Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

 discusses strategies in optimizing API syntheses and manufacturing. Participants include Jan-Olav Henck, PhD, chief scientific officer at Aptuit, Fred Fleitz, senior manager of process R&D with Cambridge Major Laboratories, and Roger McDonald, director of business development with Cambridge Major Laboratories. Also, Annemieke Timmers, CPhI brand director with UBM, discusses CPhI Worldwide, which was held in Frankfurt in October 2011 and other CPhI events.

 to a podcast with Jan-Olav Henck, PhD, chief scientific officer at Aptuit, who discusses strategies and considerations in polymorph screening. 

 to a podcast with Fred Fleitz, senior manager, process R&D with Cambridge Major Laboratories, and Roger McDonald, director of business development with Cambridge Major Laboratories, discuss recent project work in optimizing several API syntheses. Fleitz discusses the approach taken in a condensation reaction between a naphthoquinone derivative and a substituted methyl vinyl ketone. McDonald discusses the optimization of a synthetic route for a complex natural product analogue. In another project, he discusses an approach taken to maintain the desired enantioselectivity of a molecule containing a chiral cyclopropane moiety during scale-up. 

 to a podcast with Annemieke Timmers, CPhI brand director with UBM, discusses CPhI Worldwide, which was held in Frankfurt in October 2011, and other CPhI events.

Articles

Pharmaceutical Technology's podcast series from CPhI.

Technical Perspectives from CPhI Worldwide

Below is a roundup of news from exhibitors at CPhI Worldwide, which was held in Frankfurt, Germany, in late October 2011. 

 has opened a new analytical chemistry laboratory and GMP suite to extend and enhance its formulation-development capability. The new facilities at Aesica’s site in Nottingham, United Kingdom, include a dedicated analytical chemistry laboratory to test inhalation devices and a new GMP manufacturing suite, which will almost double the production capacity of clinical-trial materials across all dosage forms. Following the expansion in the UK, Aesica also plans to extend its formulation-development capabilities by launching a second site from within its formulated-products plant in Zwickau, Germany. The site specializes in the production of tablets, capsules, and pellet/beads and has a development laboratory. The launch of the new site is set for January 2012.

a commercial unit of Ashland, plans to add a GMP hot-melt extruder in its Columbia, Maryland, R&D center. The 18-mm Leistritz extruder will allow companies to scale up GMP clinical and commercial quantities produced by hot-melt extrusion. Ashland will finish installing and testing the equipment in the fourth quarter of 2011 and begin offering a full-service offering early in 2012. Earlier this year, Ashland completed its acquisition of the fine and specialty chemical company, International Specialty Products. 

Ashland Specialty Ingredients also launched Aquarius coatings based on a natural colors palette. The coatings systems use colorants based on natural ingredients that are color-stable under light and storage conditions. The company also announced the availability of three new commercial grades of Benecel hypromellose (HPMC) excipients for use in the formulation of matrix tablets: HPMC K250 PH PRM, HPMC K750 PH PRM, and HPMC K1500 PH PRM.

has developed a packaging system, PeroXeal, to protect its pharmaceutical excipient, Kollidon, which is based on polyvinylpyrrolidine, against contact with oxygen and subsequent oxidation. The system makes it possible to reduce the level of peroxide of Kollidon, thereby making the excipient suitable for use in oxygen-sensitive formulations as well. The PeroXeal packaging system consists of a multilayered and heat-sealed plastic film used as inner packaging material. The new packaging has been introduced for most Kollidon products at the company’s Luwigshafen and Minden, Germany, sites. BASF will offer all grades of the Kollidon line with the new technology starting by the end of 2013. 

 have formed a collaboration for the development of future film-coating systems using BASF’s Kollicoat SmartSeal 30D and a new Colorcon preformulated additives. Colorcon has developed a preformulated additive system for use with Kollicoat SmartSeal 30D to enable efficient preparation and application of this polymer in taste-masking applications. The preformulated additive lowers the number of materials to be dispensed by 50% and reduces the preparation time by almost 40%, according to the companies.

also has developed a portfolio of high-purity iron salts for API manufacturing. Solutions for iron-deficiency anemia, phosphate management, and magnetic resonance imaging are gaining in importance. The new iron salts have trace-metal impurities at the single-digit ppm level, therefore keeping them in compliance with EMA directives. The salts are available in quantities ranging from kilograms to commercial volumes. 

-methylpyrrolidone Life Science (NMP Life Science), which is a NMP grade with a very low level of free amines in the range of 1 part per million, equivalent to 0.0001%. The company notes that the product can be used in the solid-phase synthesis of therapeutic peptides and raise yields by more than 15%. BASF also featured its NanoSelect platform technology, which has been used to develop platinum-based catalysts for selective aromatic nitro group hydrogenation. The company says the new catalysts show high nitro group hydrogenation activity with lower platinum requirements. Additionally, the NanoSelect platform technology has enabled the production of modified platinum catalysts with good selectivity in halo nitro aromatic hydrogenation reactions, according to the company. 

, a French fine-chemicals company, has formed a strategic partnership agreement with 

, a US fine-chemicals company, to jointly market and distribute both companies’ organoboron compounds and synthetic intermediates. The partnership will help Boron Molecular better access European markets and facilities BoroChem’s access to the US market. 

 has expanded its cGMP facility in Charlottetown, Prince Edward Island, Canada, with the addition of a 1500-L fermentation unit for producing clinical and commercial products. The company will also be initiating production in a new wing dedicated to the manufacture of 50 metric tons of new drug substances and is in the design stage for the construction of new facility for manufacturing dedicated APIS. The initiatives are expected to completed in 2012. 

 were awarded to Glycotope (gold winner) for its development of the GlycoExpress platform technology to optimize the glycosylation of antibodies and other glycosylated biotherapeutics, Acuros (silver winner) for its disposable drug-delivery device that allows continuous delivery of small-volume parenteral drugs, and Johnson Matthey for its Catalyst Color-Tag Protein technology, which is used as marker for protein expression. 

, a biocatalysis company, reports that its Codex screening kits are in use or evaluation at 50 pharmaceutical companies worldwide. The company introduced the kits in October 2010. The company reported that through Sept. 30, 2011, more than 10,000 kg of various enzymes have been manufactured by the company’s enzyme production partners. Smaller 10–100 kg quantities have been manufactured at the company’s Redwood City, California, facility. 

has increased its capacity of propylene glycol by an additional 10 kilotons per year at its Stade, Germany, plant after completion of equipment optimization during scheduled routine maintenance. The capacity increase raises the plant’s propylene glycol nameplate capacity to approximately 280 kilotons per year.  Dow operates five global propylene glycol manufacturing facilities with a total global capacity of 700 kilotons per year. The company manufactures pharmaceutical-grade propylene glycol. 

, a business unit of Dow Chemical, is planning a capacity expansion project for the production of Carbowax Sentry solid-grade polyethylene glycols. The expansion project is expected to begin in 2012 and will support the global supply of Carbowax Sentry. 

, a CRO that provides custom synthesis and drug-discovery services  and 

, the testing and laboratory division of 

, have formed a strategic alliance. The new organization, GalchimiApplus, will perform R&D, scale-up and small production, as well as analytical development and validation. 

has started construction of a new, multipurpose, multiproduct API manufacturing facility, which is scheduled to be operational by June 2012. The plant will consist of two parallel streams and will accommodate 32 reactors with capacities ranging from 6 m

 for a total reactor volume of approximately 300 m

launched its Rapid Proof of Concept Study for the development of dry-powder inhalation products. The new service is intended to simplify the developing of formulations by producing a proof-of-concept formulation of a molecule in a few weeks.  Hovione also announced that it formed a nonexclusive, cooperative relationship with 

 a formulation-development company. The collaboration gives Bend Research clients access to Hovione’s commercial-scale pharmaceutical facilities on a global basis and provides Hovione’s clients access to Bend Research’s oral drug-delivery, formulation, and engineering expertise. 

 has been granted a global license to the full range of Buchwald dialkyl- biaryl- mono phosphine and related bis-phosphine ligands. The licensed patents include both the composition of matter of the family of ligands and the processes for use of catalysts containing these ligands in transition-metal catalyzed carbon–heteroatom and carbon–carbon bond-forming reactions. 

accepted an offer on Oct. 27, 2011, to divest Novozymes Biopharma Sweden to American-owned Repligen Corp. Earlier this year, Novozymes announced that the company has been looking for a potential spin off or divestment of its AMP (antimicrobial peptide) projects such as plectasin and arenicin.

also featured its ICH Q7 cGMP grade of hyaluronic acid (HA), a new 

-derived grade to improve processing and formulation of HA for medical-device and pharmaceutical applications. The HA is produced at a new Novozyme facility in Tianjin, China, and is produced using a water-based process that is free of animal-derived components and organic solvents. The HA will be commercially available in December. 

 reports that Boehringer Ingelheim has awarded the company two projects with combined revenues of more than $18 million during a three-year period. The projects are both fixed-dose combination drugs in development for treating Type II diabetes. 

reports that it is performing commercial-scale antibody–drug conjugate (ADC) manufacturing at its Grangemouth, Scotland, facility. The company is currently evaluating plans to build out additional manufacturing suites to accommodate kilogram batch sizes. Several ADC-based therapies are in late-phase clinical trials, approximately one dozen are in Phase I development, and more than 20 are in preclinical development. Earlier this year, Piramal opened a new $400,000-quality-control laboratory suite at its facilities in Grangemouth to support its ADC portfolio. 

 reports that its custom manufacturing and services business unit, 

, has completed an assessment by SafeBridge Consultants and has been granted SafeBridge certification for its commercial-scale high-potency API (HPAPI) facility in Verona, Wisconsin. Constructed at a cost of $30 million and officially opened in April 2010, the Verona site was built specifically to support manufacturing for Phase III and commercial scales up to Category IV compounds. The SafeBridge assessment also included a successful recertification of SAFC’s nearby Madison, Wisconsin, high-potency facility. 

 reports that it will build new production capacities for potent APIs at its facility in Redmond, Washington. The company will expand its production to produce and handle Category III substances. The capacity up to the kilogram range will become available at the beginning of 2012.

A roundup of news from fine-chemical suppliers, CDMOs, and CMOs from this year's installment of CPhI Worldwide.

Contract Manufacturers and Ingredient Suppliers Assemble at CPhI Worldwide

Catalysts play an important role in chemical reactions, but they are particularly important in producing fine chemicals or pharmaceutical compounds to meet desired yields, purity, and stereoselectivity. Elucidating how a catalyst may work in a specific synthesis is not only valuable for a given project, but it contributes to an overall understanding of process chemistry. Some recent advances involve asymmetric synthesis and approaches for improved enantioselectivity, oxidation catalysis, and the development of boron-based ligands. 

Researchers at the University of Amsterdam recently reported on an approach for identifying and developing catalysts to synthesize products with high enantioselectivity, a method of utility for making pharmaceutical compounds. The researchers reported on the development of an achiral bisphosphine rhodium complex, which contained a binding site for recognizing chiral anion "guests" or cofactors. Upon binding the small-molecule cofactors, the rhodium complex becomes chiral and can then be used in asymmetric catalysis. The researchers screened a library of cofactors and discovered the optimal cofactors, which led to the identification and development of hydrogenation catalysts that formed products with enantiomeric excess as high as 99%. The researchers also conducted a competition experiment to determine the optimal cofactor among a mixture of 12 cofactors. The optimal cofactor was one that binds strongest to the rhodium complex (i.e., the catalyst) and through the catalyst produced the product with greatest optical purity. The competition experiment provided the basis for creating an efficient way to screen a library of cofactors with other metal–ligand systems (1, 2). The University of Amsterdam chemists have patented the strategy and plan to develop it  alongside their other high-throughput ligand-screening strategies through a spin-off company, InCatT. 

Raising the bar in catalytic hydrogenation

Researchers at the University of Alberta recently  developed a  new ruthenium-aminophosphine catalyst with very high turnover. The catalyst system was used for the hydrogenation of a variety of acyclic and cyclic amides to the corresponding alcohols and amines. They reported catalytic activity with turnover as high as 7200. Specifically, the researchers reported that the reaction between 2 equivalents of Ph

 (cod = 1,5-cyclooctadiene) formed a highly active catalyst precursor for the selective hydrogenation of amides. The reaction proceeded with good atom economy, yield, and turnover under moderate reaction conditions (3). The researchers are working to further optimize the catalyst system, according to a Sept. 28, 2011, University of Alberta press release.  

Formulation development forum: translational pharmaceutics (FIGURE 1 IS COURTESY OF THE AUTHOR) 

Evaluating steric and electronic effects in asymmetric catalysis

In designing a catalyst system, understanding the steric and electronic effects is important, but it is particularly important in asymmetric synthesis. Researchers at the University of Utah recently reported on a systematic approach to optimize the steric and electronic factors in designing a catalyst for the selective addition of alkyne derivatives to ketones (4). The researchers applied a three-dimensional free-energy relationship that correlated steric and electronic effects to design and optimize a class of ligands (i.e., quinoline proline ligands) for the enantioselective Nozaki–Hiyama–Kishi propargylation of ketones. The data from the study suggested that steric–electronic correlations provided an efficient optimization of a catalytic system and a synergistic relationship between steric and electronic effects in reactions. The researchers assert that the approach is particularly useful for optimizing reactions with limited detailed mechanistic and structural understanding. 

Copper-catalyzed click chemistry for biomolecular labeling  

Revealing the catalytic site in oxidation catalysis

Oxidation catalysis plays an important role in the chemical, fine-chemical, and pharmaceutical industries. Approximately 80% of all compounds in the chemical and pharmaceutical industries require at least one catalytic step in their synthesis, according to some estimates. Hydrocarbon compounds used to make commodity or fine chemicals often require an oxidation step, which is mediated by a  transition metal compound (5). Advances in oxidation catalysis, therefore, are of broad interest to process chemists. 

Researchers at the University of Virginia recently provided a study that details a new type of catalytic site where oxidation catalysis occurs. Using a titanium dioxide substrate holding nanometer-size gold particles, the researchers identified a site that serves as the catalyst at the perimeter of the gold and titanium dioxide substrate, according to an Aug. 4, 2011, University of Virginia press release describing the research.  

"This site is special because it involves the bonding of the oxygen molecule to a gold atom and to an adjacent titanium atom in the support," said John Yates, professor of chemistry at the  University of Virginia and co-author of a recent research article on the study (6). "Neither the gold nor the titanium dioxide exhibits this catalytic activity when studied alone," he said.  

Using spectroscopic measurements, and computational-chemistry aproaches, the researchers were able to follow the specific molecular transformations and determine where they occurred on the catalyst. The researchers observed that significant catalytic activity occurred on unique sites formed at the perimeter region between the gold particles and their titania support, according to the release.  

Classifying it as a dual catalytic site because two dissimilar atoms were involved, the researchers observed that an oxygen molecule bound chemically to both a gold atom at the edge of the gold cluster and a nearby titanium atom on the titania support and reacted with an adsorbed carbon monoxide molecule to form carbon dioxide. They used spectroscopy to follow the consumption of carbon monoxide at the dual site. "This particular site is specific for causing the activation of the oxygen molecule to produce an oxidation reaction on the surface of the catalyst," said Yates in the university press release. "It's a new class of reactive site not identified before." 

Moreover, the study has broader implications for catalysis research. "We have both experimental tools, such as spectrometers, and theoretical tools, such as computational chemistry, which now allow us to study catalysis at the atomic level," said Yates. "We can focus in and find that sweet spot more efficiently than ever. What we've found with this discovery could be broadly useful for designing catalysts for all catalytic reactions.  

A research team lead by Guy Bertrand, a distinguished professor of chemistry at the University of California at Riverside, recently reported on the use of boron-based compounds to build Lewis bases.  

The researchers reported on the synthesis and characterization of a neutral tricoordinate organoboron isoelectronic with amines. The neutral tricoordinate boron derivative acted as a Lewis base and underwent one-electron oxidation into the corresponding radical cation. These compounds were the parent borylene and borinylium, respectively, stabilized by two cyclic (alkyl)(amino) carbenes. 

calculations showed that the highest occupied molecular orbital of the borane and the singly occupied molecular orbital of the radical cation were essentially a pair and a single electron, respectively, in the p(p) orbital of boron (7). 

"The result is totally counterintuitive," said Bertrand, in an July 28, 2011, University of California at Riverside press release. "...But we have achieved it. We have transformed boron compounds into nitrogen-like compounds. In other words, we have made acids behave like bases." 

Nitrogen- or phosphorus-based compounds are commonly used as  ligands in catalysts. "The trouble with using phosphorus-based catalysts is that phosphorus is toxic and it can contaminate the end products," Bertrand said. "Our work shows that it is now possible to replace phosphorus ligands in catalysts with boron ligands. And boron is not toxic," he added. Researchers at Philipps–Universitat in Marburg, Germany, also contributed to the study.  

., online DOI: 10.1021/ja208589, Sept. 30, 2011.  

 5. F. Meyer nd C. Limber, eds., "Preface" in 

Researchers develop various catalytic approaches for improving yield, purity, stereoselectivity, and process conditions.

Catalyzing the Synthesis

Arise in the number of developmental compounds, greater complexity in clinical trials, and an expansion of clinical-trial sites globally are raising the bar in managing the clinical-trial-material (CTM) supply chain. Pharmaceutical companies and their suppliers must align  product supply with demand at multiple sites in several countries with fluctuating patient-enrollment rates and greater complexity in dosing regimes while maintaining product quality and supply continuity.  As a result, strategies that use best practices in drug modeling, simulation, packaging, labeling, logistics, and supply-chain management are of increasing importance. 

 ILLUSTRATION BY SELVAKUMAR VEERAPUTHIRAN. IMAGES : IMAGE SOURCE/GETTY IMAGES 

Since 2000, the number of developmental drug compounds has increased as has the complexity of clinical trials. Approximately 2040 compounds were under development in 2001, and this number increased nearly 50% in 2010 to 3050 compounds, according to a recent report by the Pharmaceutical Research and Manufacturers of America (1). Between 2000–2003 and 2004–2007, the median number of  procedures per clinical trial increased by 49% while the total work burden per protocol grew by 54% (1, 2). As complexity increases, so do eligibility criteria for volunteers, which lead to lower volunteer recruitment and retention rates. The average number of eligibility criteria for volunteers has increased by 58%, and volunteer enrollment and retention rates have declined by 21% and 30%, respectively (1, 2). 

Concurrently, the number of clinical-trial sites outside the United States has increased. Eighty percent of FDA-approved marketing applications for drugs and biologics contained data from foreign clinical trials in fiscal year 2008, according to a 2010 report by the Office of Inspector General of the US Department of Health and Human Services (HHS) (3). More than half of clinical-trial subjects and sites were located outside the US (see Table I). 

Table I:  Number and percentage of foreign subjects and sites from clinical trials supporting drug and biologic marketing applications approved by FDA in fiscal year 2008.  

Western Europe accounted for most foreign clinical-trial subjects and sites (approximately 60%). Central and South America had the highest average number of subjects per site, accounted for 26% of all subjects enrolled at foreign trial sites, and 7% of foreign sites. According to estimates cited by the HHS report, between 40% and 65% of clinical trials investigating FDA-regulated products are conducted outside of the US. A recent analysis of 

, a National Institutes of Health registry and results database of federally and privately supported clinical trials, examined recruitment in industry-sponsored Phase III clinical trials and found that as of November 2007, one-third of the clinical trials of the 20 largest US-based pharmaceutical companies were conducted at foreign sites (3, 4).  

As the number of clinical-trial sites expands on a global basis, several challenges arise in managing on-time CTM delivery.  "The use of technology to track delivery and inventory is critical," says Frank Lis, vice-president and general manager of clinical-supply services with Catalent Pharma Solutions. "Because some studies involve many countries, investigators, and depots, you need tools to help track shipments and inventory." 

Others agree. "A key factor is the management of a depot/site network," says Jim Curry, president and CEO of OpStat, a consultancy specializing in supply-chain management, lean manufacturing, and inventory management. "There needs to be accurate and timely management of inventory information from those involved in the clinical supply chain, including from third-party logistics providers." Managing CTM supply requires that information on CTM be created and maintained accurately. "Problems can arise in entering or omitting data in inventory systems or interactive web response systems (IWRS). IWRS collect and provide access to clinical-trial study data. "Such errors may, for example, relate to the number of patients in a trial at a given site, level of patient recruitment, the level of patient dispensing, or other entry errors that affect the dose requirements at a given site, which in turn, affect the CTM supply chain," says Curry. 

When expanding the number of sites globally, additional challenges may arise. "Import and export permits are a challenge with some countries," says Lis. "You need to make sure all documentation is completed well in advance and that permission has been received to ship products into these countries." Once documentation and permission are received, the transport and storage of product, particularly temperature-sensitive ones in a cold chain, are crucial. "In some countries, transportation and storage of controlled-temperature products are difficult," says Lis. "Some of the investigators are not near major cities and have little experience with conducting studies and handling product."  

In addressing these challenges, experts offer various approaches to mitigate problems of on-time delivery and to align supply with demand at clinical sites. "Senior management must first have the vision to recognize the importance of the supply chain and to recognize that appropriate tools are needed to effectively manage the supply chain," says Curry. "Even for emerging pharmaceutical companies with few drugs entering Phase II and Phase III trials, the complexity grows fairly quickly in terms of levels of patient enrollment, the number of sites, various dosing schemes for a clinical product, and the related need to meet CTM supply requirements. A formal monthly demand and operations planning process that includes the supply-chain, clinical, manufacturing, quality, and R&D functions is important to synchronize the entire chain," he says. 

 Effective modeling of study forecasts, along with dynamic inventory projections, to predict and modify CTM supply is key, says Curry. He identifies several best practices for effective CTM supply management:   

Perform modeling of clinical study forecasts before initiation and re-forecasts as clinical studies are started to determine the latest projections for all studies for a given molecule. 

Include study-design arms, site activation, and patient-recruitment levels in study forecasts.  

To determine supply requirements for some drugs, depending on the study design and disease, project patient time in a study, including deactivations (i.e., patients withdrawing from the trial) and extensions because both affect the amount of supply required. 

Construct and analyze study forecasts for all clinical studies back to API manufacturing.  

Implement protocols and practices to determine reasonableness of data and for detecting omission of data from clinical sites, which includes the ability to easily adjust for errors. 

Use capabilities for extensible markup language (XML) to make data available for electronic data-capture systems, IWRS, third-party logistics providers, and manufacturers. 

Have a four-year horizon for finance projections (i.e., assuming that most studies are approximately two years in length) for R&D. Although these projections may represent a major investment for large and small pharmaceutical companies, it is strategically important to have such information in place to predict CTM supply. 

Curry offers an example of how such a simulation model works in practice. The simulation model is integrated with spreadsheet input and output capability to manage the flow of materials through all phases of the CTM supply chain. The manufacturing processes for APIs, drug product, packaged product, and patient kits are included in a synchronized flow. Inventory may be monitored at each point in the chain, and replenishment rules are established for each plant or work center involved. 

Each contract or internal manufacturing site may be modeled to the level of detailed required. A high level model of the flow includes the capability to drill down to identify time slots when production will be required based on contracted lead times. When the model is run, graphics and metrics are available that may be selected as needed. For example, the timing of batches and lots in the production flow are displayed from drug substance to drug product to packaged products and kits. It also is possible to measure how long kitted product has been in the clinical-trial pipeline because each lot is time-stamped as it goes through each process. "Monitoring expiration dates for CTM supply is crucial as the administration of clinical trials may be delayed or adjusted based on clinical results," says Curry.  

The demand for patient kits is based on the patient recruitment rate for the clinical-trial, and the usage is based on the study design for the trial. Usage is calculated based on the size of kits, which dictates how long a kit will last and when re-orders from patients will be required. In addition to the normal duration of the trial for each patient, the patient deactivation/extension rate also is factored into the model.   

 Managing the CTM supply chain when cold-chain requirements are involved requires additional knowledge, skill, and technology. Dan Gourley, director of global clinical logistics with Catalent Pharma Solutions, gave insight into the factors to consider by providing a cold-chain supply-management case study at a recent conference (5). The example he offered was a Phase III medicinal product, which was packaged in the US, but shipped to multiple countries and depots. In this particular example, the product was required to be maintained at temperatures from 2–8 °C. Large kit sizes required large shipping volumes, and active and passive shippers were used, depending on the application. An active system refers to a system that maintains temperature through battery-powered refrigeration. A passive system refers to a system that maintains temperature through the use of refrigerated and frozen gel combinations.  

In developing the appropriate cold-chain logistics and supply-chain management of the product, Gourley noted several key areas to address:  

 Security by protecting the product against damage, loss, or theft while en route or upon arrival 

 Maintenance of cold-chain conditions in the air and on the ground 

 Planning, adaptability, and contingency plans to ensure supply continuity 

 Required documentation, including  country-specific documentation 

 Regulatory compliance to ensure correct valuation of material to decrease any risk of potential delays with countries' regulatory authority agencies 

 Improvements in kit design to enable smaller, lighter, and cost-effective packaging

Real-time assurance by using technology-enabling tracking of temperature and location. 

In managing the CTM supply chain, both country-specific and clinical-site-specific requirements, which include potential depot needs, must be considered. Gourley emphasized that it is important to review the capabilities and capacity of depots receiving cold-chain materials. Issues to consider are country-specific restrictions, the capacity of the depot to store the supplies, and the type of shipment package that the depot can handle. Shipment packages can be active, passive, or phase-change. Phase-change shipments refer to reusable shipping systems.   

He also emphasized the importance of reviewing country-specific regulations for import, such as import permits or licenses, special packaging and labeling requirements, and physical pack-out of materials. Custom valuation is another important factor to consider when shipping supplies. Custom-valuation methods typically for clinical supplies include four types: the transaction value; the transaction value of identical or similar merchandise (i.e., based on the transaction value of previously imported merchandise); deductive value (i.e., the selling price in the US less certain post-importation costs); and computed value (i.e., foreign-supplier cost information for materials, processing, profit, and general expenses). To mitigate risk with respect to custom valuations, Gourley stressed the importance of receiving input from the finance, procurement, and legal departments,  documenting the method of calculation, having shipping documentation reviewed by a customs broker or consignee before shipping, and ensuring that all import license requirements have been completed.  

In terms of shipping and transportation, key issues to consider are the estimated travel time to given countries, a review of the method of shipping (i.e., active, passive, phase-change), the type of transportation (i.e., air, ground, or ocean) that will be used, validation of the shipper, and evaluation of the devices used in temperature monitoring. With respect to shipper validation, shippers may fall into three categories: nonqualified (i.e., the shipper provides no documented testing to maintain temperature), prequalified (i.e., the shipper performs documented testing to a shipping standard, such as water), and validated (i.e., the shipper performs documented testing to a shipping standard with a given product). With respect to monitoring, he noted that as part of the packaging decision, it has to be determined whether temperature monitors should be used with all shipment or with some shipments. "All of these decisions affect cost and the quality of the product," says Gourley. "The higher the cost of the delivery system, in general, the more robust." 

Another decision point is kit size, noted Gourley. Freight costs are calculated on either the physical weight of the materials or on the dimensional weight of the materials. Kit size will drive the shipping cost based on whichever of these two factors, physical weight or dimensional weight, is greater. Reduced kit size will reduce the cost of shipment.   

In these packaging and shipping decisions, packaging software can be used to reduce the size of the kit and to match the best shipper for the intended application. "Before determining the final packaging configuration, however, you will need to know how most material will be shipped and what type of cold-chain packaging will be used," he says.  

With respect to security, Gourley emphasized the need to know the capabilities and practices of the shipper to ensure their  performance. Some key issues are whether the courier can screen materials, whether the courier has been audited, whether the courier works with the consignee to clear shipments, and how the materials are handled in the couriers' presence.   

In the end, adaptability is key. "With the trend toward more complex clinical trials, the ability to remain flexible and rapidly adjust to changes in client demands has been a critical success factor for on-time delivery and receipt of clinical-trial materials," says Randall H. Guthrie, vice-president of Xcelience. He points to the value of project management, integrated supplier networks, and an understanding of regional differences from a regulatory standpoint to meet CTM requirements.  

 1. PhRMA, "Pharmaceutical Industry Profile 2011" (Washington DC, April 2011). 

 2. Tufts Center for the Study of Drug Development, "Rising Protocol Complexity, Execution Burden Varies Widely by Phase and TA" Impact Report 12, No. 3, May/June 2010. 

 3. HHS, "Challenges to FDA's Ability toMonitor and Inspect Foreign Clinical Trials" (Washington DC, June 2010).  

 5. D. Gourley, presentation at the 9th Annual Cold Chain & Temperature Management Global Forum (Philadelphia, Sept. 2011). 

Pharma companies and their suppliers are tasked with managing an evermore complex clinical-trial material supply chain.

Managing the Global Clinical-Trial Material Supply Chain

Last week, the US Senate and House of Representatives passed three separate free-trade pacts with South Korea, Colombia, and Panama. The Society of Chemical Manufacturers and Affiliates (SOCMA) welcomed the passage in a statement of support. The Pharmaceutical Research and Manufacturers of America (PhRMA) also issued a statement supporting the free-trade pact with South Korea.

President Barack Obama said he looked forward to signing the agreements as part of pro-export trade strategy. “The landmark trade agreements and assistance for American workers that passed tonight are a major win for American workers and businesses,” said the president in an Oct. 12, 2011, 

. “I’ve fought to make sure that these trade agreements with South Korea, Colombia, and Panama deliver the best possible deal for our country, and I’ve insisted that we do more to help American workers who have been affected by global competition … I look forward to signing these agreements, which will help achieve my goal of doubling American exports and keeping America competitive in the 21st century.”

SOCMA President and CEO Lawrence D. Sloan also expressed his support. “Effective trade policy is highly important to the chemical-manufacturing industry and has been among SOCMA’s legislative priorities since its inception,” he said in an Oct. 12, 2011, 

. “We are looking forward to a more active trade agenda, with increased engagement by the US looking for additional trade partners to increase market access and provide opportunities for American manufacturers.” 

Sloan singled out the value of the free-trade pact with Colombia. The chemical industry paid $480 million in duties to Colombia between 2008 and 2010, more than any other exporting sector, according to a July 1, 2011, 

 by SOMCA to Congressional leaders. “The [free-trade agreement] with Colombia would eliminate 80% of these duties once the agreement becomes effective and would eliminate the rest within 10 years,” according to SOCMA.

SOCMA noted that Korea is the seventh-largest market for US chemical exports. From 2008 to 2010, approximately $892 million in duties were paid on chemical products to the country. Duties paid to Panama for the same time period were $34 million.

PhRMA President and CEO John Castellani also welcomed the passage of the Korea–US free trade agreement. “Korea is an important market for the US research-based pharmaceutical companies, a country where we currently enjoy a trade surplus,” he said in an Oct. 13, 2011, 

. “This agreement will contribute directly to increased US exports and the expansion of highly skilled, well-paying jobs here in the US.” In 2010, US pharmaceutical exports to Korea increased by nearly 35% from 2009 to $781 million, according to data from PhRMA.

The US Senate and House of Representatives passed last week three separate free-trade pacts with South Korea, Colombia, and Panama. The Society of Chemical Manufacturers and Affiliates and the Pharmaceutical Research and Manufacturers of America both issued statements expressing support for the legislation.

SOCMA, PhRMA Welcome Passage of Free-Trade Pacts

AstraZeneca is investing $200 million in a new manufacturing site in China Medical City (CMC), Taizhou, Jiangsu province, China. The new site represents AstraZeneca’s largest investment in a single manufacturing facility globally.

The site will produce intravenous and oral solid medicines for the company’s business in China. Construction of the site is scheduled to be complete at the end of 2013.

AstraZeneca first established a presence in China in 1993 and generated more than $1 billion in revenues in that country in 2010. AstraZeneca’s other facilities and project work in China include a manufacturing and supply site in Wuxi New District, Jiangsu Province; the AstraZeneca Innovation Center China, a translational science center; an established sales and marketing operation; large-scale clinical development capabilities; and a network of collaborations with academic and medical institutions.

AstraZeneca’s plans for its new manufacturing site in China follow recent investment in emerging markets. In June 2011, AstraZeneca unveiled plans to establish a Predictive Science Center in St. Petersburg, Russia. The center will be staffed with 30 employees and focus on developing bioinformatics, data-analysis methods, software, and systems to help predict the safety and efficacy of potential new medicines. Earlier this year, the company began constructing a $150-million manufacturing facility in the Kaluga region to supply locally manufactured medicines in Russia.

Big Pharma’s Manufacturing Blueprint for the Future

AstraZeneca is investing $200 million in a new manufacturing site in China. The new site represents AstraZeneca's largest investment in a single manufacturing facility globally.