Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

Approaches centre on ways to optimise process conditions and operability.

Process chemists face the challenge of developing cost-effective and efficient commercial manufacturing routes for APIs. They encounter the challenges of increasing product yield, achieving greater stereoselectivity and regioselectivity, and improving process conditions, such as temperature and pressure, all in a means to produce a high-quality pharmaceutical compound in a safe manner A variety of tools may be used in this effort, including the application of green-chemistry approaches, such as biocatalysis, solvent replacement and continuous-flow chemistry, to help achieve more efficient chemical transformations under improved reaction conditions. 

In June 2012, Codexis, a company specialising in biocatalysis, and Yi Tang, professor in the Department of Chemical and Biomolecular Engineering at the University of California at Los Angeles (UCLA) (US), were awarded the "2012 Greener Synthetic Pathways Award" as part of the US Environmental Protection Agency's (EPA) Presidential Green Chemistry Challenge Awards for developing a biocatalytic route for making simvastatin, the active ingredient in Merck & Co.'s anticholesterol drug Zocor, which is now off patent (1). Codexis and Tang won the award this year after having made prior submissions of the new process in 2010 and 2011 (2–4).			

For the simvastatin route, Codexis licensed technology from Tang. The previous synthetic routes to simvastatin involved converting lovastatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthesis. In the first route, lovastatin was hydrolysed to the triol, monacolin J, followed by protection with selective silylation, esterification with dimethyl butyryl chloride and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2' carbon with methyl iodide and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were mass-intensive due to protection and deprotection (1–4). 

The route developed by Tang and his group circumvented protection and deprotection and resulted in greater atom economy, reduced waste and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase produced by 

 that is involved in synthesising lovastatin and that can accept nonnatural acyl donors. Recognising that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (1–5). Codexis licensed Tang's technology, engineered the enzyme further and optimised the simvastatin manufacture. 

The biocatalyst LovD selectively transferred the 2-methylbutyryl side chain to the C8 alcohol of monacolin J sodium or ammonium salt. The acyl donor, dimethylbutyryl-S-methylmercaptopropionate (DMB-SMMP), is efficient for the LovD-catalysed reaction, is safer than traditional alternatives and is prepared in a single step from inexpensive precursors, according to the awards summary report (1). Codexis licensed this process from UCLA and subsequently optimised the enzyme and the chemical process for commercial manufacture. Codexis carried out nine iterations of 

 evolution, creating 216 libraries and screening 61,779 variants to develop a LovD variant with improved activity, in-process stability and tolerance to product inhibition (1). The approximately 1000-fold improved enzyme and the new process pushed the reaction to completion at high substrate loading and minimised the amounts of acyl donor and of solvents for extraction and product separation. In the new route, lovastatin is hydrolysed and converted to the water-soluble ammonium salt of monacolin J. (1–5). 

As specified in the Presidential Green Chemistry Challenge Awards summary report, the genetically evolved variant of LovD acyltransferase from E. coli uses DMB-SMMP as the acyl donor to make the water-insoluble ammonium salt of simvastatin. The only coproduct of simvastatin synthesis is methyl 3-mercaptopropionic acid, which is recycled. The final yield of simvastatin ammonium salt is more than 97% at a loading of 75 g/L of monacolin J. It avoids the use of several hazardous chemicals including 

-butyl dimethyl silane chloride, methyl iodide and 

-butyl lithium. More than 10 metric tons of simvastatin have been manufactured using this new process (1).  

Pfizer also employed a more environmentally approach in developing a biocatalytic route to making atorvastatin, the active ingredient of Lipitor and submitted the process as an entry for consideration to the US EPA's Presidential Green Chemistry Challenge Awards (1). The new process incorporated a waterbased 2-deoxyribose-5-phosphate aldolase (DERA) enzyme at the beginning of the route to make a lactol from an amino aldehyde (i.e., 3-phthalimidopropionaldehyde; PPA) and acetaldehyde (1). The synthesis eliminated the use of cyanide or azide moieties to introduce nitrogen because it is already present in the lactol. In contrast to the original synthesis, the DERA enzyme set both stereocenters with high selectivity in water at room temperature. Converting the resulting lactol into isopropyl acetonide atorvastatin (IAA) involved only four high-yield chemical steps (oxidation, esterification, deprotection, Paal Knorr). The IAA product was isolated as a solid and IAA was converted to atorvastatin (1). The new synthesis eliminated the previous high-pressure hydrogenation step with its associated metal catalysts. It also avoided pyrophoric n-butyl lithium and its associated butane waste gas. FDA approved the new manufacturing process in April 2010, and Pfizer manufactured commercial-scale validation batches in 2011 and is currently transitioning to full-scale commercial manufacture, according to the US EPA's Presidential Green Chemistry Challenge Awards summary report (1). 

The Grignard reaction is a well established reaction in organic chemistry, but it poses some challenges in scaling up to commercial scale: strongly exothermic activation and reaction steps; heterogeneous reactions with potential problems suspending and mixing the reaction mixture; and operational hazards posed by ethereal solvents such as diethyl ether (1). Eli Lilly developed safer Grignard chemistry using a continuous stirred tank reactor (CSTR) that allows continuous formation of Grignard reagents with continuous coupling and quenching operations, a process in which the company submitted an entry to the 2012 US EPA Presidential Green Chemistry Challenge Awards (1). According to the entry, the CSTR approach mitigated hazards by operating at small reaction volumes, performed metal activation only once for each campaign, and used 2-methyltetrahydrofuran as a Grignard reagent and reaction solvent, resulting in products with enhanced chemo- and stereo-selectivity. Relative to batch processing, the continuous approach allowed steady-state control and overall reductions up to 43% in magnesium, 10% in Grignard reagent stoichiometry and 30% in process mass intensity (1).  

Improved solvents for making diaryl aldimines

Imines are intermediates used in many pharmaceutical syntheses. Diaryl aldimines, for example, are used in the synthesis of the anticancer drug Taxol (paclitaxel) and the anticholesterol drug Zetia (ezetimibe) (1). Traditional syntheses of diaryl aldimines often require hazardous solvents and include energy-intensive, multihour reflux steps. Although some imine syntheses use more benign solvents or conditions, they still require long reaction times, recrystallisation, or other environmentally harsher procedures. Jacqueline Bennett, professor in the Department of Chemistry and Biochemistry, State University of New York (SUNY) Oneonta (US) and the SUNY Research Foundation (US), developed a process that used ethyl L-lactate as a solvent to synthesize imines. The process was submitted as an enty to the 2012 US EPA's Presidential Green Chemistry Challenge Awards (1). According to the awards summary report, the method was efficient under ambient conditions, required less solvent than other methods, had a median yield of more than 92% and had a median reaction time of less than 10 min (1). The resulting imines were generally sufficiently pure h without recrystallisation as the polarity of ethyl L-lactate was modulated by adding water. The starting materials remained dissolved, but the imine crystallised out of solution as it formed (1). Although traditional methods often drive reactions forward by removing water, this method drove the reaction forward by removing the product through crystallisation, according to the summary report (1). Bennett and her research team have synthesised nearly 200 imines using this method and filed a US patent for the process (1, 6). 

Another interesting entry to the US EPA's Presidential Green Chemistry Challenge Awards involved the use of ethylene in fine-chemical synthesis developed by T. V. RajanBabu, professor in the Department of Chemistry, Ohio State University (US) (1). According to the awards summary report, practical methods using carbon feedstock sources as starting materials to form enantioselective carbon–carbon bonds are not common. A broadly applicable reaction using ethylene to install vinyl groups enantiomerically, as developed by RajanBabu, could have significant impact in fine-chemical synthesis.  

RajanBabu and his team developed highly catalytic (substrate–catalyst ratio up to 7,412:1) protocols for nearly quantitative (isolated yields of more than 99% and highly selective (approximately 100% regioselectivity; enantiomeric ratios of more than 99:1) codimerisation of ethylene and various functionalised vinylarenes, 1,3-dienes, and strained alkenes. These reactions proceeded under mild conditions (–52 °C to 25 °C; 1 atmosphere of ethylene) to produce intermediates, such as 3-arylbutenes, which can be transformed to nonsteroidal anti-inflammatory drugs (NSAIDs) in two steps. These reactions consume both starting materials, leaving no side products. Successes include highly enantioselective syntheses of common NSAIDs, such as ibuprofen, naproxen, flurbiprofen and fenoprofen, from the corresponding styrenes and ethylene (1).  

Cyclic and acyclic 1,3-dienes also underwent efficient enantioselective addition of ethylene. Syntheses of several 1-vinylcycloalkenes and 1-substituted-1,3-butadienes achieved yields up to 99%, according to the awards summary report (1). The approach has also been applied to other biologically relevant classes of compounds, including bisabolanes, herbindoles, trikentrins, steroid D-ring 20S- or 20R-derivatives, (–)-desoxyeseroline, pseudopterosin A–F, G–J and K–L aglycones, and helioporins (1).  

Chemicals, intermediates, and reagents as well as byproducts of synthetic processes can have toxic properties and be present as impurities at low levels in an API or final drug formulation. The detection and removal of these impurities are of crucial importance to process chemists, particularly in the case of genotoxic impurities. One of the potentially genotoxic impurities based on structural alerts is acrolein, an a, -unsaturated aldehyde that is used as a building block in the production of pharmaceuticals (7). Researchers at MIP Technologies, a subsidiary of Biotage, and the Universität Dortmund in Germany recently reported on an approach for selective removal of acrolein from APIs using iodixanol as a model API. The acrolein scavenging performance of polystyrene- and silica- based aldehyde scavengers in organic media in the presence of the API iodixanol was tested. Several scavengers were tested, and the resins that the showed highest binding efficiency and selectivity were further evaluated. The most effective and selective scavenging was obtained with polystryene–amine, which removed up to 97.8% of acrolein and only 2.0% of iodixanol within 20 min using a batch-mode extraction procedure (7). 

1. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2012 Award Entries and Recipients" (Washington, DC, 2012) 

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

4. US EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2011 Award Entries and Recipients" (Washington, DC, 2011). 

6. J. Bennett, Green Synthesis of Aryl Aldimines Using Ethyl Lactate, US Patent Application 20110196174 (Aug. 11, 2011).  

Articles

Scaling Up API Syntheses

Patient compliance is important when developing a drug-delivery system, particularly when treating chronic diseases that require daily administration. One possible alternative to daily injections may be a programmable, wirelessly controlled microchip with an implantable device that allows drugs to be released inside the body without percutaneous connections in or on the patient. An implantable microchip device also offers the potential for real-time dose schedule-tracking and for physicians to remotely adjust treatment schedules.

, Robert Farra, president and COO of MicroCHIPS, discusses wirelessly controlled and programmable microchip-based drug delivery as an alternative to subcutaneous injections with Patricia Van Arnum, executive editor of 

Earlier this year, MicroCHIPs reported a successful Phase I human clinical trial in which human teriparatide, a parathyroid hormone fragment [hPTH(1-34)] and anabolic osteoporosis treatment, was delivered from the device 

The primary objective of the clinical trial was to assess the pharmacokinetics (PK) of the released drug teriparatide from the implanted devices. Safety measures included evaluation of the biological response to the implant and monitoring indicators of toxicity. Secondary objectives were to assess the bioactivity of the drug and to evaluate the reliability and reproducibility of releasing the drug from the device. The device and drug combination were found to be biocompatible with no adverse immune reaction. The resulting PK profiles from the implant were comparable to and had less variation than the PK profiles of multiple, recommended subcutaneous injections of teriparatide. The study also demonstrated that the programmable implant was able to deliver the drug at scheduled intervals. Drug delivery and evaluation in patients occurred over a one-month period and provided proof-of-concept measures of drug release and device durability that support implantable device viability for 12 months or more.

Al podcast with Robert Farra, president and COO of MicroCHIPS, who discusses wirelessly controlled and programmable microchip-based drug delivery as an alternative to subcutaneous injections.

The Future of Drug Delivery: Wireless Microchip-Based Drug Delivery

 Targeted drug delivery is particularly important in the delivery of anticancer therapies to lower dosing, reduce side effects, maximize delivery of the drug substance to tumor sites. Recent research in nanolipogels and thermo-responsive lipid-based encapuslation help to advance approaches in this field. Also, a fabrication strategy for calcium carbonate microspheres also represents another interesting advance in the drug-delivery arena. 

Researchers at Yale University recently developed nanolipogels as a new drug transport technology to deliver anticancer therapies. The nanolipogels are nanoscale, hollow, biodegradable spheres, which are capable of holding chemically diverse molecules, according to a July 15, 2012, press release by the National Science Foundation (NSF), which is providing funding for the research. The nanolipogels contained transforming growth factor (TGF-β) and interleukin-2 (IL-2). 

"You can think of the tumor and its microenvironment as a castle and a moat," said Tarek Fahmy, the Yale University engineering professor and co-author of a recent paper detailing the research, in the NSF press release (1). "The 'castles' are cancerous tumors, which have evolved a highly intelligent structure—the tumor cells and vasculature. The 'moat' is the cancer's defense system, which includes TGF-β. Our strategy is to 'dry-up' that moat by neutralizing the TGF-β. We do that using the inhibitor that is released from the nanolipogels. The inhibitor effectively stops the tumor's ability to stunt an immune response." 

Specifically, the researchers developed nanoscale liposomal polymeric gels (i.e., nanolipogels) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers to deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines. The nanolipogel releasing TGF-β inhibitor and IL-2 significantly delayed tumor growth, increased survival of tumor-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration (1). 

"The cytokine can be thought of as a way to get reinforcements to cross the dry moat into the castle and signal for more forces to come in," said Fahmy in the NSF release. “In this case, the reinforcements are T-cells, the body's anti-invader 'army.' By accomplishing both treatment goals at once, the body has a greater chance to defeat the cancer,” he said. 

An important aspect of the nanolipogels is their ability to “package” two completely different kinds of molecules—large, water-soluble proteins, such as IL-2, and smaller water-phobic molecules, such as the TGF-β inhibitor—into a single delivery vehicle, according to the NSF release. The outer shell of each nanolipogel is made from an biodegradable, synthetic lipid that degrades in a controlled manner, can encapsulate a drug-scaffolding complex, and is easy to form into a spherical shell. Each shell surrounds a matrix made from biocompatible, biodegradable polymers that are impregnated with the TGF-β inhibitor molecules. Those near-complete spheres are put in a solution containing IL-2, which gets entrapped within the scaffolding, a process called remote loading, according to the NSF release. The result is a nanoscale drug-delivery vehicle that is small enough to travel through the bloodstream but large enough to be entrapped for delivery to the tumor sites. 

Inhalable and thermo-responsive, fat-encased nanoparticles

Researchers at the University of Sydney in Australia have developed inhalable and thermo-responsive, fat-encased nanoparticles as a possible treatment for lung cancer. The team designed inhalable, targetable particles that can attack tumors but leave healthy cells undamaged, reducing the side effects of cancer treatment, according to a July 27, 2012, University of Sydney press release. The particles consist of a drug encased in a lipid that can be activated using a magnetic field. The researchers incorporated budesonide and superparamagnetic iron-oxide nanoparticles (SPIONs) into lipid particles using oil-in-water emulsification (2). Particle size, chemical composition, responsiveness to magnetic field, thermosensitiveness,  and inhalation performance 

"When exposed to a magnetic field, the encased superparamagnetic nanoparticles vibrate, melting the fat, and releasing the drug," said research leader Wojciech Chrzanowski and  lecturer in pharmaceutics at the University of Sydney, in the press release. "The system we have developed addresses one of the most important problems related to the side effects of cancer-drug therapies, such as undesired interactions with healthy tissues. Since the drug is hidden in a lipid structure until it reaches the target site, the healthy cells are protected," he said. "We are able to trigger the drug release because our formulation is thermo-sensitive. External stimulus, in our case the electromagnetic field, induces the increase in local temperature within the particles, which activates the drug release. Under the microscope, the external electromagnetic field appears to shake the super paramagnetic nanoparticles in the formulation, producing heat that then breaks open the particles, releasing the drug at the tumor site. Because the formulation includes superparamagnetic particles, we are also able to guide the particles to specific sites using magnets,” he explained. 

The researchers found that particles of average diameter 2–4 μm with budesonide and SPIONs inside the lipid matrix responded to a magnetic field with 100% extraction at a distance of 5 mm. Formulations were shown to have accelerated rate of drug release at hyperthermic temperatures (45 °C)–controlled release. The produced inhalation dry powder had an inhalable fine particle fraction of 30%. The lipid system had thermo-sensitive characteristics, suitable for controlled delivery, and the model drug and SPION-loaded lipid system was magnetically active and movable using simple permanent magnets. Overall, the system was shown to have application as a targeted and controlled inhalation therapy (2). 

The research holds potential not only for inhalable formulations, but also for other drug-delivery applications. "Our system holds great potential not only as an inhalable formulation but for a wide range of applications where targeting and externally stimulating or triggering drug release is critical,” said University of Sydney Associate Professor Paul Young and recently appointed head of respiratory technology at the Woolcock Institute of Medical Research, in the release. "The important feature of the system is its ability to 'exploit' the temperature sensitivity of the formulation, so the drug release can be achieved at different temperatures. This is particularly important for multidrug delivery where different active compounds could be released at different times." 

Helmuth Möhwald and his team from the Max Planck Institute of Colloids and Interfaces in Golm, Potsdam, Germany, have developed a technique for producing microspheres for targeted drug delivery. The researchers used porous calcium carbonate microspheres as templates for the production of hollow three-dimensional balls, according to a July 2, 2012, Max Planck Institute press release. Specifically, the researchers showed that three-dimensional hybrid colloidal spheres with integrated functions and collective properties can be fabricated using common inorganic nano-objects as building blocks with polyelectrolyte encapsulation through a simple template strategy, which further opens up the fabrication strategy as an approach for developing hybrid materials with multiple functions and collective properties (3). 

 The researchers used calcium carbonate microsphere and filled the pores of the calcium carbonate spheres with nanoparticles, surrounded the filled calcium carbonate spheres with a web of long protein chains or polymer threads, and then dissolved the calcium carbonate template using acid. The nanoparticles arranged themselves into a porous sphere that was encased in the protein web, according to the release. “We can very easily combine substances to form a multifunctional unit and tailor their chemical and physical properties to the required function,” said Möhwald in the release. The protein web not only covers the hollow sphere, but also is biocompatible and can contain biochemical signalling substances that send the spheres directly to their target in the body. 

1. T. Fahmy et al., “Combination Delivery of TGF-β inhibitor and IL-2 by Nanoscale Liposomal Polymeric Gels Enhances Tumor Immunotherapy,” 

 online, DOI:10.1038/nmat3355, July 15, 2012. 

2. W. Chrzanowski et al., “Magnetized Thermo Responsive Lipid Vehicles for Targeted and Controlled Lung Drug Delivery,” 

 online, DOI: 10.1007/s11095-012-0774-9, May 15, 2012. 

3. X. Yan, J. Li, and H. Möhwald, “Templating Assembly of Multifunctional Hybrid Colloidal Spheres,” 

 online, DOI: 10.1002/adma.201200408, Apr. 23, 2012. 

Nanolipogels for anticancer drug delivery, inhalable and thermo-responsive, fat-encased nanoparticles for targeted drug delivery, and calcium carbonate microspheres are some recent developments.

Drug Delivery Insights: Nanotechnology and Microspheres

The global pharmaceutical market can be best described as a market of shifting growth between developed and emerging markets. Although growth in the global pharmaceutical market will rebound over the next five years, the strong spot will continue to be emerging markets as developed markets in the United States, Western Europe, and Japan see relatively weak growth. Growth in generic-drug spending, globally and particularly in emerging markets, will continue to be robust through 2016. 

Following several years of slowing growth, the global market for medicines is expected to rebound from a recent low of 3–4% growth in 2012 to 5–7% growth in 2016, according to a recent analysis by the IMS Institute for Healthcare Informatics. Growth will primarily be from emerging markets as growth in established markets in the United States, Western Europe, and Japan remains weak comparative to historical levels. Overall, annual global spending on medicines will rise from $956 billion in 2011 to $1 trillion by 2013, to nearly $1.2 trillion in 2016, representing a compound annual growth rate (CAGR) of 3–6%. For purposes of the IMS analysis, spending is reported as ex-manufacturer prices and does not reflect off-invoice discounts and rebates and is converted from local currencies to US dollars. Absolute growth in global pharmaceutical spending between 2012–2016 will be between $220 billion and $250 billion, compared with $298 billion in the prior five years. 

Additionally, patent expiries, which will peak in 2012, as well as increased cost-containment actions by payers, will constrain branded-medicine spending growth through 2016, at 0–3%. Developed markets are expected to experience their lowest annual growth this year, at less than 1% or $3 billion, and then rebound to $18–20 billion in annual growth in the 2014–2016 period. 

Growth in annual global spending is forecast to more than double by 2016 to as much as $70 billion, up from a $30-billion pace in 2012, driven by volume increases in what IMS terms the “pharmerging” markets and some uptick in spending in developed nations. The “pharmerging” markets are defined by IMS as counties with greater than $1 billion absolute spending growth of more than 2012–2016 and which have gross domestic product per capita of less than $25,000 at purchasing power parity. Using that criteria, China is classified as a Tier-1 country, and Brazil, Russia, and India as Tier-2 countries. Tier 3-countries are Mexico, Turkey, Poland, Venezuela, Argentina, Indonesia, South Africa, Thailand, Romania, Egypt, Ukraine, Pakistan, and Vietnam. 

Spending on medicines in developed nations will increase by a total of $60–70 billion from 2011 to 2016, following an increase of $104 billion between 2006 and 2011, according to IMS. The share of pharmaceutical spending in developed markets, which include the US, Europe, and Japan, will decline to 57% of global pharmaceutical spending by 2016 (down from 73% in 2006) as the share of pharmerging markets reach 30% of total global spending by 2016. 

Despite the highest number of patent expiries in history, spending in the US will grow between $35 billion and $45 billion during the next five years, representing an average annual growth rate of 1-4% although this growth still represents historically low levels. The US share of global pharmaceutical spending will decline from 41% in 2006 to 31% by 2016 due to patent expiries and slower brand growth, according to IMS. In the US, $103 billion, or 44% of 2011 brand spending will shift to generic-drugs through 2016. 

In Europe, growth will range from negative 1% to 2% through 2016 due to significant austerity programs and healthcare cost-containment initiatives. This weak growth compares to 3.8% for the period of 2007–2011. The share of global spending by the five major EU markets (Germany, France, United Kingdom, Italy, and Spain) will decline to 13% by 2016 due to slow economic growth and more aggressive cost-containment measures. 

The Japanese market is forecast to grow 1–4% annually through 2016, slightly lower than the rate during the prior five years and reflecting biennial price cuts scheduled for 2012, 2014, and 2016.  Japan’s share of global pharmaceutical spending is expected to remain at roughly 10% through 2016. 

Overall, patent expiries in developed markets will yield a five-year “patent dividend” of $106 billion, reflecting reduced brand spending of $127 billion offset by $21 billion in higher generic-drug spending, according to IMS. Pharma manufacturers will see minimal growth in their branded products through 2016. The market for branded medicines will experience flat to 3% annual growth through 2016 to between $615 billion and $645 billion, up from $596 billion in 2011. In the major developed markets, branded medicine growth will be “severely constrained,” according to IMS, at only $10 billion during the five-year period due to patent expiries, increased cost-containment actions by payers, and modest spending on newly launched products. The pharmerging markets are expected to contribute $25 billion to $30 billion in branded-product growth over the same period. Off-invoice discounts and rebates will offset about $5 billion of global branded medicine growth, according to IMS. 

Health systems in pharmerging markets will nearly double their medicine spending in five years, according to IMS. Annual spending on medicines in the pharmerging markets will increase from $194 billion in 2011 to between $345 billion and $375 billion by 2016, or $91 in drug spending per capita, according to IMS. The increase will be driven by rising incomes, continued low cost for drugs, and government-sponsored programs designed to increase access to treatments. Generic drugs and other products, including over-the-counter medicines, diagnostics, and nontherapeutics, will account for approximately 83% of the increase. China’s pharmaceutical market is expected to reach $161 billion by 2016, Brazil’s $47 billion, India’s $29 billion, and Russia’s $27 billion. The Tier-3 pharmerging countries are expected to collectively reach $95 billion in pharmaceutical spending by 2016, according to IMS. 

Manufacturers of small-molecule generic drugs will experience accelerating growth. Global generic-drug spending is expected to increase from $242 billion in 2011 to between $400 billion and $430 billion by 2016, fueled by volume growth in pharmerging markets and the ongoing transition to generic drugs in developed nations, according to IMS.  Between $224 billion and $244 billion of the increase in global generic-drug spending will be in pharmerging markets, according to IMS. 

Biologics are expected to account for about 17% of total global spending on medicines by 2016 and reach an overall market value of $200 billion to $210 billion in 2016, up from $157 billion in 2011, according to IMS. Seven of the top ten global medicines by spending will be a biologic within five years, according to IMS. Adoption of biosimilars as low-cost alternatives to the original biologic medicines will remain limited, according to IMS, as biologics remain protected by patents or market exclusivity in many countries. The global market for biosimilars is expected to be between $4 billion and $6 billion in 2016, representing 2% of biologics spending. In 2011, the global biosimilars market was estimated at $693 million, or only 0.4% of the global biologics market, according to IMS 

US spending on prescription drugs will increase through 2016 but at historically low levels as emerging markets are projected for double-digit growth.

A Tale of Two Markets for Global Pharmaceutical Sales

The Abbott Fund, the foundation of Abbott, announced last month that it had formed  a partnership with the US Secretary of State's International Fund for Women and Girls to aid women and girls in Burma. During the next two years, the Abbott Fund will provide $1 million to the Secretary's International Fund for Women and Girls to support grassroots organizations that are working to advance health, education, and economic opportunity for women in Burma.

 This public–private partnership follows a recent fact-finding trip to Burma in May 2012, organized by the US Department of State's office on Global Women's Issues. Under the leadership of 

, the delegation included representatives from the Abbott Fund and other private-sector organizations. Discussing critical challenges confronting Burma with Nobel laureate Aung San Suu Kyi and other leaders and members of civil society, the delegation also assessed grassroots programs with the goal of identifying partnership opportunities to further improve the lives of women in the country.

"Through decades of challenges, the people of Burma have developed a resilient and resourceful civil society," said Ambassador Verveer, in July 16, 2012, Abbott press release. "By supporting existing grassroots organizations, this public–private partnership with the Abbott Fund will help build the capacity of local organizations and communities to drive progress and development for women."

 The imperative to support women at the local level was further expounded by Abbott officials. "During our recent trip to Burma with Ambassador Verveer, we met dozens of women who are leading local organizations, making significant contributions to address critical community needs," said Katherine Pickus, vice-president, the Abbott Fund, in the release. "The Abbott Fund aims to further strengthen the capabilities of these organizations to advance health, education and economic opportunities for women—at a transformational time that holds great promise for the country's future."

All partnership funding will be provided to Burmese organizations staffed by the people of Burma. Key areas of programmatic focus include health awareness, prevention, and treatment; education and training; and expanding economic opportunities for women. Specific organizations will be identified by the Secretary's International Fund for Women and Girls in the coming months.

 The Abbott Fund's new grants in Burma follow efforts by Abbott and the Abbott Fund to provide humanitarian aid in the country in recent years, including more than $600,000 in support for relief and recovery efforts after Cyclone Nargis. The Abbott Fund provided $250,000 to advance the work of CARE, an organization focused on empowering women, and Abbott donated $386,000 in vitamins and antibiotics to AmeriCares, Heart to Heart, Direct Relief International and MAP International.

Secretary’s International Fund for Women and Girls

 is a US State Department-led, privately-funded initiative committed to providing flexible, rapid, targeted, and high-impact grants to nongovernmental organizations working to meet the critical needs of women and girls around the world. The State Department is committed to advancing the rights of women and girls as a central focus of US foreign policy interests, in partnership with the private and nonprofit sectors.

Abbott forms a partnership with the US Secretary of State's International Fund for Women and Girls to support grassroots organizations that are working to advance health, education, and economic opportunity for women in Burma.

Abbott Pledges Support for Program to Aid Women and Girls in Burma

What will be the future of pharmaceutical outsourcing? What factors will influence the relationships between sponsor companies and contract service providers and what practical solutions are both seeking? These questions were addressed at a conference this week in Philadelphia, 

Bio/Pharmaceutical Manufacturing Partnerships

		Panelists described how pharmaceutical companies are using outsourcing to respond to changing fundamentals: namely, greater globalization, increasingly complex supply networks, emerging-market opportunities, and  ongoing cost pressures. At the same time, pharmaceutical companies and their suppliers are tasked with how to better manage their relationships to mitigate risk, secure supply, and consistently manufacture a quality product. Sponsor companies spoke on how CMOs are an integral part of their supply networks, and as such, strategies for greater collaboration, improved information-sharing, and innovation are ever-more important. Some key take-aways from the conference are:

Increasing transparency between CMOs and sponsor companies

. Dan Matlis, president of Axendia, shared results from his company’s recent research on the impact of globalization and the issues pharmaceutical executives are most concerned. An overwhelming majority of executives expect that their sales outside the US to increase and their sourcing outside the US to increase. The elongation of the supply chain, however, is accompanied by certain concerns: sourcing raw materials outside the US, increased external manufacturing, and possible implications on product quality.

		To alleviate those concerns and for better management of supply networks, Matlis discussed the need to create “on-demand visibility”  between CMOs and sponsor companies through better information-sharing in the form of more timely access to detailed project information, real-time information sharing, track-and-trace capabilities, and other collaborative tools. This point was further expounded by  Shabbir Dahod, president and CEO of TraceLink, who explained how cloud and business collaboration tools can increase visibility across all external supply relationships, create access to accurate and timely data, and foster cross-functional and cross-company collaboration. The conference also featured perspectives from CMOs (DPT, CMIC, and Kemwell) on the value and ways to optimize communication and transparency between CMOs and sponsor companies, manage expectations, and evaluate performance.

. Marlene Swider, quality manager, FDA echoed the challenges of globalization on the pharmaceutical industry and provided an overview of the agency’s efforts in addressing globalization, including expanding FDA offices overseas, applying risk-based approaches in overseeing product quality and inspections, and collaborative efforts between regulatory and other bodies, such as the Pharmaceutical Inspection Co-operation Scheme (PIC/S).

. In the globalization of the pharmaceutical industry, emerging markets are increasingly important, and Thomas Salus, associate vice-president of business development of contract services for Wockhardt, examined the role of CMOs in emerging markest. A key point made was how CMOs in developing markets play a crucial role in the in-country strategy of a pharmaceutical company in accessing local markets, thereby moving certain CMOs’ value beyond just advantages of lower-cost production.

The value and interdependence of CMOs and pharmaceutical companies in executing the manufacturing and supply strategy of a sponsor company was further discussed by Amelia Mutere, audit response manager, GMP compliance, Americas and Canada with Roche’s Genentech.

. Jerilynn Carroll, operations manager, external manufacturing, Covidien, provided insight into the due-diligence and CMO selection-process as a means to build effective long-term partnerships by applying a systematic approach in assessing partner capabilities, defining project scope and the related expectations, and setting performance goals.

 And Gregg Brandyberry, formerly vice-president, procurement, global systems and operations with GlaxoSmithKline and now senior vice-president with FedBid, an online marketplace, explained how procurement has evolved in the pharmaceutical industry to a more strategic, value-based function and how certain tools, such as online marketplace, particularly in the purchase of indirect goods and services, can be used to deliver that value.

What will be the future of pharmaceutical outsourcing? What factors will influence the relationships between sponsor companies and contract service providers and what practical solutions are both seeking?