Outsourcing Survey, the results of which are published in August's 's Outsourcing Resources supplement, paints a bright picture for providers of formulation, analytical, and clinical trial manufacturing services. Nearly two-thirds of service providers surveyed say they expect revenues to grow by 10% or more in 2008, and they expect 2009 to be just as promising.

As optimistic as this outlook is, it pales beside the effervescent outlook of the clinical-research contract research organizations (CROs). In an informal PharmSource survey of exhibitors at the 2008 Drug Information Association (DIA) annual meeting held in Boston in June, 88% of clinical CROs surveyed said they expect 20% growth over last year. Respondents credited a growing number of studies as a principal factor, driven by downsizing at major pharmaceutical companies and the growth of trials in emerging markets. Respondents also emphasized the expansion of their own capabilities to meet that demand.

The greater expectations of the clinical CROs reflect the fact that outsourcing of clinical research activities has always outpaced outsourcing of chemistry, manufacturing, and control (CMC) functions. We're not entirely sure why that is, but we believe three factors are at work. First, CMC services involve fixed assets (laboratories and facilities), which are difficult and costly to shut down. Clinical research, on the other hand, involves mostly labor and information technology, which are easier to shed in favor of contract service providers. Second, CMC development often involves developing intellectual property (IP) whereas clinical research activities are less likely to expose IP to potential competitors and are more about operational effectiveness. Third, the need to access patient populations globally to recruit sufficient numbers of subjects, reduce costs, and support global regulatory submissions encourages use of clinical CROs.

Clinical-research CROs do, however, face several challenges. For starters, recruiting and retaining qualified staff is a real challenge today, especially for qualified scientific and technical professionals. Competition is driving up compensation costs, even with the hiring pool being deepened by professionals leaving pharmaceutical companies. In addition, many companies are concerned about meeting client demands and timelines. Patient-recruitment requirements, investigator needs, and site and study logistics require increasingly sophisticated management and planning. Competition was the third most frequently listed challenge for companies. Respondents cited the need to be flexible in responding to the market, and the importance of keeping costs competitive. Almost 68% of respondents plan to increase resource allocations to sales and marketing.

A recent survey of research and development (R&D) and outsourcing professionals by Jefferies & Company indicates that market conditions are highly favorable for continued growth in the clinical research sector. The survey found that R&D spending is expected to grow at a faster pace in coming years than it has in recent years, with the fastest growth in late-stage development (Phase IIb and Phase III). This undoubtedly reflects the maturing of the pipeline as rapid growth in early-phase compounds yields more late-stage candidates.

Jefferies' respondents expect the fastest growth in outsourced spend to be in early development, including preclinical toxicology and Phase I clinical testing. This reflects a growing reliance on early-phase testing to demonstrate proof-of-concept as a means of controlling R&D costs and identifying candidates likely to fail earlier in the development process.

Respondents to the Jefferies survey also expect more offshoring of clinical research activities, with a focus on data management and use of clinical sites in emerging markets. In fact, they expect the share of R&D budgets spent outside North America and Europe to almost double, from 29% in 2008 to 54% by 2011. For this to happen, however, they must overcome a variety of obstacles including IP protection, communication problems, and cultural differences.

There are already signs that outsourcing of development services for clinical-trial materials is headed in the same direction as clinical research. It may pay for nonclinical outsourcing professionals to "look over the wall" at what their clinical counterparts are doing.

 is president of PharmSource Information Services, Inc., and publisher of Bio/Pharmaceutical Outsourcing Report, tel. 703.383.4903, fax 703.383.4905, 

Articles

Outsourcing Outlook

CMC service providers are doing well, but clinical and preclinical CROs are doing even better.

Clinical Outsourcing Steams Ahead

The  US Food and Drug Administration is holding a public meeting on Sept. 8, 2008,  to gather information that will assist the agency in implementing the  recommendations of the Nanotechnology Task Force Report. The FDA's Task Force  Report on Nanotechnology addresses regulatory and scientific issues and  recommended FDA consider development of nanotechnology-associated guidances for manufacturers and researchers. FDA Commissioner Andrew von Eschenbach initiated  the task force in 2006. FDA is also part of the National Nanotechnology Initiative, a federal research and development program  established to coordinate the multiagency efforts of 23 federal agencies in nanoscale science,  engineering, and technology.

FDA’s Nanotechnology Task Force issued its  initial recommendations in July 2007. In its report, FDA explained that nanoscale  materials often have chemical, physical, or biological properties that are  different from those of their larger counterparts. These differences may  include altered magnetic properties, altered electrical or optical activity,  increased structural integrity, or altered chemical or biological activity.  Because of some of their special properties, nanoscale materials may pose  different safety issues than their larger or smaller (i.e., molecular)  counterparts (1).

In its report, the task force did not provide a  definition for nanotechnology, but rather stated: “While one  definition for nanotechnology, ‘nanoscale material,’ or a related term or  concept may offer meaningful guidance in one context, that definition may be  too narrow or broad to be of use in another.” The task force does not recommend adopting formal, fixed definitions for nanotechnology, although it  left the door open to revisit the matter later. “As FDA learns more about the  interaction of nanoscale materials with biological systems and generalizable  concepts that can inform the agency's judgment, it may be productive to develop  formal, fixed definitions, appropriately tailored to the regulation of  nanoscale materials in FDA-regulated products.” 

At its public meeting this  month, FDA will examine five key issues relating to prescription and  over-the-counter drugs (2):

 • Are there general parameters or  screening tools by which to evaluate the likelihood that a particular material  might have nanoscale-specific properties and to decide when and what sort of  further evaluation might be warranted?  Are there characteristics and  properties of materials that FDA can use to broadly categorize materials with  respect to their likelihood of having nanoscale-specific properties warranting  further review?

• What are the unique manufacturing  features of products containing nanoscale materials and how should these be  evaluated? 

• What are unique  physicochemical attributes of products containing nanoscale materials?

• What has been your  experience to date with products containing nanoscale materials and/or have you  avoided these products due to concerns about development, characterization, and  manufacturing?

• What additional  questions focusing on characterization and manufacturing aspects of products  containing nanoscale materials should be addressed in this forum or brought to  the attention of FDA's Center for Drug Evaluation and Research?

In terms of  manufacturing, FDA is interested in gaining input on whether the manufacturing  process understanding and development for nanoscale materials is different from  that of conventional drugs. It also wants to examine whether the use of  nanoscale materials affects scale-up, and whether developing a nanoscale  material-containing product under the quality by design model contributes to  process understanding and manufacturing capabilities. FDA is also interested in  evaluating whether nanoscale materials affect product formulation, components,  excipients, and processing. The agency is also evaluating how the physicochemical  properties of nanomaterials affect controls, standards, specifications, product  performance, and whether these properties complicate development and  manufacturing of these products. 

FDA hopes that the public meeting will assist  the agency in its goal of developing guidances relating to nanotechnology. FDA  is also working with the National Institutes of Health  (particularly the NanoHealth Enterprise)  to explore methods for receiving and sharing data on general product development, including research on failed product candidates, and  biological interactions of certain characteristics of nanoscale materials.  FDA hopes that such a data repository could allow the agency and other  stakeholders to share data and methods, and to develop models of biological  interaction that could provide information for  product development and review.

1.	FDA, “Nanotechnology: A Report of the US Food and Drug Administration Nanotechnology Task Force” (Rockville, MD, July 2007), available at 

http://www.fda.gov/nanotechnology/taskforce/report2007.html

 accessed Aug. 25, 2008. 
 2.	FDA, “Product-Specific Questions to be Discussed at  Nanotechnology Public Meeting” (Rockville, MD, 2008), available at 

http://www.fda.gov/nanotechnology2008/questions.html

Drug Delivery

The US Food and Drug Administration will hold a public meeting this month to gain public input on implementing the recommendations of the Nanotechnology Task Force report, taking another step closer to setting a regulatory framework for nanotechnology for pharmaceuticals and medical devices.

Setting a Regulatory Framework for Nanotechnology

Lured by improved process  conditions and economics, incorporating green chemistry into the synthesis of  active pharmaceutical ingredients (APIs) and intermediates is of ongoing  importance to the pharmaceutical industry. Solvent reduction and replacement and  biocatalysis are some of the tools  used to optimize select API syntheses. 

Each year, the  Environmental Protection Agency’s Presidential Green Challenges Awards recognize advances in green chemistry or environmentally favored approaches in all fields of chemistry. A review of entries for the 2008 awards, which were announced  earlier this year, shows several large pharmaceutical companies among the contenders. 

Eli Lilly optimizes production of neurokinin 1  antagonist


 Eli Lilly and Company  (Indianapolis, IN) developed a green-chemistry approach for the commercial  production of an investigational new drug candidate, “LY686017,” an antagonist  of the neurokinin 1  subtype of the tachykinin receptor. The drug, (2-[1-(3,5-bis-trifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]-triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,  is in Phase II clinical trials. 

Lilly demonstrated the commercial route on a pilot-plant scale in 2006 at its facilities in Indianapolis, Indiana. Two  prior synthetic routes were executed at the pilot-plant scale at the company’s  Indianapolis and Mount Saint Guibert, Belgium, facilities (1).

Eli Lilly used a metric  similar to but not identical to Sheldon’s E-factor, which measures kilograms of  waste to kilograms of product (2). Lilly’s e-factor measures the total mass of all  raw materials, including water, which are used to produce each kilogram of API.  The new route for LY686017 has a net e-factor of 146 kg/kg of API, which is an  84% reduction compared with the original route of the drug. Key technology in  the new route include a chemoselective nucleophilic  aromatic substitution, which produced  the drug in high entaniomeric excess  (> 99%) despite the complexity of the structure and potential for  positional isomers for all five aromatic rings (1,3). 

Codexis develops biocatalytic route for montelukast  intermediate

Codexis  (Redwood City, CA) developed an improved route to (S,E)-2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3- hydroxypropyl)-benzoate  (MLK-III), a chiral intermediate used in the synthesis of the anti-asthma drug  “Singulair” (montelukast sodium) using biocatalysis. In the traditional  approach, the ketone reduction to this chiral alcohol requires at least 1.8  equivalents of the reductant (–)-β-chlorodiisopinocampheylborane  ((–)-DIP-Cl) in tetrahydrofuran at −20 to −25 °C. After  quenching, an extraction removes spent borate salt waste. The reduction produces the S-alcohol in 97% ee and requires  crystallization to give 99.5% ee in 87% yield (1).

Using another approach, Codexis developed a  biocatalytic reduction for MLK-III using a ketoreductase biocatalyst evolved to  reduce MLK-II. Codexis evolved the ketoreductase to increase its activity and  stability by more than 2000-fold, replacing one-third of the amino acids in its  active site in the process and under improved reaction conditions: 100 g/L in isopropanol–water–toluene at 45 °C. Isopropanol is the reductant,  which the ketoreductase uses to regenerate its catalytic cofactor, NADPH,  producing acetone as the coproduct. The process runs as a slurry-to-slurry  conversion with product precipitation driving the reaction to completion. The  precipitated chiral alcohol is of high chemical purity and stereopurity. Codexis has scaled up the manufacture of MLK-III using this biocatalytic reduction  and has provided samples of MLK-IV to manufacturers of generic montelukast. The  company is planning commercial-scale manufacture on a multiton scale in 2008  (1).


 GlaxoSmithKline (GSK, London) developed the  “Eco-Design Toolkit” as a way to provide bench-level chemists and engineers  with access to green-chemistry information and tools for process research and  development and manufacturing. The toolkit has five modules: a green chemistry  and technology guide; a materials guide on solvents and bases with related environmental, health, and safety data; a fast life-cycle assessment for synthetic chemistry for streamlining evaluations of the environmental life cycle  and measuring green metrics, including mass efficiency; a green packaging  guide; and a chemicals legislation guide that identifies legislation phasing  out hazardous substances. Using the toolkit, GSK reported that in 2006, the  mass percent of chemicals of concern for all new products decreased nine-fold,  and the estimated average life-cycle impacts were reduced four-fold as  compounds moved to the last stage of development (1). 


 Johnson & Johnson  (J&J, New Brunswick, NJ) used green-chemistry techniques to improve the  synthesis of darunavir, the API in its protease inhibitor, “Prezista.” The  improved process reduced waste and raw materials by 46 tons, reduced hydrogen  gas by 4800 cubic meters and eliminated 96 tons  of methylene chloride in 2006, the year in which the drug was approved.

The key gains in the  route were: reduced solvent use; separation of the acidification and quenching  steps to eliminate the formation of hydrogen gas and the replacement of  hydrochloric acid with methane sulfonic acid and addition of acetone to react  with excess hydride to form isopropanol; and replacement of a solvent system  containing methylene chloride and triethylamine with a system containing  acetonitrile and pyridine (1). 

Merck develops greener process for raltegravir


 Merck & Co.  (Whitehouse Station, NJ) developed a greener process for producing raltegravir,  the API in “Isentress.” Isentress was approved in 2007 to treat HIV. An  important part of the process involves replacing the reagent methyl iodide with trimethylsulfoxonium iodide. With this change and other improvements, the  E-factor for the process was reduced from 388 for the original process to 121.  The new process also improved yield by 35% (1). 

Roche betters route for pyridinylimadazole-based  drug

Roche  developed an improved route for a pyridinylimadazole-based drug that functions  as a p38(4) mitogen-activated protein kinase inhibitor. One of the fragments  involved in the original synthetic route is 3-aminopentane-1,5-diol. This  aminodiol intermediate is highly water-soluble, making it difficult to isolate  from an aqueous reaction mixture. Extraction from the aqueous system required a  very large volume of the organic solvent, dichloromethane. Purification of the resulting  viscous liquid is either by distillation or via crystalline salt, but requires  multiple operational steps. This process was sufficient to produce the API for  Phase I and Phase II, but an improved route was needed for commercial  manufacture (1). 

In  the new process, 3-aminopentane-1,5-diol is synthesized in two isolated steps  and four chemical reactions starting from readily available and inexpensive  dimethyl acetone-
 1,3-dicarboxylate.  The company optimized the process through significant streamlining,
 resulting  in the use of a single solvent, which is easily recovered and recycled. The key  improvements involve: sodium borohydride reduction of dimethyl  3-N-tert-butoxycarbonylaminoglutarate,
 an  one-pot deprotection, and purification of the 3-aminopentane-1,5-diol using an  acidic resin under non-aqueous conditions. The overall yield of the new  synthesis is 89% and the API purity is 99.5% (1). 

 1. EPA, “The  Presidential Green Chemistry Challenge Awards Program: Summary of 2008 Award  Entries and Recipients” (Washington, DC, 2008), available at 

http://www.epa.gov/gcc/pubs/docs/ award_entries_and_recipients2008.pdf

2. R.A. Sheldon, “The E  Factor: Fifteen Years On,” 

3. M.E. Kopach “A Practical and Green Chemical Approach for  the Manufacture of NK1 Antagonist LY686017,” presented at The 12th Annual Green Chemistry and Engineering Conference, New York, June 25, 2008. 

Global Feature

The pharmaceutical majors deploy green-chemistry strategies to improve the synthesis of active pharmaceutical ingredients and intermediates.

PTSM: Pharmaceutical Technology Sourcing and Management-09-03-2008

Clinical Outsourcing Steams Ahead

Setting a Regulatory Framework for Nanotechnology

Advances in Green Chemistry for Pharmaceutical Applications