience with hot melt extrusion means we understand both its potential and its limitations. It gives us creative freedom in formulation design, but also a realistic sense of when it should – and should not – be used.
We know how to:
- modify the release profile
- identify and manage stability challenges
- design formulations that balance performance with manufacturability
It is a powerful and versatile tool, but it is complex and relatively resource intensive. For early proof-of-concept trials, simpler formulations are often preferable. Once the dosing scheme is confirmed, HME can help us develop more complex products that are difficult for competitors to replicate and may provide additional benefits for patients, including improved compliance.
What advantages do these technologies bring to a smaller biotech compared to traditional methods?
In early trials, traditional formulations give us flexibility. We can adjust dose strengths easily and respond quickly to clinical data. That speed is critical.
Technologies like HME come into play later, when we are developing a second or third-generation product – something that improves usability, enables modified release, or enhances stability. At that stage, the added complexity is justified.
From a strategic perspective, these technologies allow a smaller company to:
- differentiate its products and build defensible IP
- address niche or orphan indications with tailored formulations
- improve patient compliance once the therapeutic concept is proven
We also apply this expertise in our CRO activities, including work on generic APIs and modified formulations for partners. That practical experience feeds directly back into our internal pipeline.
How do you balance innovation in drug development with the pressures of cost, time, and regulatory requirements?
In innovative drug development, everything starts with clinical value. If a therapy does not meaningfully improve patient outcomes, no amount of technical optimisation will compensate for that.
In neuroprotection, for example, there are currently no approved therapies that directly protect neurons from damage. We are working in a space where innovation is not incremental – it has the potential to change clinical practice. That is where the real value lies.
Of course, cost and timelines matter, especially when engaging with investors and partners. The value created by the innovation must clearly outweigh the resources required to develop it.
We manage this by keeping core CMC and formulation expertise in-house, while working with carefully selected external partners for GMP manufacturing. We do not try to build everything ourselves; instead, we focus on smart outsourcing and strong technical oversight.
The balance also depends on the business model:
- for novel, first-in-class therapies, innovation and differentiation are the priority
- for generic or modified-generic products, cost efficiency becomes much more important
Hot melt extrusion fits particularly well in rare disease and niche indications, where production volumes are smaller, and the added value justifies the complexity. It is not the right tool for every product – mass-market drugs often require simpler solutions – but in the right context, it can significantly strengthen regulatory positioning, patient compliance, and IP protection.
In short, we aim to innovate where it matters most, and to stay pragmatic everywhere else.