When the Millennium  Development Goals (MDGs) were adopted in 2000 by 189 member states of the United  Nations (UN), they were considered a historic framework for focus and  accountability by setting international development objectives, including in  global public health. With five years remaining for the timetable to meet the  MDGs, however, concern exists whether they will be meet.The UN will hold a high-level  plenary meeting of world leaders later this month to review the progress,  assess obstacles and gaps, and discuss strategies and actions to help meet the MDGs by the target date of 2015. 


 The MDGs  consist of eight major objectives that require the participation of developed  and developing nations. They entail time-bound targets for addressing extreme  poverty, hunger and disease, gender equality, education, education, and  environmental sustainability (1). They also express basic human rights: the  rights of everyone to good health, education, and shelter. The eighth goal, to  build a global partnership for development, includes commitments in development  assistance, debt relief, trade, and access to technologies (1). The MDGs and  the specific targets in each goal are outlined below (2, 3). 

Goal 1—Eradicate extreme poverty and  hunger


 • Target 1.A:  Halve between 1990 and 2015, the proportion of people whose income is less than  $1.25 a day
 • Target 1.B:  Achieve full and productive employment and decent work for all, including women  and young people
 • Target 1.C:  Halve, between 1990 and 2015, the proportion of people who suffer from hunger. 

Goal 2—Achieve universal primary  education


 • Target  2.A: Ensure that by 2015, children, boys and girls alike, will be  able to complete a full course of primary schooling.

Goal 3—Promote gender equality and  empower women


 • Target  3.A: Eliminate gender disparity in primary and secondary education, preferably  by 2005, and at all levels of education, no later than 2015.


 • Target  4.A Reduce by two thirds, between 1990 and 2015, the the mortality rate for children under the age of five.


 • Target  5.A: Reduce by three quarters, between 1990 and 2015, the maternal mortality  rate. 
 • Target  5.B: Achieve by 2015, universal access to reproductive health.

Goal 6—Combat HIV/AIDS, malaria, and  other diseases


 • Target  6.A: Have halted by 2015 and begun to reverse the spread of HIV/AIDS
 • Target  6.B: Achieve by 2010 universal access to treatment for HIV/AIDS for all those  who need it
 • Target  6.C: Have halted by 2015 and begun to reverse the incidence of malaria and  other major diseases.

Goal 7—Ensure environmental  sustainability

 
 • Target  7.A: Integrate the principles of sustainable development into country policies  and programs and reverse the loss of environmental resources
 • Target  7.B: Reduce biodiversity loss, achieving by 2010, a significant reduction in  the rate of loss
 • Target  7.C: Halve by 2015 the proportion of people without sustainable access to safe  drinking water and basic sanitation
 • Target  7.D: Have achieved a significant improvement by 2020 in the lives of a least 100  million slum dwellers.

Goal 8—Develop a global partnership  for development 


 • Target  8.A: Develop further an open, rule-based predictable, nondiscriminatory trading  and financial system (including a commitment to good governance, development,  and poverty reduction, nationally and internationally)
 • Target  8.B: Address the special needs of least-developed countries (including providing tariff-  and quota-free access for exports of least-developed countries, enhancing  debt relief for heavily indebted poor countries and cancellation of official  bilateral debt, and offering more generous official development assessment for countries  committed to reducing poverty)
 • Target  8.C: Address the special needs of landlocked countries and small-island  developing states (through the Program of Action for the Sustainable  Development of Small-Island Developing States and the outcome of the 22nd  special session of the General Assembly)
 • Target  8.D: Deal comprehensively with the debt problems of developing countries  through national and international measures to make debt sustainable in the  long term
 • Target  8.E: In cooperation with pharmaceutical companies, provide  access to affordable, essential drugs in developing countries
 • Target  8.F: In cooperation with the private sector, make available the benefits of new  technologies, especially information and communication technology. 

 to assess the progress on  achieving the goals (2). As world leaders approach the meeting on Sept. 20–21  in New York, there is concern that several of the eight MDGs will not be met as  originally planned by 2015. “With five years to go to the target date of 2015,  the prospect of failing short of achieving the goals because of a lack of  commitment is very real,” according to recent UN report (1). “This would be an  unacceptable failure from the moral and the practical standpoint. If we fail,  the dangers in the world—instability, violence, epidemic diseases, environmental  degradation, runaway population growth—will all be multiplie,” said the report.  The purpose of the September meeting is to renew the international commitment  to achieving the MDGs by reviewing successes, best practices, lessons learned,  obstacles, gaps, challenges, and opportunities, according to a UN briefing on  the upcoming MDG Summit. 

The MDGs  are holistic and interconnected, and the inputs of pharmaceuticals and related healthcare efforts play an important role in achieving the MDGs  generally and for realizing specific MDGs (2). A recent assessment by the United Nations  Development Program (UNDP) and the UN MDG report outlined the successes and  gaps in achieving the MDGs, including MDGs relating to global public health,  where development, production, and access to pharmaceuticals and vaccines are  crucial issues (3). 


 The UN MDG  report says that although child mortality is declining, it is not failing  enough to reach the MDG target of reducing by two-thirds the mortality rate for  children under the age of five. Since 1990, the mortality rate of children under the age of five in developing countries has dropped 28%. Globally, the total number  of deaths from children under the age of five declined from 12.5 million in  1990 to 8.8 million in 2008. Despite these improvements, many countries still  have made little or no progress in reducing child mortality. Among the 67  countries with high child mortality rates (i.e., defined as 40 or more deaths  per 1000 live births), only 10 are on track to meet the MDG target on child  survival (2). 

A key  target to improving survival rates is to decrease the incidence of four  diseases: pneumonia, diarrhea, malaria, and AIDS, which, combined,  accounted for  43% of all deaths in children under the age of five globally in 2008. The UN MDG report  emphasized the need to refocus attention on treating pneumonia and diarrhea,  including the development and use of new treatments for pneumococcal  pneumonia and rotaviral diarrhea (2).  

Immunization against measles is another key factor in child mortality, and the dosing regime is an important factor.  In 2008, 81% of children in the developing world were immunized against measles, up from 70% in 2000, but access to measles vaccines varied among  different social and economic groups (2). Moreover, the UN MDG report said that  a single-dose vaccine strategy is not sufficient to prevent measles outbreaks,  pointing to data that showed better outcomes in countries that improved routine  immunization coverage and used a two-dose regime. The combination of these two  factors led to a 78% decline in measles-related deaths globally between 2000  and 2008, from an estimated 733,000 deaths in 2000 to 164,00 in 2008. The UN  MDG report, however, cautions that recent funding gaps in immunization programs  may make these gains short-lived. The report says that if supplementary  immunization activity is not resumed, approximately 1.7 million measles-related  deaths will occur between 2010 and 2013 (2). 

MDG 4–Combat HIV/AIDS, malaria, and  other diseases


 The latest epidemiological  data indicate that globally, the spread of HIV appears to have peaked in 1996,  when 3.5 million people were newly infected (2). By 2008, that number dropped  to 2.7 million. AIDS-related mortality peaked in 2004, with 2.2 million deaths  and dropped to 2 million deaths by 2008, although HIV remains the world’s  leading infectious killer. On a regional basis, sub-Saharan Africa is the most  heavily affected region in the world, accounting for 72% of all new HIV  infections in 2008 (2).  

A specific MDG  target in the battle against HIV/AIDS was to provide universal access to treatment  for HIV/AIDS by 2010. An analysis shows mixed results in achieving this  outcome. According to the UN MDG report, a global effort to provide 3 million  people in low- and middle-income countries with antiretroviral therapy by 2005  was launched in 2003. At that time, approximately 400,000 people were receiving  treatment. By December 2008, that figure had increased 10-fold to approximately  4 million people. The greatest gains were in sub-Saharan Africa, where by the  end of 2008, 2.9 million people were receiving treatment (2).

The UN MDG  report, however, shows that the rate of new HIV/AID cases outstrips the gains in increasing treatment. For every two individuals who start treatment each  year, five people are newly infected. In 2008, 42% of the 8.8 million people needing  treatment for HIV in low- and middle- income countries received it, compared  with 33% in 2007. Although an improvement, the figures reveal that 5.5 million  in need did not have access to treatment (2). 

. Another MDG target is to have  halted and begun the reverse of the incidence of malaria and other major  diseases by 2015. According to the UN MDG report, half of the world’s  population is at risk of becoming infected with malaria. Approximately 243  million cases led to nearly 863,000 deaths in 2008, of which 89% occurred in  Africa (2). 

The MDG  report says that there has been success in achieving sustained malaria control.  “Major increases in funding and attention to malaria have accelerated the  delivery of critical interventions by reducing bottlenecks in the production,  procurement, and delivery of key commodities,” says the report (2). These  efforts include increasing the production and delivery of insecticide-treated  mosquito nets and increasing access to antimalaria drugs (2).

One  strategy to prevent malaria is to increase the dissemination of  insecticide-treated mosquito nets. Global production of mosquito nets has increased  fivefold since 2004, rising from 30 million nets in 2004 to 150 million nets in  2009. Nearly 200 million nets were delivered to African countries by  manufacturers during 2007–2008, but this level fell short of the 350 million  nets needed to achieve universal coverage (2). 

In terms of  malaria treatments, global production of artemisinin-based combination  therapies, considered a more effective treatment, has increased from only  500,000 doses in 2001 to 160 million doses in 2009 (2). Access, however, to  these treatments varies considerably among African countries and is particularly  disparate among children. In only eight of 37 African countries did the  proportion of febrile children under five receiving any antimalarial medication  reach more than 50%. In African countries, only 10% or less of febrile children  were receiving treatment (2). 

The UN MDG  report shows that external funding for malaria control has increased  significantly from less than $10 million in 2003 to $1.5 billion in 2009 (2). This  support largely came from a public–private partnership, 

The Global Fund to Fight Aids, Tuberculosis and  Malaria

  Despite the increase in funding,  total funding for malaria fell short of the estimated $6 billion needed in 2010  for global implementation of malaria-control interventions. Approximately 80%  of external funds are targeted for Africa, which accounts for 90% of global  cases and deaths relating to malaria (2). 

The global burden of tuberculosis is  gradually declining. Incidence fell from 139 cases per 100,000 people in 2008  after peaking in 2004 at 143 cases per 100,000. The rate of population  growth, however, outweighs the reductions in incidence per capita, meaning more  people on a global basis are inflicted with tuberculosis. In 2008,  approximately 9.4 million new cases of tuberculosis were reported, which was an  increase from the 9.3 million cases reported in 2007 (2). On the plus side,  however, if current trends are sustained in terms of reducing incidence per  capita, the world as a whole will have achieved the MDG target of halting and  reversing the incidence of tuberculosis.  Although more tuberculosis  patients are being cured, the MDG UN report says that halving mortality by 2015  in certain regions such as sub-Sahara Africa is unlikely because of the  concomitant problem of HIV/AIDs infection and that sustained funding for tuberculosis-control efforts will be needed regionally and globally to  achieve sustained progress. 

MDG 8: Develop a global partnership  for development


 At a  meeting of the Gleneagles Group of Eight (G-8) Summit and the UN World Summit  in 2005, developed nations agreed to increase their level of aid to the  developing world. In 2009, net disbursements of official development assistance  (ODA) was $119.6 billion or 0.31% of the combined gross national income (GNI)  of developed countries. In real terms, this is a slight increase (0.7%)  compared with 2008, although when measured in current US dollars, ODA fell by  2% from $122.3 billion in 2003. If debt relief is excluded, the increase in ODA  in real terms in 2008 to 2009 was 6.9%. If humanitarian aid is also excluded,  bilateral aid rose by 8.5% in real terms as donor countries increased their  core development projects and programs (2). 

The global  economic downturn, however, has had an effect on future pledges, many of which  were made as a percentage of GNI. On the basis of current 2010 budget  proposals, as well as lower GNI forecasts, total ODA for 2010 is projected at  $108 billion (using 2004 pricing). Only five donor countries have reached or  exceeded the UN target for official aid of 0.7% of GNI: Denmark, Luxembourg,  The Netherlands, Norway, and Sweden. The largest donor by volume in 2009 was  the United States, followed by France, Germany, the United Kingdom, and Japan  (2).

A specific target in the MDG  partnership goals is to increase access to affordable essential medicines in  developing nations. A recent analysis by the MDG Gap Task Force found that  there are large gaps in the availability of essential medicines in the public  and private sectors and that prices vary considerably (4). The MDG Task Force  was formed in 2007 to track existing international commitments and their  fulfillment at the international and country levels in the areas of official development assistance, market access (i.e., trade), debt  relief, access to essential medicines, and new technologies. The task force  integrates more than 20 UN agencies, including participation from the World  Bank and the International Monetary Fund, the Organization for Economic  Co-operation and Development, and the World Trade Organization. The United  Nations Development Program and the Department of Economic and Social Affairs  of the United Nations Secretariat are lead agencies in coordinating the work of  the task force (4).

In a 2008 report, the task force concluded that  the availability of select essential medicines in developing countries was low  (38.1% in the public sector and 63.3% in the private sector), and that access  to essential medicines was further hampered following the global economic  crisis. Median prices were on average 2.5 times higher than international  reference prices in the public sector and 6.1 times higher in the private  sector. China, India, Iran, and Uzbekistan were the only countries surveyed in  which private-sector patient prices for generic medicines were less than twice  the international reference prices (4).  In addition to pricing and affordability, other  areas of concern were increasing access to medicines for noncommunicable  diseases, medicines for children, and medicines for chronic diseases (4). 

To address these problems, the MDG Task Force  recommended several actions to improve the accessibility and affordability of  essential medicines as follows (4):

• Governments should provide additional  protection to low-income families to cope with the rising costs of medicines as  a consequence of the global economic crisis

• In addition to national efforts, further  international efforts should be taken to improve the availability and  affordability of essential medicines such as the establishment of international  patent pools

• Countries with manufacturing capacity should  facilitate the exporting of generic medicines to countries in line with  flexibilities contained in the TRIPS (Trade-related Aspects of  Intellectual Property Rights) agreement, and  where possible, the exchange of technology between developed and nondeveloped  countries for the production of nonessential medicines. Governments of low- and  middle- income countries should reform national intellectual property to enable  TRIPS flexibilities and facilitate access to medicines for all

• The public sector, in collaboration with the  private sector, should strive to made essential medicines available at  affordable prices and improve access to healthcare

• Governments, in collaboration with the private  sector, should give greater priority to treat chronic disease and improve the  accessibility to treat them. 

The task force report concluded that increasing  access and affordability of essential medicines was crucial for realizing MDG 8  of advancing international partnerships as well as achieving the MDGs on  reducing child mortality, improving maternal health, and combating HIV/AIDS,  tuberculosis, malaria, and other diseases (4). 

A Forward-Looking Review to Promote An  Agreed Action Agenda to Achieve the Millennium Development Goals by 2015

 (United  Nations, New York, February 2010), 

www.un.org/ga/search/view_doc.asp?symbol=A/64/665

http://mdgs.un.org/unsd/mdg/Resources/Static/Products/Progress2010/MDG_Report_2010_En.pdf

What Will It Take to Achieve the Millennium  Development Goals: An International Assessment

 (United Nations Development  Program, New York, June 2010), 

http://content.undp.org/go/cms-service/stream/asset/?assetid=2620072

Millennium Development Goal 8–Strengthening  the Global Partnership for Development in a Time of Crisis: MDG Gap Task Force  Report 2008

www.un.org/esa/policy/mdggap/mdg8report_engw.pdf

Articles

CSR and Sustainability Forum

An upcoming summit will assess the progress and gaps in realizing the UN Millennium Development Goals, including outcomes from global health initiatives.

Evaluating Global Health Progress in the Millennium Development Goals

(Abott Park, IL) and its  philanthropic foundation, the Abbott Fund, are providing $335,000 in initial  humanitarian aid to help with flood relief efforts in Pakistan. The funding includes  $175,000 in grants to 

National Commission  for Human Development

. Abbott is donating antibiotics, rehydration solutions,  vitamins, and medicines valued at $160,000 to AmericaCares, 

, and the  Swat Relief Initiative. In addition, Abbott Pakistan is working in partnership  with the 

 to develop a plan for local Abbott employees to contribute cash donations and  volunteer to help package food and additional relief supplies for distribution  in affected areas. 

 (Ludwigshafen, Germany) contributed  EUR 250,000 ($317,000) to the 

United Nations Central  Emergency Response Fund

 for immediate aid to the flood victims in Pakistan.  The donation is provided by the BASF Social Foundation. 

AIDS Drug Assistance Programs (ADAP) Crisis Task Force

 have formed an agreement to assist ADAPs to provide  antiretroviral medicines to people living with HIV and AIDS. The agreement  builds on a pact, signed in March 2010, for a multiyear enhancement. The ADAP  Crisis Task Force was formed in December 2002 by state AIDS/ADAP directors  concerned about the fiscal shortfalls in funding AIDS treatment programs.  

 (Milwaukee, WI), a process control  and automation provider, is donating $130,000 in Monterrey,  Mexico, for relief efforts stemming from the aftermath of Hurricane Alex. In  addition, 157 Johnson Control employees delivered 1200 aid packages to local  residents. 

. (Whitehouse Station, NJ) reported  that the Merck Company Foundation and the Bill & Melinda Gates Foundation  are committing $60 million to support Botswana’s African Comprehensive HIV/AIDS  Partnership (ACHAP), a public–private partnership. With the current pledge and  past funding, the total cash contributions of Merck and the Bill & Melinda  Gates Foundation amount to $166.5 million. Merck will also continue the  contribution of its HIV medicines: Crixivan (indinavir), Stocrin (efavirenz),  Atripla (efavirenz, emtricitabine, and tenofovir), and Isentress (raltegravir). 

In other news, Merck & Co. is launching the 

 (BTAN), a collaborative network designed to train and mobilize advocates for  treating and caring for African-American Americans with HIV, strengthening  local and national leadership, raising HIV science and treatment literacy, and  advocating for policy change and research priorities.

A roundup of developments on corporate social responsibility from the bio/pharmaceutical industry, its suppliers, and other public and private organizations.

As pharmaceutical  companies deal with cost pressures, restructuring, and an increasingly global  supply chain, they are examining ways to improve all aspects of the value  chain, including procurement and sourcing of pharmaceutical ingredients. To  address these issues, the Drug, Chemical, and Associated Technologies  Association (DCAT), along with its partner, the Pharma Forum and Chemical Group  of the Institute of Supply Management (ISM), will be offering perspectives from  the pharmaceutical majors and their suppliers on ways to implement a proactive procurement strategy through collaborative and innovative models at an upcoming educational program, the 

DCAT/ISM Sourcing Summit ’10:Forward Thinking Sourcing. 

 The program will be held Nov. 3 and 4, 2010, in New Brunswick, New Jersey. Designed  for sourcing and supply management professionals and their suppliers, the  program is presented annually in New Brunswick.

“The focus  is on the future at this year’s Sourcing Summit,” said DCAT Executive Director  Margaret Timony. “The Supply Management Committee has pulled together a dynamic  program on the analysis, trends, and best practices that will define the future  of supply management and help supply managers deliver value to their companies.  We are looking forward to another great turnout for this event. ”


 Procurement/sourcing  plays an important role in pharmaceutical companies’ overall strategies and the  successful management of the pharmaceutical supply chain is crucial to  realizing those strategic objectives. Two executives from Merck & Co.  (Whitehouse Station, NJ) will address that topic. Richard Spoor, senior  vice-president of global procurement at Merck & Co. (Whitehouse Station,  NJ) will discuss the role of global procurement at Merck, the contribution that  the company’s procurement activities play in realizing cost-savings for the  company, and challenges facing the industry. Stephen J. Fecho Jr., manager of  supply market intelligence at Merck & Co., will discuss the role that  market intelligence plays in formulating and executing a procurement strategy. 

Increased  globalization and the attendant elongation and greater complexity of the  pharmaceutical supply are key factors for procurement organizations and  their suppliers. Robert M. Reilly, senior director and chief security officer at  Eli Lilly (Indianapolis, IN), will address security issues in the supply chain  and the need for external and internal partnerships to resolve those  challenges. Laurie J. Chipperfield, director of technology and strategic  sourcing at Pfizer (New York), will examine pharmaceutical outsourcing in China  by addressing issues such as supplier selection, intellectual-property  protection strategies, and considerations in contract structures. And Kendra A.  Martello, assistant general counsel at the Pharmaceutical Research and Manufacturers of America, will address the future legislative and regulatory landscape for  API manufacturers.


Supplier innovation is important to keep pace with the changes in the  pharmaceutical industry overall, and these dynamics oblige actions by both  procurement and sourcing organizations and their external suppliers. The  concept of “collaborative innovation” in procurement will be explored by Gregg  Brandyberry, CEO of Wildfire Commerce, senior advisor of procurement and  analytic solutions at the management-consulting firm A.T. Kearney, and former vice-president of procurement of global systems and operations for GlaxoSmithKline (London). His presentation will focus on practical ways in  which sourcing/procurement organizations can achieve not only continuous  improvement but true innovation in building value-added relationships with  suppliers. And offering a supplier perspective, Eric T. Evans, vice-president  and general manager of the global active pharmaceutical ingredient division of  Covidien (Mansfield, MA) will provide insight into risk management, including  metrics for measuring risk and risk-mitigation strategies.

Further information about the DCAT/ISM Sourcing  Summit can be found 

Sourcing

Procurement, sourcing, and partnerships with external suppliers take on greater importance as the pharmaceutical supply chain becomes increasingly more complex and global.

DCAT Conference Focuses on Procurement/Sourcing Strategies

Producing the single enantiomer of a bioactive chiral compound is an ongoing challenge. Chemocatalysis and biocatalysis often are the key in asymmetric synthesis for producing a compound with desired yield and enantiopurity.  

(IMAGE: DON BISHOP, BRAND X PICTURES, GETTY IMAGES) 

Nonnatural amino acids are important building blocks as chiral intermediates in small-molecule drug synthesis, and they also play a crucial  role in peptide synthesis. Researchers at Vanderbilt University's Vanderbilt Institute of Chemical Biology in Nashville, Tennessee, recently reported on their work  that addresses one of the limitations in peptide synthesis, the difficulty of incorporating nonnatural amino acids in peptides and controlling stereoselectivity. The team developed a novel way of making amide linkages (1).  

Amides typically are made by combining the acyl group from a carboxylic acid derivative with an amine with the elimination of water. Although dehydrative approaches generally are used in amide formation, oxidative and radical-based methods also can be used. In amide-bond formation, carbon and nitrogen bear electrophilic and nucleophilic character, respectively, during the carbon–nitrogen bond-forming step (2).   

The researchers' approach instead used a-halonitroalkanes as the acyl source. The amines and nitroalkanes were activated by an electrophilic iodine source that led directly to amide products. Preliminary observations supported a mechanism in which the polarities of the two reactants were reversed during carbon–nitrogen bond formation relative to traditional peptide synthesis. The nitroalkanes as acyl-anion equivalents provided a conceptually new route to amide and peptide synthesis and one that might allow for efficient peptide synthesis that relies on enantioselective methods (1, 2). 

A team led by Eric Jacobsen, professor of chemistry in the Department of Chemistry and Chemical Biology at Harvard University, used organocatalysts, achiral thiourea-containing catalysts, for the asymmetric version of the Strecker synthesis. The Strecker synthesis is a series of chemical reactions that synthesize an amino acid from an aldehyde or ketone. Although chemocatalysis and enzymatic methods can be used to synthesize enantioenriched a-amino acids, synthesizing nonnatural amino acids is challenging. Alkene hydrogenation may be used in the enantioselective catalytic synthesis of many classes of amino acids, but it is not possible to obtain a-amino acids bearing aryl or quaternary alkyl a-substituents using this method (3, 4).  

The researchers addressed this problem through the Strecker synthesis, but used an organocatalyst that avoids the problem of using a precious metal catalyst to control a key step in the synthesis. The Strecker synthesis, which involves the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis, is used for the  synthesis of racemic a-amino acids. In an asymmetric Strecker synthesis, stoichiometric amounts of a chiral reagent can yield enantiomerically enriched a-amino acids on gram and kilogram scales. The researchers reported that Strecker syntheses using substoichiometric quantities of a chiral reagent could be an alternative, but catalytic methods in this approach have been limited to preparative scales because of the complexity of the catalysts and the need to use hazardous cyanide sources (3, 4).  

Instead, the researchers used a relatively simple chiral amido-thiourea catalyst to control the key hydrocyanation step for the syntheses of highly enantiomerically enriched nonnatural amino acids. The catalyst is compatible with aqueous cyanide salts, which are safer and easier to handle than other cyanide sources, thereby potentially making the method adaptable to large-scale synthesis. The researchers used this method to obtain enantiopure amino acids that are not readily prepared by enzymatic methods or by chemical hydrogenation (3, 4). 

Researchers at Merck & Co. (Whitehouse Station, NJ) and Codexis (Redwood, CA,) a company specializing in biocatalysis, recently reported on their work on the biocatalytic asymmetric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the active ingredient in Merck's antidiabetes drug Januvia. The biocatalytic process replaced a rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of sitagliptin. The researchers started from an (

)-selective transaminase that showed slight activity on a smaller truncated methyl ketone analog of the sitagliptin ketone. After creating this transaminase, which had marginal activity for the synthesis of the chiral amine, they further engineered the enzyme through directed evolution to optimize its use for large-scale manufacturing. The initial (

)-selective transaminase was a homologue of an enzyme from 

)-specific transamination of methyl ketones and small cyclic ketones. For the sitagliptin synthesis, the researchers generated a structural homology model of this transaminase and found that the enzyme would not bind to the prositagliptin ketone because of steric interference and potentially undesired interactions. The evolved transaminase was a successful biocatalyst that  synthesized the chiral amines that previously were accessible only through resolution (5, 6). 

The research was given the Greener Reaction Conditions Award by the US Environmental Protection Agency's Presidential Green Chemistry Challenge Awards in June 2010, an annual recognition of green-chemistry applications. The evolved transaminase had a compounded improvement in biocatalytic activity of more than 25,000-fold with high enantiopurity and no detection of the (

-enantiomer of sitagliptin being formed. The enzymatic approach eliminated the high-pressure hydrogenation route, metal catalysts (i.e., rhodium and iron), and additional chiral purification steps in the rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of sitagliptin. The biocatalytic route improved productivity by 56%, increased yield by 10–13%, and reduced waste by 19%. Merck scaled up the process to pilot scale in 2009,  according to information from EPA (6). 

Researchers recently reported on the use of computational design of a biocatalyst for stereoselective bimolecular Diels–Alder reactions. Diels–Alder is a cycloaddition reaction between a conjugated diene and a substituted alkene to form a substituted cyclohexene system. The researchers noted that no naturally occurring enzyme has been shown to catalyze an intermolecular Diels–Alder reaction, a function that  could be valuable in increasing reaction rates and stereoselectivity. The researchers developed a 

 computational design and experimental characterization of enzymes catalyzing a bimolecular Diels–Alder reaction with high stereoselectivity and substrate specificity. The researchers studied the Diels–Alder reaction between 4-carboxybenzyl 

The researchers previously used Rosetta computational design methodology to design enzymes for catalyzing  bond-breaking reactions, so their challenge was to develop a computational design for bond-forming reactions. Bimolecular bond-forming reactions, however, present a greater challenge because both substrates must be bound in the proper relative orientation for the reaction to accelerate and achieve stereoselectivity. Their  work  involved general acid–base catalysis and covalent catalysis. The Diels–Alder reaction provided the opportunity to alter the reaction rate by modulating molecular orbital energies (7). 

Although the researchers succeeded in computationally designing an enzyme that catalyzes an enantio and diastereoselective intermolecular reaction, they noted the need to further  improve their computational design methods. Only 2 of the 50 designed enzymes tested had measurable activity, and higher success rates and higher overall activities are desirable. However, their work holds promise. In addition to catalyzing new reactions with high substrate specificity and stereoselectivity, one of the potential advantages of the 

 enzyme design is that once an initial active enzyme is engineered, it can be modified to catalyze similar reactions with other substrates.  

485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, 

1. B. Shen, D. Makley, and J.N. Johnston, 

 6. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2010 Award Entries and Recipients" (EPA, Washington, DC, 2010). 

APIs

Chemocatalytic and biocatalytic approaches in asymmetric synthesis help provide a pathway for producing single-enantiomer drugs.

Exploring Chiral Chemistry

Outsourcing by bio/pharmaceutical companies is increasing in volume and scope, but what are some factors that may constrain growth? Effective communication and effective relationship management, from both a sponsor company and contract manufacturing organization (CMO) perspective, pose a potential bottleneck to realizing the potential of outsourcing. 

Even before the current economic downturn, biomanufacturers said that "establishing a good working relationship" was the most difficult and challenging aspect of outsourcing (1). As outsourcing expands, CMOs and client companies will need to improve their respective skill sets to manage these external relationships. The great majority of CMOs surveyed in BioPlan Associates' 

7th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production 

said their customers had unrealistic timeframes (82% said so) and lacked the ability to communicate effectively (80% said so). The survey included 327 individual respondentsat biopharmaceutical manufacturers and CMOs in 35 countries. 

Insufficient communication is a well-documented managerial problem. Managers must be able to lead in a highly dynamic environment and create an organization where communication effectively flows at all levels (2), which is sometimes a skill set not adequately developed by biomedical scientists in managerial positions. Academic entrepreneurs account for 43.1% of founders of biotechnology companies, a level that is far greater than any other industry (3). There may be some correlation between this predominance of scientists in managerial roles and the relative success of biopharmaceutical organizations as businesses.  			

Perhaps as a result of the growth in outsourcing, problems in the client–contractor relationship continue to expand. The 2010 BioPlan study identified 11 crucial issues that CMOs cited  as the most common mistakes made by their clients (i.e., biomanufacturers). CMOs cited two main points: "clients don't plan their technology-transfer process" and "clients don't communicate with us effectively."   

Operational issues are also crucial.  Seventy-eight percent of the CMOs surveyed said that "clients wanting to contain cost by doing limited development runs but still expecting successful full-scale manufacturing" was either a "very important" or "important" problem. This issue involves cost containment and time-to-project completion. It also suggests that the majority of biomanufacturers, who are under increasing cost and time pressures, are pushing that stress onto their suppliers. The second relationship problem involves unrealistic expectations:  Forty-six percent of CMOs cited as a "very important" concern that "clients don't build in sufficient time for the project" (i.e., unrealistic timeframes). 

	Among the 25 factors evaluated in the BioPlan survey, relationship issues are near the top of the list of problems cited by sponsor companies (see Figure 1). Although the relationship trend improved slightly this year compared with the previous years, relationships between sponsor companies and CMOs are far from optimal Only 58% of CMOs said that "establishing a good working relationship" was "very important" in the 2010 BioPlan survey compared with 63% in the 2009 survey (see Figure 1).	

   Figure 1: Crucial issues in biopharmaceutical outsourcing (1).			

One industry expert sums up the problem. "The recent increase in pharmaceutical outsourcing activities is creating headaches at pharma companies," said Mark Mazzie, managing director at the Center for Professional Innovation and Education (Malvern, PA), a pharmaceutical training company, in a recent interview with BioPlan Associates

"This is especially true for companies that haven't trained their managers to manage these new relationships or to understand how time-consuming and difficult offsite managing can be. With the current economic crunch, everyone is being asked to do more with less, so these problems are likely to increase unless personnel are given the requisite skills to manage these tasks." 

Operational concerns are also an issue. The 2010 survey showed that 64% of respondents said that compliance with quality standards was "very important" compared with 59% in the 2009 survey. These quality issues may be the result of worries about possible cost-cutting and service reductions on the part of vendors. Biologics manufacturers may not yet be sufficiently confident that their outsourcing partners can guarantee quality standards. 

Sixty percent of respondents said that "protecting intellectual property (IP)" was critical. These IP concerns may be surfacing because of increased interest in offshore (i.e., international) outsourcing. Also, sponsor companies' worries about handling cross-contamination issues increased again in 2010. Only 20% said that it was important in 2007, but 52% of client companies identified it as important in 2009, and 58% did so in 2010.  

This year, nearly half (48.2%) of biopharmaceutical manufacturers surveyed said they expect to increase their budgets for biopharmaceutical CMO outsourcing. As more companies outsource, the need for effective project management will grow. In times when there was less available capacity, CMOs with better technologies, expertise, and facilities, would have simply been too busy and prebooked to handle new clients. Many of these shifts are the result of financial pressures, which  are creating real concerns over hiring and staff allocation. Not only do outsourcing service providers need to justify the cost benefits, they now need to evaluate the effect of outsourcing on fill-time equivalents, staff allocations, and speed to project completion. 

Until effective project-management processes are in place, and the skills to manage external relationships are established by both CMOs and client companies, the limiting factor in outsourcing may be relationship management. Human factors such as relationship building, effective communication, and risk sharing are difficult to quantify but are crucial for long-term success.  

 is president of BioPlan Associates, tel. 301.921.5979, 

 E. Langer, "How Scientist/Founders Lead Successful Biopharmaceutical Organizations: A Study of Three Companies," Antioch University, Yellow Springs, OH,  2008.  

, The Dynamics of California's Biotechnology industry

 (Public Policy Institute of California, San Francisco, 2005).

Outsourcing

Relationship management is a limiting factor to growth in biomanufacturing outsourcing.

Project Managers Wanted

US  Secretary of State Hillary Clinton spoke Aug. 16, 2010, at the John Hopkins  School of Advanced International Studies in Washington, DC, to outline the US  policy in global health and how it marries with the country’s foreign policy  objectives.


 Her  comments follow the announcement by President Barack Obama in May 2009 of the Administration’s funding for the US Global Health Initiative (GHI), a dedicated  effort by the US government in global health that seeks to create an  integrated, coordinated, sustainable system of care in working with developing countries  in providing assistance related to health and healthcare. The plan includes  funding of $63 billion for six years (fiscal year 2009 through fiscal year  2014). The Administration launched the GHI as part of a policy that seeks to create better cohesion among US efforts, develop new tools and technologies for delivering assistance, and desing better models in providing in aid. “We cannot simply confront individual preventable  illnesses in isolation,” said Obama on May 5, 2009, in a prepared statement.  “The world is interconnected, and that demands an integrated approach to global  health.” 

In her comments in August 2010, Clinton emphasized that  global health  plays an important role in the country’s foreign policy and national  security interests. “We invest in global health to strengthen fragile or  failing states,” she said, pointing to the destabilizing effect that national  health crises can have on a country such as in the impact of HIV/AIDS. “…We invest  in global health to promote social and economic progress and to support the  rise of capable partners who can help us solve regional and global problems,”  she added. “….We invest in global health to protect our nation’s security,”  pointing to the need for effective global health systems for tracking health  data, monitoring threats, and coordinating response such as in the case of severe acute respiratory syndrome (SARS) and  the H1N1 virus. “We invest in global health as a tool of public diplomacy…Giving  people a chance at a long and healthy life or helping protect their children  from disease conveys as much about our values as any state visit or strategic  dialogue ever could,” she said. 


 Clinton provided an update of on the progress and future direction of  GHI. “The United States is investing $63 billion—first, to sustain and  strengthen our existing health programs, and second, to build upon those  programs and take their work to the next level by collaborating with  governments, organizations, civil society groups, and individuals to help  broaden the improvements in public health that we can expect,” she said. “We're  shifting our focus from solving problems, one at a time, to serving people, by  considering more fully the circumstances of their lives and ensuring they can  get the care they need most over the course of their lifetimes. ... 

She pointed to several efforts underway, including  the United States President’s Emergency Plan for AIDS Relief (PEPFAR), which  was formed in 2003 under George W. Bush and has continued under the current  Administration. In 2008, funding for PEPFAR was $5 billion, and the budget  request for fiscal year 2011 is $5.7 billion to meet a goal of raising the  number of people served under the program to 12 million. She added that  the Administration is increasing support for the President’s Malaria Initiative  (PMI) with the goal of reducing the burden of malaria by 50%, or by 450 million  people. PMI was launched in June 2005 by President Bush as a five-year,  $1.2-billion program to scale up malaria prevention and treatment interventions  in 15 high-burden countries in sub-Saharan Africa. Clinton also pointed to goals  of increasing prevention of tuberculosis (TB) and efforts to improve child and  maternal health. 

These specific goals of GHI and others are detailed  by the US Agency for International Development (USAID). USAID is an independent  agency that provides economic, development, and humanitarian assistance globally  in support of the foreign policy goals of the United States. USAID details key  goals in several areas: 

• HIV/AIDS: Through PEPFAR, support  the prevention of more than 12 million new HIV infections, provide direct  support for more than 4 million people on treatment, and support care for more  than 12 million people, including 5 million orphans and vulnerable children

• Malaria: Through PMI, reduce  the burden of malaria by 50% for 450 million people, representing 70% of the  at-risk population in Africa, and expand malaria efforts into Nigeria and the  Democratic Republic of the Congo

• TB: Save  approximately 1.3 million lives by reducing TB prevalence by 50% by treating 2.6  million new TB cases and 57,200 multidrug resistant cases of TB 

• Maternal health: Reduce maternal mortality by  30% in assisted countries

• Child health: Save  approximately 3 million children's lives, including 1.5 million newborns, by  reducing under-five mortality rates by 35%in assisted countries

• Nutrition: Reduce  child undernutrition by 30% in assisted food-insecure countries, in conjunction  with the President's Feed the Future Initiative, a federal program for providing nutrition support to the developing world

• Neglected  tropical diseases: Reduce the prevalence of seven neglected tropical  diseases by 50% among 70% of the affected population and eliminate  onchocerciasis in Latin America by 2016 and lymphatic filariasis and leprosy globally  by 2017

• Reproductive health: Reduce first births by women under the age of 18 to 20%  and increase contraception in assisted countries. 


 Clinton emphasized that meeting the goals of GHI requires  addressing systemic challenges that surround PEPFAR, USAID programs, and other  US-funded health programs by improving logistical, structural, legal, and  political barriers that may be preventing the implementation of aid. “We need  to lay the groundwork now for more progress down the road by tackling some of  these systematic problems and working with our partner countries to uproot the  most deep-seated obstacles that impeded the own people’s health,” she said. “That  is how we can make our investments yield the most significant returns and save  the greatest number of lives, today and tomorrow.”

Clinton outlined six key ways in which the  Administration is pursuing these goals. The first way involves capacity-building. Under this approach,  the US is working with countries to create and  implement strategies for health based on the distinct needs and existing  strengths of assisted countries by building their healthcare  capacity toward the goal of managing, overseeing, coordinating, and operating health  programs for the long term. These efforts may involve training of community  health workers, setting up supply chains and drug protocols, and establishing  health-information systems to collect and analyze data to allow for continuous  monitoring and improvement of performance.  

A second effort involves improving maternal and  child health, particularly for girls, by  improving access to healthcare by addressing educational, economic, social, and  cultural barriers that may impede that access. Clinton said the US is working  with governments, civil society groups, and individuals, including national  health ministers, healthcare administrators, and healthcare providers to ensure that women  and girls are considered when forming healthcare policy and spending allocation in assisted countries. 

A third effort addresses the way the US measures  and evaluates its own impact. “This includes shifting our focus from ‘inputs’  to ‘outcomes and impacts’—that is determining our success not simply by how  many bed nets we distribute but by how many people actually avoid malaria by  using them correctly–a fuller picture that demands that we invest in improving  how we ourselves collect, analyze, and share data,” said Clinton. 

Clinton said that another focus would be to invest  in innovation to develop tools that help diagnose, prevent, and cure disease in  communities where  aid is administered, particularly in areas that are remote  and poor in resources. “Many of the tools and techniques we use to keep people  healthy here in the United States are unsuited to the realities of life in  other places,” she said. “So we need to be innovative about how to reach people  effectively.” For example, Clinton pointed to the use of cell phones in remote areas  that may lack health clinics as a tool for communicating critical health messages  directly to patients such as women with newborns. 

A fifth goal is to improve coordination and  integration within and among US agencies by bundling services. She pointed to  PEPFAR’s efforts in Kenya by linking HIV/AIDS programs with maternal and child  health, TB, and family planning. She also pointed to the importance of  involving multiple federal agencies in GHI, whose overall policy is directed by  US Deputy Secretary of State Jack Lew. Day-to-day operations of GHI are run by Raj  Shah, USAID administrator, Eric Goosby, US global AIDS coordinator of PEPFAR,  and Tom Frieden, director of the Centers for Disease Control. Other agencies,  including the National Institutes of Health, the Department of Health and Human  Services, the Department of Defense, and the Peace Corps are also involved in  the effort. 

The sixth point made by Clinton is of the need to  align US efforts with other donor countries and multilateral organizations. She  pointed to the public–private partnership, the Global Fund to Fight AIDS,  Tuberculosis, and Malaria, as an example of “creating a new model for how the  global community can come together to contribute and coordinate in the fight  against epidemics.”

In  concluding comments, Clinton emphasized the interrelationship between global  health, US diplomacy, and US relations with countries receiving aid. “Too  often, we’ve seen health relegated to the sidelines and treated as a lesser  priority in terms of how much money is allocated and how much attention is  devoted,” she said. “In fact, we’ve seen that the United States and other  donors come in with money, and countries actually take money away from health  thinking that we’re going to make up the difference. The United States is willing  to invest our money, our time, and our expertise to improve health in  countries, but were are now asking governments to demonstrate a similar  commitment in terms of human resources, serious pledges to build capacity, and  where feasible, financial support.”

Secretary of State Hillary Clinton details the progress and future direction of the US role in the Global Health Initiative.

PTSM: Pharmaceutical Technology Sourcing and Management-09-01-2010

Evaluating Global Health Progress in the Millennium Development Goals

CSR and Sustainability Forum

DCAT Conference Focuses on Procurement/Sourcing Strategies

Exploring Chiral Chemistry

Project Managers Wanted

Secretary of State Clinton Outlines US Role in Global Health