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01 March 2003

Batching 'blockbuster drugs'

Building better batches one genome at a time

By Ellen Fussell

The term "designer drugs" might conjure up images of an elusive futuristic time—out of reach by today's standard pharmaceutical processes. But thanks to biotechnology, the reality isn't all that far-fetched. Scientists and drug manufacturers are closer than some might think at building designer, or custom, drugs. And they're getting closer to reining in the heretofore elusiveness of one-to-one health care.

The idea stems from the Human Genome Project, begun in 1990 to identify and map all the genes in the human body by 2005. The project promises to locate the estimated 100,000 genes (packets of DNA) on our 23 pairs of chromosomes to help scientists better understand the genetic code and thus build drugs to help cure diseases based on this knowledge. (For more information, visit the National Human Genome Research Institute at www.genome.gov.)

Take a devastating disease such as breast cancer. "In the traditional pharmaceutical paradigm, scientists would develop a drug, and after it was approved, manufacturers would give out thousands of samples to doctors to distribute to their patients. It was hit and miss" as to whether the drug would work, said Roddy Martin, vice president of industry strategy at AMR Research in Boston.

Now, a biotech research company called Genentech has developed a drug for breast cancer: Herceptin. "If you have breast cancer and you have a certain type of gene, there's a 40% chance the drugs will work," Martin said. "But if you don't have that gene and have breast cancer, the drug won't work at all. The drugs that will come about as a result of the genome model will help us understand the nature of disease or even cure or change the nature of disease—it won't just take the pain away. That's why it's such a breakthrough."

Human Genome Project The U.S. Human Genome Project was begun in 1990 by the U.S. Department of Energy and the National Institutes of Health. The main goal is to identify all of the approximately 30,000 genes in human DNA and determine the sequences of the 3 billion chemical base pairs that make it up. Ultimately, the project hopes to help doctors and researchers more effectively cure diseases through a better understanding of how drugs interact with certain genetic makeups. Researchers are also studying the genetic makeup of nonhuman organisms: the common human gut bacterium Escherichia coli, the fruit fly, and the laboratory mouse. Latest news on the project A team of French and American scientists has completely sequenced chromosome 14, eliminating gaps and inconsistencies in the draft sequence of the human genome published in February 2001. This makes the fourth and largest human chromosome finished to the Human Genome Project's standards. Others completed so far include 22, 21, and 20, published in December 1999, May 2000, and December 2001, respectively. In addition to the 506 genes already known to exist on chromosome 14, the research team at Genoscope, France's National Sequencing Center, identified 344 more genes. Two genes linked to chromosome 14 play important roles in the immune response. Researches have associated about 60 genes on this chromosome with a variety of genetic disorders: early-onset Alzheimer's, leukemia, Graves' disease, spastic paraplegia, and ovarian cancer. Source: Oak Ridge National Laboratories (www.ornl.gov)

CHALLENGES AHEAD

The challenge for manufacturers of biotech drugs will be accommodating the constraints of time and science. Unlike the old pharmaceutical model, building around a process and packaging a drug, biotech drugs require fermenting with biological reactions and reagents. "It's like a brewing process—you can't predict how it will behave," Martin said. Manufacturing plants are set up for chemical modules, but it's difficult to build to biotech space because it's a biological process. It requires science on the shop floor. That's the challenge for process engineering in the future."

Another challenge is finding communities of people with a certain gene makeup, "so there's another problem with making drugs for individuals' [one-to-one health care]," Martin said. "It's one thing to find the individual, but to make it economically justifiable, you have to find a community of them."

Finding communities to match a certain genetic makeup is also precluded by the constraints of the Health Insurance Portability and Accountability Act, a federal act to streamline industry inefficiencies and detect and prosecute fraud and abuse. It also includes standards for privacy of an individual's health information and medical records.

"If you're developing a cure for something as common as a migraine, and you can establish a big community with a common denominator, then you can solve the problem at a higher level," Martin said. "But as you get to these highly specialized diseases, you can only identify the nature of the disease using the human genome model, and it's more difficult to find that community."

BIOTECHS WORKING WITH MOLECULES

At Vacaville, Calif.-based Genentech, scientists are conducting clinical trials using batch fermentation and batch recovery facilities. Biotech drugs are developed from a cell that's modified, "and we grow the cell to a certain level [until] we have enough to make a particular drug," said Hans Koning Bastiaan, Genentech's associate director of process automation. The drugs are modified to make a specific protein. So "even though these molecules are identified, there are billions of them, and I need to test them," Bastiaan said. "That's what the research is all about—figuring out how those proteins and molecules react with other compounds and how they can fight disease."

Even so, controlling the processing and collecting information is a big step in the success of biotech drugs' batch manufacturing process. Between the efforts of ISA's SP88 Batch Control standards committee and the World Batch Forum, Bastiaan said he believes control will come easier. "There won't necessarily be more automation but more control over the process," he said. "I think a big part of [control] is collecting useful data and information and knowing what to do with that information."

BATCH CONTROL PERSPECTIVE

One batch automation supplier that's reaping the benefits now of such information gathering is Honeywell in Phoenix, Ariz. The company has dedicated an entire organization to the life sciences market, with a sales force, product managers, and development teams to build key compliance features (such as tracking electronic signatures to comply with the 21CFR11 standard), integration, manufacturing execution systems, batch automation, and revision management into their products.

"The basic difference between traditional pharmaceuticals and biotechnology is that small molecules are used with traditional pharmaceuticals, and the larger molecules are used with biotechnology," said Mary Carpine, global marketing manager for Honeywell's life sciences division. The biotech batch process is an inoculation process where initial cell growth occurs. Then comes the purification and recovery process. After that it goes into labeling and distribution.

The biotech process is more complicated than a traditional batch process because it requires more manual actions integrated with automation. "It's actually manufacturing larger molecules that makes it more difficult. There are so many more things that can go wrong with the large molecules," said Pamela Mars, Honeywell's batch product manager. "In traditional batch manufacturing, you're adding more ingredients and chemicals. With large molecules, you're growing. It's more difficult to grow a batch, and it takes longer," she said.

And time is actually the biggest drawback in biotech drug processing. "There's a long cycle time in a chemical process; your batch may take hours or days," Mars said. "And in a cell growth process, a single batch may take weeks to grow." That leaves more stages in which something could go wrong, she said.

Yet the upside is the fact that it's a growing market. "So there are a lot of drugs being developed that require this type of manufacturing," Carpine said. Plus, there's a greater ability to patent the drugs, which gives them a higher margin. In the traditional pharmaceutical realm, there are so many drugs whose patents are expiring, she said. "So they're looking to invest in these blockbuster drugs." IT