November 1, 2006 (Vol. 26, No. 19)
Communication and Execution from Both Sides of the Table Equal Drug Discovery Success
Outsourcing is no longer an option but is essential for pharmas that want to stay competitive was the dominant sentiment expressed by speakers at the recent “PABORD” meeting in London. “This is not a new trend,” said Arvind Mathur, Ph.D., external resources, drug discovery chemistry, Bristol-Myers Squibb (BMS; www.bms.com). “We have been outsourcing in big pharma for 20 years, and the difference is that now this has become a strategic function and a recognized company asset.”
Duncan Judd, outsourcing manager, discovery medicinal chemistry of GlaxoSmithKline (GSK; www.gsk.com), added, “The number of companies providing molecular building blocks in 1994 was around 20. Now in 2006 there are over 200, and I believe the use of this type of chemistry service by big pharma is going to increase even more.” Judd also predicted that 95% of peptide synthesis could be outsourced and more hit generation, as well as virtual library screening, will also be performed externally.
Speakers at “PABORD” agreed that cost-saving is not the dominant reason for using external partners but increasing efficiency of small molecule discovery and manufacture is. “We outsource to complement internal resources and add more capacity without investing in capital equipment,” Judd said. “This provides added value and flexibility in a project. Using external providers is an effective method for attaining an endpoint quicker. At GSK we expect them to achieve a four-week turnaround on chemical synthesis. It is efficiency that is the main driver, but outsourcing also allows us to access unique building blocks which can produce NCEs.”
GSK used external chemistry services to speed up development of a chemokine (CCR3) receptor antagonist to inhibit inflammatory activity. From an amide library GSK scientists identified a lead morpholine compound, which had dose-related activity and oral pKA in rats and dogs but to increase the compound’s potency needed the synthesis of a significant number and quantity of building blocks. This part of the project was outsourced to a number of external service providers and, according to Judd, helped GSK to rapidly synthesize arrays of the lead to find the most potent compound, quickly establish structure activity relationship data, and manufacture enough of the lead molecule for the start of Phase I trials.
Outsourcing can also provide access to specialist expertise that is not available within the company. Stephen Hammond, Ph.D., CEO of Scottish Biomedical (www.scottish-biomedical.com), presented an example of how his company helped speed up drug discovery for one of its pharma clients. “We developed an HCS-based assay to find an inhibitor of a protease activated receptor (PAR-2). This is a G-coupled receptor, which is an attractive target in many inflammatory diseases. Using a cell line transfected with a plasmid carrying PAR-2 and a luciferase reporter gene, we screened 50,000 compounds and identified 87 that inhibited PAR-2 and from further research of the 87 hits identified two lead candidate molecules,” Dr. Hammond explained.
Offshoring
As well as outsourcing within Europe and the U.S. there is now a much greater interesting in working with contract organizations in developing markets. “Offshoring to India and China offers access to a well-established chemical industry and large pools of well-trained manpower,” Dr. Mathur stated.
“GSK is looking to emerging markets as outsourcing possibilities. We are reviewing Asian and Eastern European providers by the value a company has to offer rather than FTE rates and will decide which companies to work with in each business area, as value propositions change according to the area of the business we are working in,” added Judd.
However, big pharmas face a number of challenges when outsourcing their chemistry manufacturing to emerging markets. “The shipment of chemicals is still an issue, in the U.S. you can have them delivered to your lab within 24 hours, in Asia it still takes around seven days, so you have to factor that into project plans,” noted Dr. Mathur. “Also because there has been a huge expansion in chemistry service companies in India and China, a lot of staff poaching goes on. You have to ensure qualified personnel are secured with incentives.”
How to Make Outsourcing Work
According to “PABORD” speakers you need to be able to select partners that can meet the needs of the projects to have any chance of having a successful outsourcing relationship. “We look at their track record in process development and scale up, what level of regulatory compliance they work to, facilities, capacity, and cost. However, once we have established that all of this meets our project’s criteria we tend to go for the company with the best quality chemists in its team because you can have the best building and equipment in the world but if the people are poorly trained, you’ll never get the right results,” Dr. Mathur said.
Once a new partner is in place, outsourcing is not all smooth sailing. According to Jim Rennie, Ph.D., COO of contract research organization Prova (www.prova.co.uk), common chemistry manufacturing and controls (CMC) mistakes can be a problem.
Some firms use just one CMO as a one-stop shop for all their drug development needs. This is ill-advised because no single provider can supply everything. “There are different drivers for different projects so you need to look for providers that specialize in these areas, for example it is no good asking a Phase I specialist to manufacturer hundreds of kilos of a compound,” Dr. Judd commented.
Other issues, such as lack of solubility data and a shortage of appropriate pharmaceutical ingredients, were cited as sure-fire methods of preventing scale-up of a molecule and escalating production costs. Mistakes, such as expressing the amount of drug as a free base rather than a salt, can lead to the drug being formulated at an incorrect dose. Also discussed were drug formulation. The more complex the formulation, the more expensive it is to develop and manufacture.
Speakers agreed that to overcome or prevent these types of CMC problems, regular communication was essential. “No matter how bad the problem is I want to know. Good news can wait two weeks, but I need to be told bad news within 24 hours,” said Dr. Mathur.
“A collaboration is easy to manage when everything is going well, but the five percent of the time when we have problems, if this is not properly communicated, it can take 95 percent of our time to manage,” Judd added.
“Practice good project management with regular meetings, agendas, and action plans or nothing will get done,” Dr. Mathur concluded. “Treat your external chemistry manufacturers as partners by providing both negative and positive feedback. And most importantly, be realistic in your expectations. For example, don’t outsource them a synthesis you can’t do in-house as it is unlikely they will be able to do it either. They are chemists, not magicians.”
