Dr. Margarethe Richter, Application Specialist at Thermo Fisher Scientific, tells The Medicine Maker how twin-screw extrusion and continuous technologies are helping biotechs de-risk scale-up, improve precision, and accelerate innovation from lab to pilot production.
How are twin-screw extruders addressing the biggest challenges in scaling up from R&D to pilot production?
Twin-screw extruders solve several scale-up challenges by enabling continuous processes. Unlike batch processes, twin-screw extruders enable pharmaceutical manufacturers to maintain the same temperature, pressure, shear rates and other required process parameters across different scales, ensuring that the material properties and product quality remain uniform when scaling-up from R&D to pilot production.
One key advantage for scale-up comes from geometric similarity, which ensures that the geometric, kinematic, and dynamic similarities are maintained, regardless of batch size. Extruders designed by this principle are scalable by design, meaning that, when extruders share the same screw and barrel design ratios across different sizes, then the material experiences nearly identical conditions. For example, a formulation developed on an 11-millimetre lab extruder transfers smoothly to a 24 –millimetre production unit with minimal adjustment.
Real-time monitoring adds another layer of control over the extrusion process. With this, operators can track torque, temperature, and pressure continuously, catching any issues immediately. This matters especially when working with expensive active pharmaceutical ingredients (APIs) where waste must be minimal. By identifying anything amiss, operators can quickly respond to any deviations which leads to improved product consistency and reduced batch-to-batch variability that are crucial during scale-up.
Continuous processes also offer flexibility in scaling. Rather than buying larger equipment – a large capital investment – manufacturers can simply run the process longer or add parallel lines. This “scale-out” approach often proves more cost-effective than traditional scale-up methods and can lead to even more reliable manufacturing.
Why is precision and repeatability becoming more critical in pharmaceutical manufacturing?
Patient safety drives everything in pharmaceutical manufacturing. When producing medications, even small variations can affect how well a drug works or, in the worst case, cause unexpected side effects or harm. Modern regulations, including tighter Good Manufacturing Practice (GMP) guidelines, reflect this reality – they’re stricter because they need to be. Precision and repeatability ensure every dose contains the right amount of each API, minimize contamination, and increase cost-efficiency.
Beyond patient safety, advanced technologies like twin-screw extrusion can help ensure precision and repeatability, which can streamline manufacturing, enhance cost-effectiveness, and optimize the use of scarce or expensive raw materials. New drug candidates may be poorly soluble or require expensive ingredients. 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, reducing material waste.
The push for precision medicine also enables new drug forms, like fixed-dose combinations. This is where two or more APIs are contained in a single dosage form, requiring exact control over each ingredient’s distribution. Though not possible with previous batch methods, advanced technologies in continuous processes allow for this level of control.
What advantages do technologies such as continuous granulation and 3D printing bring when integrated with extrusion-based processes?
In addition to twin-screw extrusion, technologies like 3D printing and continuous granulation are also enabling drug developers to create more efficient, customized solutions. These solutions offer precision and repeatability while also reducing the amount of processing steps, lowering the chance of errors.
Continuous granulation transforms how we make tablets. Traditional wet granulation requires multiple steps, including mixing, granulating, drying, and milling, whereas continuous granulation with twin-screw systems combines these into one continuous process. This shortens time in R&D, allows for more flexibility to react on the market demand, and reduces the amount of possible handling errors due to process analytical technology (PAT).
Additionally, hot-melt extrusion is the standard for making filaments for 3D printing by fused filament fabrication (FFF). A twin-screw extruder can merge several unit operations within one processing step: melting, compounding, drug dispersion, and filament shaping. This creates process efficiency and reduces heating steps, which is critical for reducing impurities.
How are technologies accelerating innovation for biotechs working on complex or rare disease treatments?
For biotechs working on complex or rare disease treatments, continuous technologies are key. They face unique challenges compared to other biotechs, like working with limited quantities of expensive APIs for conditions that typically affect small patient populations. This makes the ability to scale down critical – the smaller the niche or need for a product, the more important flexibility and short development times become.
Modern twin-screw extruders are helping to change this equation. Lab-scale units can process as little as 20 grams per hour, which is perfect for early development work. Then, when ready for clinical trials, the same formulation scales directly to pilot production without extensive reformulation.
The technology is particularly beneficial for rare drug development. According to the Food and Drug Administration’s (FDA) quantification of rare diseases, these medications target diseases affecting fewer than 200,000 people. With smaller market sizes, manufacturers need flexible systems that can efficiently produce varied batch sizes.
Any tips on reducing risk during the transition from lab-scale to pilot-scale production?
Try to run the process adiabatically, meaning without any exchange of heat. In small extruders, material heats and cools quickly, and conversely, larger systems retain more heat, which can change how a formulation behaves. By running processes as close to adiabatic conditions as possible, this makes scale-up more predictable.
Additionally, match specific mechanical energy consumption (SMEC) between scales. SMEC measures the mechanical energy applied per kilogram of material, and when this value stays constant, material experiences similar processing, regardless of extruder size.
Documenting everything during development – not just successful runs, but also failures and near-misses – often reveals critical process boundaries you’ll need to consider during scale-up. Lastly, use the same screw configuration across scales when possible. While this can’t always be matched exactly, maintaining similar mixing zones and conveying elements helps ensure consistent product quality.
What are the main misconceptions biotechs have about implementing advanced manufacturing technologies, and how do you address them?
A common misconception is the expectation that once an advanced system is installed, production can start right away. But process development can never be skipped, as each formulation needs optimization. Pharmaceutical manufacturers must consider variables including temperature profiles, screw configuration, feed rates, and polymer selection. Advanced manufacturing technologies enable success, not guarantee it.
Two other misunderstandings are around regulatory requirements and cost assumptions. For the former, some companies may fear that continuous processing can complicate FDA approvals. Regulators encourage these technologies as they provide better process control and documentation. Additionally, while twin-screw systems require an upfront investment, they reduce costs in the long run through higher yields, less waste, and faster development cycles.
How do you see the role of proven, efficient scale-up solutions evolving in an increasingly competitive biopharma landscape?
The pharmaceutical industry faces mounting pressure to develop drugs faster and cheaper while maintaining the same quality. However, adopting proven, efficient scale-up methods drives innovation and can create a real market advantage. Companies that do this can move from discovery to market quicker, reduce development costs, and capture a higher market share.
The healthcare industry’s shift toward personalized medicine demands flexible manufacturing. To accommodate this, future systems must handle smaller batches of specialized medicine efficiently, and the scalability that twin-screw extrusion enables makes it fit into this equation perfectly.
Continuous processes are also a more sustainable option, as they typically use less energy and generate less waste than batch methods. In a shifting environmental regulation landscape, these advantages may very well become competitive necessities.
What emerging technologies or process innovations do you believe will most influence the next decade of drug development and manufacturing?
There is a growing interest in injectable implants, representing a major shift in drug delivery. These tiny implants, which are often made through hot-melt extrusion, release medication over weeks, months or even years. For patients, especially those requiring long-term treatment, implants can improve compliance and enhance health outcomes. Instead of flooding the whole body with medication, drugs can be released exactly where they’re needed, reducing side effects and improving efficacy.
Anything else you'd like to add?
Biotechs must understand that success requires more than equipment – it requires an investment in understanding the science behind these processes. Organizations that combine technological capability with deep process knowledge will be at the forefront of pharmaceutical innovation. While the tools exist, the challenge remains for biotechs to apply them creatively to solve some of healthcare’s most pressing problems.
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