Human cell experts from Germany’s CO.DON AG are again cutting the edge: they have launched human cells production on an industrial scale. The demanding quality standards required of the manufacturing conditions for human cell transplants led to the development of Integrated Isolator Technology (IIT) alongside industrial partners, which went into operation at CO.DON´s Teltow site in 1999.
What makes this “clean room within a clean room” so special is that all the equipment required for producing advanced therapy medicinal products and for quality control is integrated in isolators that meet the highest clean room standards. These isolators are located in an environment that also qualifies as a clean room and are only accessible via airlocks. Pressure differences between the different rooms prevent contamination between one room and another.
But now CO.DON has taken the next step using all their experience as human cell experts: A plant for the industrial-scale production of human cells in Leipzig.
CO.DON´s expertise in cartilage regeneration
CO.DON AG manufactures cell-based therapies of the highest purity and to the highest quality standards. Its products represent a revolutionary process in the biological regenerative treatment of articular cartilage defects. CO.DON AG is certified in accordance with European Guidelines for Good Manufacturing Practice (EU-GMP) since 1997. In 1997 CO.DON AG was the first biopharmaceutical company in Europe to be granted a permit for the manufacture of an autologous chondrocyte implantation product under section 13 of the German Drugs Law (AMG). In July 2017 CO.DON received EU-wide marketing authorisation for its product Spherox, with approval for Switzerland following in March 2019.
Autologous chondrocyte implantation (ACI) is a well-established surgical method to treat focal cartilage defects and prevent progressive cartilage degeneration and osteoarthritis. It is a two-stage procedure. During a first arthroscopy, a biopsy is taken from healthy cartilage. From this biopsy, the patient´s cartilage cells, chondrocytes, are isolated and culture expanded. In a second surgery, the cartilage cells are implanted into the cartilage defect. In the first generation of ACI, the chondrocytes were covered under a periosteal flap, which was replaced by a collagen cover or bioresorbable film in the second generation. The third generation cultured the chondrocytes on an open-structured collagen scaffold with could be applied without sutures, enabling the possibility of arthroscopic implantation.
Spherox is the newest generation ACI; the chondrocytes are cultured in spherical aggregates and their self-synthesized extracellular matrix makes them sticky, eliminating the need for covers, sutures, glue or scaffolds for implantation. The product is 100% autologous and free of additives, setting the stage for the highest level of personalized treatment. Because no exogenous materials are used, the risks of rejection, inflammation, and infection are low. Due to a minimally invasive or arthroscopic application of the product, surgery and rehabilitation time can be reduced.
CO.DON´s Second Production Site
In 2017 CO.DON started building a second production site in Leipzig to satisfy the additional demand since central EU marketing authorisation has been granted. The production site is one of the world’s largest and most modern plants for the industrial-scale production of human cells. Going forward, it will continue to ensure that cell therapy products of the highest quality are supplied to users in Germany and other European countries.
The adoption of Modular Cell Culture Isolators within aseptic processing, compared to the same processes performed in standard, open clean room environments, has clearly demonstrated the advantages of isolation technology. The newly developed generation of Isolators designed for Regenerative Medicine application allows Biotech centers as well as Tissue Engineering laboratories to continuously make advancements while still operating within the ever restrictive confines of various regulatory bodies (FDA, EUP, USP) and industry guidelines (GMP, PDA).
Simultaneously, the operational costs normally associated with traditional clean room use (HVAC, utilities, personnel gowning, etc.) and sterilization cycles of the entire clean room suite are substantially, if not completely, eliminated. This is mainly because Isolators with their own integrated decontamination system are designed for installation in class D environments. This specific product line dedicated to Regenerative Medicine includes a few pre-designed modules to be used for tissue regeneration as well as custom solutions to address the specific requirements in terms of process, layout and expected manufacturing capacity.
The primary goal of this product line is to integrate the entire cell manipulation process within a closed Class A environment. This requirement of Class A continuity throughout the process is crucial for the sterility of the final product. As far as the characteristics of the Isolator, the design is mainly driven by the GMPs and PIC/S as design principles and also by the reference standard and guidelines in aseptic processing within isolation technology.
CO.DON´s pioneering vision has been challenged again after EU-approval: the foreseen increase of production requirements (flexibility, traceability, sustainability) concerned with the expected increasing demand, forced the company to look to a new approach, while not changing significantly the process features. The question was: “How do we increase and maximize production capacity while keeping or improving the quality standards, allow for best product management and contain the production costs for an optimal cost-efficiency ratio?”.
Performance Requirements
The new plant needed to have the capacity to manufacture 4,500 autologous cartilage regeneration medicinal products per year. Translated in process actions, this means 18.000+ days of quarantine for the biopsies coming from the surgical suites, 72.000+ IN/OUT operations for checks and media changes, and 220.000+ days of incubation time. On the other hand, to contain costs, the space available was limited (300 sqm for the laboratory area in total) and the request to keep the lowest possible environmental classification was a must. These tight constraints suggested that a change in the approach was needed, as well as the development of an innovative space management concept and the introduction of a degree of automation for simplifying and making a robust procedural approach. The principle behind the Integrated Isolator Technology originally invented and developed for Teltow site has been refined. It all falls into place with suitable comprehensive process control architecture, including hardware and corresponding controls, as well as high-level operator and resource planning for maximization of the plant performances.
Solution Highlights – 3 Isolators and 144 decentralised mobile incubators
To accomplish the tasks outlined above, CO.DON selected the combination of FlexycultTM docking incubators and Modular Cell Therapy Isolators by Comecer.
The Modular Cell Culture Isolator (MCCI) is a Comecer concept offering an Isolator integrated with all the necessary equipment to perform Cell Therapy processing (incubators, microscope, centrifuge, refrigerator, freezer and more).
A Flexycult mobile incubation docking system compliments the isolator equipment. Flexycult is a Comecer patented concept, consisting of an incubator running under grade A, docked into a ground base where all the utilities are managed, along with the aseptic and operational conditions (temperature, CO2, O2, relative humidity) are set and controlled. The system is completed with a sterile interface to the Isolator Systems allowing a fast aseptic exchange of materials between the 2 grade A environments.
The CO.DON plant is composed of 3 MCCI units, as described above, installed in Grade D and 144 FlexycultTM individual incubators in 16 docking stations, with automatic/robotic module transportation controlled by dedicated software (FlexycultTM Management System – FMS), interactive communication among modules, isolators and operators, automatic tracking and full SOP assistance for the operators. Comecer was able to deliver a Facility of the Future, today.
In January 2020 CO.DON was awarded a manufacturing licence for its newly built GMP production plant in Leipzig. The licence covers CO.DON´s product as well as the ability of cell production on a resource dependent contract manufacturing basis. This means that both the Teltow and the Leipzig site are certified as GMP-compliant. The current time-consuming technology transfer from Teltow to Leipzig, which must be monitored and reported to the EMA in order to ensure high product quality at the new location in the interest of patient well-being, follows the granting of the manufacturing license.
Dr. Andreas Eberle, Vice President and Plant Manager Leipzig: “Building a new production site in compliance with all the regulatory requirements and legal standards for the pharma industry is always a time-consuming and cost-intensive process. CO.DON AG has been successful in mastering this challenge, from the start of the project to the award of the manufacturing licence, within the original budget, in just over two years. This success was made possible above all because we succeeded in filling important key positions during the project with suitably experienced specialist personnel and in forming a highly motivated team of competent employees. Besides, we worked together with strong external partners for the technical implementation”.
Tilmann Bur, Executive Board of CO.DON AG: “Our modern production facility in Leipzig enables us to manufacture human cell products on an industrial scale using state-of-the-art technology. CO.DON AG is thus in a position to ensure the market supply of novel, cell-based pharmaceuticals in the future under continuously increasing quality requirements for the benefit of our patients and customers”.
CO.DON’s technological, production and regulatory expertise makes the company a first mover in the market for biological cartilage regeneration and a provider of highly effective, safe treatment options between pain therapy and endoprosthetics with the aim to become a market leader in the prevention of osteoarthritis. Moreover, CO.DON´s product is currently the only cell-based medicinal product for the regenerative treatment of knee cartilage defects that is authorized EU-wide. CO.DON founded subsidiaries in the UK (2017) and the Netherlands (2018) to develop this promising market in line with the company’s strategy Currently, the product is distributed in Germany, the Netherlands, UK, Switzerland, and Austria.
About CO.DON AG
CO.DON AG develops, produces and markets autologous cell therapies for the minimally invasive repair of knee cartilage defects following trauma or degeneration. The medicinal product is a cell therapy product that uses only the patient’s own cartilage cells (“autologous chondrocytes”). CO.DON’s method is currently used in over 200 clinics in Germany and more than 15,000 patients have already been treated. In July 2017 CO.DON received EU-wide marketing authorisation for its product, with approval for Switzerland following in March 2019. The shares in CO.DON AG are listed on the Frankfurt Stock Exchange (ISIN: DE000A1K0227). Executive Board: Tilmann Bur.
About Comecer
Comecer was established in the mid-70s in Castel Bolognese (Ravenna), Italy. Comecer develops and manufactures high technology systems for aseptic treatment and containment in the pharmaceutical and nuclear medicine industries, including isolation technology solutions for Advanced Therapies and Regenerative Medicine (Cell & Gene Therapy). The company vision is to contribute to progress and preserve life by developing highly innovative technologies and sustainable solutions, pursuing the latest rules of GMP (Good Manufacturing Practices). Comecer products are well known and used in hospitals, universities, pharmaceutical companies, biotech start-ups and large industrial groups worldwide. Since 2019 Comecer is a part of ATS Automation, a global industry-leading solutions provider with multiple offices in the U.S. and Canada. Together, Comecer and ATS are continuously at the forefront of innovation and maintain an advantage over its competitors.
*Feature Photo Credit: Courtesy of CO.DON Ag