AMNews: Jan. 14, 2002. Getting drugs made can be harder than creating them ... American Medical News

[Guest guest]

Getting drugs made can be harder than creating them

Street Smarts. By Gottlieb, MD, AMNews contributor. Jan. 14, 2002.

Since May 2001, patients prescribed the monoclonal antibody Enbrel have

carried a special card, verifying for their pharmacist that they are

eligible to receive the medicine.

Sounds like a page out of a methadone clinic, right?

These tight checks, however, aren't performed because Enbrel is a

controlled narcotic. The drug is part of a revolutionary new class of

compounds that must be specially crafted with mammalian cell cultures.

The drug's creator, Seattle-based biotechnology company Immunex Corp.

simply cannot make enough of it.

Was it poor planning, or the result of a flood or a fire on the Immunex

production line? No. As badly as the company wants to bring more

manufacturing space on line, it has been hobbled by a morass of FDA

regulations that stretch months into years and prevent them from building

new plants.

Because most small companies can't risk investing in a $300 million to

$500 million manufacturing site years before their drugs pass regulatory

muster, there are few facilities coming anytime soon. Contract

manufacturers with outsourced production plants are full, and biotech

companies with their own facilities are running at capacity. The result

is a worldwide shortage in manufacturing space for monoclonal antibodies

and long waiting lists for Enbrel.

Americans want safeguards built into the process by which drugs and

vaccines are manufactured. But the process for certifying new

manufacturing space has become so Byzantine that it now takes a year to

build a plant, then three years to get it inspected and approved.

Next time your patients ask why flu vaccines have been in short supply

this season, tell them it is also a problem with manufacturing and the

ability of the few remaining suppliers to get permission from the FDA to

bring their facilities up to full production.

Diagnostic agents also have been scarce, including chemicals used in

gallbladder scans and the blue dye used in sentinel lymph node biopsies

after breast cancer surgery (AMNews, Dec. 24/31, 2001). In this

marketplace, gummed up as it is with costly and time-consuming

regulations, manufacturers cannot adjust their supply to meet rising

demand.

One reason it takes so long to bring manufacturing facilities on line is

that calling the FDA is more akin to calling the phone company than the

fire department. Inspectors don't show up on time. At each of dozens of

regulatory pauses, pharmaceutical and biotechnology companies must stop

and bring in FDA inspection teams, who take weeks or even months to come

on site for their inspections. Even expanding an existing facility can

take three years or more and cost more than $250 million.

The issue has drawn attention because of Bayer's lucky response to

surging demand for the anthrax-busting antibiotic Cipro. The

pharmaceutical firm was able to convert a facility that formerly produced

Baycol, a cholesterol-lowering drug recently withdrawn by the FDA. The

FDA crash-inspected the new line. Had the facility not been available, it

is possible that Cipro could have run short.

Regulatory rules on vaccine production are also getting in the way of

preparations for a hypothetical smallpox attack. The government plans to

rush inspection of new vaccine production lines. FDA regulators have said

they can do the approvals in months, instead of the usual years.

BioPort Corp., Lansing, Mich., manufacturer of an anthrax vaccine for the

U.S. military, has upgraded its anthrax-vaccine manufacturing space a

half-dozen times. Since 1999, it has been given an ever-expanding list of

required changes for the FDA to validate the plant. The FDA completed the

latest pre-approval inspection last month. The high cost of regulatory

compliance is one reason some major drug companies have left the vaccine

business altogether.

The future looks grim. More than 200 companies are involved in developing

about twice that number of monoclonal antibodies. When other blockbuster

drugs are added to those figures, it is clear the production crunch is

just beginning. Monoclonal antibodies account for more than 20% of all

drugs in clinical development.

Antibodies are particularly vulnerable because they need more

manufacturing space than other biologics, for two reasons. The average

dose is larger than for the typical hormone or enzyme, and antibodies are

large, complex proteins that tend to aggregate or be expressed in

insoluble forms.

Some manufacturers have been forced to bet the farm -- literally -- on an

alternative manufacturing method called transgenics.

Biotechnology companies Genzyme Transgenics Corp., Framingham, Ma.;

Viragen Inc., Fort Lauderdale, Fla.; and CropTech Corp., Blacksburg, Va.,

are transferring human genes into--respectively--goats, chickens and

tobacco plants, in order to produce protein drugs more efficiently. A

recombinant human alpha-1-antritrypsin made by transgenic sheep milk will

enter phase III trials for emphysema this year.

One bit of good news is that regulatory strictures have created new

industries. Whole slates of companies specialize in the outsourced

production of these drugs, freeing research-intensive firms from the risk

of anticipating demand for experimental drugs that may not be approved.

But as demand takes off, even these facilities are not enough to fill the

crunch.

Overregulation of pharmaceutical manufacturing drives up the cost of new

medicines and keep others off the production lines altogether. If the

inspection process were not so slow and expensive, companies would be

likelier to mothball spare production lines, anticipating future demand.

And Washington might find the necessary capacity the next time we have an

unexpected problem like a terrorist attack.

http://www.ama-assn.org/sci-pubs/amnews/pick_02/bica0114.htm