Kristin Brooks, Managing Editor, Contract Pharma05.10.23
Efficiency, fast changeover, production yields, and flexibility remain key drivers for today’s manufacturing equipment to keep up with pharma and biopharma pipelines and R&D trends. Leveraging data, automation, and digitalization, are some of the key trends impacting manufacturing and equipment.
Dr. Andreas Mattern, Vice President Strategy & Global Product Management Pharma at Syntegon, discusses R&D trends, manufacturing challenges, latest advances in manufacturing equipment, and production innovations. –KB
Contract Pharma: What are the pharma/biopharma trends impacting manufacturing equipment?
Dr. Andreas Mattern: One of the main trends, which will continue to drive new equipment developments is specialized treatments. While blockbuster medicines and traditional, large batch drugs were and continue to be important contributors to human health, personalized medicine is quickly becoming the focus for future treatment breakthroughs. Many types of cancer and genetic disorders can only be treated with highly specialized drugs. These, in turn, require production in ever smaller batch sizes. For example, according to GlobalData, 28% of the parenteral drug pipeline are cell and gene therapies.
Small and micro batch production
An exact definition of “small batch” does not exist, however interpretation taken from the FDA’s “Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers” for generic parenterals lists small batches as at least 10 percent of the proposed maximum size commercial batch or less than 15,000 - 60,000 containers, based on fill volume. Batch sizes shrink to a few thousand containers for parenterals used in clinical trials. For very specialized treatments (e.g. autologous cell therapy), one patient equals one batch of approximately 5-10 containers.
Flexibility for RTU containers
This trend calls for dedicated production platforms with fast batch changeovers and the lowest possible product loss. At the same time, pharmaceutical manufacturers require utmost flexibility in the use of containers. Hence, it comes as no surprise that the market for ready-to-use (RTU) containers has been growing at a rapid pace over the past years. Drug manufacturers benefit from reduced time-to-market and total cost of ownership (TCO), as well as increased flexibility and greater integrity of the drug product. While RTU containers have been the de-facto standard for pre-filled syringes for some time, they are now also increasingly being used for vials and cartridges in both bulk and small batch applications. P&S Intelligence predicts that the RTU vials market revenue will reach $1.2 billion worldwide by 2030.
CP: What are some manufacturing challenges clients look to overcome?
Dr. Mattern: The revision of Annex 1, which was published in August 2022 after ten years of discussion within the industry, will have a big impact on all companies that produce sterile medicinal products. They must comply with Annex 1 regulations if they want to market their products in the European Union. Moreover, the document has also been harmonized between the EMA and PIC/S with its 54 member countries, including the U.S. From an aseptic production point of view, Annex 1 tackles exactly the right topics to further improve drug quality. Next to many other important topics, chapter 2 prominently recommends the use of appropriate technologies to separate operators from products with barrier systems such as RABS and isolators with a higher degree of automation.
Isolator biodecontamination
With more and more isolators being used in the industry, another challenge is the biodecontamination of isolators. It is an essential step before the actual fill-finish process and involves exposing the surface of an isolator to a specific concentration of decontaminant for a set period to create an aseptic atmosphere within the process core. The approach from Syntegon using vaporized hydrogen peroxide spans four phases: preparation, conditioning, biodecontamination, and aeration. The goal is to achieve a residual H2O2concentration of typically 1 ppm (parts per million) or less before production begins. From the first automated biodecontamination in the early 1990s to today’s solutions, the biodecontamination cycle has shrunk from 10 hours to less than 60 minutes for fully loaded commercial isolator lines. This not only speeds up processes and leaves more time for the actual production (which is especially important for smaller batches with more frequent change overs); it also contributes to more energy-efficient operations.
Sustainability in pharma operations
Sustainable use of energy and other resources is currently one of the greatest challenges in the pharmaceutical industry – not just since the rapid rise in energy prices. Manufacturing companies are setting themselves ambitious sustainability targets in order to minimize their environmental impact and resource consumption as far as possible. For example, energy-intensive equipment such as sterilization tunnels present enormous challenges. To help pharmaceutical manufacturers master the balancing act between energy efficiency, consistent quality, and validated parameters, Syntegon has developed a method for determining and evaluating emissions from equipment over its entire life cycle – the Life Cycle Assessment (LCA). The certified, software-based calculation model, which was developed for the machines of the Syntegon portfolio, covers parameters such as electricity, compressed air, media, and packaging materials. It relates the defined parameters to the individual CO2 emissions, identifying consumption in a holistic and customer-specific manner.
CP: What are some of the latest advances in manufacturing equipment?
Dr. Mattern: Transparency through digitalization
The more data is available, the easier it is to optimize parameters such as energy consumption. However, even the largest amount of data is worth nothing when it remains unused. Here, new cloud-based software solutions such as Synexio from Syntegon provide a remedy. 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. The second package “Uptime”, which will be presented at this year’s Interpack, determines concrete potential for improvement, for example by visualizing the most frequently occurring reasons for stops.
Gloveless micro batch filling
Automation is another trend that is gaining ground in the (bio)pharmaceutical industry. Following the modular Versynta FFP (Flexible Filling Platform) for outputs of up to 3,600 containers per hour, Syntegon has taken the next step towards fully automated pharmaceutical filling: the highly flexible production cell Versynta microBatchwith an output of 120 to 500 containers per hour enables a complete batch-to-batch changeover of less than two hours. Syringes, cartridges, and vials made of glass or plastic can be filled with virtually no product loss. The gloveless isolator with integrated air treatment significantly reduces the risk of contamination since it eliminates manual intervention. Fully automated filling and 100 percent in-process control ensure continuously high quality.
Vegan capsule alternatives
In OSD production, the dynamically growing markets for oncological therapeutics, phytopharmaceuticals and dietary supplements calls for new capsule filling solutions. The focus is on especially robust processes to achieve the highest yields and maximum process stability. At the same time, the trend towards vegan alternatives has boosted the use of hard capsules made of HPMC or pullulan. The latter share one important challenge with their non-vegan hard gelatin counterparts: both require an additional seal, a so-called banding, to close them tightly and to respond to regional tamper-evident requirements. At this year’s interpack, Syntegon will present the new GKB 2100 machine, which comes with an output rate of up to 125,000 capsules per hour and user-friendly format changes. In addition, a structured dashboard with central 21-inch touch HMI and large glass surfaces for a good process view simplify the operators’ daily work.
Starchless depositing of functional gummies and jellies
Functional gummies and jellies contain valuable ingredients such as vitamins or minerals. They require special handling along the entire production line, for example precise dosing to ensure the right additive content per individual piece. Functional gummy and jelly products can be deposited into reusable plastic molds instead of starch powder beds for moisture removal, resulting in significantly shorter process times. State-of-the-art starchless production systems further optimally protect heat-sensitive ingredients from excessive thermal stress since functional additives are only added shortly before depositing. This cost-efficient, fast, and contamination-free approach opens the field to more nutraceutical and pharmaceutical applications such as jellies with API content.
CP: In what areas do you see production innovation and/or new technologies being used?
Dr. Mattern: Continuous Manufacturing
Continuous manufacturing for OSD forms has been trending for a few years. As usual, the highly regulated pharmaceutical industry requires some time to change existing processes. At Achema 2022, Syntegon introduced the fluid bed laboratory unit Solidlab 2 Plus. It is the only solution available on the market for the development of both batch and continuous manufacturing processes, offering pharmaceutical manufacturers maximum flexibility in terms of both process development and the subsequent transfer to production scale. When combined with a feeder-blender unit, the Solidlab 2 Plus becomes the Xelum R&D, Syntegon’s development platform for continuous manufacturing. Process parameters from the Xelum R&D can be transferred directly to the Xelum production unit. The latter doses, mixes and granulates individual packages, so-called X-keys, which continuously run through the process chain and are removed from the system successively. This way, even smallest amounts of APIs of less than one percent can be dosed precisely.
Digitalization
Automation and digitalization are highly sought after in the pharmaceutical industry. As Syntegon’s new Versyta solutions (and many other developments) show, pharmaceutical manufacturers are looking for a higher degree of automation in their equipment. The use of robotics is taking the industry a huge step further towards even higher product protection and quality, as it eliminates the main cause for contamination, i.e. human intervention. On the other hand, digitalization makes it possible to monitor machine conditions in real time, which helps drug producers take data-based decisions and optimize operations. Syntegon is currently expanding its Digital Solutions portfolio to offer pharmaceutical manufacturers and CMOs even more data transparency.
Dr. Andreas Mattern, Vice President Strategy & Global Product Management Pharma at Syntegon
Dr. Andreas Mattern, Vice President Strategy & Global Product Management Pharma at Syntegon, discusses R&D trends, manufacturing challenges, latest advances in manufacturing equipment, and production innovations. –KB
Contract Pharma: What are the pharma/biopharma trends impacting manufacturing equipment?
Dr. Andreas Mattern: One of the main trends, which will continue to drive new equipment developments is specialized treatments. While blockbuster medicines and traditional, large batch drugs were and continue to be important contributors to human health, personalized medicine is quickly becoming the focus for future treatment breakthroughs. Many types of cancer and genetic disorders can only be treated with highly specialized drugs. These, in turn, require production in ever smaller batch sizes. For example, according to GlobalData, 28% of the parenteral drug pipeline are cell and gene therapies.
Small and micro batch production
An exact definition of “small batch” does not exist, however interpretation taken from the FDA’s “Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers” for generic parenterals lists small batches as at least 10 percent of the proposed maximum size commercial batch or less than 15,000 - 60,000 containers, based on fill volume. Batch sizes shrink to a few thousand containers for parenterals used in clinical trials. For very specialized treatments (e.g. autologous cell therapy), one patient equals one batch of approximately 5-10 containers.
Flexibility for RTU containers
This trend calls for dedicated production platforms with fast batch changeovers and the lowest possible product loss. At the same time, pharmaceutical manufacturers require utmost flexibility in the use of containers. Hence, it comes as no surprise that the market for ready-to-use (RTU) containers has been growing at a rapid pace over the past years. Drug manufacturers benefit from reduced time-to-market and total cost of ownership (TCO), as well as increased flexibility and greater integrity of the drug product. While RTU containers have been the de-facto standard for pre-filled syringes for some time, they are now also increasingly being used for vials and cartridges in both bulk and small batch applications. P&S Intelligence predicts that the RTU vials market revenue will reach $1.2 billion worldwide by 2030.
CP: What are some manufacturing challenges clients look to overcome?
Dr. Mattern: The revision of Annex 1, which was published in August 2022 after ten years of discussion within the industry, will have a big impact on all companies that produce sterile medicinal products. They must comply with Annex 1 regulations if they want to market their products in the European Union. Moreover, the document has also been harmonized between the EMA and PIC/S with its 54 member countries, including the U.S. From an aseptic production point of view, Annex 1 tackles exactly the right topics to further improve drug quality. Next to many other important topics, chapter 2 prominently recommends the use of appropriate technologies to separate operators from products with barrier systems such as RABS and isolators with a higher degree of automation.
Isolator biodecontamination
With more and more isolators being used in the industry, another challenge is the biodecontamination of isolators. It is an essential step before the actual fill-finish process and involves exposing the surface of an isolator to a specific concentration of decontaminant for a set period to create an aseptic atmosphere within the process core. The approach from Syntegon using vaporized hydrogen peroxide spans four phases: preparation, conditioning, biodecontamination, and aeration. The goal is to achieve a residual H2O2concentration of typically 1 ppm (parts per million) or less before production begins. From the first automated biodecontamination in the early 1990s to today’s solutions, the biodecontamination cycle has shrunk from 10 hours to less than 60 minutes for fully loaded commercial isolator lines. This not only speeds up processes and leaves more time for the actual production (which is especially important for smaller batches with more frequent change overs); it also contributes to more energy-efficient operations.
Sustainability in pharma operations
Sustainable use of energy and other resources is currently one of the greatest challenges in the pharmaceutical industry – not just since the rapid rise in energy prices. Manufacturing companies are setting themselves ambitious sustainability targets in order to minimize their environmental impact and resource consumption as far as possible. For example, energy-intensive equipment such as sterilization tunnels present enormous challenges. To help pharmaceutical manufacturers master the balancing act between energy efficiency, consistent quality, and validated parameters, Syntegon has developed a method for determining and evaluating emissions from equipment over its entire life cycle – the Life Cycle Assessment (LCA). The certified, software-based calculation model, which was developed for the machines of the Syntegon portfolio, covers parameters such as electricity, compressed air, media, and packaging materials. It relates the defined parameters to the individual CO2 emissions, identifying consumption in a holistic and customer-specific manner.
CP: What are some of the latest advances in manufacturing equipment?
Dr. Mattern: Transparency through digitalization
The more data is available, the easier it is to optimize parameters such as energy consumption. However, even the largest amount of data is worth nothing when it remains unused. Here, new cloud-based software solutions such as Synexio from Syntegon provide a remedy. 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. The second package “Uptime”, which will be presented at this year’s Interpack, determines concrete potential for improvement, for example by visualizing the most frequently occurring reasons for stops.
Gloveless micro batch filling
Automation is another trend that is gaining ground in the (bio)pharmaceutical industry. Following the modular Versynta FFP (Flexible Filling Platform) for outputs of up to 3,600 containers per hour, Syntegon has taken the next step towards fully automated pharmaceutical filling: the highly flexible production cell Versynta microBatchwith an output of 120 to 500 containers per hour enables a complete batch-to-batch changeover of less than two hours. Syringes, cartridges, and vials made of glass or plastic can be filled with virtually no product loss. The gloveless isolator with integrated air treatment significantly reduces the risk of contamination since it eliminates manual intervention. Fully automated filling and 100 percent in-process control ensure continuously high quality.
Vegan capsule alternatives
In OSD production, the dynamically growing markets for oncological therapeutics, phytopharmaceuticals and dietary supplements calls for new capsule filling solutions. The focus is on especially robust processes to achieve the highest yields and maximum process stability. At the same time, the trend towards vegan alternatives has boosted the use of hard capsules made of HPMC or pullulan. The latter share one important challenge with their non-vegan hard gelatin counterparts: both require an additional seal, a so-called banding, to close them tightly and to respond to regional tamper-evident requirements. At this year’s interpack, Syntegon will present the new GKB 2100 machine, which comes with an output rate of up to 125,000 capsules per hour and user-friendly format changes. In addition, a structured dashboard with central 21-inch touch HMI and large glass surfaces for a good process view simplify the operators’ daily work.
Starchless depositing of functional gummies and jellies
Functional gummies and jellies contain valuable ingredients such as vitamins or minerals. They require special handling along the entire production line, for example precise dosing to ensure the right additive content per individual piece. Functional gummy and jelly products can be deposited into reusable plastic molds instead of starch powder beds for moisture removal, resulting in significantly shorter process times. State-of-the-art starchless production systems further optimally protect heat-sensitive ingredients from excessive thermal stress since functional additives are only added shortly before depositing. This cost-efficient, fast, and contamination-free approach opens the field to more nutraceutical and pharmaceutical applications such as jellies with API content.
CP: In what areas do you see production innovation and/or new technologies being used?
Dr. Mattern: Continuous Manufacturing
Continuous manufacturing for OSD forms has been trending for a few years. As usual, the highly regulated pharmaceutical industry requires some time to change existing processes. At Achema 2022, Syntegon introduced the fluid bed laboratory unit Solidlab 2 Plus. It is the only solution available on the market for the development of both batch and continuous manufacturing processes, offering pharmaceutical manufacturers maximum flexibility in terms of both process development and the subsequent transfer to production scale. When combined with a feeder-blender unit, the Solidlab 2 Plus becomes the Xelum R&D, Syntegon’s development platform for continuous manufacturing. Process parameters from the Xelum R&D can be transferred directly to the Xelum production unit. The latter doses, mixes and granulates individual packages, so-called X-keys, which continuously run through the process chain and are removed from the system successively. This way, even smallest amounts of APIs of less than one percent can be dosed precisely.
Digitalization
Automation and digitalization are highly sought after in the pharmaceutical industry. As Syntegon’s new Versyta solutions (and many other developments) show, pharmaceutical manufacturers are looking for a higher degree of automation in their equipment. The use of robotics is taking the industry a huge step further towards even higher product protection and quality, as it eliminates the main cause for contamination, i.e. human intervention. On the other hand, digitalization makes it possible to monitor machine conditions in real time, which helps drug producers take data-based decisions and optimize operations. Syntegon is currently expanding its Digital Solutions portfolio to offer pharmaceutical manufacturers and CMOs even more data transparency.
