Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Anson Ma, an assistant professor of chemical engineering at the University of Connecticut (UConn) has received a two-year National Science Foundation Early Concept Grant for Exploratory Research (EAGER) award to test the use of nanoparticles for drug delivery and to understand how nanoparticles flow in the bloodstream. 

Nanoparticles are being considered to improve the delivery of cancer-fighting drugs to tumors while reducing the toxic side effects to normal tissues. “But blood is a very complicated fluid, and we don’t precisely know how the particles travel,” said Ma in a recent University 

.  The research team will build novel microfluidic devices that simulate the bloodstream and study the flow dynamics of nanoparticles within these simulated blood flows. The research will also consider the roles of blood constituents and of particle shape and size in delivering drugs to the tumor site and will investigate how certain factors like particle shape and surface chemistry influence the hydrodynamics of the nanoparticles.

“This project will be the first step in understanding the problem from an engineering perspective,” said Ma in the release. Ma and his student project team are collaborating with professors Leslie Shor from the Chemical Engineering department, Xiuling Lu from Pharmaceutical Sciences, and Suzy Torti from the UConn Health Center.

Articles

A University of Connecticut chemical engineering professor received a National Science Foundation grant to study how nanoparticles flow in the bloodstream, which is crucial for their use in drug delivery.

University of Connecticut Studies Drug-Carrying Nanoparticles

Although glass retains its dominant market share as the traditional material for packaging pharmaceutical parenterals, plastic is also finding use as concerns about glass breakage and delamination and desire for increased functionality lead pharmaceutical companies to consider alternatives. 

The biggest change in primary containers has been in Japan, where it is estimated that 60–70% of all prefilled syringes are plastic (1). Interest in plastic is also increasing in Europe and the US. “Recent surveys have placed interest in plastic at different levels, but it is West’s understanding that the majority of pharmaceutical and biopharmaceutical companies are at least considering plastic as an alternative to glass,” says Graham Reynolds, vice-president of marketing and innovation of Pharmaceutical Delivery Systems at West. 

Although most use of plastics so far has been in syringes, a growing concern with glass vials is the issue of delamination. FDA has initiated several recalls in recent years due to the risk that glass particulates may enter a patient through drug products and has cautioned manufacturers about glass fragments in vials (2). Glass-vial suppliers have responded with coated vials and by developing analytical tests for delamination, notes Gary Waller, North American vice-president of sales and marketing for Schott Pharmaceutical Systems.

Another concern with glass vials and syringes is breakage, which can occur during production, transport, or use. “With the increasing use of devices as part of a combination product, a glass container may not be visible, resulting in concerns about breakage when a device is dropped and a tendency to err on the side of caution. For example, patient instructions may suggest an auto-injector should be discarded if dropped due to the risk of glass breakage,” notes Reynolds. 

In prefillable syringes, residuals on glass components may cause problems with some biologics. For example, silicone oil on glass can cause formation of protein/silicone aggregates. Plastic syringes eliminate the need for silicone oil. In addition, plastic offers improved design flexibility and dimensional precision, which can be important for use with devices, such as a self-injection system or needle-safety system. “The inherent variability in the dimensions of glass can lead to challenges when designing a device because many devices put stress on glass products, particularly in the flange area, where breakage can occur,” says Reynolds. Plastic prefillable syringes can be designed with an integrated luer lock, which is a more robust design than attaching a separate luer-lock adapter to a glass syringe, adds Waller. 

Polymers have some drawbacks, however. One is scratch sensitivity; scratches can impair camera inspection, says Waller. Polymers typically have inferior oxygen permeability compared to glass, which can be a concern for oxygen-sensitive drugs. Compared to the long history of glass in parenteral containers, the short history of polymers can be a disadvantage. In many cases, however, polymers have been tested to ensure biocompatibility and acceptability for some drugs and have been approved and marketed for packaging.

Polymers used commercially in containers for parenterals include cyclic olefin copolymer (COC) and cyclic olefin polymer (COP). COP is a transparent material with an impact strength twice as high as that of glass used in standard syringes, which makes it shock- and break-resistant, says Wolfgang Dirk, product manager of plastic parenteral vials at Gerresheimer. Gerresheimer’s Multishell vials, which won the German Packaging Award in the Retail Packaging category in November, 2011, have a three-layer structure of polyamide (PA) sandwiched between two COP layers. PA is a good oxygen barrier, and the multilayer structure reduces oxygen transmission by 40 times compared to that of a monolayer COP vial. Multiple layers also provide additional break resistance, notes the company.

Top Clean Packaging Group, whose Unicadose polypropylene vial was a finalist for the Best Sustainable Packaging award by CPhI in October 2012, says that it was designed to increase consumer convenience and safety for single-dose drugs by preventing breakage and by providing an easily distinguishable appearance. The vial can be customized using different colors and by printing directly on the individual vial.

“Glass has been around for many years and will continue to be a suitable material for drug containment for many years to come. However, as newer and more sophisticated drug products and delivery technologies are developed, containment systems must evolve,” predicts Reynolds.  Suppliers conclude that, while polymers are now an option, each drug product and delivery system should be evaluated to determine what packaging material and form is most appropriate on a case-by-case basis.

K. Constable, presentation at the Universe of Pre-filled Syringes and Injection Devices Conference (Las Vegas, NV, 2012).

FDA, “Advisory to Drug Manufacturers: Formation of Glass Lamellae in Certain Injectable Drugs” (Rockville, MD, Mar. 2011).

Plastic is finding increased use in vials and syringes as concerns about glass breakage and delamination and desire for increased functionality lead pharmaceutical companies to consider alternatives.

Plastic Shows Benefits in Parenteral Packaging

	How to optimize continuous processing and make it work in pharmaceutical manufacturing is a crucial issue. Real-time devices for continuous feeding processes, among many other topics, were discussed at a seminar I attended last week. The seminar, “Advances in Pharmaceutical Processing”, was sponsored by K-Tron, which supplies material handling and feeding systems.

	Feeders set the precise throughput to a downstream, continuous process, explained Sharon Nowak, global business development manager for food and pharmaceuticals at K-Tron, in a presentation at the seminar.  Feeding performance can thus largely affect the performance of subsequent unit operations. Continuous processes generally use gravimetric (rather than volumetric) feeders because gravimetric feeders use loss-in-weight controllers that give more real-time information and are therefore more accurate than volumetric feeders. The need for accuracy in the pharmaceutical industry is even greater than that of the plastics or food industries, and the accuracy of feeders is now being examined at shorter intervals, down to one-second sampling. In addition, feeders are being tested and optimized for accuracy at very low rates. Nowak’s presentation explored various ways to optimize feeders and improve accuracy.

	Real-time data can also be used to control other aspects of material flow.  For instance, hopper flow aids, such as vibrators or agitators, are commonly used to keep poorly flowing material from forming ratholes or bridges that would prevent consistent material flow out of the hopper. Conventional vibrating devices, however, can cause material packing because of too much vibration. K-Tron’s ActiFlow device uses real-time feedback about flow conditions to start and stop vibration so that the hopper is vibrated just enough to restore good mass flow. I think this is an interesting example of applying real-time data to process control.

	Better understanding of how to use real-time data, built-in calibration, and on-line controls are a good step towards implementing continuous manufacturing in pharmaceutical processes.

How to optimize continuous processing and make it work in pharmaceutical manufacturing is a crucial issue.

Real-time Data Aids Continuous Manufacturing

The US Supreme Court agreed on Friday, Dec. 7, 2012, to hear a case that will decide whether brand-name drug companies may pay generic drug companies to delay introduction of lower-cost generic drugs. At the request of the Federal Trade Commission (FTC), the US Solicitor General petitioned the Supreme Court to review a federal appeals court ruling that upheld a “pay-for-delay” arrangement between Solvay Pharmaceuticals, now owned by Abbott Laboratories, and generic-drug makers, such as Watson Pharmaceuticals, Paddock Laboratories, and Par Pharmaceutical. A decision on the case of 

Federal Trade Commission v. Watson Pharmaceuticals Inc. et al. (No. 12-416)

The FTC filed a complaint in 2009 alleging that the companies violated antitrust laws when Solvay paid the generic firms in exchange for their agreement to abandon patent challenges and refrain from marketing a generic version of AndroGel until 2015, noted the FTC in an Oct. 4, 2012 

. A district court dismissed the FTC complaint, and, in April 2012, the 11th US Circuit Court of Appeals also ruled against the FTC and upheld the arrangement. 

Drug companies say the settlements, also known as reverse payments, are a legitimate way to settle patent disputes. The FTC, however, says that the arrangements hurt American consumers. Other court cases over the last several years have dealt with the pay-for-delay practice, and the Supreme Court ruling is anticipated to set a national standard.

The US Supreme Court accepted an appeal by the Federal Trade Commission of a decision that upheld an arrangement of payments by Solvay Pharmaceuticals to generic drug companies to postpone introduction of generic versions of its branded testosterone-replacement drug.

US Supreme Court to Hear Pay-for-Delay Case

, an independent, not-for-profit, research and development organization that is headquartered at the New Jersey Institute of Technology (NJIT), has expanded its mission of working with industry and government to advance the field of polymer processing to include generating and using fundamental knowledge related to incorporating APIs into polymer excipients through hot-melt extrusion. I recently visited with the PPI researchers and toured their facilities.

		PPI was founded 30 years ago at Stevens Institute of Technology in New Jersey and relocated to NJIT in 1998. It is recognized in the plastics industry for its expertise in polymer processing and its relationship with NJIT, through which PPI collaborates with the University’s faculty and provides research opportunities and experience to NJIT graduate students at PPI’s laboratory facilities. PPI became actively involved with pharmaceutical extrusion about four years ago and has ongoing collaborations with pharmaceutical-industry companies, such as Merck, BMS, FMC, BASF, Evonik, and Colorcon.

		Dr. Nicolas Ioannidis, PPI polymer research engineer, gave me a tour of PPI’s laboratories, which are located on the NJIT campus. The extrusion laboratory includes a 16-mm Leistritz co-rotating twin-screw extruder, a 15-mm APV co-rotating twin-screw extruder, and a 34-mm Leistritz co-rotating twin-screw extruder that is capable of foaming, all dedicated to pharma HME applications. I also had an opportunity to see the characterization laboratory, managed by rheologist Dr. Herman Suwardie, which has a wide range of polymer characterization equipment that is a focus of some of PPI’s current pharma research.

		Recent research at the PPI Center for Fundamental HME Studies and the Department of Chemical, Biological, and Pharmaceutical Engineering (CBPE) at NJIT has focused on establishing simple and reliable methodologies for determining the solubility and dissolution kinetics of API-polymer excipient pairs. Currently, common tools for determining solubility include hot-stage polarized optical microscopy (HS-POM) and differential scanning calorimetry (DSC). HS-POM, however, is qualitative, and DSC may result in thermal degradation, because the sample must be exposed to heat for a long time, explained Dr. Ioannidis. PPI has developed an alternative method that uses rheometry, which avoids degradation and results in quantitative data that can be correlated to DSC results. PPI researchers are now focusing on determining dissolution kinetics, which is important for design and scale-up of the HME process for given API/excipient pairs, said Ioannidis. Other HME work at PPI includes studying foamed structures and formulations used in HME.

		Complementary to its focus on fundamental knowledge development, PPI focuses on innovation and technology transfer and, therefore, continually seeks new industry partnerships, explained Dr. Costas Gogos, distinguished research professor at NJIT’s CBPE and chairman of the board of PPI.

The Polymer Processing Institute (PPI), an independent, not-for-profit, research and development organization that is headquartered at the New Jersey Institute of Technology (NJIT), has expanded its mission of working with industry and government to advance the field of polymer processing to include generating and using fundamental knowledge related to incorporating APIs into polymer excipients through hot-melt extrusion.

Non-Profit Research Organization’s Mission Includes Hot-Melt Extrusion Studies

 its intent to increase ownership in GlaxoSmithKline Consumer Healthcare Ltd, its publicly-listed subsidiary in India, from 43.2% to up to 75% and, in a separate 

, announced an agreement in principle on a proposal to increase ownership in GlaxoSmithKline Consumer Nigeria PLC from 46.4% to 80%. The offers represent the maximum possible stake allowed while maintaining a public listing in the respective countries and are part of GSK’s strategy to invest in emerging markets. 

“GSK Consumer Healthcare is a well-established business in India, and its leading product, Horlicks, is an iconic household brand.  This transaction represents a further step in GSK's strategy to invest in the world's fastest growing markets and, we believe, offers a liquidity opportunity at an attractive premium for existing shareholders," said David Redfern, GSK chief strategy officer, in the press release. 

The transaction in India, valued at up to approximately $940 million, will be funded through GSK’s existing cash resources, will be earnings neutral for the first year and accretive thereafter, and will not impact expectations for the Group’s long-term, share-buyback program. Subject to regulatory clearance, the offer period is expected to begin in January 2013.

The board of directors of GSK Nigeria unanimously approved the proposal and intends to recommend it to shareholders. Under the terms of the deal, GSK would acquire approximately 321 million shares in the company on a 

 basis from public shareholders for a total value of almost $98 million. The transaction in Nigeria will be funded through GSK’s existing cash resources, will be modestly earnings accretive immediately, and will not impact expectations for the Group’s long-term, share-buyback program. The proposal will be subject to requisite shareholder, regulatory, and court approvals including those of the Nigerian Stock Exchange and the Securities and Exchange Commission.

GlaxoSmithKline announced its intent to increase ownership in its publicly-listed, consumer-healthcare subsidiary in India and in GlaxoSmithKline Consumer Nigeria as part of its emerging-markets investment strategy.