Today’s drug products demand the utmost versatility and flexibility in equipment to accommodate both large-scale and small batch manufacturing, containment requirements for highly potent drug products and complex biologics, and operating efficiency. Leveraging continuous manufacturing technologies, automation, and digitalization, the latest advances in equipment are helping to address some of the industry’s toughest manufacturing challenges.
Dr. Andreas Mattern, Vice President of Strategy & Global Product Management Pharma at Syntegon, shares insight into the latest R&D trends, challenges, and advances in today’s manufacturing equipment.
Contract Pharma: What pharma/biopharma trends are having the most impact on manufacturing equipment?
Andreas Mattern: August 25, 2023, was an important date in the history of the pharmaceutical industry: the new Annex 1 of the EU Good Manufacturing Practices for the production of sterile medicinal products came into force. The document has far-reaching consequences for sterile filling operations – not only within the EU but for the global pharmaceutical industry. On the one hand, the specifications affect the manufacturing processes of drugs imported into the EU. On the other hand, the coordination of the document between EMA, WHO and PIC/S and the publication of equivalent documents by these organizations underline its global relevance.
While the production of drugs in large quantities used to be the benchmark for decades, today rare diseases require ever more costly drugs. These in turn require a high level of commitment in research and development, also regarding new machine concepts, e.g. to process small and micro batches flexibly and with a higher degree of automation.
On the other hand, some drugs and new trends lead to the continued requirement for high-performance equipment with large batch turnovers, including both state-of-the-art filling and inspection equipment. For example, the FDA approval of a high-dose injectable version of the incretin mimetic semaglutide in June 2021 (January 2022 in the European Union) that needs to be administered only once a week has boosted demand. It is approved as anti-obesity medication for long-term weight management in adults, and consequently also reduces a major risk factor for one of the fastest-growing diseases of our time: type 2 diabetes.
In oral solid dosage (OSD) production, continuous manufacturing is still being explored by many companies who are investigating into changing from batch processes to continuous manufacturing. This is further promoted by the FDA’s publication of the International Council for Harmonization (ICH) final guidance on the use of continuous manufacturing in drug production on March 1, 2023 – a proactive step to ease the industry’s transition. Hence, 2024 and the coming years are likely to see many innovations in this field. Syntegon is already working in several strategic partnerships to further promote its own continuous manufacturing platform Xelum throughout the world.
Contract Pharma: What are the more significant manufacturing challenges clients look to overcome?
Andreas Mattern: Among the major challenges of the new Annex 1 is the separation of the aseptic process area from the operator environment. Pharmaceutical manufacturers therefore require at least RABS for the approval of new products. In the year following the publication of the guideline, the industry witnessed a veritable “run” on RABS upgrades of existing cleanroom lines, which continues to this day. Pharmaceutical manufacturers must decide whether to retrofit an existing cleanroom line for a new product or invest in new filling equipment that runs with isolator or RABS. We expect isolator technology to become the new “normal”, as automatic bio-decontamination processes and the pressure difference from the operator environment provide additional safety, while RABS is more likely to come into play for frequent product changes and with experienced operators.In the second chapter of Annex 1, automation and robotic systems are highlighted under the heading “Appropriate technologies”. By using these technologies, gloves and human intervention in barrier systems can be reduced to an absolute minimum or even eliminated. The issue of gloves presents many challenges, which are acknowledged in separate paragraphs. For example, gloves are to be additionally tested in operation during longer campaigns – which is not possible with the glove testing equipment used to date without risking the integrity of the sterile room. A switch to gloveless systems with robotics that handle these manipulations represents the “grail of solution scenarios”. One example is Syntegon’s new Versynta microBatch.
Syntegon Versynta microBatch
The fully automated isolator production cell fills between 120 and 500 containers per hour and caters to another important requirement in the fill-finish operations for expensive small and micro batches: high flexibility combined with high yields. A wide variety of products must be filled into different container sizes and types such as vials, syringes, or cartridges. Another criterion for flexibility is the reduced number of format parts, which obviates the need for lengthy format changes. In addition, these very small quantities require maximum product yield or low rejects. In a nutshell, any product loss must be avoided.
Contract Pharma: What are some of the latest advances in manufacturing equipment?
Andreas Mattern: Following the official launch of Versynta microBatch at CPHI Barcelona, Syntegon announced the first sale of the Annex 1-compliant production cell with gloveless isolator and integrated air handling to its development partner Vetter, a leading global CDMO. According to Vetter, the new joint development enables the company to achieve the desired flexibility, regulatory compliance, and high level of automation it wants to offer its customers.
The trend towards small batches is also true for OSD forms. Syntegon’s Xelum platform offers continuous solutions, from fluid bed granulation to direct compression. In both cases, the same feeder-blender module can be used. It doses and mixes individual packages, so-called X-keys. They ensure easy traceability and precise dosing, even and especially for active ingredients of less than 1%. In the new configuration presented this year, the packages are continuously fed into the TPR 200 Plus tablet press, which enables efficient and user-friendly downstream processing. It features a light containment concept with dust-tight machine protection up to OEB 3. With the APD feeder, including automatically adjustable powder infeed in the filling shoe and the APD software, manufacturers can determine the optimum parameters for the formulation feed into the die.
Another highlight from Syntegon’s OSD portfolio includes the U.S. launch of the new GKF Capsylon 6005 at SupplySide West – a capsule filler ideally suited for the growing nutraceutical industry. It achieves an output of 360,000 capsules per hour, making it the perfect fit for manufacturers who want to increase the production capacity of vitamins, proteins, and other dietary supplements. Powders, pellets, granules, and even special products with a wide range of properties can be processed on the same machine with minimal modifications. The most important innovations include a much higher output, two dosing stations operating in parallel, as well as 48 instead of 21 segment bores in four instead of two rows. Thanks to the patented slide-gate technology, the GKF Capsylon 6005 achieves higher product yields with lower dust impact, while offering the highest flexibility. Moreover, the click system developed by Syntegon ensures significantly faster format part changeovers.
Syntegon Smart Liquid Filling
Following the trend towards more digitalization, Syntegon also introduced a number of digital solutions for liquid pharmaceutical filling in 2023. For example, Syntegon’s Single Object Data Acquisition (SODA) assigns all object and process-specific data of primary packaging materials to individual batches and containers – even after they have left the machine. In combination with the smart containers EVERIC smart from primary packaging manufacturer SCHOTT, SODA offers a very special advantage: the pre-coded containers are already equipped with a unique data matrix code that can be read via cameras. Another innovation is the intelligent piston pump – the “Smart Pump” from Syntegon carries its memory with it on an RFID chip, even when it is not installed in the machine. The system automatically recognizes the pump, for example after cleaning – which significantly increases process reliability, reduces human error, and saves a lot of time in ongoing production.
Contract Pharma: In what areas do you see production innovation and/or new technologies being used?
Andreas Mattern: As mentioned before, Annex 1 has triggered a high demand for new machines and barrier technology upgrades. In the case of older machines, the question is whether to upgrade or invest in a completely new line with pre-installed barrier technology. Syntegon offers both options and analyzes customer requirements in detail to recommend the ideal solution to become “Annex 1-ready”. The numerous RABS upgrades offer customers an extensive choice of options, including peripheral topics such as viable monitoring, new stopper infeed solutions, or glove integrity testing devices.
Syntegon is further setting new standards in (digital) services. The cloud-based software solution Synexio enables the acquisition, evaluation, and visualization of equipment and production data. The entry-level package “Monitor” visualizes various KPIs and creates greater transparency in production and is already successfully used by many customers. The second Synexio package “Uptime” goes into further detail: in addition to machine availability, concrete potential for improvement can now also be determined, for example by visualizing the most frequently occurring reasons for stops. At CPHI Barcelona, visitors also got a sneak peek into the third and last Synexio package “Empower”, which includes component monitoring and will be launched later this year.
Syntegon Synexio
Synexio is part of Syntegon’s new Service Agreements, which form the basis for effective equipment and maintenance management at fixed prices. Seven dedicated levels enable customers to minimize production risks, make service costs more transparent, and simplify complex processes – enabling them to focus on their core business. With each level, the scope of the covered services increases, from basic service including inspection and remote service to guaranteed production performance of their machines.
As far as sustainability is concerned, technology providers like Syntegon can support their pharmaceutical customers by continuously optimizing their machines and developing new, more energy-efficient solutions. For example, “cold” WFI units produce up to 90 percent fewer CO2 emissions than the established “hot” processes. Even WFI from cold processes that use hot storage reduces emissions by more than 40 percent compared to hot WFI. Another important lever is the calculation of the carbon footprint. It includes the average service life of the equipment, but also the times for commissioning, heating up tools, and performing maintenance activities, as well as downtimes. Moreover, the impact of packaging materials on emissions can also be calculated.
Dr. Andreas Mattern, Vice President Strategy & Global Product Management Pharma, Syntegon.