1 June 2006

Chemicals to Cell Culture

Biotech becomes a growing trend, aligned with traditional pharmaceutical culture

By Ellen Fussell Policastro

The drug industry is undergoing a metamorphosis as biotech firms weave themselves into the fabric of traditional pharmaceutical manufacturing practices. In fact, the relationship between the two is becoming more interdependent as big pharmaceutical companies align themselves through contracting services or acquisitions with these medicine makers of the future.

"Traditional pharmaceutical companies realize the future model is in biotech," said Roddy Martin, general manager and vice president of pharmaceuticals at AMR Research in Boston, Mass. "So wherever they see opportunities, they license using the biotech manufacturers, pulling them into partnerships so they can eventually make the transition from chemical to molecule." One such partnership is the Hoffman LaRoche pharmaceutical company, which bought Genentech, Martin said. "That acquisition was clearly to keep Hoffman LaRoche in the running for when the biotech model takes."

Biotech in a nutshell

Process development is the main ingredient of biotech firms. Durham, N.C.'s Diosynth is a manufacturer of products such as heparin, gonadotrophins, and insulin, produced from animal tissues using biochemistry. The processes themselves tend to be more expensive because you're dealing with live organisms you have to keep alive. It's a tedious process because when manufacturing those organisms, "you need to keep out foreign organisms that are detrimental to the process," said Diosynth's staff engineer and automation team leader Mike Baldauff. "You can get a virus in your media and contaminate the process. So we have to concentrate on keeping the processes sterile and isolated from any foreign organisms."

A chemical-based product may use harsh chemical processes, which may be hard for organisms to survive. "Our processes are designed to grow organisms so you can see if a foreign organism were to invade the process how detrimental to the process that could be," he said. "Instead of feeding the production cells, a foreign organism may grow without bound, consuming the nutrients intended for the host cell line."

Customizing their services based on a drug product a customer wants to produce is Baldauff's team's specialty. The team will take a protein or peptide or antibody fragment that's spliced into a cell line used to reproduce that protein, such as E-coli, picchia, yeast, or insect cell lines (NS0, CHO, NS21), in the fermentation or cell culture reactor. Protein production happens as cells naturally divide, and the amount of protein doubles. "Each cell type has different mechanisms for growth division and expression of proteins that can be used in the production of biotech products," Baldauff said.

The difference between traditional and biotech manufacturing is, instead of keeping reacting chemicals alive, "you're keeping bugs alive," he said. The E-Coli is the actual manufacturer of the drug product. "We're just feeding the insect or insect cell or bug to produce that product. The tank isn't really the manufacturer of the product. I'm not using a chemical reactor that will have chemical reactions within that reactor producing byproduct to that chemical reaction. That little bug is actually producing the drug product. We're just helping him do it more efficiently."

Challenges for drugs makers

Biotech is "definitely the model of the future," Martin said, but with significant challenges. "The amount of investment in drug products already exists in the pharmaceutical industry. That won't go away overnight. If you have the patent for Lipitor, you don't want to put new drugs on the market. But as that patent expires, they look at other molecule models to take its place. There may be a patent around the Lipitor chemical model, but ultimately there may be DNA-specific models that will go on that same disease therapy."

And the shift will continue as trends such as genetic therapy (truly personalized medicine and therapy) evolve, said Dan Matlis, president of Axendia, a Yardley, Penn.-based research firm that analyzes business, regulatory, and technology issues in the life sciences and healthcare markets. "Depending on your genetic makeup and DNA, [scientists] will be able to target specific medical treatments to address your condition," he said. "What's happening with biotech is the beginning of that, so there is going to be a shift from traditional chemical entity-based treatment in pharmaceuticals to more of a biotech/genetics based personalized medicine. That's actually starting to happen already," he said.

Steven Ferguson, division director in the office of technology transfer at the National Institute of Health in Rockville, Md., takes the concept of the relationship even further by suggesting pharmacogenomics (the study of how an individual's genetic inheritance affects the body's response to drugs) and personalized medicine "create greater interdependence between the biotechnology industry and the pharmaceutical industry- the former producing the upstream research tools that enable the latter to develop downstream products."

Ferguson believes in sharing the knowledge between the two. In fact, the relationship should grow stronger between government labs, universities, and industry in order for advances in genomic research and personalized medicine "to foster a philosophy of wide access for research purposes," he said.

With the advantages of personalized medicine becoming safer, the pharmaceutical industry could see "reduced complications due to adverse drug reaction (ADR)," he said. The relationship could also foster the possibility of reaching nearly all patient populations by "creating blockbusters for the majority responder class and the customized multi-busters for the minority non-responder and adverse-responder classes," he said.

This is the case with trastuzumab (Herceptin), a humanized monoclonal anti-body from Genentech approved by the FDA in 1998 for treating human epidermal growth factor receptor -2 (HER2) positive metastatic breast cancer (either alone or in conjunction with standard anticancer drugs like paclitaxel), Ferguson said. However, a narrow patient population (as low as 6%) hindered the development of trastuzumab as a drug. Yet developers realized trastuzumab binded specifically to the product of the HER2 gene when selectively amplified in HER2-positive patients. In this case, the future of pharmacogenomics holds great promise.

Effects on traditional manufacturing

This shift to genetic-based medicine is affecting the traditional pharmaceutical manufacturing process now because "we're starting to see combinations, not only in pharmaceutical and biotech but with pharmaceutical and medical device companies," Matlis said. Medical device companies are producing coated stents (for keeping arteries open after bypass surgery). In addition to ballooning (the traditional method of keeping arteries open), they use the coated stents, and "we're starting to see both processes coming together for pharmaceutical and medical device manufacturers," he said. "The traditional way of making pharmaceutical products, as well as medical device and biotech products, are all coming together through some of these combination products."

Companies such as Eli Lilly and Abbot Labs are already aligning themselves with these biotech companies, Matlis said. "Most medical device or traditional pharmaceutical companies are looking out of the box. They're realizing in order to survive they'll have to look at these other options. You're seeing the latest rounds of mergers and acquisitions around large traditional companies acquiring small biotech firms because they're looking for innovations and new ways to treat conditions."

Process control a driving factor

One of the essential differences between the traditional chemical molecule-driven pharmaceutical industry and protein-based biotech industry is "process control is a much bigger and important characteristic of the biotech industry. The interesting perspective is that the biotech industry opens the way for what they call targeted treatment solutions," Martin said. In traditional pharmaceutical manufacturing, a molecule could result in one drug with thousands of samples to cure a headache. But in the biotech industry, they use the DNA model and design specific drugs for combinations of genes that will be effective, Martin said. "If you have certain genes, there's a 60% chance [the biotech drug, Herceptin] will work. The basic modus operandi of industry changes from a chemical-based sample model to a set of products that are designed around specific diseases rather than just chemical interactions."

Not only is small-molecule production (traditional pharmaceutical manufacturing) a different type of manufacturing activity all together, the types of expertise are different, and the regulatory is completely different, said Diosynth's chief scientific officer, George Koch. "The complexity of the biotech products is such that the manufacturer needs to control the process very tightly because, in a sense, the process defines the product," he said. "With small molecules, one can determine the atomic coordinates of every single atom in the small molecule. That's not possible with biotech drugs. They're so sensitive to environmental conditions from start to end, you need to have exquisite control over the conditions of processing. Or you end up with a drug that's not active."

So the emphasis on controlling the process is something different from standard pharmaceutical manufacturing, Koch said. "How will our processes affect theirs? The regulatory expectation will be that the small molecule process will evolve toward biotech. There will be more regulatory emphasis on controlling the conditions of manufacturers of the small molecules. If you control your process, an organization can rely on the fact you have a higher level of assurance the product will meet its quality standards. It's based on results. If you're designing a plant to produce small molecules, the engineers will use contemporary design standards and process standards in their design of that plant. Those standards now include tight control over the process."

Pharmaceutical's future

So what does this all mean for the future of traditional pharmaceutical manufacturers? Academic laboratories and small biotechnology companies often develop end products "worthy of patent protection for commercial development and financial gain," Ferguson said. "For the pharmaceutical companies, these same products are research tools for downstream drug development. Hence, they have greater incentive to help keep these resources open to be shared." In this way, they'll be available and able to manage the time and cost of R&D for the ultimate drug products. "Greater availability also assists academic laboratories in their ongoing research," Ferguson said.

Ferguson admits there's controversy over whether "such a customized approach will require less R&D investment due to smaller clinical trials and fewer regulatory hurdles." In fact, the industry will need to resolve legal, social, regulatory, and ethical issues, he said. "On the regulatory side, the FDA has voiced its support for the role of pharmacogenomics in clinical trials and drug development and is looking at such data, when available," he said. On the other hand, "because customized drugs only cater to a narrow segment of the population, others argue that the cost of bringing such drugs to the market would disinterest small pharmaceutical companies. Some are concerned costs would be higher and only few could afford personalized medicine.

One of the things the FDA is pushing is process analytical technology (PAT), Baldauff said. "PAT is essentially using online techniques to verify you are producing your product in line with that approved by the FDA. This is in contrast to doing analytical testing to the drug after it is produced to verify it has been made to specifications." Baldauff's team is looking at ways to incorporate it into biotech processing and engineering. "Currently, we use different parameters like dissolved oxygen, phm, and conductivity, which are some typical parameters to determine if the product is being produced properly," he said.

Fast Forward

  • Biotech is at the forefront of new methods of drug production.
  • Traditional pharmaceutical manufacturers are aligning themselves with the new trend for several reasons.
  • Patents and FDA approvals are some of the challenges facing the future of these trends.
 

Biotech is Now

By Mike Baldauff and George Koch

Large drug companies have been producing biotech products for years. You could classify insulin or even Penicillin as a biotech product. In the past, those proteins may have developed by accident. Now biotech firms are engineering proteins to solve specific problems. Biotech products may be expensive to produce, but they're likely more effective because you can engineer them for a person or groups of people or cell types, rather than having a chemical drug that has a general effect. So when you go through clinical trials, you have to look at the entire health of the individual. Because biotech drugs are targeted, we can produce them in much smaller quantities to be effective.

In producing a biotech drug, you're targeting a specific cell type of ailment. It's not just a chemical that can affect the entire body. Using biotech speeds the clinical trial process and FDA approval. A traditional pharmaceutical drug could take up to 14 years for approval, whereas it could only take 7-10 years for a biotech drug to reach the marketplace because it's engineered for a specific ailment rather than just having a chemical reaction with all the cells in your body.

Some of the older more conventional drugs, such as aspirin, are based on small molecules. The biotech drugs are much larger molecules, sometimes 1,000 times as large, and they're proteins, sometimes the actual protein your body normally makes. With biotech, we can now see the genes that make up the human body. We know how those genes are affected by different types of drugs, so we can engineer specific proteins to target those genes. Some biotech drugs are given to patients to remedy a deficiency in that natural molecule, insulin for diabetes, and human growth hormone, for children of short stature.

Our contribution to that effort starts with putting the natural gene inside a cell and growing up those cells, and while those cells are growing, they'll express that gene in the form of a protein. Then we'll isolate that protein from the mixture, purify, and prepare a bulk solution from the protein. We purify and deliver to people who hold the contract, the virtual biotech company or large pharmaceutical company or whoever has hired us. They take responsibility after that for putting it in vials and distributing it to customers, such as pharmacies.

About the Authors

Mike Baldauff is staff engineer and automation team leader at Diosynth in Durham, N.C. George Koch is Diosynth's chief scientific officer.

RESOURCE

Biotech usurping some traditional processes
www.isa.org/link/bioprocess