Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

In late January, 13 pharmaceutical companies, the governments of the United States, the United Kingdom, and the United Arab Emirates, the Bill & Melinda Gates Foundation, the World Bank, and other global health organizations announced a new, coordinated push to accelerate progress toward eliminating or controlling 10 neglected tropical diseases (NTDs) by the end of the decade. An 

of pharmaceutical companies’ pledges was announced by the International Federation of Pharmaceutical Manufacturers and Associations in late January 2012. Other groups and pharmaceutical companies have further detailed public, private, and public–private efforts in combating NTD following a meeting in late January at the Royal College of Physicians in London. 

In a large, coordinated effort  to combat NTDs, the groups said that they would sustain or expand existing drug-donation programs to meet demand through 2020, share expertise and compounds to accelerate R&D of new drugs, and provide more than $785 million to support R&D efforts and strengthen drug-distribution and implementation programs. Partners also endorsed the “London Declaration on Neglected Tropical Diseases,” in which they pledged new levels of collaborative effort and tracking of progress. 

“Inspired by the World Health Organization’s 2020 Roadmap on NTDs, we believe there is a tremendous opportunity to control or eliminate at least 10 of these devastating diseases by the end of the decade,” said the London Declaration. “But no one company, organization or government can do it alone. With the right commitment, coordination and collaboration, the public and private sectors will work together to enable the more than a billion people suffering from NTDs to lead healthier and more productive lives, helping the world’s poorest build self-sufficiency.” The declaration was signed by Abbott, AstraZeneca, Bayer, Becton Dickinson, the Bill & Melinda Gates Foundation, Bristol-Myers Squibb, the Children’s Investment Fund Foundation (CIFF), the Department for International Development (DFID) (a department of the British government), the Drugs for Neglected Diseases Initiative (DNDi), Eisai, Gilead Sciences, GlaxoSmithKline, Johnson & Johnson, the Lions Club International, Merck KGaA, Merck & Co., Mundo Sando, Novartis, Pfizer, Sanofi, the United States Agency for International Development (USAID), and the World Bank. 

These partners committed to the following: 

 • Sustain, expand, and extend programs that ensure the necessary supply of drugs and other interventions to help eradicate Guinea worm disease and help eliminate by 2020 lymphatic filariasis, leprosy, sleeping sickness (human African trypanosomiasis),  and blinding trachoma

• Sustain, expand, and extend drug-access programs to ensure the necessary supply of drugs and other interventions to help control by 2020 schistosomiasis, soil-transmitted helminthes, Chagas disease, visceral leishmaniasis, and river blindness (onchocerciasis) 

• Advance R&D through partnerships and provision of funding to find next- generation treatments and interventions for neglected diseases 

• Enhance collaboration and coordination on NTDs at national and international levels through public and private multilateral organizations 

• Enable adequate funding with endemic countries to implement NTD programs necessary to achieve these goals, supported by strong and committed health systems at the national level 

• Provide technical support, tools, and resources to support NTD-endemic countries to evaluate and monitor NTD programs 

• Provide regular updates on the progress in reaching the 2020 goals and identify remaining gaps. 

“Today, we have joined together to increase the impact of our investments and build on the tremendous progress made to date,” said Bill Gates, cochair of the Bill & Melinda Gates Foundation, in a Jan. 2012, press release. “This innovative approach must serve as a model for solving other global development challenges and will help millions of people build self-sufficiency and overcome the need for aid.” The Gates Foundation announced a five-year, $363 million commitment to support NTD product and operational research. 

 To guide the effort against NTDs, WHO unveiled a new strategy, 

Accelerating Work to Overcome the Global Impact of Neglected Tropical Diseases—A Roadmap for Implementation,

 which sets targets for what can be achieved by the end of the decade. “The efforts of WHO, researchers, partners, and the contributions of industry have changed the face of NTDs,” said WHO Director-General Dr. Margaret Chan, in the release. “These ancient diseases are now being brought to their knees with stunning speed. With the boost to this momentum being made today, I am confident almost all of these diseases can be eliminated or controlled by the end of this decade.” 

Speaking on behalf of the CEOs of the 13 pharmaceutical companies involved, Andrew Witty, CEO of GlaxoSmithKline, said, “Many companies and organizations have worked for decades to fight these horrific diseases. But no one company or organization can do it alone. Today, we pledge to work hand-in-hand to revolutionize the way we fight these diseases now and in the future,” he said in the release. With new and existing pledges totaled, companies will donate an average of 1.4 billion treatments each year to those in need, according to IFPMA. In addition, new R&D collaborative efforts and access agreements with 11 companies and the R&D organization DNDi are providing access to compound libraries. Other research tools include access to WIPO Re:Search, a database of research compounds, knowledge and expertise. 

To close the funding gap for Guinea worm eradication, Sheikh Khalifa bin Zayed Al Nahyan, president of the United Arab Emirates, the Gates Foundation, and CIFF are donating  $40 million to the Carter Center. These commitments complement an October pledge from the DFID that it would contribute £20 million ($31 million) if others come forward—part of a four-year, £195 million ($307 million) commitment to NTDs announced by DFID. 

USAID also announced an $890million appropriation by the US Congress to strengthen drug-delivery and distribution programs, building on its $212 million investment since 2006. In addition, the World Bank will extend its financing and technical support to help African countries build stronger community-health systems that will integrate NTD elimination and control, as well as work with other partners to expand a trust fund to combat river blindness to other preventable NTDs in Africa. The governments of Bangladesh, Brazil, Mozambique, and Tanzania, where NTDs are endemic, announced that they would implement integrated plans to defeat NTDs and devote political and financial resources to combat these diseases. All partners pledged accountability by exploring mechanisms to regularly track progress toward the 2020 goals. 

All companies with NTD drug-donation programs pledged to sustain or extend their programs to the end of the decade, and some pledged to increase their commitments. These commitments include the following: 

 • Sanofi, Eisai, and the Bill & Melinda Gates Foundation will work together to provide 120 million diethylcarbamazine tablets to WHO for its Global Lymphatic Filariasis Elimination program. Combined with Eisai’s donation commitment that will start in 2014, these new tablets will ensure a sufficient supply of diethylcarbamazine from 2012 through 2020. 

• Bayer will double its existing donation of nifurtimox to treat Chagas disease.

• Eisai will extend its existing donation of 2.2 billion tablets of diethylcarbamazine for lymphatic filariasis to 2020. 

• Gilead, which announced a donation of AmBisome for visceral leishmaniasis in2011, will continue its program at cost and commit to investigate and invest in technologies and processes that could reduce that cost in resource-limited countries. 

• GlaxoSmithKline will extend its existing donation of albendazole to treat soil- transmitted helminthes by providing 400 million tablets per year for an additional five years to 2020, as well as continuing its donation of 600 million tablets per year to combat lymphatic filariasis. 

• Johnson & Johnson will extend its existing donation of mebendazole for soil- transmitted helminthes by providing 200 million tablets per year to 2020. 

• Merck & Co. will continue its unlimited donation of ivermectin to combat river blindness and lymphatic filariasis (where co-endemic with river blindness), as well as discuss the use of ivermectin to combat other diseases. 

• Merck KGaA will significantly increase its annual donation of praziquantel tablets from 25 million to 250 million tablets per year, extending the program indefinitely.

• Novartis will extend its commitment to provide multidrug therapy (rifampicin, clofazimine and dapsone) to leprosy patients worldwide. 

• Pfizer will continue its donation of azithromycin for blinding trachoma until at least 2020, as well as donate the drug and placebo to a study on the reduction in mortality of children treated with azithromycin. 

• Sanofi will extend its existing donation of eflornithine, melarsoprol, and pentamidine for sleeping sickness to 2020, as well as provide logistical support to ensure that the drugs continue to reach patients at the point of care cost-free. 

Product-development partnerships under the coordination of DNDi with Abbott, Johnson & Johnson, and Pfizer are underway to develop new drugs to treat helminth infections, notably a macrofilaricide, which kills adult worms that cause river blindness and lymphatic filariasis. Abbott is conducting initial drug reformulation studies and providing scientific expertise for preclinical development with technical and supply assistance from Johnson & Johnson. If preclinical development is successful, Johnson & Johnson will cofund clinical development and collaborate with other partners, including technical support from Pfizer’s staff scientists. Johnson & Johnson would obtain regulatory approval. 

Additionally, innovative licensing or collaboration agreements with DNDi by 11 companies (Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Johnson & Johnson, MSD, Novartis, Pfizer,and Sanofi)—are in negotiation or underway for the sharing of compounds and knowledge  to generate new drugs for diseases including river blindness, lymphatic filariasis, sleeping sickness, Chagas disease, and visceral leishmaniasis, according to the release. For example, DNDi and Sanofi announced a product-development collaboration to codevelop a new drug candidate for sleeping sickness, oxaborole/SCYX-7158, in addition to fexinidazole, which is already in clinical development. 

Articles

Several major pharmaceutical companies detail their contributions for combating neglected tropical diseases.

Examining Project Work for Neglected Tropical Diseases

Contract API manufacturers and fine-chemical producers assembled in New Orleans last month for Informex, an annual trade show for custom and batch manufacturers, which was held Feb. 14–17. Below is a roundup of news from exhibitors, including an 

 with the organizers of Informex on this year’s show. 

has opened a new purpose-built $4.6-million high-potency manufacturing facility for the manufacture of formulated products and plans to upgrade its API manufacturing facilities to enabling manufacture of high-potency APIs at commercial scale. The upgrade will allow Aesica to manufacture SafeBridge Category 3 APIs and formulated products from pilot to commercial scale from two of its sites in Europe. The new facilities will enable Aesica to successfully manage high-potency API production at quantities from 1 kg to 200 kg. Further investment in API manufacturing capability in 2013 will equip Aesica to produce batch sizes up to 600 kg.

 is doubling its analytical capacity at its 240,000-ft

 North American headquarters in Souderton, Pennsylvania. The facility offers full-service, integrated clinical packaging, drug-supply management, and technology services to pharmaceutical and biotechnology clients. Almac’s additional laboratory investment will include polymorph and salt screening and solid-form development. The new facility is also equipped with a bathless dissolution apparatus for comparative dissolution studies.

In other news, Almac also has acquired two new pieces of encapsulation equipment for its North American headquarters in Souderton, Pennsylvania: the Bosch GKF 702 capsule filler with integrated KKE 1700 checkweigher. The Bosch cGMP-compliant system is able to produce 42,000 capsules per hour compared to the 2,700-4,500 output of Almac’s current machine in the United States. Further capabilities of the new equipment include powder, pellet, tablet, and placebo fill as well as multifill.

Laboratories (Tianjin) reported on the opening its new large-scale manufacturing facility, Jilin Asymchem Laboratories, in Dunhua, Jilin province, China.  Phase I completion of Dunhua’s manufacturing facility included 5000–20,000 L vessels for cGMP manufacture of raw materials to intermediates. Phase II involved completion of a second module for a total capacity of 532 m

. This site offers manufacturing as a standalone service and also back-integration for internal downstream cGMP targets to be further processed in Asymchem’s Tianjin 2 GMP facility. Phase III construction in Dunhua for a GMP API manufacturing plant is on schedule and is expected to be completed later this year. 

 has opened an industrial biotechnology and microbiology research center in Tarrytown, New York. The company uses biotechnological methods to produce products such as vitamins, enzymes, pharmaceutical intermediates, and specialties for the personal care, food and feed industries. One focus of the research laboratory work is to develop even more efficient and resource-conserving production processes. The use of metabolic engineering, or the targeted modification of metabolism, is used to enhance the efficiency of the microorganisms used in these production processes. The laboratory will also be used to develop bacterial biofilms. 

 reported in February 2012 that its Bubendorf, Switzerland, API manufacturing site had successfully an FDA cGMP inspection. The inspection was completed in September 2011. The Bubendorf site supports 160 employees and is focused on process optimization and supply of late-phase and commercial APIs and highly potent APIs. 

 has completed the acquisition of the clinical-trial supplies business of Aptuit. The transaction was previously announced in August 2011. 

 CEO Alan Shaw has resigned from the company to pursue other interests. Peter Strumph, head of the firm’s pharmaceuticals business, was named interim CEO as the company searches for a new CEO. 

, a developer of connectors, is further enhancing its DrumQuik PRO and DrumQuik PUR chemical-dispensing systems with the addition of a new tethered protective dust cover and extended shipping plug. In addition to storing and protecting the DrumQuik coupler for extended use, the tethered cover provides a place to store the drum-insert shipping plug when the coupler is connected. 

reported on InnoSyn, a route-scouting service that supports R&D as well as implementation of economical and scalable routes. The service offering includes consulting, route scouting, biocatalyst/catalyst screening, prefeasibility studies, full feasibility studies, mini-plant campaigns, and support in transfer and implementation. Various technical packages are provided for biocatalysis, homogeneous catalysis, organic chemistry and process R&D and continuous chemistry (i.e., microreactor technology). 

 recently introduced a new synthetic method for carbon-carbon bond formation as it detailed in a new brochure, "Silicon-Based Cross-Coupling Reagents." The brochure contains more than 160 references, including reviews on the formation of biaryl, styrene, diene, triene, aryl acetylene, diaryl acetylene, pyridine and enyne derivatives and Heck coupling/cross-couping cascade reaction sequences. 

reported on its cytotoxic and high-potency manufacturing facilities in Biasca, Switzerland and multiyear expansion in this area. The company’s capabilities include pilot-scale, small-scale, and commercial-scale capabilities for manufacturing highly potent APIs. It cytotoxic capabilities include isolated and dedicated cytotoxic quality control and R&D laboratories, raw-materials and finished-goods warehousing, and finishing and sampling areas. A new laboratory has been constructed exclusively for small-scale cytotoxic production, design of experiment, and initial process development. The company also has pilot-scale, small-scale, and commercial-scale capabilities for manufacturing cytotoxic small molecules.

will be held Feb. 19–22, 2013, in Anaheim, California. Highlights of the 2012 installment of Informex are discussed in a 

 have formed a partnership to manufacture Eclipse’s cancer therapeutic antibody, ET-101. Lonza will produce Phase I clinical material at its facility in Slough, England.

, a contract manufacturer of APIs, intermediates, and peptides, launched a new mobile app version of its GuarD project-management system. GuarD was developed to support customers’ participation in project planning and real-time tracking. GuarD uses the principles of critical-chain project management, which emphasizes resource availability and flexibility to maintain project timelines. GuarD allows for a detailed project plan that is viewable in an online template to provide a customer progress of its project, information on the latest task updates, expected time of completion, and other information important to the project. 

 has commenced construction of its new 24,000-ft 

 cGMP aseptic fill–finish manufacturing facility in Hunt Valley, Maryland. Targeted for completion in the fourth quarter 2012, the new facility will more than double the company’s current sterile GMP manufacture capacity. Fill–finish suites will include automated vial- and syringe-filling, inspection and labeling equipment capable of producing batch sizes of 100,000 plus units. The facility expansion follows the company’s recent FDA pre-approval inspection, which allows the company to commercially manufacture an aseptic vial in its existing Hunt Valley aseptic facility. 

 reported on its recent $350-million acquisition of BioReliance, a provider of global biopharmaceutical testing services, from Avista Capital Partners. BioReliance provides biologic, specialized toxicology and animal health testing to pharmaceutical, biopharmaceutical, diagnostics, and other life-science companies. BioReliance employs more than 650 people and is headquartered in Rockville, Maryland, with additional operations in Glasgow and Stirling, Scotland, and sales offices in Tokyo, Japan, and Bangalore, India. The acquisition complements SAFC’s industrial media position, and its CompoZr zinc finger nuclease technology is synergistic with BioReliance's toxicology and animal-health services operations for the development of new assays, cell lines, and animal models, according to the company.

, part of Lanxess, appointed Joerg Scheider to assume management of the agrochemical and fine chemicals business line at Saltigo, effective Feb. 1, 2012. He was previously managing director of Lanxess Elastomeros do Brasil. 

Society of Chemical Manufacturers and Affiliates

 reported that several new companies joined the Bulk Pharmaceutical Task Force (BPTF), an affiliate of SOCMA in 2011. SOCMA is the trade association representing custom and batch manufacturers, including contract manufacturers of APIs and fine-chemical producers. Joining BPTF were Ampac Fine Chemicals, Cambridge Major Laboratories, DSM, Evonik, Hovione, and Polypeptide Laboratories. Created in 2002, BPTF’s primary focus is drug-ingredient quality issues, such as cGMPs and drug supply-chain safety. 

Also, in the fourth quarter of 2011, six new member companies joined SOCMA. These companies were BioChemInsights, a provider of databases of life-sciences molecules; Cardno, an environmental consulting firm; Heritage Environmental Services, another environmental firm; Inventys, a provider of organic chemicals for the pharmaceutical and agrochemical sectors; Pharmatek Laboratories, a pharmaceutical-chemistry firm, including a provider of highly potent compounds; and SARmont, a provider of medicinal chemistry and lead-optimization services. 

 reported on their partnership for custom research and manufacturing services, which was announced in October 2011. The preferred but nonexclusive partnership provides services from route scouting to commercial manufacturing. Solvias brings expertise in chemical, analytical and solid-state development, and RohnerChem brings experience in scale-up and commercial-scale custom synthesis of complex, small-molecule fine chemicals and APIs. Key capabilities from Solvias include high-throughput screening methods, which have been used in asymmetric homogeneous catalysis, CX-couplings, racemate resolutions, carbonylations, hydroformylations, biocatalysis development, and various other transformations. Solvias’ solid-state development group also is equipped to assist in developing crystallization processes, perform polymorphism studies, and provide guidance in the development of the best solid form for an API. After process optimization, which can be performed either at Solvias’ or at RohnerChem’s kilo laboratories, commercial quantities can be manufactured at RohnerChem facilities. 

The latest developments from contract API manufacturers and fine-chemical suppliers from Informex, held in New Orleans last month.

A Roundup of Informex

Strategies to improve drug solubility are of crucial importance to the pharmaceutical industry. Advancement of high-throughput screening techniques for lead identification in drug discovery has had the benefit of generating more potential drug candidates, but with this increase in the diversity and number of drug molecules comes challenges (1). Most notably, more leads are being identified with high-molecular weights and lipophilicity and thus have poor water-solubility (1). Industry estimates are that as much as 60% of drugs currently in development may be classified as poorly water-soluble (2). Poor solubility is problematic because of the resulting decrease or variability in bioavailability, which affects clinical efficacy and safety, such as through necessitating higher dosing regimens to achieve therapeutic effects (1). Enhancing bioavailability of poorly water-soluble drugs, therefore, has strong clinical and commercial significance.  

(DATACRAFT CO LTD/GETTY IMAGES; CAPSULE ILLUSTRATION: DAN WARD)			

The Biopharmaceutics Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability (2). When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption: dissolution, solubility, and intestinal permeability. According to the BCS, drug substances are classified as follows: 			

Class I: high solubility and high permeability  

Class II: low solubility and high permeability 

Class III: high solubility and low permeability 

Class IV: low solubility and  low permeability (3).

				Various approaches can be used to address problems of solubility, such as particle engineering, salt selection, amorphization of the compound, use of surface-active agents or cosolvents, polymeric stabilizers to achieve supersaturation, and solid dispersions and solutions (2). Physical modifications may occur through such techniques as micronization, nanonization, and sonocrystallization (4). Although micronization of powders can be useful to improve solubility, the resulting particle size of drug powders of between 1 and 10 µm to increase the surface area and the dissolution velocity may be insufficient to overcome bioavailability problems of many poorly soluble BCS Class II drugs (4). Nanonization moves beyond micronization to further reduce particle size as a means to increase dissolution rates and bioavailability of poorly water-soluble drugs (4). Nanozination strategies include increasing the surface area-to volume ratios of drug powders, changing crystalline forms, and developing nanomaterials for drug delivery (5).

Several drug-delivery companies and specialty pharmaceutical companies have developed technology platforms involving nanozination. Perhaps the most well known and established technology is the NanoCrystal technology of the former Elan Drug Delivery Technology, which was acquired by Alkmeres in 2011 (4). The technology has been manufactured at a commercial scale since 2001, according to company information. NanoCrystal technology involves reducing the size of drug particles, typically to less than 2000 nm. By reducing particle size, the drug's exposed surface area is increased. The nanoparticles are then stabilized to maintain their reduced particle size. The result is a stable drug formulation that shows  an increased dissolution rate. Five products have been launched using the company's NanoCrystal technology, according to the company (6). 

The specialty pharmaceutical company SkyePharma has several technologies in its solubilization toolbox: the IDD (insoluble drug delivery) platform, which coats particles with phospholipids; DissoCubes, which reduces drug particle size to enable rapid absorption; and SLN (solid lipid nanoparticles), which takes advantage of lipid digestion to promote drug absorption by the gastrointestinal tract (4, 7). 

DissoCubes are crystalline nanoparticles of active substance obtained by a liquid state high-energy process using a high-pressure piston gap homogenizer to reduce the drug particle size in the presence of surface modifiers that associate at the freshly generated drug interface (4, 8). A particle-size reduction from approximately 50 µm to about 0.5 µm is achieved resulting in a homogenous and stable formulation. The nanosuspensions can be formulated into various dosages forms (8). 

The IDD platform consists of three main technologies focused on dispersible narrow particle-size distribution dosage forms derived from surface-modified micrometer to submicrometer-sized particles or droplets stabilized by surface modifiers, specifically phospholipids. The IDD-P (MicroParticle) is a microparticulate variation of the IDD drug-delivery system, which consists of a pure solid drug in the core of the particle. IDD-D formulations (MicroDroplet) involve liquid drug substances (8). 

IDD-P and IDD-D formulations are produced by application of high shear, cavitation, or impaction (e.g., attrition, homogenization, microfluidization, milling, ultrasonication) to reduce the drug particle size in the presence of phospholipids (and/or other surface modifiers) that associate at the freshly generated drug surface. A particle-size reduction from approximately 100–200 µm to about 1 µm is achieved resulting in a homogeneous and stable formulation (8).  

The company's IDD-D and IDD-P technology apply physical or mechanical processes to achieve the desired particle size. The third technology in SkyePharma's IDD platform, IDD-SE (Self-Emulsifying), involves self-generation of surface-stabilized micrometer- to submicrometer-sized particles or droplets when the dosage form is exposed to an aqueous medium such as those in gastrointestinal or vascular compartments (8). 

An example of a commercial drug using SkyePharma's IDD technology platform is Triglide (fenofibrate), an oral treatment for elevated blood lipid disorders, launched in 2005 and marketed in the United States by Shionogi Pharma. Some fenofibrate-based products are insoluble in water, which may result in variable uptake from the stomach and require the patient to take the tablets with food. Triglide, SkyePharma's formulation of fenofibrate, uses the company's IDD platform technology, which has comparable absorption under both fed and fasting conditions. Triglide is manufactured at the company's Lyon, France, manufacturing facility leased by SkyePharma to Aenova (8). 

Aptalis Pharma, a specialty pharmaceutical company formed from the merger of Axcan and Eurand in 2011, provides bioavailability-enhancement technology through Aptalis Pharmaceutical Technologies, which includes its Biorise technology. The Biorise technology breaks down the crystalline drug into nanocrystals and/or an amorphous (noncrystalline) drug that is stabilized in a carrier system to maintain the drug in its activated form for the duration of its shelf life (9). This approach creates a greater surface-area-to-volume ratio that increases the intrinsic solubility and dissolution rate of poorly water-soluble drugs, thereby enhancing their rate and extent of absorption. The analgesic megestrol acetate and the nonsteroidial anti-inflammatory drug nimesulide are two examples of drugs using the Biorise technology (9).  

Researchers at the Novartis–MIT Center for Continuous Manufacturing, Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), recently reported on the development of nanocrystals in a continuous manufacturing environment. Specifically, they used an electrospray technology followed by annealing at high temperatures to produce nanocrystals of carbamazepine, a poorly water-soluble drug, in a continuous manufacturing process. The researchers reported that the solubility and dissolution rates of carbamazepine nanocrystals increased significantly as compared with carbamazepine bulk particles (10).   

Dispersing a poorly soluble compound in a polymeric matrix to improve solubility and therefore bioavailability is another strategy. To produce the solid solutions or solid dispersions, various methods can be used, such as hot-melt extrusion, spray-drying, melt congelation, and nanocrystal technology (11, 12). Veloxis Pharmaceuticals (formerly called LifeCycle Pharma), a technology spinoff from the Danish pharmaceutical company H. Lundbeck, uses a proprietary process, MeltDose, based on controlled agglomeration, to address the problem of poorly soluble drugs (12–13). 

Under the MeltDose approach, a low water-soluble drug substance is dissolved in a vehicle system that is optimized for each drug substance. The drug substance is spray-dried on an inert particulate carrier using fluid-bed equipment and solidified when disposed on the carrier. The carrier captures the active drug in a nanocrystalline or microcrystalline state or as an amorphous solid dispersion. This step is followed by agglomeration that is controlled by optimizing temperature and feed rate to produce the granules, which are directly compressed into tablets. Once in tablet form, the dissolution profile and particle size remain stable (12-13). 

The selection of the vehicle to match the physiochemical properties of the API is an important consideration in the process. In some formulations, the API will be present as an amorphous solid dispersion, such as in hot-melt extrusion and spray drying, but in other formulations, the API will be present as crystals in nanometer or micrometer size, resembling nanoproducts more (12–13). 

MeltDose, the proprietary process that Veloxis Pharmaceuticals has developed, centers on the controlled agglomeration process. The controlled agglomeration process has some similarities to fluid-bed granulation. Controlled agglomeration involves placing solid carrier particles in a conventional fluid bed, unto which a liquefied vehicle containing the API is sprayed. When the liquid vehicle is cooled down on the carrier, it agglomerates and forms granules. The controlled agglomeration process is water-free, and in contrast to conventional fluid-bed granulation, uses liquefied (i.e., melted) polymers as the polymeric vehicle. The polymeric vehicle is melted in a specially designed heated melt unit that controls temperature and pressure of the melted vehicle, which passes from the melt unit to a specially designed spray nozzle in the fluid bed. The produced granules are compressed to tablets using conventional tablet presses (12–13). 

The polymer vehicles used in the MeltDose process can include a range of hydrophilic and lipophilic materials and are selected for their solubility-enhancing properties and compatibility with subsequent processing steps. Examples of vehicle systems are solid or semisolid polymers with a melting point between 40 and 80 °C, such as polyethylene glycol 6000, poloxamers, and various types of gelucires. The resulting granule size varies with the choice of excipients and lies typically in the range of 200 to 500 µm. The vehicle temperature, the spray rate, the atomizing air volume, and product temperature all are important process parameters to consider during the controlled agglomeration step. Also, the addition of different surfactants can result in different sizes of API crystals in the granule (12-13). 

Fenofibrate, a lipid-regulating agent to control cholesterol and marketed as Fenoglide in the United States, was the first product approved in the US using the MeltDose technology. Veloxis Pharmaceuticals is working on other formulations that use the MeltDose process. The company has developed a once-daily modified-release formulation of tacrolimus, a poorly soluble compound with a water solubility of 4–12 µg/m, and the same API as in Astellas's Prograf, an immunosuppression drug used in kidney and liver transplants. Veloxis Pharmaceuticals has developed an amorphous solid-dispersion formulation of tacrolimus. The API was dissolved in a melted vehicle at elevated temperature. The solution was sprayed onto an inert carrier in a fluid bed. The resulting granulate was blended with a disintegrant and lubricant and compressed into tablets. The modified-release tablet formulation using the MeltDose technology was developed and tested in humans and is currently in late Phase III testing for the prevention of organ rejection with kidney transplants. Veloxis Pharmaceuticals expects to file for regulatory approval for the product, LCP-Tacro, in the US and European Union in the first half of 2013 (12). 

On the horizon: carbon nanoparticles in drug delivery

A mixture of current drugs and carbon nanoparticles shows potential to enhance treatment for head-and-neck cancers, according to research by Rice University in Houston and the University of Texas MD Anderson Cancer Center. The therapy uses carbon nanoparticles to encapsulate chemotherapeutic drugs and sequester them until they are delivered to cancer cells.  

The new strategy by Rice chemist James Tour and Jeffrey Myers, a professor of head-and-neck surgery at MD Anderson, combines paclitaxel and cetuximab with hydrophilic carbon clusters functionalized with polyethylene glycol, known as PEG-HCC, according to a Feb. 16, 2012, Rice University press release. Cetuximab, the targeting agent, is a humanized monoclonal antibody that binds exclusively to the epidermal growth factor receptor (EGFR), a cell-surface receptor overexpressed by a large percentage of head-and-neck squamous cell cancers. Because paclitaxel is hydrophobic, the substances are generally combined with Cremophor EL, a castor oil-based carrier that allows the compound to be delivered intravenously to patients. The researchers found a simple way to mix paclitaxel and cetuximab with carbon clusters that adsorb the active ingredients. The new compound is water-soluble and is more effective at targeting tumors than when paclitaxel is administered with Cremophor, according to the release. 

 1. R.O. Williams, A.B. Watts, and D.A. Miller, "Preface" in 

, R.O. Williams, A.B. Watts, and D.A. Miller, Eds. (Springer, 2012), p. v–viii.  

 2. K.P. O'Donnell and R.O. Williams, "Optimizing the Formulation of Poorly Water- Soluble Drugs," in 

, R.O. Williams, A.B. Watts, and D.A. Miller, Eds. (Springer, 2012), pp. 27–28.  

Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification 

 6. Alkermes, "NanoCrystal Technology" company information, 

www.alkermes.com/Contract-Services/Technologies/Bioavailability-Enhancement

 7. SkyePharma, "2011 Half-Year Results" (London, Aug.  18, 2011).  

 8. SkyePharma, "Insoluble Drug Delivery Platform" company information, 

www.skyepharma.com/Technology/Oral_Technology/Particle_Engineering_Technologies/Insoluble_Drug_Delivery_Platform/Default.aspx?id=80

 9. Aptalis Pharmaceutical Technologies, "Biorise Technology" company information, 

www.aptalispharmaceuticaltechnologies.com/tech_biorise.html

 13.  J.Q. Thomassen and P. Holm, presentation at the Nanomedicine and Drug Delivery Symposium (Toronto, Nov. 2008). 

Nanosupensions are among the ways formulation scientists seek to address the problem of solubility.

Tackling Solubility Challenges

Securing the pharmaceutical supply chain is of crucial importance to drug companies, suppliers, and consumers. The problem of supply-chain security has taken center stage with a number of recent initiatives. 

Although the problem of counterfeit drugs traditionally has centered on solid dosage drugs, recent drug shortages for injectable cancer medications have triggered concerns over counterfeit versions of these types of drugs. In January 2012, FDA advised that current shortages of injectable cancer medications may present an opportunity for introduction of non-FDA approved products into the drug supply (1). FDA advised healthcare providers to obtain and use only FDA- approved injectable cancer medications purchased directly from the manufacturer or from wholesale distributors licensed in the United States.  

FDA advised in January 2012 of promotions and sales of unapproved injectable cancer medications direct-to-clinics in the US, which most likely were administered to patients. Products purchased include a high percentage of sterile injectable medications and medications whose quality could be adversely affected if they are not stored or transported under specific temperatures. Examples of products include unapproved versions of FDA-approved medications, such as Faslodex (fulvestrant), Neupogen (filgrastim), Rituxan (rituximab) and Herceptin (trastuzumab). 

In certain circumstances, FDA may authorize limited importation of medications that are in short supply. Such medications are imported from approved international sources and distributed in the US through a controlled network and would not be sold in direct-to-clinic solicitations. If FDA has arranged for limited importation of the foreign version of a medication, information on obtaining that medication is available on the FDA drug shortages website (1).  

FDA's notification in January was followed by another problem of a counterfeit version of an injectable drug, Avastin (bevacizumab). In mid-February 2012, FDA warned healthcare professionals and patients about a counterfeit version of Roche's/Genentech's anticancer drug Avastin 400 mg/16 mL, which may have been purchased and used by some medical practices in the US. Avastin is an injectable medicine and is administered to patients in clinics, hospitals, and doctors' offices. The counterfeit version of Avastin does not contain the medicine's active ingredient, bevacizumab, which may have resulted in patients not receiving needed therapy (2).  

In a related action, FDA issued letters to 19 medical practices in the US that purchased unapproved cancer medicines that may include the counterfeit Avastin.  The counterfeit version is labeled as Avastin, manufactured by Roche. Roche is the company that  manufactures Avastin approved for marketing outside of the US. The only FDA-approved version of Avastin for use in the US is marketed by Genentech (a member company of Roche). The FDA-approved version does not include the Roche logo on the packaging or vials.  In addition, Genentech's FDA-approved version of Avastin vials and packaging have a 6-digit numeric batch number and expiration dates in a three-letter month and four-digit year format (e.g., JAN 2014).  Genentech's Avastin products are safe and effective for their intended uses. 

The 19 medical practices in the United States purchased unapproved cancer medicines and, potentially, the counterfeit Avastin, from Quality Specialty Products (QSP), a foreign supplier that may also be known as Montana Health Care Solutions, according to FDA documentation (2). Volunteer Distribution in Gainesboro, Tennessee, is a distributor of QSP's products. FDA requested that the medical practices stop using any remaining products from these suppliers. FDA cannot ensure the safety or efficacy of any of these unapproved products. Based on information to date, FDA determined that none of the unapproved cancer medicines received by these medical practices from Volunteer Distribution are in shortage in the US. FDA-approved versions of these medicines are available in adequate supply to meet current demand.  

In March 2011, several US government agencies and departments—FDA, the Office of the Intellectual Property Enforcement Coordinator, the US Customs and Border Protection (CBP), US Immigration and Customs Enforcement, the US Departments of Justice, State and Commerce, and the Agency for International Development—issued a joint report recommending a series of items to combat the problem of counterfeit medicines entering the US (3). The report called for better data and information-sharing among government agencies and departments to address counterfeit medicines entering the US. For example, as part of a process for developing an Import Operation Strategic Plan, FDA and CBP examined the flow of imported pharmaceutical products through different ports of entry, identified available legal authorities, and worked to develop best practices to enhance collaborative enforcement efforts. (3).  

CBP and FDA are engaged in ways to ensure that only compliant pharmaceuticals are imported into the US and that appropriate enforcement action is taken against illegal pharmaceuticals. For example, FDA and CBP will explore ways to ensure that, under appropriate circumstances, products are destroyed rather than returned to the  sender. CBP and FDA also are exploring ways to improve targeting of counterfeit pharmaceuticals. And CBP, in coordination with FDA, will access civil penalties to deter repeat offenders of importation of counterfeit medicines (3).  

Part of this effort also involved the development of a Secure Supply Chain  (SSC) pilot program by FDA's Center for Drug Evaluation and Research and Office of Regulatory Affairs. The program is part of FDA's risk-based approach to ensure the safety of imported drugs. The program is designed to help expedite shipments of drugs that meet the SCC pilot criteria because FDA has greater confidence in the drugs that are imported by a company in control of its supply chain.  

The Counterfeit Pharmaceutical Inter-Agency Working Group Report also called for increased measures for improving coordination among international bodies for combating counterfeit medicines, improving public awareness of counterfeit medicines, and improving government-to-government enforcement training. The report also called for continued involvement and support by FDA in the World Health Organization's International Medical Product Anti-counterfeiting Task Force (IMPACT). IMPACT brings together private and public sector experts to address the public health aspects of drug counterfeiting and is developing technical tools for countries to use and adopt to fight drug counterfeiting. These tools can be used to strengthen legislative, regulatory, technological, enforcement and communication infrastructure and build capacity for surveillance, identification, and prevention of counterfeit drugs from reaching patients. (3). 

WHO and FDA are collaborating to build global rapid alert surveillance/monitoring systems for combating counterfeit and falsified medicines and risks in supply-chain security. The goals of this effort are to generate sound and reliable evidence of where the incidence of falsified medicines is most serious, and promote exchange of information (e.g., case reports and descriptions of actions taken) and expertise between countries to stimulate action. Also, FDA and WHO are partnering to make available a system to be used for collecting and disseminating information based upon the requirements shared by all partners (3).  

In January 2012, the US Pharmacopeial Convention (USP) proposed a set of recommended best practices to help ensure that medicines can be traced back to their original manufacturer, are not adulterated or counterfeited, and are transported to their intended destination with their quality intact. USP is seeking broad feedback on these recommendations on supply-chain integrity. The new standard being proposed is not mandatory and is contained in the proposed USP General Chapter <1083> 

Good Distribution Practices—Supply Chain Integrity.

 The proposal is intended to serve as a central guidance document outlining the essential elements of an effective strategy.  

"While individual pharmaceutical companies have their own approaches to addressing this issue, the size and sophistication of companies and their suppliers vary widely, as do their quality systems and risk management approaches," noted USP in a Jan. 4, 2012, press release in announcing the proposed standard.  "Broad consensus around issues such as track-and-trace technology does not exist, and smaller companies that may be relied upon for sourcing pharmaceutical ingredients may or may not have security approaches comparable to their larger counterparts. Supply-chain integrity involves minimizing risks that arise anywhere along the supply chain, from sourcing pharmaceutical raw materials to their manufacture and distribution," noted USP in its release.  

"There is incentive for all players in the pharmaceutical industry—large and small companies, regulators and standards-setting bodies—to come to some agreement on hot-button issues such as track-and- trace technology and, at the larger level, to codify what constitutes a solid, universal approach to global supply-chain integrity," said Praveen Tyle, chief science officer for USP, in the release. "USP has developed an initial proposal that we expect to evolve as industry, FDA and others weigh in. Our role as an independent body provides an opportunity to convene all these parties and advance this critical issue. While some pockets of information are available via FDA guidances, trade organizations and other sources, an overall approach is lacking. USP can move forward something more concrete than a technical report, as part of a mechanism that can be regularly updated to best meet the needs of all." 

The proposed standard covers four main areas:  

—Details three primary initiatives importers should undertake to help prevent and detect potential risks: supply-chain risk management, development of effective supplier partnerships and building a supply-chain quality system 

—Documents types of counterfeit drugs, medical consequences, and distribution and extent of counterfeit drugs and devices 

Best practices to combat counterfeit drug and medical devices

—Covers topics including packaging technologies (tamper-evident designs, authentication technologies and serialization); drug pedigrees; machine-readable data carriers (2D bar codes and RFID tags); repackaging guidance, information retention and security; international standards; and best anticounterfeiting practices. 

—Addresses factors that raise the risk of theft of drug products, drug components and medical devices; security systems, devices and procedures that should be implemented to reduce risk; and critical information to be gathered following discovery of a theft. 

USP envisions the general chapter will be of use to all organizations and individuals involved in the global supply chain, including manufacturers; transportation companies involved in automobile, truck, rail, sea and air services; third-party logistics providers, freight forwarders and consolidators; brokers, importers, and exporters; packaging and repackaging operations; wholesalers and distributors; retail, mail-order, hospital, nursing home and other pharmacies; and mail distributors, including the US Postal Service and other expedited shipping services. 

The formal proposal will be published in 

(2), March–April 2012. This is the vehicle through which USP accepts public comment on its standards. The draft general chapter and comments submitted to USP will be a central topic of a Supply Chain Integrity Workshop that USP is convening May 22–23, 2012, in Rockville, Maryland. This meeting will be a further opportunity to provide input, including whether additional information needs to be included in the chapter.  

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

 1. FDA Statement, "FDA Notifies Healthcare Providers about the Risks of Purchasing Unapproved Injectable Cancer Medications from Unlicensed Sources"  (Rockville, MD, Jan. 13, 2012).  

 2. FDA Statement, "Counterfeit Version of Avastin in US Distribution" (Rockville, MD, Feb. 14, 2012).  

 3. Counterfeit Pharmaceutical Inter-Agency Working Group, "Counterfeit Pharmaceutical Inter-Agency Working Group Report to the Vice-President of the United States and Congress (Washington, DC, March 2011).

Regulatory bodies, standard-setting organizations, and industry seek to tackle the problem of counterfeit drugs and securing the flow of pharma ingredients.

Securing the Pharma Supply Chain

Patient compliance is important when developing a drug-delivery system, particularly when treating chronic diseases that require daily administration. Researchers at the Massachusetts Institute of Technology (MIT) recently reported on an alternative to daily injections: 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.  

The MIT researchers reported positive results of a human clinical trial using such a device. The primary objective of the rial was to assess the pharmacokinetics (PK) of the released drug, teriparatide, from the implanted devices. Safety measures included evaluating 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. 

In the trial, human teriparatide, a parathyroid hormone fragment [hPTH(1-34)] and anabolic osteoporosis treatment, was delivered from the device 

The microchip-based devices contained discrete doses of lyophilized hPTH(1-34) and were implanted in eight osteoporotic postmenopausal women for four months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses (1).  The human trial began in Denmark in January 2011. The chips used in the study stored 20 doses of teriparatide, individually sealed in reservoirs capped with a thin layer of platinum and titanium that melted when a small electric current was applied, thereby releasing the drug.  

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, according to a Feb. 16, 2012, press release of MicroCHIPS, which has licensed the technology from MIT. The MIT researchers began work on the implantable chip in the 1990s (2).  

The microchip-based implants can sense biochemical changes, deliver drug therapies, and wirelessly communicate status to networked patients and clinicians. The technologies use microreservoir arrays to hermetically store and protect pharmaceuticals or sensors for extended periods of time. The microchip is controlled by microprocessors, wireless communications, or sensor feedback loops for dynamic control of drug delivery or sensing. MicroCHIPS is developing new designs of its microchip-based implant to include as many as 400 doses per device for providing daily dosing for one year or multiyear therapy for less frequent dosing regimens. 

d. online, DOI: 10.1126/scitranslmed.3003276. Feb. 16, 2012. 

Wirelessly controlled microchips may offer an alternative to injection-based drug delivery

Formulation Development Forum: Programmable, Wirelessly Controlled Microchips for Drug Delivery

The pharmaceutical industry, equipment and machinery companies, and academic researchers are investing to develop applications in continuous processing for drug production. Supported by quality-by-design principles, a regulatory environment that is encouraging the industry's move to continuous manufacturing, and lured by the promise of improved production economics and greater operating efficiencies, the industry is moving forward with select projects in continuous solid-dosage manufacturing. 

Although pharmaceutical production is a batch-processing operation, specific unit operations in solid-dosage manufacturing, such as milling or tablet compression, may be run in semicontinuous and continuous processing steps (1). The feasibility of developing continuous processes for specific unit operations requires advances in pharmaceutical equipment design and operation. For example, to make continuous mixing, granulation, and drying possible for small-scale operations, such as in the pharmaceutical industry, systems need to be developed with limited or no start-up and shutdown waste to enable reaching steady state in an extremely short time (2). A commercial example is GEA Pharma Systems' ConsiGma continuous granulation, and drying system. Designed in a modular way, the system consists of a patented twin-screw granulator, a segmented continuous fluid-bed dryer, and a granule-conditioning unit to prepare granules for a tablet press (2). 

One advantage of continuous operations is the elimination of scale-up, which may be difficult overall and in specific operations, such as granulation (1). As hot-melt extrusion is gaining popularity for solubilization of insoluble drugs, twin-screw extrusion also is gaining attention as a continuous alternative to traditional high-shear granulation. This continuous process enables faster throughput and easier scale-up. Ashland  Specialty Ingredients recently presented results on how hydroxypropylcellulose (Krucel), povidone (Plasdone), and hypromellose (Benecel) performed in continuous low-temperature extrusion granulation as compared with traditional wet granulation. The results showed twin-screw extrusion as a promising method for high-dose formulations and highlighted how tablets made by means of extrusion showed improved strength and low friability compared to traditional wet granulation, according to an Oct. 13, 2011, company press release.  

Researchers at Ghent University in Belgium and Complutense University in Madrid recently evaluated the strengths and weaknesses of several complementary process analytical technology (PAT) tools implemented in a continuous wet-granulation process, which was part of a fully continuous from powder-to-tablet production line (3). The use of Raman and near infrared spectroscopy and a particle-size distribution analyzer was evaluated for the real-time monitoring of critical parameters during the continuous wet agglomeration of an anhydrous theophylline-lactose blend. The solid-state characteristics and particle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the API. The researchers reported that a higher barrel temperature and a higher powder feed rate resulted in larger granules (3). 

Researchers at Pfizer and the University of Cincinnati recently reported on work regarding optimization for a continuous extrusion wet-granulation process (4). Three granulating binders in high drug-load acetaminophen blends were evaluated using high-shear granulation and extrusion granulation. The researchers reported that a polymethacrylate binder enhanced tablet tensile strength with rapid disintegration in simulated gastric fluid, and polyvinylpyrrolidone and hydroxypropyl cellulose binders produced less desirable tablets. Using the polymethacrylate binder, the extrusion granulation process was evaluated with respect to the effects of granulating liquid, injection rate, and screw speed on granule properties. Response variables considered in the study included extruder power consumption (screw loading), granule bulk/tapped density, particle-size distribution, tablet hardness, friability, disintegration time, and dissolution (4). 

Continuous manufacturing also is being advanced by industrial, public, and academic partnerships. For example, in October 2011, FDA awarded a $35-million, five-year grant to the National Institute for Pharmaceutical Technology and Education (NIPTE), a nonprofit research center focused on pharmaceutical product development and manufacturing, to improve drug manufacturing standards. NIPTE's goal is to increase science and engineering-based understanding, so technologies can be developed and science-based regulations can be implemented. The FDA grant will in part by used to promote continuous manufacturing as well as other issues, such as improving small-batch production, reducing the environmental impact of manufacturing pharmaceutical products, and rectifying other drug-development and manufacturing problems.  

NIPTE is partnered with 10 US universities involved in the pharmaceutical sciences and engineering. The member universities are Duquesne University, the Illinois Institute of Technology, Purdue University, Rutgers University, the University of Puerto Rico, the University of Connecticut, the University of Iowa, the University of Kentucky, the University of Maryland–Baltimore, and the University of Minnesota. 

In April 2011, the United Kingdom's Engineering and Physical Sciences Research Council (EPSRC) established the EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization. EPSRC is the main UK government agency for funding research and training in engineering and the physical sciences. The University of Strathclyde is leading the EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization, which also involves the Universities of Bath, Cambridge, Edinburgh, Glasgow, Heriot-Watt, and Loughborough. Industry partners include GlaxoSmithKline, Pfizer, AstraZeneca, Fujifilm, Croda, Genzyme (now part of Sanofi), NiTech Solutions, Phoenix Chemicals, Solid Form Solutions, and British Salt. 

The EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization has identified several key research challenges:   

Achieving precise control over manufacturing of solid particles using continuous-manufacturing technologies 

Understanding the control of nucleation and growth of particles by means of crystallization under continuous flow

Developing continuous crystallization platforms, process analysis tools, and strategies to manufacture particles for different applications

Delivering the tools to control crystal structure, particle shape, and particle-size distribution

Facilitating continuous manufacture of medicines and nanomaterials with kinetic, cocrystallization, and impurity control (5).

In 2007, Novartis formed a $65-million, 10-year research collaboration with the Massachusetts Institute of Technology (MIT) to launch and fund the Novartis–MIT Center for Continuous Manufacturing to develop new technologies to replace the pharmaceutical industry's conventional batch-based system with continuous manufacturing processes. 

The Engineering Research Center For Structure Organic Particulate Systems, a multi-university consortium consisting of Rutgers University, Purdue University, the New Jersey Institute of Technology, and the University of Puerto Rico at Mayagüez, is another academic-partnership involved in continuous processing. The center, which is funded by National Science Foundation and industrial partners, includes 35 pharmaceutical manufacturers and equipment producers involved in R&D for continuous processing (2). 

Researchers at Rutgers University recently reported on an enhanced model-based control of a continuous direct-compression pharmaceutical process. The control-loop performance was assessed 

 and results obtained will be incorporated into the pilot-plant facility of the continuous direct-compaction process at the National Science Foundation's Engineering Research Center at Rutgers University. The models used in the study were obtained by means of a system identification from a combination of first principles-based dynamic models, experimental data, and/or literature data. The purpose of the study was to formulate an effective control strategy at the basic/regulatory level for the integrated continuous operation of the direct-compaction process and to maintain the process at the desired set-points, taking into account the multivariable process interactions and disturbances (6). 

 3. M. Fonteyne et al., "Real-time Assessment of Critical Quality Attributes of a Continuous Granulation Process," 

., online, DOI 10.3109/10837450.2011.627869, Oct. 24. 2011.  

 5. EPSRC, "EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization," 

www.epsrc.ac.uk/funding/centres/innovativemanufacturing/Pages/imrccontinuousmanufacturing.aspx

The article examines some recent developments for this process step and for continuous manufacturing overall.