Since its founding in 1981, Genzyme Corp. has prided itself on a strong base of innovation (Box, below). The company now has over 70 facilities operating in over 30 countries, including 17 manufacturing plants and nine genetic testing laboratories, and a technology platform that encompasses protein, cell and gene therapies, monoclonal and polyclonal antibodies, genetics, small molecules, biomaterials, therapeutic polymers and rapid diagnostics (Box, below).
Approved for commercial production by the FDA in 1996, Genzyme Corp.’s Allston Landing Facility in Allston, Mass. is one of the largest cell-culture manufacturing plants in the world. The 185,000-sq.-ft. plant, which produces orphan drugs for rare diseases, employs 400 people. It first began producing Cerezyme, an enzyme replacement therapy for Type 1 Gaucher disease, in 1996. Today, Fabrazyme, an enzyme replacement therapy for Fabry disease, and Myozyme, an enzyme replacement therapy for Pompe disease, are also made at the plant.
Increasing manufacturing capacity by 50% in 2005 allowed for additional simultaneous cell-culture and purification, and the plant currently boasts a 12,000-L perfusion capability. Although the facility has no formal Six Sigma or Lean initiatives under way, its management is committed to a continuous improvement program that uses tools from both methodologies, selecting those that are most relevant to each specific stage of manufacturing and quality control (QC).
Utilizing detailed process mapping and cycle time analysis, manufacturing professionals at the plant have eliminated nonproductive steps, says Frank Byron, vice president and site manager at Allston. Meanwhile, both manufacturing and QC teams analyze first-pass yields and corrective and preventive actions (CAPA) to prevent any deviations. The facility is now investigating rapid microbiological analysis, Byron says, as well as implementation of a new finite scheduling system, which he believes will optimize and integrate its production and maintenance scheduling technologies.
At Allston, employee-directed cross-functional improvement teams use tools that include statistical process control charting, statistical analysis on process variables and a process data historian that captures key process variables, to analyze process trends. Trend data are distributed to all via an interactive intranet system, Byron says, and plans call for an integrated process monitoring system to be installed at the plant in the future.
QC Walks the Line
QC is key to operational excellence at the Allston facility, and the typical validation run for any product at the facility averages 100 days.
Media preparation, the first step in the manufacturing process, results in nutrient solutions that help support cell culture operations. In order to keep cultures productive, 50,000 liters of media must be supplied weekly. While sterility is of utmost importance at each step in the manufacturing process, it is particularly critical during media preparation, since any contamination may interfere with protein synthesis. Genzyme uses automated processes to manufacture over 30 varying forms of buffer solutions; raw materials are dissolved with water in mixing vessels and media conditions then adjusted appropriately. “Critical data points such as temperature, density and overall process quality are monitored continually,” explains Andrew Croteau, associate director of QC microbiology.
The importance of process safety and process control cannot be overemphasized during production, says Croteau. “From the time you design a facility like this, you have to think about safety mechanisms, and the varying safety hazards here.”
For instance, there are very strict safety programs such as HAZCOM training to avoid accidents involving high pressure systems, hot-water injection fluids running at 80° C or higher, caustics or bacteria infiltration. “Everyone here, from scientists to manufacturing administrators, is required to go through multiple hazard and technology programs to update our precautions continually,” he points out.
Using CFD to get inside a bioreactor
Genzyme’s bioreactors have been designed and validated for multipurpose functionality; this is supported by diligent monitoring and QC.
Nearly one million gallons of bioprocess fluid and growing cells flow through Allston’s six-gallon stainless bioreactors each year. To better understand what is going on within these reactors, Genzyme plans to use computational fluid dynamics (CFD) to model the cell-culture process.
Multipurpose functionality guides manufacturing, and the bioreactors have been designed and validated so that they can be used to manufacture different materials. A delicate system of checks and balances is at work, Croteau explains. “The bioreactors are dedicated at any one time to each particular drug, however, upon validation we are able to make other products in the same bioreactor,” he says. “We do have to prove that we are able to clean the equipment as required between runs, but we have a very concise system of operations that allows for multipurpose functionality.”
In the case of the enzyme replacement therapy for Fabry disease, Fabrazyme, the CHO (Chinese hamster ovary) cell line was chosen because it is less vulnerable to contamination by human viruses than cells of human origin. Production begins with genetic modification of a host cell to produce -GAL from human DNA. The human gene is isolated, spliced into a bacterial plasmid, and inserted into the CHO host cell in the seed lab. Genetically modified hamster ovary cells are used for Cerezyme and Myozyme as well, and stored in this facility.