Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

The Indian Supreme Court ruled against Novartis in the company’s appeal to be granted a patent for the company’s anticancer drug, Glivec/Gleevec (imatinib mesylate) in India.  The ruling, which was issued on Apr. 1, 2013, has broader implications for intellectual property protection and the role of innovator drugs in the Indian market.


In a statement on the ruling, Novartis said that it had never been granted an original patent for Glivec in India. Novartis filed a Special Leave Petition with the Indian Supreme Court in 2009 challenging the denial of the Glivec beta-crystal form patent on two grounds based on Sections 3(d) and 3(b) of the Indian patent law. In addition to seeking a patent for Glivec, the company filed the case to help clarify these unique aspects of the patent law.
 "Novartis has never been granted an original patent for Glivec in India,” said Ranjit Shahani, vice-chairman and managing director, Novartis India Limited, in the company’s statement. “We strongly believe that original innovation should be recognized in patents to encourage investment in medical innovation especially for unmet medical needs. We brought this case because we strongly believe patents safeguard innovation and encourage medical progress, particularly for unmet medical needs. This ruling is a setback for patients that will hinder medical progress for diseases without effective treatment options."

At issue in the case was whether Glivec was considered an innovative product and, therefore, afforded protection under Indian patent law. Novartis had argued that the beta-crystal form of imatinib mesylate was novel and that it should be given patent protection under India law. India, which is part of the World Trade Organization, had amended its patent law in 2005 to assert that pharmaceutical companies had to prove enhanced clinical efficacy of their drugs over already patented compounds. In its ruling against Novartis, the Indian Supreme Court cited a 1996 patent (US Patent No. 5,521,184), which included several derivatives of 

phenyl-2-pyrimidine-amine, including imatinib, in a free-base form (1). Novartis asserted that it had first developed the methanesulfonic acid addition salt, imatinib mesylate, and later the beta-crystalline form of the salt, which had improved properties, such as flow, thermodynamic stability, and lower hygroscopicity compared with the alpha-crystal form. The India Supreme  Court, however, ruled that the beta-crystalline form of imatinib failed to meet the tests of “invention” and “patentability” under Indian law. 

“PhRMA is very disappointed with the Indian Supreme Court’s decision to deny a patent on Glivec,” said Pharmaceutical Research and Manufacturers of America (PhRMA) President and CEO John Castellani, in an Apr. 1, 2013 statement. “This decision marks yet another example of the deteriorating innovation environment in India....In order to solve the real health challenges of India’s patients, it is critically important that India promote a policy environment that supports continued research and development of new medicines for the health of patients in India and worldwide. Protecting intellectual property is fundamental to the discovery of new medicines. The research-based pharmaceutical industry is committed to working closely with the Indian Government and other stakeholders to find appropriate solutions to this challenge.”


 The Novartis ruling follows other high-profile cases regarding intellectual-property protection in India. In March 2012, Natco Pharma was granted a compulsory license for sorafenib tosylate, the active ingredient in Bayer’s Nexavar, a drug to treat liver and kidney cancer.  The compulsory license enables Natco to sell the drug at a price not exceeding Rs. 8880 ($163) for a pack of 120 tablets (one month’s therapy) compared with the Rs. 284,428 ($5225) as the cost of Nexavar sold by Bayer. The license is valid until the expiry of the patent in 2021. The order is subject to certain conditions such as maintaining account of sales, and payment of royalty at 6% of the net sales on a quarterly basis .  The order also makes it obligatory for Natco to supply the drug freeof cost to at least 600 needy and deserving patients per year.

The Natco ruling was significant as it was the the first time the Indian controller general of patents, designs, and trademarks granted a compulsory license to a generic-drug maker (2) and it has since opened the door for other such applications.  In March 2013, BDR Pharmaceuticals applied to the Indian patent office for a compulsory license to sell a generic version of Bristol-Myers Squibb’ anticancer drug Sprycel (dasatinib) after unsuccessfully seeking a voluntary licence from Bristol-Myers (3). 

In another ruling, in November 2012, the Intellectual Property Appellate Board in revoked the patent of Roche’s hepatitis C drug Pegasys (peginterferon alfa-2A). Roche had received a patent for Pegasys in India in 2006, which was subsequently challenged by the Indian generic-drug maker Wockhardt and a nongovernmental organization, Sankalp Rehabilitation Trust, on the grounds that that drug was not novel and did now demonstrate inventiveness (4). In its decision to set aside Roche's patent, the appellate board supported the company's claims that its work on Pegasys was novel but asserted that the technology involved in the invention was "obvious" and could be replicated easily (4). Also, in October 2012, Pfizer had its patent for its anticancer drug Sutent (sunitinib malate) revoked (5). 

J. Zimmerman, “Pyrimidine Derivatives and Processes for the Preparation Thereof (US Patent No,521,184), May 28, 1996.   

G. Anand and R. Ahemd, “Bayer Loses Drug Ruling in India,’ 

K. Kulkarni,“BDR Pharma Seeks License for Bristol-Myers Squibb Drug,” 

R. Ahmed, Pfizer India: Patent for Cancer Drug Sutent Revoked,” 

Articles

Ruling has implications for intellectual property protection for innovator drugs in India.

Indian Supreme Court Rejects Patent for Glivec by Novartis

In late March, AstraZeneca CEO Pascal Soriot outlined the company’s plan to revitalize growth and a series of strategic priorities. The moves come as the company deals with declining revenues in part due to increased generic-drug incursion. These priorities include:•	Driving its on-market growth platforms to return to growth as the company moves through a period of patent expiries and revenue declines 

•	Progressing its Phase II pipeline, which the company says has the potential to double Phase III asset volume by 2016, and to deliver growth from its biologics portfolio

•	Rebuildinh its R& supported by co-location of R&D teams and better access to globally recognized science clusters

•	“Dramatically” simplifying the business, improving productivity, and building a culture that supports long-term success

•	Leveraging business development and acquisitions to execute the company’s base plan and to strengthen the pipeline further. 

Soriot said that the company will focus on three core therapy areas: respiratory, inflammation and autoimmunity; cardiovascular and metabolic disease; and oncology. “We will continue to be active in infection and vaccines and in neuroscience, though our investments will be more opportunity-driven,” he said.“Within our chosen therapy areas, we will tighten our disease focus. This approach is designed to improve our likelihood of success while allowing us to meet our goal of funding our growing portfolio of late stage assets on a broadly flat R&D spend to 2016.” 

By accelerating development of several new molecular entities (NMEs), Soriot said the company has the potential to double its Phase III pipeline by 2016. “Acceleration of these key assets, combined with our ongoing efforts to progress a strong Phase II biologics pipeline into late-stage development, will create a portfolio more weighted toward specialty care, balancing our traditional strengths in primary care. We are also increasing our investment in lifecycle management to support key on-market and late-stage pipeline products such as Brilinta, Forixga, Bydureon, and lesinuard.”

On the R&D side, AstraZeneca will increase its proximity to bioscience clusters and centralizes its R&D at three strategic locations: Cambridge, Massachusetts’ Gaithersburg, Maryland; and Möindal, Sweden. “These proposals will make it easier for our researchers to collaborate with external partners and with each other. The creation of autonomous biologics and small- molecules biotech units is designed to improve innovation and accelerate decision-making,” said Soriot. “Additionally, we will increase our emphasis on novel biology and personalized healthcare, and we will continue to partner with leading academic institutions to increase our understanding of disease biology.” 

To that end, AstraZeneca announced collaborations with the Swedish medical university Karolinska Institutet and an agreement with the biopharmaceutical company Moderna Therapeutics. In late March, AstraZeneca and the Swedish and the Karolinska Institutet announced their intention to create an Integrated Translational Research Center for cardiovascular and metabolic disease and regenerative medicine located at Karolinska Institutet’s site in Stockholm, Sweden. The centre will be set up to conduct preclinical and clinical studies aimed at advancing the understanding of cardiovascular and metabolic disease pathophysiology and assessing new drug targets for AstraZeneca’s two biotech units, AstraZeneca Innovative Medicines and Early Development (iMed) and MedImmune. The center will  initially run for a period of five years and will be made up of between 20 and 30 scientists, including a number of AstraZeneca scientists. In addition, AstraZeneca will contribute up to $20 million per annum, and Karolinska Institutet will contribute expertise and facilities. The center is expected to be operational by mid-2013. 

In March 2013, Moderna Therapeutics signed a five-year strategic agreement with AstraZeneca to discover and develop messenger RNA Therapeutics. Under the agreement, AstraZeneca has exclusive access to Moderna’s mRNA therapeutic platform in the area of cardiometabolic diseases as well as selected oncology targets. Moderna will be responsible for designing and manufacturing the messenger RNA against selected targets, and AstraZeneca will lead the preclinical development, clinical development, and commercialization of messenger RNA Therapeutics resulting from the collaboration. 

These moves come as AstraZeneca navigates revenue decline due to generic-drug incursion. In terms of organic growth, the company is focused on its oral antiplatelet medication Brilinta (ticagrelor), working with its partner Bristol-Myers Squibb in the noninsulin diabetes market, investing in emerging markets, particularly in China, maximize the potential of its respiratory portfolio, and also increase growth from established products and in certain established markets, such as Japan. 

The company projects that it would reach revenues of $21.5 billion by 2018. Key contributors to that revenue target are Brilinta (projected 2018 revenue of $1.3 billion), its diabetes franchise (2018 revenue estimate of $2.3 billion), emerging markets (2018 revenue estimate of $7.6 billion), its respiratory franchise (2018 revenue estimate of $3.7 billion), Japan (2018 revenue estimate of $2.3 billion), and pipeline contributions (2018 revenue estimate of $1.1 billion estimate). AstraZeneca also says it is intensifying product development in biologics. Approximately 50% of its Phase I–III development pipeline is in biologics. The company says it is on track to deliver one new biologic license application per year beginning in 2016. 

Concurrent with its growth initiatives, AstraZenneca is further restructuring that will lead to a global headcount reduction of 2300. This efforts are combined with two previously announced restructuring efforts: a headcount reduction of 1600 related to the proposed R&D footprint changes announced on Mar. 18, 2013, and the balance of the Phase 3 restructuring program announced in February 2012, which amounts to 1150 roles. The total combined Phase 4 program entails an estimated global headcount reduction of about 5050 over the 2013-2016 period. The combined program of changes is estimated to incur $2.3 billion in one-time restructuring charges, of which $1.7 billion are expected to be cash costs. Benefits of approximately $800 million per annum are expected by 2016.

Restructuring and a strategic focus on three hubs in research and development are part of a plan to restart growth.

The Plan by AstraZeneca CEO Pascal Soriot to Revitalize the Company

imagewerks/GETTY IMAGESContinuous-flow technology involves the continuous introduction of a stream of chemical reactants into a flow or microreactor to yield a desired reaction product on a continuous basis (1, 2). Continuous-flow technology offers potential advantages compared with traditional batch manufacturing of pharmaceuticals, such as greater optimization and control of the process, improved safety and environmental profiles for a given process, and a reduced manufacturingfootprint (1,2). Pharmaceutical companies, fine-chemical producers, and academia are pursuing continuous-flow chemistry in the production of APIs and related relevant reactions with several interesting developments in this field.  

In general, microstructured devices with small internal volumes and high surface-to-volume ratios offer transport capabilities for rapid mixing, enhanced heat transfer for good temperature control, and intensified mass transfer (1, 3). Microstructured devices operate in a continuous-flow environment, which can provide controlled process conditions, high flow rates, and high mass throughput. Continuous operations also may allow for bulk-chemistry processes to have high production capacities. Fluid dynamics determine the characteristics of continuous-flow equipment, such as pressure loss, heat-transfer characteristics, residence time,  and mixing time (1-4). The high surface-area-to-volume ratio comparative to a batch reactor enables better temperature control overall, including for exothermic reactions, which improves processing conditions. Scale-up issues may be minimized due to maintaining improved mixing and heat transfer. 

These benefits are attracting investment and R&D in continuous-flow chemistry. In February 2013, DSM Pharmaceutical Products signed an agreement with Chemtrix, a supplier of flow-chemistry equipment and services, for providing equipment, development, and manufacturing services to the pharmaceutical industry. Chemtrix specializes in ready-to-use laboratory and kilo-scale microreactors as well as reactor and process design for industrial reactors. DSM provides drug-synthesis route development, scale-up, and implementation of continuous-flow processes for manufacturing. DSM has FDA approval for using microreactors for making a pharmaceutical product at commercial scale under cGMP at its facility in Linz, Austria, where its dedicated commercial-scale installation is located. Initially, the DSM–Chemtrix collaboration will offer an industrial flow process-development package for customized scalable flow-chemistry solutions. The package covers all phases of process design, scanning chemistries, chemistry development, route scouting, equipment design, and scale-up for fully continuous or integrated processes. 

Reflecting growing interest in microreactor technology for fine-chemical manufacturing, Lonza invested in what it terms the “Factory of Tomorrow,” at its facility in Visp, Switzerland. The investment, made in 2012, enables production of multitons of intermediates and/or APIs based on continuous-flow processing. Lonza operates assets that can produce several kilograms to several tons of small-molecule APIs using microreactors, and the new unit in Visp adds an integrated solution where all common unit operations in flow can be streamlined in a flexible fashion using microreactors (FlowPlate, Lonza) (1). This new unit integrates a range of flow reactors, such as continuous stirrer-tank reactors or ultrasounds and streamlines flow processes, including work-up unit operations, such as liquid–liquid extraction and distillation (wiped-film, thin film). Higher pressure applications are enabled as well by allowing gas–liquid reactions, such as ozone and HCN chemistries. The technology can be used for chemical reactions under severe and extreme conditions, such as high temperatures or cryogenic conditions (1). 

Scientists at Eli Lilly recently reported on reactions in a continuous mode in plug-flow tube reactors (PFRs) to enable chemistry that would be difficult to perform by means of batch processing. Specifically, they developed two different continuous flow approaches for producing a 1H-4-substituted imidazole intermediate. In a first-generation approach, rapid optimization and scale-up of a cyclization reaction was shown in a PFR under GMP conditions to produce 29 kg of protected product. This material was further processed in batch equipment to deliver the di-HCl salt. This approach showed the development of chemistry in research-scale PFRs and speed to material delivery through linear scale-up to a pilot-scale PFR under GMP conditions (5). In a second-generation effort, a more efficient synthetic route was developed, and PFRs with automated sampling, dilution, and analytical analysis allowed for reaction optimization of a cyclization reaction and thermal removal of a Boc protecting group. This work culminated in 1-kg demonstration runs in a 0.22 L-PFR for both continuous steps and showed the potential of commercialization from a laboratory hood footprint (1–2 metric tons/year), according to the researchers (5). 

In another project, researchers at Eli Lilly reported on a fully continuous process, which involved an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization that was designed, developed and demonstrated at pilot scale. Production of 144 kg of product was made in laboratory fume hoods and a laboratory hydrogenation bunker over two continuous campaigns (6). Maximum continuous flow vessel size in the laboratory hoods was 22-L glassware, and maximum PFR size in the bunker was73 L (6). The researchers reported that main safety advantages of running the hydrogenation reaction continuous rather than batch were that the flow reactor was smaller for the same throughput, and the tubular hydrogenation reactor ran 95% liquid-filled at steady state. The amount of hydrogen in the reactor at any one time, therefore, was less than that of batch. Additionally, a two-stage mixed suspension–mixed product removal cascade was used for continuous crystallization (6). The researchers reported that impurity rejection by continuous crystallization was better than by batch because scalable residence time and steady-state supersaturation allowed for repeatable control of enantiomer rejection in a kinetic environment (6). The researchers reported that a fully continuous wet-end process running in a laboratory infrastructure achieved the same weekly throughput that would be expected from traditional batch processing in a plant module with 400-L vessels (6). 

Researchers at the Massachusetts Institute of Technology (MIT) recently reported on the application of compact crystallization, filtration, and drying for producing APIs. Specifically, they developed a combined crystallization and hybrid filtration-drying-dissolution apparatus for a compact manufacturing platform. Crystallization experiments using a conventional stirred tank and a newly designed scraped surface crystalliser showed advantages in terms of crystallization rates, yields, and the ease of automation (7). 

The scraped surface crystallizer used an anchor impeller to create a closed clearance between the crystalliser wall and impeller. The researchers reported that the design prevented crystallization on the wall, generated large crystals to facilitate filtration, and improved draining and washing for automation. The hybrid device intensified three unit operations (filtration, drying, and dissolution/suspension) into a single unit. Intensifying these unit operations potentially reduces the time and material lost due to pumping and reduces contact between the API, the environment and operators. Postcrystallization operations were operated step-wise using the custom hybrid device that delivered satisfactory results for each operation. Fluoxetine HCl was dried in less than 20 minutes, with 99% yield after dissolution in a liquid excipient (7). 

Effectively applying continuous-flow technology involves a multidisciplinary approach of chemistry and engineering. As an example, other MIT researchers reported on the development of a Suzuki–Miyaura cross-coupling reaction in a continuous-flow microreactor system. Suzuki coupling is a palladium-catalyzed coupling between organoboron compounds and organohalides and is an important reaction in organic chemistry in general and for pharmaceutical compounds specifically. The researchers developed a continuous-flow Suzuki–Miyaura cross-coupling reaction that started from phenols and produced various biaryls in good yield using a microfluidic-extraction operation and a packed-bed reactor. The project used a multidisciplinary approach with the research on microreactor technology developed by a team led by Klavs F. Jensen, department head,  Warren K. Lewis professor of chemical engineering, and professor of materials science and engineering at MIT. The organic synthesis portion of the project was developed by a group led by Stephen Buchwald, Camille Dreyfus professor of chemistry at MIT (1, 4, 8, 9). 

Scientists at LyraChem, based in Newcastle-upon-Tyne, United Kingdom, and Newcastle University reported on intensified azeotropic distillation as an approach for optimizing direct amidation (10). The direct synthesis of amides from the corresponding carboxylic acids and amines was shown to operate under varying degrees of mixed kinetic and mass-transfer rate control when water was removed by azeotropic distillation (10). A systematic approach was developed to quantify the contribution of boil-up rate to conversion rate and decouple the physical rates from the chemistry. Intensive boiling was used to improve the removal of water during azeotropic distillation and enhance conversion. The researchers reported that some acylations previously thought to be difficult or impossible could be achieved in the absence of coupling agents under green conditions. A cascade of continuous stirred-tank flow reactors operating under intensified conditions was assessed for scale-up of direct amidation reactions and compared to a production-scale batch reactor. The researchers reported that the use of the continuous stirred-tank flow reactors operating under intensified conditions could provide the necessary high rates of heat transfer and, therefore, offer advantages over a conventional batch reactor system (10). 

Asymmetric synthesis is an important area of research for producing single enantiomer drugs. Researchers in the Department of Chemistry, School of Science at the University of Tokyo, recently reported on the use of continuous-flow chemistry with chiral heterogeneous catalysts in asymmetric carbon–carbon bond formation (11). They developed and applied a chiral calcium catalyst based on calcium chloride with a chiral ligand to the asymmetric 1,4-addition of 1,3-dicarbonyl compounds to nitroalkenes as a model system (11). The researchers sought to improve the low catalyst turnover number (TON) of asymmetriccarbon–carbon bond-forming issues (12). To address product inhibition, the calcium catalyst was applied to continuous flow with a chiral heterogeneous catalyst. The continuous-flow system, using a newly synthesised, polymer-supported Pybox, was successfully used, and the catalyst TON was improved 25-fold compared with those of the previous Ca(OR)2 catalysts (11). 

Researchers at the Department of Synthetic and Biological Chemistry in the Graduate School of Engineering, Kyoto University Nishikyo-ku, in Kyoto, Japan applied a flash-chemistry approach using flow microreactors to produce a highly reactive palladium catalyst with a tri-tert-butylphosphine (tBu3P) ligand for a Suzuki–Miyaura coupling (12, 13). The flash chemistry enabled the use of highly reactive unstable species as a catalysts for chemical synthesis. Fast micromixing of a solution of [Pd(OAc)2] and that of tBu3P in an 1:1 mole ratio gave a solution of a highly reactive unstable species, which was transferred to a vessel by using a flow microreactor, in which Suzuki–Miyaura coupling was conducted (13). The coupling reactions were completed in 5 minutes at room temperature, thereby preventing deboronation of the used aryl and heteroarylboronic acids (12). 

In another study, researchers from the Institute of Science and Technology in Ikoma, Japan, and the School of Pharmacy and Molecular Sciences at James Cook University in Townsville, Australia reported on the diastereoselective [2+2] photocycloaddition of a chiral cyclohexenone with ethylene in a continuous flow microcapillary reactor (14). The researchers reported that the microcapillary reactors have higher conversions and selectivity than the batch system even after shorter irradiation times due to better temperature control, light penetration and generation of gas–liquid slug flow with improved mass transfer in the microreactor (14). 

In another development, researchers at the Institute of Organic Chemistry at Aachen University in Germany reported on the asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors using Fourier transform infrared (FTIR) spectroscopy in-line analysis (15). Reaction monitoring was achieved by using an in-line ReactIR flow cell, which allowed for optimization of the reaction parameters. The researchers reported that the reductions proceeded well, and the desired products were isolated in high yields and with good enantioselectivities (15). 

2. J. Hamby, “API Synthesis, Formulation Development, and Manufacturing” supplement to 

3. N. Korman et al., “API Synthesis, Formulation Development, and Manufacturing” supplement to 

, online, DOI: 10.1021/op400011s, Mar.17,  2013. 

  online, DOI: 10.1002/anie.201101480, 17 May 2011. 

11. T. Tsubugo, Y. Yamashita, and S. Kobayashi et al., 

15.M. Rueping, T. Bootwicha, and E. Sugiono, Beilstein 

Continuous flow chemistry offers potential for greater control, improved safety and environmental profiles, and efficient chemical transformations.

Advancing Flow Chemistry in API Manufacturing

Informex, the exhibition of custom and batch manufacturers, which was held in February in Anaheim, California, provided an opportunity to review recent activity in the fine-chemicals and contract API market. In examining developments from 2012 and 2013 to date, companies are proceeding with select investments to expand manufacturing capacity and enhance service capabilities. High-potency manufacturing continues to be an active area of investment among CMOs, and several CMOs also are expanding overall manufacturing capacity. 

Lonza, the bellwether of the contract API manufacturing sector, proceeded with several expansions in its small-molecule custom-manufacturing business in 2012. Earlier this year, Lonza reported that its custom manufacturing and bioscience sectors will be regrouped into one pharmaceutical market segments group.In 2012, Lonza completed the first two build-out phases of its large-scale multipurpose cGMP API plant in Nansha, China, following FDA approval of several customer projects in late 2011. Also, the company successfully brought on line a small-scale manufacturing train and a GMP kilo-laboratory in Nansha. The company’s large-scale antibody drug conjugates project in Visp, Switzerland was finalized on schedule, and the plant received FDA approval in the third quarter of 2012. A second expansion phase has started and will be finalized toward the end of the first half of 2014. Five additional high-potency API (HPAPI) laboratories in Visp, with capabilities for cytotoxic substances, are operational and utilized, and new investment in additional cytotoxic API manufacturing capacity in Visp was started up in 2012. Lonza also increased peptide-manufacturing capabilities at its site in Braine, Belgium. 

Other companies are proceeding with investments and alliances to build HPAPI capabilities. In 2012, Carbogen Amcis and ADC Biotechnology formed a partnership to provide customers with development and manufacturing services for antibody drug conjugates. ADC Bio will provide access to proprietary solid-phase immobilization technologies for conjugation and long-term storage of antibody drug conjugates. Carbogen Amcis will focus on small- to large-scale GMP supply and on the formulation of antibody drug conjugates. 

In October 2012, Fujifilm Diosynth Biotechnologies formed a strategic alliance with Piramal for antibody drug conjugate production, whereby the two companies will offer contract development and manufacture of antibody drug conjugates. Piramal offers antibody drug conjugate production at its site in Grangemouth, Scotland. In 2012, Fujifilm also expanded its cGMP manufacturing facilities at its sites in Research Triangle Park, North Carolina and Billingham, United Kingdom. Novasep announced in 2012 a $3.9-million (EUR 3 million) investment to expand its HPAPI manufacturing capabilities at its facility in Le Mans, France. The plant expansion was scheduled to be fully operational by the beginning of 2013. 

In addition to its HPAPI capacity expansion, Novasep is investing EUR 30 million ($39 million) to build a chromatography plant for the large-volume production of commercial APIs. The plant is being built on Novasep’s existing site in Mourenx, France and is expected to be operational and validated in 2014 . The new plant will contain Varicol continuous chromatography systems with 1200-mm diameter columns operated at up to 70 bars. 

Several companies have announced overall manufacturing capacity additions. For example, Albemarle is expanding its manufacturing facility in Tyrone, Pennsylvania. The $30-million expansion builds on an earlier expansion that began operations in November 2012, which will result in an eventual 40% increase in reactor capacity for the company’s custom-manufacturing business. The first increment of new capacity will be operational late in the first quarter of 2014. 

In February 2013, PharmaZell added an additional manufacturing site to its European manufacturing network. The company acquired a manufacturing site in Liestal, Switzerland previously operated by AbbVie (formerly Abbott).  Abbott’s pharmaceutical business was spun off in a separate company,  AbbVie, in January 2013. The Liestal site consists of multipurpose manufacturing equipment with 150 m3 of reactor volume with drying and milling capacity, packaging cleanrooms, a pilot plant, quality-control laboratories, and warehouses for manufacturing small-molecule, large-volume APIs. 

In 2012, Almac expanded its API manufacturing facility at its European headquarters in Craigavon, United Kingdom, with a scheduled completion for the end of 2012. The upgrade included installation of two 1000-L reactors and a pressure-filter dryer, which allows production of GMP APIs up to 150-kg batches. 

In September 2012, Cambridge Major Laboratories (CML) reported that it is expanding its large-scale API manufacturing facility in Germantown, Wisconsin. The expansion comes three years after commissioning the new site. The expansion includes additional reactor capacity and isolation equipment as well as additional investments in engineering controls.  Also, in 2012, Cedarburg Hauser Pharmaceuticals expanded its capacity at its Wisconsin-based API manufacturing plant and made additional upgrades for improving safety and GMP systems. 

Other companies are making targeted investment in select manufacturing activities. In 2012, Dr. Reddy’s Custom Pharmaceutical Services expanded its activated mPEG manufacturing capabilities at is facility in Mirfield, United Kingdom. SAFC, part of Sigma-Aldrich, is expanding its operations in Scotland by investing in the development of a new powder-manufacturing facility at its Irvine site. SAFC’s new facility in Irvine is its second powder manufacturing facility, which will support SAFC’s risk-management program, which provides  an internal back-up supplier for its customers. The new facility will be used to serve customers across Europe. 

Almac and DSM Pharmaceutical Products recently reported the successful transfer of enzymes for enzyme screening, process development and scale-up as part of the companies’ agreement in biocatalysis, which was announced in October  2012. The agreement grants both companies access to their enzyme platform technologies and services for the manufacturing of APIs. The collaboration also enables Almac to offer its customers a preferred partner for large-scale production. In February 2013, DSM Pharmaceutical Products signed an agreement with Chemtrix, a supplier of flow-chemistry equipment and services, for providing equipment, development and manufacturing services to the pharmaceutical industry. Chemtrix specializes in ready-to-use laboratory and kilo-scale microreactors as well as reactor and process design for industrial reactors. DSM provides drug-synthesis route development, scale-up, and implementation of continuous-flow processes for manufacturing. DSM has FDA approval for using microreactors for making a pharmaceutical product at commercial scale under cGMP at its facility in Linz, Austria, where its dedicated commercial-scale installation is located. The DSM–Chemtrix collaboration will initially offer an industrial flow process-development package for customized scalable flow-chemistry solutions. The package covers all phases of process design, scanning chemistries, chemistry development, route scouting, equipment design, and scale-up for fully continuous or integrated processes. 

Ajinomoto plans to invest approximately JPY 1.3 billion ($13.9 million) to double production capacity for amino acids for use in pharmaceuticals and foods at its subsidiary Shanghai Ajinomoto Amino Acid in Shanghai. The expansion is scheduled to come on line in October 2013. Ajinomoto estimates the current global market for amino acids for pharmaceuticals and foods at 30,000 tons, and with growth in emerging markets, expects demand to rise to 45,000 tons by 2020. Several fine-chemical producers and contract API producers also recently announced activity in support of finished product manufacturing. For example, earlier this year, Ajinomoto agreed to acquire Althea Technologies, a San Diego-based contract provider of fill–finish services. Aesica and the CDMO EmulTech are partnering on the commercial development of ET4ME, an emulsion technology for product formulation. ET4ME is a microencapsulation technology that uses a microfluidic process to create a measurable microparticulate suspension. The technology can be used for small molecules and biologics. 

Cambrex agreed to contract manufacture Dow Chemical’s hydroxypropyl methylcellulose acetate succinate, an excipient provided by Dow as part of a solubilization partnership that Dow and Bend Research formed in 2012 under which Dow is commercially supplying solubility-enabling excipients. Cambrex has begun construction of the new facility at Cambrex’s site in Karlskoga Sweden with commercial product availability set for year end 2013. In another development, ScinoPharm and Foresee Pharmaceuticals agreed to form a joint venture to develop a series of peptide injectable drugs, with the first being a leuprolide injectable drug product, by which leuprolide will be formulated in a proprietary controlled-release drug delivery system originally developed by Foresee and transferred to the joint venture. ScinoPharm is investing $3.6 million for a minority ownership in the new company. 

Contract API manufacturers proceed with select investment in capacity and service additions.

Fine-Chemical Producers Make Targeted Investments

The Indian Supreme Court has ruled against Novartis in the company’s appeal to grant a patent for the company’s anticancer drug, Glivec/Gleevec (imatinib mesylate) in India.

 on the ruling, Novartis said that it had never been granted an original patent for Glivec in India. Novartis filed a Special Leave Petition with the Indian Supreme Court in 2009 challenging the denial of the Glivec beta-crystal form patent on two grounds, based on Sections 3(d) and 3(b) of the Indian patent law. In addition to seeking a patent for Glivec, the company filed the case to help clarify these unique aspects of the patent law.

"Novartis has never been granted an original patent for Glivec in India,” said Ranjit Shahani, vice-chairman and managing director, Novartis India Limited, in the company’s statement. “We strongly believe that original innovation should be recognized in patents to encourage investment in medical innovation especially for unmet medical needs. We brought this case because we strongly believe patents safeguard innovation and encourage medical progress, particularly for unmet medical needs. This ruling is a setback for patients that will hinder medical progress for diseases without effective treatment options."

phenyl-2-pyrimidine-amine, including imatinib, in a free-base form (1). Novartis asserted that it had first developed the methanesulfonic acid addition salt, imatinib mesylate, and later the beta-crystalline form of the salt, which had improved properties, such as flow, thermodynamic stability, and lower hygroscopicity compared with the alpha-crystal form. The India Supreme  Court, however, ruled that the beta-crystalline form of imatinib failed to meet the tests of “invention” and “patentability” under Indian law.

“PhRMA is very disappointed with the Indian Supreme Court’s decision to deny a patent on Glivec,” said Pharmaceutical Research and Manufacturers of America (PhRMA) President and CEO John Castellani, in an Apr. 1, 2013 

. “This decision marks yet another example of the deteriorating innovation environment in India....In order to solve the real health challenges of India’s patients, it is critically important that India promote a policy environment that supports continued research and development of new medicines for the health of patients in India and worldwide. Protecting intellectual property is fundamental to the discovery of new medicines. The research-based pharmaceutical industry is committed to working closely with the Indian Government and other stakeholders to find appropriate solutions to this challenge.”

1. J. Zimmerman, “Pyrimidine Derivatives and Processes for the Preparation Thereof (US Patent No,521,184), May 28, 1996.

Novartis loses an appeal in seeking patent protection in India for its anticancer drug.

Novartis Suffers Setback in Indian Patent Case for Glivec

Innovation is the mainstay of drug development, and it is particularly important to overcome challenges in improving global health outcomes. A recent analysis by the  International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), which represents the research-based pharmaceutical companies and associations on a global basis, examines the role of “incremental innovation” in serving that role. The report was issued late last month concurrent to the Nineteenth Session of the World Intellectual Property Organization (WIPO) Standing Committee on the Law of Patents. WIPO is an United Nations agency focused on the use of intellectual property as a means of stimulating innovation. The report emphasizes the importance of incremental innovation in improving medicines, explaining its scientific rationale, its medical value, and the economic incentives needed for its development. 

“Evidence-based discussions are key to advancing global health,” says IFPMA Director General Eduardo Pisani, in a Feb. 25, 2012 IFPMA report. “This publication provides facts and tangible examples to illustrate how biopharmaceutical innovation benefits patients and dispel the misperception that incremental medicines are trivial.” 

 Innovation may be classified as revolutionary, radical, and incremental, according to the IFPMA report. In the context of drug development, a revolutionary innovation would be discovery of a new biological or metabolic pathway. Revolutionary innovation is defined as conceptual advances, such as new scientific theories or principles, which form the basis for subsequent research. A radical innovation puts these principles into practice. A “first-in-class” drug, meaning the first drug in a new drug class is an example of a radical innovation, notes the IFPMA report. Incremental innovation involves exploring and improving radical products.  Incremental innovation advances medicines by expanding therapeutic classes, increasing the number of available dosing options, discovering new physiological interactions of known medicines, and improving other properties of existing medicines, according to the report. 

“There are countless examples of the significant public health impact of incremental innovation,” said Pisani in the release. “R&D efforts based on existing medicines have led to wide-ranging therapeutic improvements, such as a new use for an antifungal medicine’s metabolite to treat Chagas disease, a neglected tropical disease affecting nearly 10 million people. Improved health outcomes have also been achieved by reducing the antimalarial dosing of ASAQ from eight to two tablets daily. A case study cited in the report highlights an improved treatment of hepatitis C, which has boosted cure rates from 38% to 54%.” 

ASAQ, which stands for Adapted, Simple, Accessible, Quality,  is the project name given to a collaboration between Sanofi and Drugs for Neglected Diseases initiative (DNDi) to develop a new and more easily administered combination of two antimalaria drugs, artesunate and amodiaquine. The project yielded a new fixed combination drug  that reduced dosing from eight tablets to two tablets daily. According to the IFPMA report, more than 150 million ASAQ treatments have been distributed in more than 33 countries. 

 In another example of incremental innovation, Eisai and DNDi  partnered to further explore the effects of the antifungal medicine ravuconazole against the pathogen that causes Chagas disease, a neglected tropical disease. Once administered to patients, ravuconazole naturally metabolizes other compounds or prodrugs, one of which E1224, is being evaluated to treat Chagas disease. With its partnership with Eisai, DNDi is executing clinical trials to determine  the safety and efficacy of the prodrug E1224, and Eisai is supplying the drug for the clinical trials and related scientific expertise. 

Incremental innovation advances medicines by expanding therapeutic classes, increasing the number of available dosing options, discovering new physiological interactions of known medicines, and improving other properties of existing medicines