Why Is Biomanufacturing So Hard?

Earlier this year, the Cambridge-based biotech firm Genzyme announced the latest in a series of manufacturing delays for Fabrazyme, a biological drug that treats a rare genetic disorder, after one lot of the drug was found to be contaminated. The news followed a more severe setback in 2009, when both Fabrazyme and another drug were contaminated with a virus; the problem closed the manufacturing plant and created major shortages.

Genzyme isn’t alone in these issues. Biologics—drugs made through a biological process rather than chemical synthesis, a category that includes recombinant proteins, vaccines, and antibodies—are the fastest-growing segment of the pharmaceutical industry. In 2008, nearly 30 percent of revenue from the top 100 drugs came from biologics, a figure that is expected to rise to 50 percent by 2014.

But the same factors that make biologics powerful drugs also make them a challenge to manufacture. They typically mimic proteins and other molecules found in living organisms and can target harmful entities, such as some cancer cells, with great accuracy; many of the most promising new drugs for cancer and other diseases fall into this class. Biologics tend to be larger, more complex molecules than drugs synthesized through chemical reactions, which adds to production challenges and makes them costly. A single dose of some biologic therapies can cost $10,000.

Biologics are most often produced by cells growing in a bioreactor, a vat designed to maintain carefully calibrated conditions. Because the cells are alive, “every time you run a reactor, the result can be a bit different,” says Chris Love, a chemical engineer who is part of MIT’s Biomanufacturing Research Program. This inherent variability makes the process both expensive and unpredictable.

Another issue is that for biologics to win approval from regulatory agencies, it’s not enough for the drug itself to be approved, as is the case with small-molecule drugs; the manufacturing procedure must be approved as well. While this is important for safety’s sake, it also makes it costly to change the production process after it’s been approved, and that discourages innovation. “By the time the drug is in the marketplace, you are working with old technology,” says Charles Cooney, a chemical engineer at MIT. “You have to lock in the technology many years before launch of a commercial product.”

And even when developing experimental drugs, makers tend to stick with methods that have previously been proved safe. As a result, new advances in systems biology and microtechnology have not been integrated into biomanufacturing, says Love.

He and other researchers hope to change that by making biomanufacturing more predictable. One of Love’s goals is to make sure the cells that produce these expensive drugs are as productive as possible, which should bring costs down. To do that, researchers take advantage of the natural differences in productivity among cells. They foster mutations to create genetic variability and then use microchips to analyze the behavior of individual cells, choosing the most prolific for larger-scale production.

A second major challenge in biomanufacturing is ensuring the quality of the drugs, which is complicated because protein-based drugs must fold into a three-dimensional shape and must have the appropriate chemical tags. And because these drugs are produced under conditions favorable to microbes, they can be infected with viruses. “Many mistakes are made because we don’t have the right analytics to measure the product or process,” says Cooney. “Manufacturing sits on a critical path between science and the patient and should be integrated into the continuum of drug development. I think most companies know they need to invest early on in manufacturing, but they don’t put enough effort into process development early on.”