High-purity skids

1st April 2013

Pompe disease is a rare and fatal muscle disorder that affects an estimated 5000–10000 people worldwide. In its infantile form the disease is usually fatal before 12 months of age due to heart failure and respiratory weakness.

Based in Cambridge, Massachusetts, USA, the biotechnology drug company, Genzyme has focused its talents on the development of therapies for a number of difficult diseases. One such disease, known as Pompe disease, caused by a deficiency of an enzyme. This enzyme is responsible for breaking down glycogen into glucose within the cells.

Glucose is a major source of energy for the body; it is stored in the form of glycogen and later released with the help of enzymes. Without the proper function of this enzyme, the glycogen is not broken down but continuously accumulates and disrupts the normal functions of the cell. In muscle tissue (primarily in muscles involved in respiration), this eventually causes the cells to become dysfunctional and die.

Manufacturing recombinant enzymes, such as rhGAA, to treat Pompe Disease, is a highly complex and time-consuming process. The manufacturing process involves cultivating millions of living mammalian cells under carefully controlled conditions within sophisticated vessels called bioreactors. These cells are engineered to produce high levels of the desired human enzyme. Over the course of several months of cell culture, the enzyme is harvested from the bioreactor, highly purified, tested for quality, and prepared for administration to patients. When companies such as Genzyme first begin manufacturing these enzymes, they first develop the process on a small scale within a small bioreactor in order to refine and optimise it, before moving on to a larger scale.

When Genzyme needed to produce this enzyme in larger quantities to meet the needs of clinical trials, it turned to ITT Pure-Flo Solutions Group (PFSG). The Pure-Flo Solutions Group is part of ITT’s Engineered Process Solutions Group (EPSG) and is dedicated to serving the biopharmaceutical industry with high-purity products including hygienic valves, piping, vessels, process modules, skid systems, and architectural and custom fabrications. Within PFSG, the expertise of the Pure-Flo Cotter unit is in the development of packaged high-purity skid systems for the biopharmaceutical industry.

Genzyme, is currently conducting two clinical trials to evaluate the use of the rhGAA enzyme to treat infantile-onset Pompe disease. The program is currently the largest and most advanced research and development initiative at Genzyme.

As Genzyme develops the treatment for Pompe Disease, the drug compound goes through a number of rigorous phases for testing. Phase 1 in the development of a new biopharmaceutical compound is dedicated primarily to toxicology. Phase 2 is focused on treatment efficacy. Phase 3 is an expansion on phase 2 – and a company such as Genzyme would normally enroll more patients to complete the trials.

As a matter of policy, once a patient is enrolled in a Genzyme drug trial, treatment does not stop once the trial is over. In the case of Genzyme, the move to phase 3 clinical trials meant that the production of rhGAA needed to be scaled up quickly. In a typical phase 3 study, a drug is tested in several hundred to several thousand patients. This large-scale testing provides the company and the regulatory agency with a more thorough understanding of the drug’s effectiveness, benefits, and the range of possible adverse reactions.

To meet the aggressive production schedule set by Genzyme, Pure-Flo Cotter designed one ultrafiltration (UF) skid and two chromatography skids. The production of the ultrafiltration skid was performed at Pure-Flo’s Cotter facility in Danvers, Massachusetts and Pure-Flo’s MPC facility in Kenosha, Wisconsin.

The most critical delivery of the three skids was the UF skid. One of the unique features of this skid is that it was going into an existing building with small entryways. As a result, the structural frame for the skid had to be built in four separate sections that could be disassembled for installation. This also required creating air line transfer panels so the skid could be easily disassembled. The ultrafiltration skid is used in the downstream phase of the drug production. The two chromatography skids are also employed in the downstream process after the fluids from the bioreactor are decanted. The fluid goes through a series of chromatography steps where the proteins are separated by affinity until they are very concentrated and ultrapurified.

According to Michael Tanner, Operations Manager at Pure-Flo Cotter: “Pure-Flo has a multi-site fabrication capability and these sites work together to ‘pool’ resources to meet customer requirements. The customer sees the benefit of our collaboration in reduced delivery time.”

Genzyme and Pure-Flo reviewed options to meet schedule and agreed to have two skids mechanically fabricated at Pure-Flo’s Wisconsin facility. This cut several weeks off of the final skid delivery.

Phase 3 studies typically last several years. Once a phase 3 study is successfully completed, a company can request marketing approval for the drug from the US Food and Drug Administration.

As noted by Henry Fitzgerald, Vice President, Facilities Operations for Genzyme, “the median survival age for a person afflicted with Pompe Disease in the infantile form is about nine months, so scaling up to larger scale production is an incredibly important step”. Continuing, Fitzgerald said that, “Pure-Flo Cotter is not just delivering a skid, but making a skid that is affecting people’s lives.”

Tanner noted that: “Pure-Flo worked very closely with Genzyme to exploit every possible opportunity for schedule reduction and to streamline the approval cycle and to minimise change orders. Fitzgerald said that Pure-Flo Cotter has provided ‘many, many skid for us over the years’. While there are many companies in this business, Fitzgerald notes: “Pure-Flo Cotter has certainly excelled and we are incredibly grateful for their efforts on this job.”

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