The pharmaceutical industry is beholden to the strictest requirements for manufacturing and the equipment used must comply with good manufacturing practices (GMPs). As drug development trends change, so too must manufacturing processes, much of which can now be automated. Andreas Mattern, Ph.D., Director of Product Management Pharma for Syntegon Technology, discusses how the pandemic has impacted equipment needs, the latest technologies being leveraged in manufacturing equipment, as well as the continued challenges and where have advances been made across Cell and Gene manufacture, Single Use Technologies, Continuous Manufacturing, and Digital Technologies. What are the latest pharma/biopharma trends impacting manufacturing equipment?
Andreas Mattern: The fight against Covid-19 was the dominant topic in 2020 and will continue to be so for at least the coming months. The demand includes basically everything from laboratory services to processing, fill-finish equipment, inspection technology to services.
Apart from Covid-19, biotechnologically produced drugs, for example for the treatment of cancer, autoimmune diseases, or rare diseases affecting only a small patient population, are still being developed in large numbers and call for ever smaller batch sizes and highly flexible equipment. This trend is accompanied by the need for the highest product quality and protective measures. Containment technologies are highly requested, not only for liquid fill-finish lines, but also increasingly for oral solid dosage (OSD) forms. Here, containment equipment has the very important task of protecting operators from increasingly toxic substances.
Digitalization and automation are further trending topics in the pharmaceutical industry. For example, the use of robots in liquid filling operations reduces the risk of contamination through human contact. Robots offer a high degree of flexibility in manufacturing processes. Machine operators no longer need to perform repetitive tasks, which makes processes safer, more precise, reproducible and validatable. In the future, more and more robotic solutions will be used; the boundaries will continue to shift due to decreasing costs and new technologies such as Artificial Intelligence (AI).
Syntegon Inspection Deep Learning
The latter is already being used for the visual inspection of pharmaceutical liquids. In fact, Syntegon recently installed the first fully validated visual inspection system utilizing AI in a fully automated machine in a customer’s production line. AI applications have the potential of further increasing detection rates and decreasing the number of false rejects in difficult products like highly viscous parenteral solutions with air bubbles, which are sometimes hard to differentiate from harmful particles. The required Deep Learning vision applications are already available. What they need is profound pharmaceutical and software knowledge to adapt them for pharmaceutical purposes, which essentially also includes validation.
Another trend, which is related but not limited to the challenges of Covid-19, consists in digital service offerings. For example, many customers use remote services when they need assistance with machine settings or troubleshooting.
How has the pandemic impacted equipment needs?
AM: The corona crisis presents enormous challenges to the pharmaceutical industry. For example, more than 1,200 clinical trials have been delayed or stopped, according to Globaldata. On the other hand, more than 1,800 vaccines and drugs against Covid-19 are currently being investigated in over 4,000 clinical trials. Existing laboratory and manufacturing capacities must accordingly be reallocated or rebuilt in record time. For contract manufacturers, this need has resulted in an order increase of at least 200% in the infectious disease segment in 2020 compared to 2019.
Many of the publicly known producers and developers of Covid-19 vaccines and active ingredients for the treatment of corona patients use Syntegon technologies. These include formulation systems, filling lines especially for vial filling, and inspection machines. Among our customers are the largest vaccine manufacturers worldwide. In total, Syntegon solutions for the production of classical vaccines are used more than 100 times by different customers worldwide. Our experience with biotechnological drugs also enables us to support in the production of novel mRNA vaccines with cold filling. Inspection machines from Syntegon are in fact already used in the production process of mRNA Covid vaccines.
Our service has specialized in spare parts and format parts for converting customer facilities for Covid-19 vaccines and therapies. We have also reworked used machines available on the market and upgraded them to meet the new and current requirements in record time.
For us and our customers, the challenge is the speed in which new facilities must be built and existing production capacities converted without jeopardizing product quality and safety. We have also developed and pre-tested modular concepts for vaccine production, such as the SVP process system from Syntegon’s product brand Pharmatec, to enable faster delivery and production on the customer side. We can offer pre-configured full vaccine production lines from formulation to inspection with very fast delivery times to meet the increasing demand for a global vaccination program.
What are the latest technologies being leveraged in manufacturing equipment?
AM: Digital Services: Syntegon introduced a number of new digital services. One of them is MIRA (Machine Intelligence Reporting & Analytics), which was developed especially for predictive maintenance. Leveraging intelligent algorithms, the modular software solution detects wear and tear on process-critical components such as fans. Up to six weeks before a potential failure, it announces that a component needs replacing. The system does not intervene with the machine controls and retrofitted systems do not have to be re-qualified and validated.
Robotics and small batch filling: At Syntegon, we currently use robotic solutions primarily for gentle transport of containers, e.g. to avoid glass-to-glass contact. One example is our Flexible Filling Portfolio (FFP), in which our own four-axis robots (Pharma Handling Units) transfer packaging materials from one station to the next. The individual work steps can be changed at any time so that customers can individually adapt the processes depending on the product and packaging material.
Syntegon Flexible Filling
Syntegon’s FFP is an individually configurable, modular machine concept for processing small and medium batches. Whether syringes, vials or cartridges: pharmaceutical manufacturers can select the different modules individually and obtain a filling line completely tailored to their needs, including an integrated isolator for aseptic and high-potent active ingredients.
New coater series: Syntegon introduced an entirely new machine series in 2020: the Sepion coater series combines experience of the former Manesty product brand with the expertise in tablet coating and process technology of the Hüttlin product brand. The state-of-the-art equipment for tablet coating enables closed material handling during filling, sampling and emptying. This makes the Sepion coaters suited for the coating of tablets with highly potent active ingredients, as well as for sugar coating. The optimized drum geometry with its sophisticated spraying system offers better guidance of the process air and shorter processing times. Moreover, the coaters feature an automatically adjustable spray arm and ensure high flexibility from 10 to 100 percent batch size.
Lab equipment and services: The new OSD Customer Center Waiblingen, complements Syntegon’s range of specialized laboratories and customer centers for both solid and liquid pharmaceuticals. It includes everything customers need for the formulation, development and production of their OSD forms: from laboratory equipment to production scale machines, TPR tablet presses for mono and bilayer tablets as well as GKF capsule filling machines are available for all formats and products in different cleanroom classes – up to the highest containment level OEB5.
Software developments: Apart from the use of AI in pharmaceutical applications, further software solutions are important for state-of-the-art processes. For example, the new Automated Process Development (APD) tool from Syntegon determines the optimum parameters for capsule filling processes. While such manual evaluations used to take days or even weeks, the APD tool not only achieves faster but also more precise results. It does so by determining correlations between parameters critical to material, quality and processes, thus ensuring a better understanding of the process – which in turn has a positive effect on product quality.
What are the challenges and where have advances been made in these areas?
AM: Cell and gene therapies: Pipeline analyses show an increasing trend towards allogeneic therapies. This correlates with typical batch sizes of several hundred containers. These are larger than personalized autologous therapies and not suitable for manual filling. On the other hand they are too small for traditional filling lines. This gap is closed with the new Syntegon Microbatch gloveless working cell.
Syntegon Xelum
Continuous Manufacturing is an unbroken trend in OSD production. Syntegon has developed a slightly different approach: as opposed to the common complex mass flow rate based approach, excipients and active ingredients are dosed as a discrete mass on both the Xelum production platform and the Xelum R&D unit. This makes it possible to dose even smallest amounts of APIs of less than one percent reliably.
Digital Technologies/paperless processes: Advances in digital solutions are still slow in pharma. Serialization has been implemented in nearly all regions. Further digitalization takes time due to the strict regulatory and validation requirements. Still, the pandemic and travel restrictions have boosted the use of digital communication options. Key customer project appointments, such as model presentations and factory acceptance tests, are partly carried out virtually. When it comes to services, Syntegon also accommodates its customers with digital solutions such as remote maintenance and the new MIRA (Machine Intelligence Reporting & Analytics), which was developed especially for predictive maintenance (see details above).
Andreas Mattern, Ph.D., is Director Product Management Pharma for Syntegon Technology, a leading global process and packaging technology provider with 6,100 employees at 30 locations in more than 15 countries. Headquartered in Waiblingen, Germany, Syntegon (formerly Bosch Packaging Technology), has been providing solutions for production, processing, filling, inspection and packaging of liquid and solid pharmaceuticals for more than 50 years.
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