When biotechnology company Genzyme announced the presence of a contaminating virus at its drug-manufacturing plant in Allston, Massachusetts, in 2009, patients were told not to worry. Only a small stockpile of uncontaminated drugs existed, but the company said that it would resume production within two months.
Two years and a host of manufacturing problems later, Genzyme still cannot supply enough of its treatment for Fabry's disease, a rare and potentially lethal enzyme deficiency. Genzyme's replacement-enzyme drug, Fabrazyme, which is made at the Allston plant, has been rationed since 2009 so that patients receive smaller doses than initially recommended. And those diagnosed with the disease after rationing began are barred from receiving Fabrazyme. The restrictions understandably make patients uneasy: many see their symptoms worsening under the new dose regime, and some have started a lawsuit against the firm. In 2010, the European Medicines Agency reported that adverse events in patients with Fabry's disease had risen since the shortage, and advised doctors to prescribe the full dose again. Genzyme's stock price dived amid screams from investors, and the company agreed early this year to be acquired by Paris-based pharmaceutical company Sanofi-aventis.
The fiasco sounded alarm bells across an industry familiar with the difficulty of manufacturing biological molecules such as antibodies and enzymes for use as drugs. These 'biologics' were once the domain of speciality biotechnology firms, but are now being produced in large quantities. The number of clinical trials involving a biologic increased from 1,197 between 2000 and 2005 to almost 6,000 in the following five years. And in 2010, the drugs brought in US$40 billion in sales worldwide.
“Viruses are stealthy intruders and can lie undetected in a culture for weeks.”
But success has its price. Unlike the manufacture of small-molecule drugs, which typically relies purely on large-scale chemical synthesis, biomanufacturing usually involves massive cultures of live cells maintained in rich, contamination-prone media. Anyone who has struggled to keep a 1-litre laboratory cell culture sterile will appreciate the challenge of doing the same for a 10,000-litre reactor. Viruses are stealthy intruders and can lie undetected in a culture for weeks, while the infected cells move down the pipeline to spread the scourge through the manufacturing facility — into those 10,000-litre reactors and through million-dollar chromatography columns.
This means that viral contamination can shut down drug production for months and cost a company millions of dollars, interrupting drug supplies and leaving patients vulnerable.
At least 17 incidences of viral contamination in biologics have been reported, but industry insiders say that many more go unreported. Rather than risk negative publicity and lawsuits, companies have largely chosen to keep the details of contamination, and even their occurrence, secret — even, at times, from government regulators. Genzyme's experience, which legally had to be made public because it caused a significant drug shortage, may have only deepened industry's fears of going public. But although secrecy may make short-term business sense, it hampers industry's collective ability to learn from these catastrophes.
Down the road from Genzyme's troubled plant, researchers at the Massachusetts Institute of Technology in Cambridge are forming a consortium with industry to tackle the problem. The academic organizers hope that it will encourage greater openness and allow industry partners to divulge confidential information under the protection of non-disclosure agreements. The consortium plans to draw lessons from contamination data that could benefit the industry as a whole, and to publish answers to questions such as where viral contaminants originate and what the best way to detect and eradicate them is, or how to prevent them altogether.
These are crucial questions as interest grows in lucrative biopharmaceuticals. The answers should be able to guide research to reduce the incidence and impact of viral contamination on drug manufacturing.
At present, only six companies have signed up to participate in the study's pilot phase, and the organizers say they will eventually need at least twenty more to draw meaningful conclusions. More biotechnology companies should embrace this rare and valuable opportunity to pool resources without compromising their business interests. It could benefit patients and investors alike.