"Logjam" and "bottleneck" became popular words as the industry entered what became called the "post-genomic era" (and grew into yet another oft-used phrase). But everybody was talking about data, not drugs and that, of course, became the problem. While there was plenty of information, not much in the way of new treatments was coming out of it quickly.

Meanwhile, another logjam-type, bottleneck-oriented dilemma was rising slowly in the background, and it does have to do with drugs. Specifically, it has to do with making drugs. Or not.

The manufacturing capacity for biologics has reached almost its full capacity, loads of compounds are lined up on the approval runway, and none of the answers looks easy.

"You have to build a [new] facility, which many are doing, or improve the efficiency of your current process, or employ other production technologies, such as transgenics," said David Molowa, managing director and senior biotechnology analyst at J.P. Morgan H&Q.

"Only a small portion is done by contract manufacturing," he said.

The best solution for biotechnology companies: "Brick and mortar," Molowa said.

In considering woes related to manufacturing, the first name that may come to mind is Immunex Corp., bedeviled last year by shortfalls related to the making of its rheumatoid arthritis drug Enbrel (etanercept). As Immunex readies for a merger with Amgen Inc., the company said it had fixed the threat.

Molowa wasn't so sure.

"They're having a problem today," he told BioWorld Financial Watch. "The future is now at Immunex, and they are the 'poster child' for this [issue]."

Immunex, he noted, "keeps saying third quarter for the Rhode Island facility [to begin operating]," but the FDA has told Immunex the approval process for such plants takes four months and standards are closely monitored by regulators.

The large-scale manufacturer of protein-based therapeutics must describe the cell line created, and prove that it's not contaminated with bacteria, fungi, mycoplasm, adventitious viruses or retroviruses. Each lot of unprocessed bulk material must be tested. Once purified, it has to be proven pathogen-free, pure and sterile, and its "molecular integrity" demonstrated. The finished "filled" product is tested, too.

Manufacturers seldom pass the FDA's muster the first time around, Molowa said.

"Typically, there are deficiencies," he said. "They always pick out something."

The agency has told Immunex to expect a four-month approval process.

"That's why Amgen has more conservatively said 2003 [for startup of the plant]," Molowa said. "That's a doubling of capacity, but they will still have a problem."

A year ago, Molowa warned in a report, "The State of Biologics Manufacturing," that trouble was brewing. By 2005, the report said, manufacturing demand would exceed supply levels by a factor of at least two, and maybe as much as four.

He is updating the report, and will release the new version in a week or so. Although it has been fine-tuned somewhat, not much has changed, and the picture is still grim, Molowa said.

"The data is a little more complete and accurate," he added.

Given the manufacturing problems ahead, "delays in development and commercialization of some products" are inevitable, and "clearly, those with excess capacity will have tremendous leverage over those in need. To our knowledge, Biogen [Inc.] is the only company that will have excess capacity in the next two years," Molowa wrote.

Others have seen the impending crunch. Peter Ginsberg, senior research analyst with US Bancorp Piper Jaffray, issued a report in January, "The Road Ahead for Biologics Manufacturing." The road, Ginsberg predicted, will be rocky for some companies.

With 99 protein-based therapeutics in Phase II and Phase III trials (and six recently approved), Ginsberg estimates at least 34 new biologics will be approved and launched over the next several years. The required mammalian cell culture-based manufacturing capacity, given these new drugs combined with products already on the market, will be 940,000 liters by 2005 going into 2006.

Current capacity is about 413,000 liters, and 938,000 liters will be added by 2005-2006, an increase of more than 200 percent "driven largely by significant investment from the biotechnology sector, rather than by traditional contract manufacturers," Ginsberg wrote.

By the middle of the decade, he said in the report, four companies will control more than half of the world's biologics production. Those companies are Amgen, Biogen, Boehringer Ingelheim International GmbH (which is the contract manufacturer for Enbrel), and Genentech Inc.

Ginsberg wrote that Biogen is well positioned, and so is IDEC Pharmaceuticals Corp., "given their investments in large-scale manufacturing facilities."

IDEC's recent news highlights the difficulty of getting the FDA's nod, when making biologics. In January, the agency told the company that it must resolve manufacturing compliance issues related to Zevalin (ibritumomab tiuxetan) before the treatment for non-Hodgkin's lymphoma can be approved.

The fill/finish provider of Zevalin, Catalytica Pharmaceuticals Inc., also was the focus of concern by the FDA with regard to Eli Lilly and Co.'s sepsis product, Xigris (drotrecogin alfa), which was approved Nov. 21.

Even Genentech could ultimately find itself in difficult manufacturing straits, Molowa said.

"If they're successful in developing their late-stage pipeline, they could have a problem which is amazing, since they have half about half the world's [manufacturing] capacity," he said.

How did it happen?

In the space of a few years, five blockbuster biologics won approval: Genentech's Rituxan (rituximab), for relapsed or refractory low-grade or follicular, CD20-positive, B-cell, non-Hodgkin's lymphoma; Herceptin (trastuzumab), the same company's anti-HER2 antibody for breast cancer; Synagis (palivizumab), MedImmune Inc.'s product to prevent serious respiratory syncytial virus in certain high-risk infants; Enbrel; and Remicade (infliximab), Centocor Inc.'s rheumatoid arthritis drug.

"We had this period in 1997 and 1998 that has caused the problem today," Molowa said. "We're a victim of their success."

Also, he said, the industry may have been "planning for failure," remembering what happened in the early to mid-1990s regarding the much-ballyhooed monoclonal antibodies.

What's more, the approved products "ended up doing a lot better, and dosages ended up being a lot higher" than most people expected.

Not only are the manufacturing fixes few, but they also all have drawbacks.

"The biggest issue you have with transgenics is the regulatory pathway it's uncharted," Molowa said. Especially in Europe, suspicion reigns over "transgenically derived anything," he added.

Makers might also try to "tweak the culture conditions, which [Boehringer Ingelheim] has done with Enbrel, to improve yield 10 percent to 30 percent," Molowa said. "Or you can try to alter downstream processes and come up with a better purification scheme."

Those are challenging ploys. An even harder approach, "and what people really need to be doing, but don't have time or inclination to do, is re-engineer the original cell line," he said.

But that, also, is highly regulated, Molowa pointed out. The wisest approach turns out to be building more facilities FDA regulations and all. Molowa is not quite as optimistic as Ginsberg, but both seem to believe the biologics manufacturing pileup is remediable, even if the winners may not be many.

"It's going to cost a ton of money, and it's a question of whether it's going to be able to come on line fast enough," Molowa said.