With the increasing number of biologics, complex oncology therapies, and rare and orphan drugs comprising pharma and biopharma pipelines, manufacturing equipment must provide substantial flexibility. Additionally, the COVID-19 pandemic and vaccine production is significantly impacting equipment needs.
As batches and regimens trend shorter and more customized, the need for flexible equipment to accomplish more than one task is essential. The latest trends impacting pharmaceutical manufacturing equipment include flexibility in product and container types, digitalization in pharma production, and processing of Advanced Therapy Medicinal Products (ATMPs). Additionally, the level of automation is increasing.
Dr. Andreas Mattern, VP Strategy & Global Product Management Pharma at Syntegon discusses some of the latest advances in manufacturing equipment.
Contract Pharma: What are the pharma/biopharma trends impacting manufacturing equipment?
Andreas Mattern: Covid-19 (vaccine production): According to the World Health Organization, 4.9 billion people, or 61.6 percent of the world population have received at least one dose of a Covid-19 vaccine, gradually decreasing the pathogen’s virulence. Despite these first successes, the virus’ threat remains persistent, as new variants like Omicron are changing the game time and again. This urges leading vaccine manufacturers to continuously adapt existing vaccines and keep up global supply. Besides the vaccines themselves, their packaging and administration is also changing – from vials to pre-filled syringes. They contain a single dose and can be administered even more quickly. We are already experiencing this changing demand. While we supported drug producers with new vial lines and modernizations of existing equipment during the first years of the pandemic, we now see a rising demand for high-performance and highly accurate syringe filling machines. According to our analysis, about half of the global Covid production sites listed on the UNICEF Covid dashboard have processing or packaging equipment from Syntegon installed.
Specialized treatments (small batch sizes): The specialized treatments of a wide range of conditions, including many types of cancer and rare diseases like genetic disorders all share a common trait. In addition to their high potency, which requires effective containment solutions, they are produced in increasingly small batch sizes. The latter call for dedicated production platforms that cater to the production requirements of only several hundred containers per batch in the most extreme cases, asking for pioneering small batch manufacturing solutions that allow for fast changeovers between batches with the lowest possible time and product loss. Leading equipment manufacturers like Syntegon have taken on the challenge and are developing matching platforms.
Re-localizing antibiotics production: Besides all specialized treatments, the production of more common drugs like antibiotics cannot be neglected. They are essential for curing a wide range of conditions, including pneumonia or tonsillitis. Over the past few decades, however, the production of these drugs has been outsourced to lower-cost markets, mainly in Asia. Especially the Covid-19 pandemic has shown how fragile supply chains are and how important it is to re-localize production of life-saving antibiotics such as penicillin and cephalosporins. Apart from local investments by heath authorities and governments, pharmaceutical manufacturers need efficient equipment and comprehensive knowledge of the highly regulated powder filling processes.
Digitalization has been changing processes for some years. The ability to monitor machine conditions in real time helps drug producers to take data-based decisions and optimize operations. Digital service offerings such as remote maintenance, virtual training and even FATs have proven their worth during the pandemic with its travel restrictions – and have come to stay. Another important software-based trend is Artificial Intelligence (AI).
CP: What are some of the latest advances in manufacturing equipment?
AM: Small and micro batch production: In the wake of the biopharmaceutical and specialized treatments surge, equipment manufacturers like Syntegon have started developing solutions for small and micro batch filling that meet several requirements at once. For high-priced biotech drugs, it’s all about low output and high product yield. Syntegon’s small batch solution Versynta Flexible Filling Platform (FFP) with an integratable isolator, which was launched last year, ensures maximum flexibility and product safety. Versynta FFP consists of pre-tested modules that can be selected individually, including different filling systems and Syntegon’s four axis handling robot specifically developed for aseptic operation. For even smaller batch sizes of only several hundred containers per hour, the fully automated, gloveless production cell Versynta microBatch is currently being developed. Typical use cases are fill/finish of drugs for clinical trials or production of gene and cell therapies. Both solutions will be presented to the public at this year’s Achema in Frankfurt, Germany.
Parenteral drug production: as the Covid-19 pandemic has shown, shorter delivery times are becoming increasingly important to drug manufacturers. With the new SVP Essential, the Syntegon subsidiary Pharmatec has launched a modular, cost-efficient system for the production of small-volume liquid pharmaceuticals, which can be supplied within just six months. Just like Versynta FFP, the SVP Essential is based on a large portfolio of pre-tested modules, which can be assembled to produce simple parenterals such as analgesics or insulin, as well as generic drugs. Especially start-ups and pharmaceutical manufacturers in price-sensitive markets benefit from the fully automated, completely closed system for volumes of 50 to 1,000 liters.
OSD drug development: Speed is also important when bringing new drugs to regulatory approval. The new GKF 60 lab-scale capsule filling machine enables the development of new drugs and formulations with a wide variety of dosing systems that can also dose pure APIs. It is mobile, highly flexible, scalable, and can be adapted for both simple and highly potent formulations up to OEB5 high containment in just a few steps. The level of automation is also increasing in lab-scale equipment: with the Automated Process Development (APD) tool developed by Syntegon, pharmaceutical manufacturers can determine the optimum parameters for capsule filling and automatically adjust them during the process.
Artificial intelligence: Albeit slowly, AI is starting to make its way into pharmaceutical production steps, such as inspection technology, promising greater precision and efficiency than ever before. In fact, AI is already a reality in some pharmaceutical manufacturing operations. Here, Syntegon set new standards in 2021 with the first fully validated visual inspection system utilizing AI for Amgen. With the new AI capabilities, the inspection machine can increase its particle detection rate by 70 percent, while reducing the false detection rate by 60 percent. Syntegon is set to implement AI in further inspection and other pharmaceutical equipment in the future. In July 2021, Syntegon already added a new member to its highly successful AIM 5 inspection range: the fully integrated syringe inspection line not only features a de-nester and a re-nester, but also comes with an AI function by default.
CP: What capabilities do clients look for in manufacturing equipment? What specific manufacturing challenges do clients look to overcome?
AM: As mentioned above, fast time-to-market, short delivery times, digitalization options with reduced validation efforts, and the highest flexibility in batch sizes with minimal product loss are among the major prerequisites of pharmaceutical manufacturers.
Another important challenge is product and operator protection. High-containment systems up to OEB5 are required in both parenteral and OSD production to make sure the sometimes highly potent products have no effect on the operators’ health. Take the example of antibiotic powders: their consistency requires special air handling concepts. In the filling areas, dust-tight barriers and a sealed air supply with efficient and powerful filter systems are a must. A UDAF ventilation system cleans and tempers the circulating air of the filling area and regulates humidity. Machine cleaning is also particularly complex with powders, as the fine dust particles can settle anywhere within the machine. An open design, easy accessibility, and CIP-SIP for cleaning the product in-feed system provide an effective remedy. In liquid filling operations, robotic systems are increasingly used to reduce operator intervention to a minimum. The Pharma Handling unit of the Versynta FFP is a good example. It offers a high degree of flexibility in manufacturing processes, while making them safer, more precise, reproducible and validatable.
Flexibility is just as important in the choice of pack styles and filling systems. Advances in specialized treatment increase the need for systems that make it possible to process more than one container type on a single platform, without compromising on yields or changeover times. Innovations like Syntegon’s Versynta portfolio but also proven fill-finish machines like the FXS Combi platform for syringes, vials and cartridges specifically address this trend. The choice between different filling systems such as piston pump or peristaltic pump (which has become the standard for filling proteins in combination with disposable filling systems) further speeds up production.
CP: Where does the industry stand with adopting production innovations or new technologies?
AM: The pharmaceutical industry is not known for its fast adoption of new technologies or processes. This is mainly due to the strict regulatory guidelines, which are in place to ensure maximum product and patient safety. In many cases, working on pilot projects or in strategical partnerships has shown to speed up innovation significantly.
Artificial intelligence is the most prominent example. Deep Learning vision tools, which only require moderate software modifications, have been available for a while. It took a machine manufacturer (Syntegon) with sound software, process, and validation expertise, and a pharmaceutical producer (Amgen) with the wish to make processes even safer and more reliable to implement the first fully validated visual inspection system utilizing AI.
Partnerships have also been driving innovations in small batch liquid fill-finish operations. Versynta microBatch, the highly flexible and fully automated production cell with a gloveless isolator, is a joint development of Vetter and Syntegon. Together, both companies are addressing the need for ever more flexible platforms that process smallest batches of highly effective drugs. In fact, Syntegon and Vetter were awarded the PDA Drug Delivery Innovation Award in the „Partnership Innovation“ category for Versynta microBatch.
Continuous manufacturing for OSD forms has also been trending for a few years. Developments like the Xelum platform form the Syntegon subsidiary Hüttlin have already set new standards: the platform 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. Syntegon has now entered a strategic partnership with Bayer to further advance this process and establish it as a standard in the pharmaceutical industry. In the same vein, Syntegon and Shanghai Pharmaceuticals signed an agreement to build a joint laboratory for continuous manufacturing technology in China.See Syntegon’s latest equipment