Bavarian Nordic A/S was

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1 S I N G L E - U S E IMPLEMENTATION Rapid Implementation of a Smallpox Vaccine Facility A Case Study in Single-Use Technology Karin Wassard and Miriam Monge Bavarian Nordic A/S was founded in 1994 and listed on the Copenhagen Stock Exchange in Headquartered in Denmark with operations in Germany, the United States, and Singapore, the company employs more than 230 people. Its main focus is on developing prophylactic and therapeutic vaccines against infectious diseases and cancer. Bavarian Nordic s technology platform is based on its patented MVA-BN virus (modified Vaccinia ankara), which is the active ingredient in the IMVAMUNE vaccine, the company s third-generation smallpox vaccine in development. Since 2003, Bavarian Nordic has collaborated with the US National Institutes of Health (NIH) under its request-for-proposal program (RFP-1 and RFP-2) for the development and production of this safe, MVA-based smallpox vaccine. In 2006, the company delivered half a million doses to NIH under the RFP- 2 contract, and in second quarter of 2007 it expects to be awarded the RFP-3 contract for 20 million doses. As part of that contract, Bavarian Nordic expects to register the vaccine in the United States as a safe smallpox vaccine also for those who are contraindicated from traditional smallpox vaccines. Bavarian Nordic s other core business areas are HIV and cancer. The company has several MVA-BN based Photo 1: Arrival of growth media at Bavarian Nordic docked through the wall using Biosafe aseptic transfer technology from Stedim Biosystems BAVARIAN NORDIC A/S ( vaccines in clinical phase 1 and 2 trials. Furthermore, the company has preclinical programs in measles, respiratory syncytial virus (RSV), Japanese encephalitis, and dengue fever. Bavarian Nordic has supplied several governments with smallpox vaccines. With its increased production capacity, the company can supply a growing demand, particularly for safe smallpox vaccines. With global manufacturing capacity including the new state-of-the-art production facility in Kvistgård, Denmark (minimum capacity of 40 million doses per year, which can be expanded to 180 million doses per year) and an ongoing partnership with the German vaccine producer, Impfstoffwerk Dessau-Tornau (IDT, Bavarian Nordic has ensured supply of its current and future vaccines. A Key Supplier: With more than 25 years of experience, Stedim Biosystems pioneered the design and manufacture of single-use systems for biopharmaceutical manufacturing. The company has four manufacturing sites totaling over 5,000 m² of class 10,000 (ISO 7) cleanroom space, and it is registered as a medical device manufacturer with the US Food and Drug Administration. Stedim s four 2 BioProcess International MAY 2007 SUPPLEMENT

2 sites are certified to the 2000 version of ISO 9000 and the 2003 version of ISO As disposable systems become a critical part of biopharmaceutical industry manufacturing, Stedim Biosystems accompanies its clients through a comprehensive service offering of engineering, validation, regulatory compliance, and security of supply. THE CHALLENGE To be better prepared for the upcoming third RFP for large-scale production of a safe, third-generation smallpox vaccine for the US government, Bavarian Nordic management decided that the best strategy would be for the company to have its own production facility. By having control over bulk production, the company could control all steps in the value chain, thereby ensuring production schedules and the ability to take action early in case of any obstacles to timely production. To be ready for CGMP production in an approved facility with an annual capacity of 40 million doses (or more) of bulk for the company s IMVAMUNE vaccine, Bavarian Nordic needed to act fast. First, the company selected a site in Kvistgård, buying a facility from another pharmaceutical company. Second, the strategy for this fast-track project was set with the engineering partner NNE A/S ( which had also assisted in site selection (1). A key parameter in the strategy was the ability to work on several parts of the project in parallel, so partnering with companies whose expertise and competencies matched those needed in the project was the chosen approach. Figure 1 describes the project activities and timeline, outlining the many parallel activities. Because process industrialization and optimization took place during part of the project timeline, and as part of on-going partnerships with IDT and Amsterdam Molecular Therapeutics ( it was also important to decouple the process flow design from the layout and construction. Already in the process development work, disposables had been part of Figure 1: Project activities and timeline Bavarian Nordic s process for MVA- BN virus, so it was decided to use disposables to achieve that decoupling. The disposable work was done in close collaboration between Bavarian Nordic staff and the key suppliers chosen: Sartorius AG ( com), Stedim Biosystems (www. stedim.com), Wave Biotech (www. wavebiotech.com), and certain media suppliers. Between them, they cover expertise in single-use process systems, media supply in disposables, filtration, aseptic transfer and bioreactors. Manufacturing Requirements: MVA-BN technology involves a live virus, which must remain so to induce an immune response when used for vaccination. In addition, the vaccine must of course be sterile. MVA viruses (among them the MVA-BN virus) are the largest known DNA viruses and are thus too big to be sterile filtered. Therefore, the only way to meet both requirements is to ensure an aseptic production process from start to final vial. That can be achieved by developing a completely closed process or by combining a closed manufacturing process with handling of all open processes in a class 100 environment. The company decided to go for class 10,000 and class 100 production areas, combined with minimizing the number of open manipulations. This was achieved by extensive use of sterile single-use bags, tubes, connectors, and aseptic zone-to-zone transfer technology for sterile raw materials. For a live virus, both CGMP requirements and environmental regulations for biocontainment must be respected, and minimizing open handling is a good solution for both. Bavarian Nordic s MVA-BN virus is a biosafety level 1 (BSL1) organism, and it was decided to build for BSL2 with separate heating, ventilation, and air conditioning (HVAC) systems for the virus areas; HEPA filters on room air exhaust; and inactivation of liquid and solid virus waste. Building for BSL2 also ensures production flexibility for future products in Bavarian Nordic s pipeline. MANUFACTURING STRATEGY USING DISPOSABLES Looking more specifically at the manufacturing strategy, challenges facing Bavarian Nordic included ensuring a short project timeline, optimizing layout and flow throughout the facility, preventing bottlenecks, and most important minimizing risks of contamination. The keystone in its strategy to rise to these challenges was implementation of disposables from the design phase of the new facility to ensure an aseptic process while offering maximum flexibility. Following audits of the key disposables suppliers, specifications were developed in early That gave those suppliers a six-month timeline to develop and produce completely from scratch Bavarian Nordic s disposable process systems. At Stedim Biosystems alone, for example, this represented the development of 50 single-use custom designs for process and for raw materials, engineered to meet Bavarian Nordic specifications. A close collaboration between both companies was the first prerequisite SUPPLEMENT MAY 2007 BioProcess International 3

3 for a reliable, practical, and economic process design. Stedim s applications engineers worked alongside the Bavarian Nordic team to ensure successful design, in-house validation, and production of the disposable items for single-use manufacturing in compliance with CGMP and regulatory requirements. Wherever a single-use solution does not exist for a particular operation, Bavarian Nordic uses disposables in combination with dedicated production equipment. Such equipment is cleaned and steamed by conventional means: clean-in-place (CIP), manual washing, utensil washers, steam-in-place (SIP), or autoclaving. Part of the required validation for an aseptic bulk production process is similar to that better known for filling operations: process simulations using growth media. For Bavarian Nordic, those simulations are an integral part of validation for a full production set-up including connections made by operators, hold times after sterilization of equipment, and so on. Implementation of the disposable systems at Bavarian Nordic was part of test production. This allowed for the very important step of operator training to be performed at the new production site while testing the applicability of the single-use systems in an actual production setup. Because the Kvistgård site was completely new, and Bavarian Nordic s first full-scale production plant, there was a specific need to produce multiple test batches for operator training and equipment qualification. This gave the company an added benefit of being able to further optimize process yields at full production scale, which has led to high yield increases. Facility Design: As mentioned, one key challenge in the design of this facility was to minimize contamination risks. Bavarian Nordic selected the design concept endorsed by regulatory authorities of segregating support solutions from higher classified cleanroom areas. To create that segregation, Stedim s Biosafe ports for aseptic transfer were integrated into the facility design. They enable aseptic transfer of largevolume solutions (e.g., growth media and buffers) through walls from lower classification support zones to higher classification process zones (Photos 1 and 3). Input from authorities and other auditors regarding this facility layout and design, including the use of disposables, has been generally positive. They express a general interest in the single-use technology and how things are handled using this approach. Types of Disposables Used: Bavarian Nordic uses several types of disposable connections. These include Steam-Thru connectors to equipment from Colder Products Company ( Colder MPC/ QDC quick-disconnect couplings in class 100 LAF/BSC between disposables, and Kleenpak connectors from Pall ( in class 10,000 and class 100,000. Welding is used only for disconnections. Disposables are used throughout bulk processing for the following applications (with practical examples illustrated in Photos 1 3): Connections to dedicated process equipment Bags for solution storage (e.g., raw materials, process intermediates, and waste) Bags for processing (e.g., in cell preparation, for virus propagation, and purification) Bag manifolds for QC samples (welded off) Transfer sets for product and raw material transfer Bags for transfer and cooling of product Biosafe ports and/or rapid aseptic fluid transfer (RAFT) ports for media transfer from lower to higher classification zones Single-use filters for sterile filtration, air venting, and purification. DISPOSABLES VALIDATION STRATEGY Suppliers of disposables were approved by Bavarian Nordic s QA group following a production site audit, which in some cases includes auditing of film and gamma irradiation suppliers. As a preliminary step within the validation plan, Bavarian Nordic was able to work with supplier validation packages on all product contact materials (e.g., contact films, tubings and couplers). For example, the interaction study database at Stedim Biosystems details studies that have been performed using a wide range of process fluids. In Photo 2: Virus propagation using Cellbag bioreactors from Wave Biotech BAVARIAN NORDIC A/S ( Photo 3: Virus purification (RAFT system for buffer transfer and product input and output in bags) BAVARIAN NORDIC A/S ( 4 BioProcess International MAY 2007 SUPPLEMENT

4 addition to existing data, some suppliers offer their customers specific interaction study support with data from leachables and chemical compatibility studies. Those studies are performed using real products and/or media under simulated process conditions. Bavarian Nordic generally evaluates and selects disposable products to be tested using a risk-analysis approach based on criticality of process step and a number of other factors. Leachables Testing: Regulatory authorities require that a real drug product be tested for leachables and that they be identified at the molecular level (2 8). The resulting information is used to demonstrate the nontoxicity of such substances under normal processing conditions. A panel of sensitive detection and identification methods are used for comprehensive screening and complete characterization of leachables. Total organic carbon (TOC) analysis quantifies organic leachables. Inductively coupled plasma (ICP) analysis detects and quantifies the presence of metals extracted from plastic materials. Gas and liquid chromatographies detect volatile and nonvolatile compounds, respectively. And mass spectrometry is then used to identify the actual molecule (CAS number, of each detected leachable. Compatibility Testing: The second important type of interaction study tests chemical compatibility. These tests are performed to assess the mechanical and physical compatibility of disposable systems with specific fluids and processing conditions. Objectives of chemical compatibility studies are to test mechanical resistance and physical properties of disposable systems with solutions from their users. Results from before and after contact are compared according to an ASTM standard (9). Gamma Irradiation Validation: In receiving preassemblies and presterilized components, industry end-users are effectively outsourcing work that would otherwise have been done in-house (e.g., by SIP of equipment). To validate and claim a sterility assurance level (SAL) of 10 6 for each system, single-use technology suppliers must demonstrate full compliance with ISO11137 (10). For example, Stedim Biosystems validates the SAL of 10 6 for a three-year shelflife. That vendor establishes its maintenance of sterility through routine control of product densities and irradiation dose distribution; continued trending, identification, and resistance assessment of product bioburden levels; and periodic sterilization dose audits. Performance of the irradiation process and consistency of dosing are addressed during qualification efforts at the irradiation plant. WHAT WAS LEARNED Bavarian Nordic learned a few things from this project that could help others who may be considering disposables implementation in a new facility or for a new product. First and foremost, consider your final production set-up as early as possible in development so you can then better keep product contact materials the same throughout the development phases and to final production. Also, keep in mind the specific requirements of your quality control group. These will probably include sampling strategies for raw materials, particularly if they need to be sterile; retention requirements such as temperatures; the similarity of film in actual product contact layers to that sampled; and the ratio of surface area to volume. For single-use bag systems, transfer sets, and so on, identify requirements for storage, transport, and (particularly) practical handling in aseptic production (e.g., weight and transfer into production area). Also compare media characteristics with contact layer characteristics (e.g., ph and temperature requirements) and reduce connection errors with design improvements (e.g., connector sizes and markings). When planning to use customized items, allow more time for approval processes and start-up production at the suppliers, where additional validation of specific tube tube or tube connector combinations can be needed. The six months Bavarian Nordic and its suppliers spent for this work would be considered a fast-track project. Remember to set time aside for specific operator training, necessary changes to batch documentation, and so on, to reflect that operators now have to build a process flow system anew every time by making the correct connections. For the Bavarian Nordic project, use of disposables worked as planned by allowing the company to decouple process flow design from the construction project, thereby reducing the overall project timeline. Thus, the company had extra time for process industrialization and optimization because it could move final processflow design to a later stage. The initial investment cost for this manufacturing facility was reduced compared with conventional technology, as was the cleaning validation needed. The risk of batch-to-batch carry-over is eliminated wherever disposables are used, and such systems are presterilized, which reduces preparation times. Flexibility is increased because change-over times are shorter than with stainless steel, and there is no need for shut-down. FINAL THOUGHTS Disposable production systems are here to stay, and they are actually very similar to the systems the biotech industry has been using for many years. You simply replace 316L stainless steel, welding documentation, and classic piping and valve choices with contact-layer evaluation, plastic welding integrity, tubing, connectors, clamps, and so on. Disposable systems continually improve just like the traditional systems do, and they now include solutions that were never considered just a few years ago. The only thing we can t yet imagine in disposable form is a pressurized production system but that may not even be needed. For future production projects, the industry should get used to considering the single-use solution in SUPPLEMENT MAY 2007 BioProcess International 5

5 comparison with traditional materials, and in some cases the disposables will be advantageous in cost and/or handling. Sometimes the traditional approach or maybe a mixture of both concepts will be a better choice. It all depends on your specific needs. For this project, disposables were a key factor in enabling Bavarian Nordic to achieve its objectives: a very short project timeline, a highly flexible facility for future product manufacturing needs, and minimized contamination risk. ACKNOWLEDGMENTS We would like to thank all those who were involved in supplier approval, specifications, preparation, and testing of the disposable systems used at Bavarian Nordic s new facility, as well as the operators, QA/QC, and others at the company for their continued input for improvements. Thank you also to all the partner suppliers referenced herein, particularly their applications engineering and regulatory groups. REFERENCES 1 Becker EB, Matsen J. Vaccine Production Facility Built in 11 Months: Combining Opposing Requirements for Aseptic Production and the Regulations Covering Biosafety. Gen. Eng. News 26(14) August CPMP/QWP/4359/03, EMEA/ CVMP/205/04: Guideline on Plastic Primary Packaging Materials. European Medicines Agency: London, UK, 19 May 2005; www. emea.eu.int/pdfs/human/qwp/435903en.pdf. 3 CBER/CDER. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics. US Food and Drug Administration: Rockville, MD, May 1999; 4 Q3A(R2): Impurities in New Drug Substances (Revised Guideline). Federal Register 68(68) 11 February 2003: ; ID=422&@_MODE=GLB. 5 Q3B(R2): Impurities in New Drug Products (Revised Guideline). Federal Register 68(220) 14 November 2003; ; ID=421&@_MODE=GLB. 6 Q3C(R3): Impurities Guideline for Residual Solvents. Federal Register 62(247) 24 December 1997: 67377; MediaServer.jser?@_ID=423&@_ MODE=GLB. 7 TC 194, ISO Standards Committee. ISO :2002. Biological Evaluation of Medical Devices Part 4: Selection of Tests for Interactions with Blood (Second Edition). International Organization for Standardization: Geneva, Switzerland, TC 76, ISO Standards Committee. ISO 15747:2003. Plastics Containers for Intravenous Injection. International Organization for Standardization: Geneva, Switzerland, Subcommittee D Active Standard D543-06: Standard Practices for Evaluating the Resistance of Plastics to Chemical Reagents. ASTM International: West Conshohocken, PA, TC 198, ISO Standards Committee. ISO 11137:1995/Cor 1:1997. Microbial Validation. International Organization for Standardization: Geneva, Switzerland, Corresponding author Karin Wassard is production director at Bavarian Nordic A/S, Bøgeskovvej 9 DK-3490 Kvistgård, Denmark; karin.wassard@bavarian-nordic.com, www. bavarian-nordic.com. Miriam Monge is marketing director for Stedim Biosystems; m-monge@stedim.fr, 6 BioProcess International MAY 2007 SUPPLEMENT