Honeywell Process Solutions
 A smart pressure transmitter is redesigned for improved performance

Carl Zeiss Microscopy
 Microscopy is used to monitor cleanliness and evaluate particles

Articles

Products from Honeywell Process Solutions and Carl Zeiss Microscopy

December 2012 Editor's Picks: Products from Honeywell Process Solutions and Carl Zeiss Microscopy

) gas can provide manufacturers of parenteral drug products with a truly room temperature means of sterilizing the external surfaces of single-dose drug containers that are intended for use in a sterile field.  Other sterilization options, such as ethylene oxide (EO), hydrogen peroxide (H

), and radiation, may expose the drug products to elevated temperatures over extended times or penetrate the container and closure systems. Both of these scenarios can adversely affect drug products or biologics, especially those that have limited stability at elevated temperatures. NO

 is compatible with many of the materials that are common to parenteral drug containers and closure systems including glass, cyclic olefin copolymers (COC), polypropylene, silicone rubber, thermoplastic elastomers, and pharmaceutical rubbers. As a surface sterilant, NO

 does not penetrate containers or closure systems during the sterilization process, leaving the drug product unaffected.

 possesses some specific chemical and physical properties that make it well-positioned for use as a sterilant for pressure- and temperature-sensitive parenteral drug products. Because it boils at 21 °C, the NO

 sterilant can be introduced into the chamber with minimal to no vacuum.  Sterilization is typically carried out using NO

 concentrations that are in the range of 1–2% of the saturated vapor pressure. Because of this, condensation of the sterilant is not likely to occur, even in complicated geometries. Heating of the NO

 sterilization chamber is not required to maintain the sterilant gas phase, which allows sterilization and aeration to be carried out at room temperature. Both EO and H

 sterilization, however, generally require some degree of heating, which can result in destabilization of sensitive products.

 sterilization provides rapid and effective inactivation of both vegetative and spore forms of bacteria. This rapid lethality allows a sterility assurance level of 10-6 to be achieved in a cycle with a typical door-to-door time of 60–120 minutes, thereby minimizing the time that the drug product is exposed to room temperature. There is no preconditioning phase, and aeration of residual sterilant from the product is included in the overall cycle time.

 is compatible with many of the sterile barrier packaging options on the market, such as Tyvek pouches and plastic trays with Tyvek lids. As NO

 is a surface sterilant, the gas requires access to the product, which is afforded by the breathable Tyvek. Sterilization with NO

 would typically be carried out in the primary packaging, and any instructions for use would be included in the secondary package.

 sterilant, while a toxic gas, is noncarcinogenic and nonflammable, which makes it attractive as an option to bring sterilization onto the manufacturing floor for higher volume manufacturers. In-house sterilization offers potential savings in terms of both transportation and inventory carrying costs associated with contract sterilization. Sterilization can be placed in-line between primary and final packaging operations. For manufacturers whose volumes are not large enough to warrant on-site sterilization, yet who require room-temperature sterilization, contract NO

Evan Goulet, PhD, is technical applications manager at Noxilizer, 

In the Mixer

Room-temperature sterilization using nitrogen dioxide gas provides benefits for sterilizing the external surfaces of single-dose, parenteral drug containers.

Sterilizing Parenteral Drug Containers with Nitrogen Dioxide

Q. We have fine ferrous metal contamination in our pharmaceutical product, a free-flowing powder, even though we have a magnet. How can we remove the contamination?

A. Ferrous metal contamination can be reduced-if not virtually eliminated-with the use of magnetic separation equipment.  An understanding of the various types of magnetic separators, however, and their interaction with the physical nature of the product being purified is important. Temperature, flow rate, flow characteristics, and process issues are crucial factors for effective removal.

Magnetic materials lose strength when exposed to elevated temperatures, although some strength is recovered when the temperature returns to normal. Permanent magnets heated beyond certain temperatures may also suffer irreversible loss (i.e., a reduction in strength that cannot be recovered by cooling). It is important to note ambient and any clean-in-place (CIP) temperatures when choosing a magnet suitable for long-term separation performance. Rare earth (RE) magnetic separators, although more expensive, capture contaminants better at higher temperatures than conventional magnets. Standard RE magnets can work in temperatures up to 150 °F, while other RE models are designed to operate in temperatures up to 250 °F and even up to 400 °F. 

Magnetic separators perform best when the contamination is presented to the surface of the separator. It is ideal to select a magnetic separator that provides for a thin burden depth over or under the magnet to ensure the magnet will have the most opportunity to capture the ferrous contamination. Plate, grate, and trap magnets have different characteristics for removing contaminants from different types of materials. 

Many products exhibit different flow characteristics when damp or moist. Are there large chunks that may plug an opening or gap in the separator? Will the product flow freely through the selected magnetic separator? For example, a pharmaceutical powder with any significant moisture content will not flow between the tubes in a grate magnet assembly, even if they are positioned nearly one inch (25 mm) apart from each other. 

The process design is also important. Issues include how the material is presented to the separator, whether the material is metered or has surge flow that needs to be handled, and where the magnetic separator is installed (e.g., prior to a filling/packaging machine, at the discharge end of a conveyor, beneath a hopper, or before the material drops into a bulk bag).  

A magnetic survey and appraisal of plant operations by an experienced professional can help to determine if your current magnetic installations are giving optimum protection, to learn what magnets can and cannot do, and to discover the advantages of newer technologies.

—Bill Dudenhoefer is manager of Separation Products at Eriez.

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

, editor of Equipment and Processing Report, and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

Magnetic separation equipment reduces ferrous metal contamination.

Using Magnetic Separation to Remove Contamination

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).

Production Lines

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.

Equipment and Processing Report-12-19-2012

December 2012 Editor's Picks: Products from Honeywell Process Solutions and Carl Zeiss Microscopy

Sterilizing Parenteral Drug Containers with Nitrogen Dioxide

Using Magnetic Separation to Remove Contamination

Plastic Shows Benefits in Parenteral Packaging