At long last, four pharmaceutical facilities--two at AstraZeneca, and one each at Schering-Plough and Allergan--have earned EPA's much coveted Energy Star recognition.

The Green Processing conference brought more on pure chemistry, with Kevin Shaughnessy of the University of Alabama talking about recyclable catalyst systems using aqueous phase cross-coupling reactions catalyzed by palladium.

However, the next few presentations were very "hands on" and discussed actual implementations of green chemistry.  Ingrid Mergelsberg, director of chemical development at Schering-Plough, discussed the industrial aspects of green chemistry and some successes that she and her team have achieved so far. 

The main driver is not "responsible care" or corporate stewardship, but cost reduction (the other is a side benefit).  It can also add new intellectual property to a company's portfolio. In Schering's case it brought continuous processing into the mix.

The company has developed a Process Sustainability Index (PSI) benchmark for solvents, process materials, total material use, total reactants, total water. Schering also tracks the materials used per kilogram of API produced.  Generally, dramatic decreases are seen as a drug moves from preclinical to phase 2, 3 and then commercial phase. The earlier in the cycle, the more waste is generated. Mergelsberg says, understandable since only a few candidates will make the cut.  "The challenge is to find the right balance," she said, and to know how much to invest in a process before you know whether or not it will result in a successful drug.

"We try to make people aware very early on, in discovery, to build green chemistry right from the start of process development and get it right the first time….build in quality from the beginning of process development….that way we don’t have to change the processes later on. This requires some changes in behavior and attitude, she noted.  "We need to increase awareness very early on and involve discovery teams."

Typically, she noted, chemical development chemists are involved 6-12 months before a molecule is recommended for chemical development R&D has  developed tools to help chemists find alternatives….screening solvents and reagents with respect to different criteria including carcinogenicity, mutagenicity, reproductive toxicity, solubility, partition coefficient and biodegradability.

From this, they have developed a  “Chemical Selection Guide,” which currently contains data for some 400 chemicals. When a new chemical comes into development, Dr. Mergelsberg said, the chemist must issue new notification sheet, list all solvents required and their impact, must explain clearly why the risk of using a solvent that psoes risks is worth it.
In addition the company doesn't just list possible solvents, but gives alternatives for extraction, chromatography, precipitations, in a chart that goes from red to yellow to green. This information is included early on with discovery chemists. "It's rare that we get processes from discovery with chlorinated solvents," she said. "If we get them there’s a reason."

The company has developed a web based process sustainability index data base….capture process changes from early phase of development to commercial synthesis, tracking kg of raw materials/kg of API. PSI trend charts are then developed, so that one can get to root cause of problems (e.g. when there’s an upward spike during commercialization----in one case, solvents used for cleaning reactor added to total level.)
She then discussed some successful applications of green chemistry, which were achieved before the compounds went into commercial production:
Solvent substitution and recycling, TCH solvent substitution, which eliminated 2000 L of MTBE during workup…reduced 2250 L of organic wastes
Replacement of lithium hydroxide with sodium hydroxide in one process, which reduced costs overall by 6.3% compared with original process chemistry, including energy and waste disposal and treatment costs. "The product gets a lot purer, cleaner," she explained. "Originally we had to recrystallize," she said.
Another example is the in situ elimination of cyanide waste….in a one pot conversion involving in-process oxidation of cyanide wastes. The process eliminated KCN and cyanide bearing aqueous and organic wastes, offering consistent 78% yield and 98% purity.  "This is as green as cyanide can get," she noted, and the new process reduced waste by about 30%.

Geez Louise, could the pharma employment picture get much bleaker? On Friday, Schering-Plough announced it would cut 10% of its 55,000 global employees within the next two years, and that the company's Kenilworth, N.J. headquarters would feel the most pain. Let's empathize for a moment: slowly say, "fifty-five hundred people out on the street." Ouch. Double ouch.

Today's news, while on a scale that is several orders of magnitude lower, is plenty painful in its own right. The San Francisco Business Times reports that local biopharma company VaxGen Inc. "will lay off about 16 or 17 of its 22 remaining employees, including chief financial officer Matthew Pfeffer, to save money after its proposed merger with Raven Biotechnologies Inc. fell through."

So a company that had a few dozen people on its payroll two years ago is reduced to a five- to six-person startup? San Francisco Business Times writer Steven E.F. Brown noted, "VaxGen has been struggling since it lost a contract with the federal government in December 2006. That deal, in which VaxGen would make 75 million doses of anthrax vaccine for use against possible bioterror attacks, was worth $877 million. After that, the company stopped all development of its recombinant anthrax vaccine and cut all the people working on it. " Ouch again.

In an article that both reported and remarked on the Schering-Plough news, the Associated Press provided an answer to the question every pharmaceutical professional must be asking -- "When will it end?":
"There are a lot of things going on making this the perfect storm for the industry," said Argus Research health care analyst Martha Freitag. "My sense is maybe we're halfway through" the cost-cutting.
And in case, like me, you've lost count, because your head is reeling from reading headline after headline about pharma job cuts during the past three years, our friends at AP were thoughtful enough to tally it up for us: "Since 2007, eight of the world's biggest drug makers have announced the elimination of more than 42,000 jobs; two other major companies have eliminated another 12,200 jobs in the last few years," the article pointed out. 

Holy aching stomach, Batman! I can't help but appreciate the irony as I reach for the Zantac . . .

-HP

P.S. The only good news (if you call deriving enjoyment from someone else's misfortune 'good news') on the employment scene today was an article in the Charlotte Observer noting that even some local law firms are being hit by the layoff bug. If anyone's going to have to experience the kind of pain that pharmaceutical professionals are enduring, it might as well be "those who deal with the legal side of complex transactions such as commercial mortgage-backed securities and other real estate investment deals," don't you agree?

Clinical trials may have uncovered a possible link between inhaled insulin and lung cancer. In testing its blockbuster manque Exubera, Pfizer said six of the 4,740 Exubera-treated patients versus one of the 4,292 patients not treated with Exubera developed lung cancer. One lung cancer case was also found after Exubera reached the market.  However, all those affected were smokers, so connections are still somewhat unclear, although Pfizer is adding to warning labeling for whatever product might still be out there.  More from a news brief issued this morning.

What might be clear, though, is the role that a true Quality by Design approach could have played in developing this product.  Pfizer's "Right First Time" appears to have failed, utterly, in this case.  This is not playing Monday morning quarterback but pointing to a case where pharma lost billions by failing to connect more closely with customers and with its own work force.  There's another case playing out right now, which shall remain nameless, with huge implications for industry professionals , particularly those based in New Jersey.  

The Exubera product concept was brilliant, from the stabilization process that allowed its active ingredient to be manufactured to the delivery device itself.  But nobody wanted a large device with complicated dosing instructions, so Exubera violated Toyota's "customer focus" rule.  (Not to mention the fact that Pfizer transferred some manufacturing folks from its Brooklyn location to a fairly remote site to make the product.  In the end the company only wound up laying them off...so it wound up violating Toyota's "respect for the worker" rule, too.)

Both Lilly and Novo Nordisk have reportedly stopped inhalable insulin development, and Nektar has suspended discussions with other potential partners.  A shame because, if the kinks were worked out, inhalable insulin could solve a great many problems and be much easier for patients to take, particularly in parts of the world where needle availability and safety might be in question (assuming its costs went down, of course). 

 So perhaps it's time to go back to the drawing board.  But, this time, maybe with the right tools (and many more physician and patient customer focus groups) in place? (And an eye to "right sizing" staffing requirements for the next blockbuster, up front)