August 1, 2006 (Vol. 26, No. 14)
Combining Opposing Requirements for Aseptic Production and the Regulations Covering Biosafety
Aside from being established in only eleven months, Bavarian Nordic (www.bavarian-nordic.com) views its new vaccine facility as unique because its design and technology combine the opposing requirements for aseptic production and biosafety regulations. The cGMP and biocontainment facility produces 40 million doses or more a year of smallpox vaccine with novel solutions to some of the problems associated with genetic engineering production, according to the company.
Bavarian Nordic previously had limited production facilities but when it bid on a U.S. government contract to supply millions of doses of its third-generation Imvamune smallpox vaccine, quickly increasing manufacturing capacity became necessary. Bavarian Nordic will now invest $45 million to establish its own 9,000-m2 vaccine manufacturing facility in Kvistgaard, north of Copenhagen.
The engineering company, NNE (www.nne.biz) was enlisted to assist in site-selection, feasibility studies, and a conceptual design for the facility. NNE supplied the experience necessary to design genetic engineering production facilities and manage building, installation, and commissioning.
“The speed of the fast-track project was essential to our company. We are participating in the U.S. government’s Department of Health and Services’ program to develop a safe smallpox vaccine based on the modified vaccinia ankara (MVA) virus. A fully operational vaccine facility improves our position in the competition,” says Karin Wassard, production director at Bavarian Nordic.
“Upon completion of the basic design, the companies quickly decided to decouple the construction of the production facility from the detailed process-equipment design to optimize the time schedule and increase flexibility,” adds Mette Bregendahl, engineering manager at NNE.
The cooperation between the two companies extended to the joint selection of suppliers and equipment. NNE prepared the detailed design and managed the construction of the facility, as well as the project management.
Bavarian Nordic concentrated on process development, contact with U.S. stakeholders, organizational development, final decisions on the major aspects of the project, and equipment. Bavarian Nordic staff also worked with NNE to test the critical process equipment.
The 11-month project, from detailed design to handover (which normally takes 24-32 months), is especially noteworthy considering the size and classification of the cleanrooms, as well as the level of complexity in the parallel phases of the construction project, points out Wassard.
The facility is designed for Bavarian Nordic’s MVA-BN production process, which has special sterility and biocontainment requirements. Generally, these requirements often oppose one another; GMP is based on the concept of keeping contaminants out, whereas bio-containment is based on the concept of keeping product in.
“Sterility requirements stem from several factors,” explains Wassard. “MVA-BN is a live virus and must remain both live and sterile in the bulk and final product stage if it is to generate an immune response in vaccination. The product cannot be sterilized by heat treatment because it would kill the virus. Filter sterilization is also not possible due to the large size of the virus (>0.2 um). Thus, sterility could only be ensured if the entire production process was completely sterile.”
This necessity impacted the level of cleanroom classification. The facility includes cleanrooms that are three times the size of industry standards and meet or exceed both FDA and EU standards for complianceU.S. 10,000/100=ISO 7/5 and European class B/A.
“Biocontainment requirements for MVA-BN call for a BioSafety Level-1 (BSL-1) facility,” adds Wassard. However, to ensure flexibility and maintain the possibility of producing other products in the facility at a later date, it was decided to build to comply with BSL-2 requirements. To offer more flexibility, the facility can meet BSL-3 regulations with minor modifications.
“Biocontainment requirements mainly affected the design of the ventilation systems in the areas where the virus is produced and the handling of waste from virus production. The ventilation system for the virus production area was kept as a separate system designed to provide a pressure barrier around the area, says Bregendahl. “Inside the production area, a ventilation system supports the overall sterility of the cleanrooms by providing different levels of air pressure between individual production areas, hallways, and airlocks. In addition, ventilation exhausts are equipped with HEPA filters to ensure that the virus is not released to the external environment.”
It was also decided to include a waste-inactivation system for liquid virus process waste. Virus waste is inactivated through heat, then cooled and neutralized to a pH value suitable enough for discharge into the public sewage system. Similarly, disposable materials and other solid items are heat inactivated before removal or cleaning for reuse. After inactivation, solid waste is accepted by the local county authority as normal industrial waste.
“On the process side, the original idea was to use standard, stand-alone equipment that met the requirements for CE approval for use in the E.U., which could also be combined with presterilized disposable materials. This allowed for the de-coupling of the process flows from the construction of the facility,” says Wassard.
“Another advantage of disposable materials is the ability of the facility to change to the production of other MVA-based vaccines or vaccine products in the future,” adds Wassard. “In this case, disposable items would simply be replaced while cleaning validation for rooms and permanent equipment would be performed. If a different production process is decided upon in the future, permanent equipment can be changed, removed, or added.”
Sterility requirements for the production process included specific requirements for steam sterilization of equipment. This precluded the use of some standard equipment, and in other cases some of the standard equipment did not have CE approval. This was overcome by requiring equipment suppliers to find ways of improving their technologies to allow for steam sterilization. In addition, NNE helped them in the CE-approval processes.
Bavarian Nordic decided not to implement an overall data-collection system and process-control system because of the time needed for validation. Everything except for process utilities is controlled and recorded in the master batch journal or by local data-collection systems at appropriate locations in the production process, with a possibility for inclusion later in an overall data-collection system.
The production facility has been granted local and national environmental approval and E.U. authorization for performing quality control analysis and release of sterile vaccines. Danish governmental authorities are expected to grant final authorization for manufacturing of pharmaceutical products later this year.