Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

Cocrystals are solids that are crystalline materials composed of two or more molecules in the same crystal lattice. Cocrystals are used to improve the performance of APIs that have non-ideal physiochemical properties by cocrystallizing the API with a second compound that modulates the API to provide a way to improve a drug's bioavailability, stability, and processability. Cocrystals, however, are different from traditional pharmaceutical solid-state forms. Unlike polymorphs, which generally contain only the API within the crystal lattice, cocrystals are composed of an API with a neutral guest compound conformer in the crystal lattice (1). Unlike a salt form where the components in the crystal lattice are in an ionized state, the molecules in the cocrystal are in a neutral state and interact by means of nonionic interaction, thereby providing a way to produce solid-state forms even for APIs that lack ionizable functional groups needed for salt formation (1). 

Researchers at the University College London (UCL) and the University of Bradford in the United Kingdom recently reported on the use of thermal ink-jet (TIJ) printing as a way to prepare pharmaceutical cocrystals. The researchers identified cocrystals in all cases where the coformers could be dissolved in water and/or water/ethanol solutions (2). The researchers prepared a metastable form of the anti-epileptic drug carbamazepine by first depositing small droplets of template solution followed by droplets of the drug solution, which led to rapid evaporation and crystallization (3). Although applied successfully, TIJ technology to make cocrystals presents certain challenges, such as controlling solution, stage temperature, or stoichmetry (3). Also, the approach is limited to using water or mixtures of ethanol and water as the solvents because other organic solvents may react with the plastic cartridges of the printer (3).  

The research was led by Simon Gaisford, reader in pharmaceutics at the UCL School of Pharmacy, whose research is focused on using TIJ technology to produce pharmaceutical forms. Instead of using ink in a print cartridge, the ink is removed and replaced with a drug solution. A TIJ system consists of a reservoir of liquid to be jetted mounted above a printhead.  The printhead, usually produced with photolithography, consists of a number of small chambers, filled with liquid from the reservoir, each in contact with a resistive element. Pulsing a current through the element results in a rapid rise in temperature, causing vapourization of some of the liquid, nucleation and then expansion of a vapor bubble. As the bubble expands, some liquid is ejected from the chamber, forming a droplet. The fine control of liquid deposition can be used for pharmaceutical applications (4). 

Other applications of TIJ technology from Gaisford's research have included making personalized-dose oral films of salbutamol sulfate by replacing the paper in the printer with a sheet of polymer film that allowed the drug to be jetted onto the surface (4). A printer cartridge was modified so that aqueous drug solutions replaced the ink (5). The film strips were then cut. Varying the concentration of drug solution, area printed or number of print passes allowed the dose to be controlled (4, 5). The print solution viscosity and surface tension were used to determine the performance of the printer. A calibration curve for salbutamol sulfate was prepared, which showed that drug deposition onto an acetate film varied linearly with concentration. The printer was then used to deposit salbutamol sulfate onto an oral film made of potato starch. The researchers found that when doses were deposited in a single pass under the print head, the measured dose was in good agreement with the theoretical dose. With multiple passes, the measured dose was always significantly less than the theoretical dose (5). The researchers surmised that the losses result from the printed layer eroding by shearing forces during paper handling.  

Draft Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals 

 "Printing Crystalline Drugs," online, 8 Feb. 2013, 

http://www.rsc.org/chemistryworld/2013/02/co-crystal-drugs-inkjet-printer

4. UCL, "Profile (S. Gaisford): Research Summary," 

http://iris.ucl.ac.uk/iris/browse/profile?upi=SGAIS88

Articles

Cocrystals are used to improve the performance of APIs that have non-ideal physiochemical properties by cocrystallizing the API with a second compound that modulates the API to provide a way to improve a drug's bioavailability, stability, and processability.

Using Thermal Ink-Jet Printing Technology to Produce Pharmaceutical Cocrystals

ANDRZEJ WOJCICKI/Getty ImagesNanotechnology is an important area of research, particularly in certain therapeutic areas, such as anticancer therapies to control dosing and target drug delivery to the tumor site. A review of the literature shows several interesting developments in this field.

Superparamagnetic iron oxide nanoparticles

Swiss researchers have discovered a method that allows for the controlled release of an active agent on the basis of a magnetic nanovehicle. The research was conducted as part of the National Research Program “Smart Materials,” a cooperation between the Swiss National Science Foundation and the Commission for Technology and Innovation. The specific work was conducted by researchers at ETH Lausanne, the Adolphe Merkle Institute, and the University Hospital of Geneva in Switzerland.

The researchers demonstrated the feasibility of using a nanovehicle to transport drugs and release them in a controlled manner as explained in a Jan. 24, 2013 press release from the Swiss National Science Foundation. The nanocontainer used was a liposome with a diameter of 100 to 200 nm. The membrane of the vesicle was composed of phospholipids and the inside of the vesicle offered room for the drug. Superparamagnetic iron oxide nanoparticles (SPIONs) were integrated into the liposome membrane; the SPIONs become magnetic in the presence of an external magnetic field. Once they are in the field, the SPIONs heat up. The heat makes the membrane permeable, and the drug is released. The SPIONs also are a contrast agent in magnetic resonance imaging (MRI). A simple MRI shows the location of the SPION and allows for the release of the drug once it has reached the targeted spot (1, 2).

In their study, the researchers noted that liposomes have been characterized by cryogenic electron microscopy (CryoTEM) as well as in combination with nanoparticles in SPIONs incorporated inside the liposomal membrane. CryoTEM maintains the native state of the liposomes. The quick freezing of the sample immobilizes particles and liposomes exactly at their position in the suspension, which allows localization information to be extracted from the images. The researchers reported on the analysis of cryoTEM images of liposome-particle hybrids, including the estimation of the contrast transfer function (CTF) and electron dose as well as the correct positioning of the sample holder and tomography for accurate localization (1, 2).

Another challenge was to reach a temperature sufficiently high to open up the liposomes, according to the release. This problem was addressed by increasing the size of the SPION from 6 to 15 nm. The membrane of the vesicles had a thickness of only 4-5 nm. The researchers regrouped the SPION in one part of the membrane, which made the MRI detection easier. Before starting 

 tests, the researchers plan to study the integration of SPION into the liposome membrane in greater detail, according to the release.

Researchers at Yale University developed nanolipogels as a new drug transport technology to deliver anticancer therapies. The nanolipogels are nanoscale, hollow, biodegradable spheres, which are capable of holding chemically diverse molecules, according to a July 15, 2012 press release by the National Science Foundation (NSF), which is providing funding for the research. The nanolipogels contained transforming growth factor (TGF-β) and interleukin-2 (IL-2). Specifically, the researchers developed nanoscale liposomal polymeric gels (i.e., nanolipogels) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers to deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines. The nanolipogel releasing TGF-β inhibitor and IL-2 significantly delayed tumor growth, increased survival of tumor-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration (3, 4).

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

An important aspect of the nanolipogels is their ability to “package” two completely different kinds of molecules--large, water-soluble proteins, such as IL-2, and smaller water-phobic molecules, such as the TGF-β inhibitor--into a single delivery vehicle, according to the NSF release. The outer shell of each nanolipogel is made from a biodegradable, synthetic lipid that degrades in a controlled manner, can encapsulate a drug-scaffolding complex, and is easy to form into a spherical shell. Each shell surrounds a matrix made from biocompatible, biodegradable polymers that are impregnated with the TGF-β inhibitor molecules. Those near-complete spheres are put in a solution containing IL-2, which gets entrapped within the scaffolding, a process called remote loading, according to the NSF release. The result is a nanoscale drug-delivery vehicle that is small enough to travel through the bloodstream but large enough to be entrapped for delivery to the tumor sites (3, 4). 

Researchers at the Massachusetts Institute of Technology (MIT) developed nanoparticles that can be controllably triggered to synthesize proteins. The hope is that particles could be used to deliver small proteins that kill cancer cells and eventually larger proteins such as antibodies that trigger the immune system to destroy tumors. The nanoparticles consist of lipid vesicles filled with the cellular machinery responsible for transcription and translation, including amino acids, ribosomes, and DNA caged with a photo-labile protecting group. These particles served as nanofactories capable of producing proteins including green fluorescent protein (GFP) and enzymatically active luciferase. 

 protein synthesis was spatially and temporally controllable and could be initiated by irradiating micron-scale regions on the timescale of milliseconds (5).

The researchers designed the new nanoparticles to self-assemble from a mixture that includes lipids, which form the particles’ outer shells, plus a mixture of ribosomes, amino acids, and the enzymes needed for protein synthesis. Also included in the mixture are DNA sequences for the desired proteins. The DNA is trapped by DMNPE, which reversibly binds to it. This compound releases the DNA when exposed to ultraviolet light. In this study, particles were programmed to produce either GFP or luciferase. Tests in mice showed that the particles were successfully prompted to produce protein when UV light shone on them, according to an Apr. 9, 2012 MIT press release. Although more testing must be done to show that the nanoparticles can reach their intended destination in humans and that they can be used to produce therapeutic proteins, the research is an interesting start. The researchers are working on particles that can synthesize potential cancer drugs by targeting protein production that could be turned on only in the tumor, thereby avoiding side effects in healthy cells. The team also is working on new ways to activate the nanoparticles. Possible approaches include production triggered by acidity level or other biological conditions specific to certain body regions or cells, according to the MIT release.

Researchers at the University of Sydney in Australia, led by Nial Wheate, senior lecturer in the Faculty of Pharmacy, and researchers from the University of Strathclyde and the University of Glasgow in Scotland recently reported on delivering the anticancer drug cisplatin using gold-coated iron oxide nanoparticles for enhanced tumor targeting (6, 7). The researchers used this approach to overcome some challenges of cisplatin, namely poor bioavailability, severe dose-limiting side effects, and rapid development of drug resistance. The iron oxide core was coated in a protective layer of gold before the anticancer drug cisplatin was attached to the gold coating using spaghetti-like strings of polymer, according to a May 31, 2012 University of Sydney press release.

The iron oxide nanoparticles (FeNPs) were synthesised via a coprecipitation method before gold was reduced onto its surface (Au@FeNPs). Aquated cisplatin was used to attach {Pt(NH3)2} to the nanoparticles by a thiolated polyethylene glycol linker forming the desired product (Pt@Au@FeNP). The nanoparticles were characterized by dynamic light scattering, scanning transmission electron microscopy, UV visible spectrophotometry, inductively coupled plasma mass spectrometry, and electron probe microanalysis. Nanoparticle drug loading was found to be 7.9 × 10-4 moles of platinum per gram of gold. External magnets were used to show that the nanoparticles could be accumulated in specific regions and that cell-growth inhibition was localized to those areas (6, 7).

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

., online, DOI: 10.1021/nl2036047, Mar. 20, 2012.

, online, DOI10.1016/j.ica.2012.05.012, May 30, 2012. 

Parenteral drug delivery offers a variety of challenges but also opportunities. The author examines recent developments in nanotechnology-based drug delivery and other advances in injection-based drug delivery.

Delivering Complex Drugs With Nanotechnology-Based Solutions

Alfred Pasieka/Getty Images; Dan WardRestructuring and manufacturing rationalization have been the order of the day for the large bio/pharmaceutical companies during the past several years. Small-molecule and solid-dosage operations have been the largest target for such cost cutting, but there are bright spots on the manufacturing investments. Several Big Pharma companies are investing in biologic drug-substance, vaccine, and parenteral drug finished product manufacturing. 

. Bristol-Myers Squibb is investing approximately $250 million to expand its large-scale biologics manufacturing facility in Devens, Massachusetts. The expansion will introduce biologics development and clinical-trial manufacturing capabilities to the site while adding approximately 350 employees to the Devens workforce over time. The Devens site is home to the company’s large-scale bulk biologic manufacturing facility. Construction of the Devens site was completed in 2009. It represented the company’s largest single capital investment ($750 million) and provided Bristol-Myers Squibb with large-scale bulk biologics production capacity. In May 2012, the company received FDA approval to manufacture its arthritis drug Orencia (abatacept) at the Devens facility. 

The new $250-million investment will be used to construct two new buildings on the 89-acre Devens campus: one building for process development and one for clinical manufacturing. Together, the two buildings will add approximately 200,000 ft

 of laboratory and office space to the Devens site, which is now comprised of six major buildings in a 400,000-ft2 complex. Work on the expansion is expected to begin in late 2013 and be completed in 2015. In the interim, Bristol-Myers Squibb has leased 30,000 ft

  of laboratory space in nearby Hopkinton, Massachusetts, to begin moving some biologics process-development functions closer to Devens during construction. The company intends to maintain this space until construction is completed. 

. In the fourth quarter of 2012, Novartis announced the planned construction of a new biotechnology production site in Singapore with an investment valued at more than $500 million. The new facility will focus on drug- substance manufacturing based on cell-culture technology. Construction will begin in 2013, and the site is expected to be fully operational in 2016. It will be colocated with the company’s pharmaceutical production site in Tuas, Singapore. In the future, Novartis expects its Singapore site to be a technological competence center for both biotechnology and pharmaceutical manufacturing. 

In December 2012, Novartis acquired a 16,000-m

  FDA-approved manufacturing facility in Morris Plains, New Jersey from the biopharmaceutical company Dendreon for $43 million. Novartis purchased all fixed assets at the site, including all equipment, machinery, utilities, and cell- therapy-related plant infrastructure. The land and building will continue to be leased from a third party. The facility, and certain former Dendreon personnel that were retained will support clinical and commercial production of potential new products and therapies that emerge from the Novartis–University of Pennsylvania (Penn) collaboration announced in August 2012. These drugs include CTL019, a drug in Phase I/11 development for treating certain blood cancers. Under the Novartis–Penn pact, the parties will research, develop, and commercialize targeted chimeric antigen receptor immunotherapies for the treatment of cancers as well as build on the Penn campus in Philadelphia the Center for Advanced Cellular Therapies, which will be dedicated to developing and manufacturing adoptive T-cell immunotherapies. 

Novartis also is proceeding with a multiyear vaccine-production project. In 2008, its Vaccines and Diagnostics Division broke ground on a new rabies and tick-borne encephalitis $330-million manufacturing facility in Marburg, Germany. Construction is complete and the facility is in the process of executing the necessary validation activities with regulatory  approvals for products planned for 2013. 

In 2009, Novartis opened a new cell culture-based influenza vaccine-manufacturing site in Holly Springs, North Carolina. As of Dec. 31, 2012, the total amount spent on the project was $426 million, net of grants reimbursed by the US government. The total investment in this new facility is expected to be at least $900 million, partly supported by grants from the US government and prior investments in influenza cell-culture technologies at the Novartis vaccines site in Marburg, Germany.

The company is also proceeding with the building of a new $475-million vaccine-manufacturing facility in Recife, Brazil. The manufacturing plant is part of Novartis vaccines’ strategy to enter the Brazilian market and is aligned with the government’s goal to become self-sufficient in vaccines. The technical start-up of the facility is planned for approximately 2015. 

. As part of its growth strategy in diabetes, Sanofi’s Frankfurt, Germany site, its principal manufacturing center for Sanofi diabetes products, is being equipped with a new aseptic processing area that uses isolator technology to significantly improve the aseptic-filling process. This investment will be operational in 2016. The Sanofi diabetes industrial network also is expanding its manufacturing footprint in emerging markets, both in Russia and in China (Beijing), where a new facility that was inaugurated in 2012 has begun assembly and packaging of SoloSTAR, the prefilled injection system for Lantus (insulin glargine). Also, during 2012, Sanofi’s Ankleshwar Pharma site in Gujarat State, India, handled packaging and quality control through to release the first commercial batches of AllSTAR, the company’s insulin pen specifically intended for the India market.

Its Frankfurt site is one of three dedicated biotechnology hubs that Sanofi is developing in Europe. In 2012, its facility in Vitry-sur-Seine, its biggest integrated cell-culture facility, produced the first technical batches of aflibercept, the API in the company’s anticancer drug Zaltrap. Its facility in Lyon Gerland, France, is a new world center dedicated to the production of thymoglobulin, a drug to prevent and treat transplant rejection. During 2012, teams at Lyon prepared a dossier for the healthcare authorities as part of the process of transferring production to this site. 

In the United States, Sanofi, through its subsidiary Genzyme, has major investments underway, including at its Framingham, Massachusetts biologics site, which was approved by FDA and EMA in 2012 for the manufacture of Fabrazyme (agalsidase beta) to treat Fabry disease. Its site at Allston, Massachusetts has initiated a major investment program in connection with the implementation of its compliance-remediation workplan, approved by FDA in January 2012. In 2012, Sanofi’s Genzyme acquired the Bayer Healthcare facility in Lynnwood, Washington, which specializes in the manufacture of Leukine (sargramostim).

On the vaccine side, Sanofi Pasteur, the company’s vaccine arm, is undergoing a major investment phase, which includes a new dedicated dengue fever vaccine facility in Neuville, France, which is scheduled to produce its first batches in 2014. Two new, dedicated influenza vaccine-manufacturing facilities are in the start-up phase. Sanofi’s facility in Shenzhen, China is currently testing its production processes, and its facility in Ocoyoacac, Mexico was approved by Mexican regulatory authorities at the start of 2012 and began production in time for the Mexican influenza vaccination program in September 2012. In response to observations made by FDA during routine inspections conducted in 2012 at its facility in Toronto and Marcy l’Etoile, France, Sanofi Pasteur initiated a compliance program to addres quality issues that had been identified. 

. Roche is investing CHF 240 million ($257 million) at its facility in Penzberg, Germany to expand raw-material manufacturing for its Elecsy immunoassays, to be completed by the end of 2014, as well as to increase compounding, filling, and lyophilization capacity, which is planned for 2016. At its sites in Basel and Kaiseraugst, Switzerland Roche is investing approximately CHF 230 million ($246 million). Three projects were completed in 2012: a new pharmaceutical quality control and assurance building, expansion of cold-chain storage capacity, and a filling line upgrade for Herceptin (trastuzumab) subcutaneous formulation. The company is also expanding capacity to increase capacity for high-potency drugs. 

. GlaxoSmithKline (GSK) announced plans to invest more than £500 million ($798 million) in the UK across its manufacturing sites, which included selecting Ulverston in Cumbria as the location for the first new GSK manufacturing facility to be built in the UK in almost 40 years. The company also will invest in sites in Montrose and Irvine, Scotland. GSK’s announcement followed plans by the UK government to implement a “patent box” to encourage investment in R&D and related manufacturing in the UK by introducing a lower rate of corporation tax on profits generated from UK-owned intellectual property. Following a feasibility study conducted through 2011, GSK said it will locate a new £350 million ($559 million) biopharmaceutical manufacturing facility in Ulverston, Cumbria. Detailed planning and design of the new facility is underway with an anticipated start date for construction of 2014–2015, dependent on portfolio timing and obtaining necessary planning and related consents. Once construction starts, it is likely to take at least six years before the plant is fully operational.

. In 2012, Eli Lilly reported that it is investing EUR 330 million ($430 million) in a new biopharmaceuticals facility at its Kinsale campus in Cork, Ireland. 

Despite overall manufacturing rationalization in the pharmaceutical/biopharmaceutical industry, the large pharmaceutical companies continue to invest in biologic-based manufacturing. The author provides an update in recent investment activity among the pharmaceutical majors in biologic-drug substance, vaccine, and parenteral drug manufacturing.

Big Pharma's Manufacturing Investments in Biologics

 Quality by Design (QbD) is changing drug development and manufacturing. The science- and risk-based approach inherent in a QbD paradigm increases process understanding and leads to better drug development and manufacturing. Sharing lessons learned and strategies for applying QbD in solid dosage development and manufacturing is valuable. 

A Pragmatic Application of QbD: Turning Theory into Tangible Success

” this Thursday May 2 from 11:00 to 12:00 PM EST.

				Two industry experts will share their experience with QbD and offer insight into how the practical application of QbD contributed to the success of their projects. Through several case studies, these experts will provide lessons learned and advice on the measures they took that enabled the success of their projects; steps that can be universally applied to other projects.

				Don Barbieri, associate director of formulation and process development at Patheon, will present case studies demonstrating different aspects of the QbD approach, including identifying CQAs (critical quality attributes) and CPPs (critical process parameters) as well as how to perform risk assessment, incorporate risk mitigation into a process, and how to develop a design of experiments (DoE).

				David Smith, pharmaceutical specialist, formulation and process development at Patheon, will present a case study where the pragmatic application of QbD enabled a successful technology transfer of a film-coated tablet from Phase III to commercial scale.

				Further information, including how to register for the complimentary webcast, may be found  

Quality by Design (QbD) is changing drug development and manufacturing. The science- and risk-based approach inherent in a QbD paradigm increases process understanding and leads to better drug development and manufacturing.

PharmTech Webcast: QbD in Solid Dosage

Bristol-Myers Squibb is investing approximately $250 million to expand its large-scale biologics manufacturing facility in Devens, Massachusetts. The expansion will introduce biologics development and clinical-trial manufacturing capabilities to the site while adding approximately 350 employees to the Devens workforce over time. 

The Devens site is home to the company’s large-scale bulk biologic manufacturing facility. Construction of the Devens site was completed in 2009. It represented the company’s largest single capital investment ($750 million) and provided Bristol-Myers Squibb with large-scale bulk biologics production capacity.  In May 2012, the company received FDA approval to manufacture its arthritis drug Orencia (abatacept) at the Devens facility. 

of laboratory and office space to the Devens site, which is now comprised of six major buildings in a 400,000- ft

 Work on the expansion is expected to begin in late 2013 and be completed in 2015. In the interim, Bristol-Myers Squibb has leased 30,000 ft

 of laboratory space in nearby Hopkinton, Massachusetts, to begin moving some biologics process-development functions closer to Devens during construction. The company intends to maintain this space until construction is completed. 

The company expands to add process-development and clinical-manufacturing capabilities at its large-scale bulk biologics facility.

Bristol-Myers Squibb Plans Expansion of Massachusetts Biologics Facility

 to the Pfizer subsidiary Wyeth Lederle SpA for GMP violations of finished pharmaceuticals at the company’s facility in Catania, Italy. The Warning Letter, dated March 27, 2013, cites violations regarding endotoxin testing for the diluting agent for the company’s anticancer drug Torisel (temsirolimus). 

The Warning Letter cites violations based on an inspection of the facility made July 9 to July 20, 2012, which showed that a batch of the diluent was released without finding the cause of out-of-specification (00S) endotoxin results. The failures began on April 17, 2012, and the plant continued to test and retest samples from this lot through August 14, 2012, which resulted in inconsistent results. In an attempt to find the root cause of the OOS results, FDA said the company used different endotoxin testing platforms, tested at three different laboratories, and wiped external vials with sanitizer to try to mitigate endotoxin failed results, but that at no point did the company conduct quantitative endotoxin testing to determine the extent of the endotoxin specification failure. It also said that the company’s explanation that secondary packaging components (i.e., cardboard) were the interfering components, which resulted in the OOS results, was “inadequate” because the company did not substantiate that the interference was the source of the endotoxin OOS results and if it were the source, how the cardboard entered the samples. 

The agency concluded that the company did not have “justifiable route cause” for the inconsistent results. Moreover, the agency said that it was also concerned that the company did not extend its initial investigation on the reported endotoxin failures to include a portion of the batch that had been earlier released to the US market in January 2012. FDA, however, said the company later decided to recall this portion of the batch after discussions with FDA. FDA, however, said the company failed to submit a Field Alert Report (FAR) within the required three days of receipt of knowledge of the contamination. FDA did not receive the initial FAR concerning the OOS endotoxin results until Aug. 9, 2012

FDA is requesting that the company provide additional evidence to support repeated endotoxin failures were the result of secondary packaging. If not the case, the agency is requesting that the company provide an updated manufacturing investigation outlining potential sources for endotoxin contamination in the lot and proposed preventive actions.

Company is notified of GMP violations at facility in Catania, Italy.