Manufacturing a drug therapy--one patient at a time

FIG. 1. THE INSULATED, REFRIGERATED CONTAINER FOR MOVING PROVENGE BACK TO THE PATIENT. credit: Dendreon

Fig. 1 is not particularly impressive to look at—a corrugated cardboard box, with a label saying “Medical Shipment” on it. But it represents a revolutionary step in pharmaceutical commercialization and personalized medicine: the delivery of genetically manipulated cells, from a prostate cancer patient’s own blood, shipped to a manufacturing plant, and then shipped back for infusion in the patient. Dendreon’s Provenge (sipuleucel-T) treatment, regulated as a drug by FDA, is one of the first instances of personalized medicine to reach the market. The company generated $228 million in 2011 with the product, which had been approved in the first half of 2010, which, as CEO Mitchell Gold, MD, puts it, places Provenge “as one of the top 10 product launches in oncology.”

Stock-market watchers would note that the company underwent a severe downturn in August 2011, when it announced less-than-expected revenue growth; however, the product’s market has grown throughout the entire period, and the company’s CFO expects “modest quarter-over-quarter growth” going forward, while it works on cost-reduction programs.

Robert Poulton, EVP for technical operations at the Seattle, WA, company, details the inbound and outbound logistics processes for delivering Provenge. “In my 30 years in the pharma industry, I’ve never seen a process like this—we think it’s unique, with unique challenges. But to date, we’ve had 100% success in receiving and delivering the therapy to patients.”

Robert Poulton, EVP for technical operations

Provenge, which has been called a cancer “vaccine,” makes use of the T cells in a patient’s own blood. The cells are collected from patient blood with an apheresis (centrifugation) process at the patient’s clinic. Technical assistants, who have undergone training by Dendreon, then package the T cells, and ship the package to one of Dendreon’s three US centers (California, New Jersey and Georgia).

Next flight out

“We have validated a shipping container that is utilized for both inbound and outbound shipments,” says Poulton. “It is specially designed to maintain the temperature of the cells at 2-8°C as they are shipped from the apheresis centers to the manufacturing plant. It also keeps the final manufactured cells at room temperature (20—25°C) as it is shipped from the plant to the infusion centers. The temperature is controlled with special gel packs inserted into the box to maintain the correct temperature during shipments.” Generally, the shipments travel with courier services on a next-flight-out (NFO) basis; Poulton says that the inbound shipment has a tight, 18-hour deadline from the apheresis center to entering the manufacturing process, and a similar time frame exists for the outbound shipment.

Dendreon’s proprietary genetic manipulation of the T cells involves exposing the cells to antigens that activate them to attack cancer cells. Once activated, the cells are mixed with infusion liquids, packaged, and shipped back to the patient’s clinic for reinfusion. Typically, patients require three such treatments over a four-week period.

Poulton says that the patient’s T cells are barcoded at the collection point, and this barcode system is maintained throughout the transportation, manufacturing and reinfusion process. The company could find no off-the-shelf software system to manage the tracking to its specifications, so it developed its own system, known as Intellivenge, to manage the process. Intellivenge interacts with an Oracle ERP at the company.

“When you develop any complex system like this there are learnings as you bring it forward as demand grows,” says Poulton. “In our case, we’re looking at ways to maximize the efficiency of the overall process.” One key enhancement, he says, is to improve the user interface at the oncology clinic side, so that ordering and tracking steps can be more easily followed.

FIG. 2. (LEFT TO RIGHT) MANUFACTURING BEGINS WITH PATIENT CELLS IN A TREATMENT MEDIUM; ENTERING THE WORKSTATION; AND PACKAGED IN AN INFUSION BAG FOR SHIPMENT BACK TO THE TREATMENT CENTER

Dendreon has filed a Marketing Authorization Application (MAA) with the European Medicines Agency, and expects approval in 2013. The company is lining up a contract manufacturer to handle the genetic manipulation steps within the European market. Additionally, it has several other immunotherapy products in development that follow a similar personalized medicine pathway, including a drug, DN24-02, for HER2-positive breast cancer that has entered Phase II trials.

In the early years of the biotechnology revolution, the prospect of tailoring individualized treatments to patients was questioned, in that the conventional model for pharmaceutical development focused on small-molecule formulations that could be supplied to thousands or millions of patients. But Dendreon’s success, to date, establishes a baseline for future development in the area, including such advanced-research projects like regenerative medicine. The supply chain of tomorrow’s biopharma industry will look quite different from today’s.