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Biotech Drug Developers Open New DoorsDemands for quick response, high quality, and FDA validation are driving innovations in the design of biotech research labs.by Tim Studt
Tempered glass swing showcase lab doors are easy to clean and sterilize. Source: Terra Universal | The biotechnology-based drug development community is populated by a few large organizations like Amgen, Genentech, Biogen Idec and a large number of smaller organizations. The large biotechs are similar to large pharmaceutical companies in that they've been in business for more than 25 years and have long- and well-established research, development and production organizations and associated facilities that are supported by multiple lines of successful (and patented) biotech products. At the same time, the larger biotechs are often burdened with an infrastructure that may not be as up to date as they would like it to be.
The small biotech firms are just that—small, with limited resources as they establish the acceptance of their more limited line of products and work to expand their research and build their production capabilities. Both types of organizations require similar levels of research, quality and production capabilities for each product. They both require similar types of analytical tools and similar levels of process, operational and validation requirements. For the smaller firms, those requirements may often appear to be overwhelming when faced with more limited financial and technical resources. Satisfying those requirements, then, requires innovative and creative design approaches, especially when designing and building the facilities to house and showcase their operations.
For Epeius Biotechnologies in San Marino, Calif., “we wanted to create a single-product-dedicated research and production facility that would bring biotech manufacturing into the 21st century,” says Frederick Hall, president, CEO and co-founder of Epeius.
Epeius Biotech is a privately held biopharmaceutical company that's focused on the development and commercialization of oncology-based products and tumor-targeting gene delivery systems. Epeius is a spin-off from a Univ. of Southern California, Los Angeles, incubator with several USC investors. It's leading oncology product, Rexin-G, is designed to seek out metastatic cancers and deliver a selective and highly active genetic payload against a broad spectrum of chemotherapy-resistant tumors. Rexin-G was granted Orphan Drug Status by the U.S. Food and Drug Administration (FDA) for pancreatic cancer in 2003. The following year, Epeius obtained the licensing rights for core molecular biotechnologies from USC and for retro-vector tumor-targeting systems from BioFocus, Saffron Walden, UK.
Epeius' multiple suite stainless steel BioSafe facility with gowning room has adjacent BSL-2 clean rooms. Source: Terra Universal | Rapid advances in clinical development provided Epeius with the opportunity to generate revenues starting in 2006 from the export and sale of Rexin-G to The Philippines and other Southeast Asian countries. In 2008, Epeius again obtained FDA Orphan Drug Status approval for two additional cancer indications and formed a strategic alliance for commercial production of Rexin-G.
The design, development, and construction of the Epeius' production facility has become an integral component of the overall Rexin-G story and serves as a guide as to how small biotechs can develop the capabilities to successfully manufacture new biological drugs.
“Frederick Hall is quite the evangelist of drug development on a small scale that allows tight cost controls, rapid development, independence from the politics and delays of big pharma, as well as quality and efficiency,” says Mike Buckwalter, publications director for Terra Universal, Fullerton, Calif. Terra is a strategic partner with Epeius.
Hall's vision for his production facility had three components:
1 – He wanted a facility that could support current and potential future GMP protocols for sterile drug manufacturing that met Epeius' specific functionality requirements and exceeded FDA validation requirements.
2 – He also wanted a facility that utilized the modularity of Terra's existing cleanroom designs to make modifications and refinements as the final design proceeded. An over-designed facility was conceived to the maximum performance limits which were then balanced against acceptable economics.
3 – And finally, says Buckwalter, Hall wanted “a physical, visible, and palpable embodiment of the engineering sophistication that went into his development of Rexin-G. He wanted a facility that would reflect a literal landscape of the elegant molecular design engineering.”
Designer Gene Targets TumorsScientists at Epeius Biotechnologies in San Marino, Calif., are primarily focused on the development and manufacture of Rexin-G, an injectable genetic medicine that is targeted at metastatic cancer tumors, while avoiding the toxic side effects of conventional chemotherapy treatments. Rexin-G consists of tumor-targeted nanoparticles that are programmed to deliver tumor-killing designer genes to high levels in tumors. These lethal gene constructs are dominant-negative (dn) constructs of the human cyclin-G1 gene, a pivotal cycle-control element. The capsule containing the dnG1 gene is based on a murine retroviral core devoid of viral genes and which has been rendered certifiably replication incompetent, or capable of delivering a therapeutic gene once and only once. The tumor-targeting function allows it to penetrate both primary and metastatic cancers, as well as cancers within the lymphatic system within hours. Rather than targeting the cancer cells themselves, Rexin-G targets a common histopathological property of all invasive tumors. This pathotropic targeting allows Rexin-G to seek out and destroy tumors regardless of their location in the body, thereby reducing the tumor burden, prolonging patient survival, and enhancing the patient's quality of life. Each Rexin-G nanoparticle is about 100-nm wide, while containing a complex structure that contains an envelop, matrix, capsid, enzymes, and genetic material that work in concert to selectively kill cancer cells and their associated blood supply. Once injected into the blood stream, the nanoparticles are partitioned into the tumors within hours. The therapeutic genes delivered to the cancer cells and their proliferative neovasculature acts over the next 24 hours to induce active cell death, which is seen as degeneration, anti-angiogenesis, and necrosis within the regressing tumors. The therapeutic genes are deliverable to dividing genes only, sparing normal blood vessels, tissues, and organs, thus focusing the effects and improving patient safety. | |
Initially, Hall sought advice from FDA lab consultants, before deciding to work with (and extensively modify) the Terra modular design. Following three years of design and six months of fabrication the results are shown in part in the accompanying pictures.
The resulting Epeius production facility is a modular 500-m2 stainless steel and glass laboratory sitting in a 4,000-m2 hanger-like free-standing facility in Carlsbad, Calif. The lab floors are seamless epoxy and the lab ceiling is 3.5-m tall. There are BSL-2 areas, negative pressure containment in most processing areas, and division of the lab facility into two separate production suites—one for Rexin-G and another for scale-up future products such as tumor-targeted vaccines.
Unlike other conventional modular labs, the double-walled stainless steel and glass modular cleanrooms designed and constructed for Epeius are completely free-standing structures with the inherent rigidity and durability one expects from a free-standing type of construction.
“Implementation of a project this complex is always a process of discovery,” says Terra's Buckwalter. “Success hinges on the ability to accommodate change. Our BioSafe Clean Rooms are now very different structures from their original design as a result of our work with Hall and Epeius.”
“We had a perfect partnership with Terra,” says Hall. “They had a keen sense of our mission.”
Hall likes to refer to his design as having the economy of an instrument. “It's like having a UL-type certification,” he says. “The modularized arrangement is like a plug-and-play instrument.”
The modular design allows the incorporation of many features that would normally be considered complex and expensive options with other rigid structures, while the dedicated space allows for faster FDA validation. “We know where all our electrical connections and lines are,” says Hall referring to the electrical panels that are built into the double-envelope stainless steel walled structure.
The mostly stainless steel and glass construction materials also are suited to the production of biological products. These materials are rugged enough to be entirely UV-sterilized, while all the stainless steel is treated to be antibacterial. There are also ports for hydrogen peroxide for additional sterilization capabilities. “The controlled environments in the dual structures allows it to be simple and overbuilt at the same time,” says Hall. “The sterilization capabilities also make it an order of magnitude cleaner than it needed to be [for FDA certification].”
The design also exudes an aura of technology, with numerous touchpad controls, clean room gowning areas, large open spaces and tall ceilings, and the knowledge of the type of cancer-fighting biologics being researched and produced behind those walls.
Hall also points to the elegance of the stainless steel and glass design, noting that while it was designed primarily as a facility for the production of cancer drugs, it also serves very well as a showcase for Epeius investors, FDA inspectors, potential collaborators, and prospective scientist-employees. The ability to see through to every corner of the facility from the outside provides visitors with confidence as to the high level of biological research and production being performed.
In the end, the dedicated modular production facility created for Epeius followed a faster development cycle than could be done for a conventional production facility design. The developers believe that this type of design can be franchised for other biotech organizations. It allows the biotech firms to compress their development cycles, keep their capital investments at a minimal level (that might have killed some small biotech programs), and bring their innovative products to the marketplace faster. This design approach also allows small biotech firms to bring their products to the commercial phase without relying on the resources or control of a major pharmaceutical backer. The molecular design and operations of the facility serves as a flagship for Epeius to globally expand its biopharmaceutical operations.
As noted by the FDA regarding Epeius Biotechnologies' state-of-the-art production: “The progressive R&D program and implementation of significant improvements in Rexin-G BioManufacturing Protocols is in accordance with the basic needs of the cancer patient and in harmony with the 'Critical Path Initiatives' outlined and encouraged by the U.S. FDA. In this regard, the general mandates for 'Moving BioManufacturing Into the 21st Century' are met by (i) the adoption of new technological advances, (ii) accommodations of significant innovations in manufacturing science, (iii) reduction of product variability, and (iv) incorporation of scalable, aseptic, single-use, and disposable technologies.” Clearly, Epeius and Terra have followed these criteria.
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