
	A number of barrier materials debuted in 2014, including Flexi FoilFree HB film from Ampac. Laminations that include this ultra-high-barrier film achieve moisture, oxygen, and water-vapor barrier properties similar to aluminum foil laminates. Because of its strong barrier properties, a two- or three-ply Flexi FoilFree HB composite will provide barrier readings equivalent to three- and four-ply foil-based laminates, thereby reducing material costs.

	In addition, Flexi FoilFree HB barrier laminates offer better flex-crack and puncture resistance versus foil-based structures and provide easier “tear open” properties. As a result, packaging based on the barrier film tolerates handling better, preventing the shop-worn appearance that can occur with foil-based packaging.

	With higher yield and lighter weight, Flexi FoilFree HB barrier laminates generate lower greenhouse gas emissions and require less energy consumption in manufacturing and distribution. “Flexi FoilFree HB-based laminates provide an excellent alternative to more costly aluminum foil composites, with the added benefits of increased puncture and flex crack resistance, as well as improved package appearance and sustainability,” said Dave Bartish, vice-president of Marketing at Ampac, in a statement (1).


	The October 2014 announcement by Ineos that it is exiting the Barex acrylonitrile-methyl acrylate copolymer business and expects to close the sole plant producing the resin during the first quarter of 2015 has converters and end users scrambling to secure supplies and identify alternatives for barrier films (2). Suppliers offering Barex alternatives include Amcor Flexibles, Bemis, Rollprint Packaging Products, and Tekni-Films, a division of Tekni-Plex. Amcor has secured a three-year supply of Barex resin and has developed an alternative film, which is undergoing trials and is available for sampling (3). 

	Bemis recommends Barex-based healthcare applications transition into its PerfecPharm P616 or PerfecPharm P619 polyester/foil laminations. In addition to meeting common barrier property requirements for transdermal packaging, these films exhibit low permeation and absorption characteristics. Designed for the healthcare market, the PerfecPharm P616 material features Bemis’s CXB Sealant and exhibits superior seal strength, barrier properties, and inertness. “This new sealant is incorporated into a proprietary laminated structure designed to deliver effective chemical resistance and low absorption rates, exhibiting low reactivity with the medical-grade chemical contents of the package,” explained William E. Jackson, vice-president and chief technology officer at Bemis, in a statement (4).

	Clear, high-barrier Exponent 2 film from Rollprint combines its ClearFoil barrier-coated polyester with a coextruded non-crystalline polyester sealant with enhanced sealing properties. “In fact, Exponent 2 offers improved sealing characteristics over Barex due to easier-to-create hermetic seals and improved line speeds,” reported Dwane Hahn, vice-president sales and marketing, Rollprint, in a statement (5). 

	When compared to traditional, foil-based, high-barrier structures, Exponent 2’s reduced number of layers and gauge offer cost-savings and create an improved environmental profile for lidding, premade or inline pouching, and flow wrap applications. The structure’s clarity and high-barrier properties also make it a lower cost, break-resistant replacement for glass vials. Exponent 2 film has been engineered to provide a chemically neutral, ultra-high oxygen and water vapor barrier with chemical resistance. Maximum barrier properties currently stand at 0.0008 cc/100in

–24 h for oxygen transmission and 0.0008 g/100in

	Tekni-Films offers stock and custom thermoformable blister/tray film structures as well as heat-sealable pouch/lidding options that reportedly equal or exceed the performance attributes of Barex-based materials. Thermoformable options include polyethylene (PE), polypropylene (PP) and Aclar polychlorotrifluoroethylene inner and outer layers, coupled with barrier layers of ethylene vinyl alcohol (EVOH) and/or cyclic olefin copolymer. Heat-sealable pouch/lidding materials consist of paper/foil/plastic (PE, low-density PE, or polyethylene terephthalate) and EVOH laminations for applications such as transdermal patches and solid- and liquid-dose drug delivery systems (6).

		Ampac, “Ampac Introduces Flexi FoilFree HB Ultra High Barrier Film,” Press Release, Oct. 22, 2014.	

		Ineos, “Ineos Announces Planned Closure of Barex Plant,” Press Release, Oct. 29, 2014.	

		Amcor Flexibles, “Amcor Flexibles Secures Three Years Supply of Barex Resins and Launches Alternative High-Performance Film,” Press Release, Nov. 4, 2014.	

		Bemis, “Bemis Proprietary Films Provide Commercial Alternatives to Barex Resin-Based Packaging Solutions,” Press Release, Nov. 19, 2014.	

		Rollprint Packaging Products, “Rollprint Introduces Exponent 2 Chemically Resistant, Clear Flexible Film for High-Barrier Pharmaceutical Applications,” Press Release, Oct. 31, 2014.	

		Tekni-Films, division of Tekni-Plex, “Tekni-Films Announces Extensive Line of High-Barrier, Barex-Alternative Specialty Films for Thermoformable, Heat-Sealable Packaging Applications,” Press Release, Nov. 19, 2014.

	For further discussion of barrier packaging advances, including desiccant technology and a predictive model to optimize blister geometry and materials, read the full article in the January issue of 

Building a Barrier in Solid-Dosage Drug Packaging

Articles

Packaging

Packaging film suppliers offer new materials and alternatives to Barex copolymers.

Barrier Films Protect Pharmaceuticals

	Rommelag's bottelpack bp430, which uses blow–fill–seal (BFS) technology, is a fully electric aseptic packaging system. The mold is designed so that the point of filling within the parison is completely encapsulated from the surrounding environment. The modular system allows the separation into dark/white sides, so that a minimal cleanroom size (to contain approximately ¼ of the machine) is needed. The equipment can handle standard production rates up to 6.75 pieces per hour. Filling is carried out using standard time–pressure dosing or a disposable filling system with peristaltic pumps. This disposable system eliminates the need for clean-in-place validation and guarantees almost no product loss, which is crucial for high-value products. Typical fields of applications are the aseptic filling of products such as eye-drops, injection solutions, inhalation solutions, or oral solutions in the pharmaceutical industry.

Rommelag's all-electric aseptic blow-fill-seal packaging system encapsulates the filling point and can be installed in a cleanroom.

Blow-Fill-Seal Equipment Can Be Installed in Cleanroom

	Single-use technologies can offer significant benefits compared with traditional stainless-steel systems. The key driver is overall time savings. There are risks associated with single-use technologies, however, that can include product loss and questions around sterility assurance and product safety. These risks are magnified in the filling operation because of its closeness to the product in its final form. A thorough evaluation of the assembly design process, manufacture, and use can assist in identifying and mitigating these risks. By mitigating these risks, single-use assemblies can be successfully implemented in all process steps including formulation, filtration, and filling.
	
	


	In a traditional stainless-steel system, the end user has significant control over the design, construction, use, and maintenance of the system. When implementing a single-use system, the dynamics of the situation change and the relationship between the supplier and the end user needs to be a partnership. The design of the “system” becomes a collaborative effort between the two parties within the manufacturing capabilities of the supplier. In this article, design is defined as the selection of each individual component, how the components connect to create an assembly, how the assembly performs in the process, and ultimately how the assembly impacts the final drug product.
	
	The design guidelines should follow good engineering practices, such as ASTM E2500, with consideration for items such as reduction in the number of parts, error-proofing assembly design, avoiding tight tolerances, ease of assembly, and using modular products. It is also beneficial to apply quality-by-design concepts during specification and assembly design, including critical process parameters (CPPs) and any prior production experience. As typical assemblies are custom designs that may include custom components, project timelines can range from 9 to 18 months depending on scope and complexity. Often, a good portion of this time is required for drawing revisions, prototype testing, and drawing finalization in conjunction with equipment testing and validation. These requirements need to be accounted for in the project planning process.

	During assembly design, ease of operator use, product yield, sterility assurance, and product safety should be considered to help minimize the risks associated with single-use assemblies. By combining these attributes with key needs for formulation, filtration, and filling, a technically sound design can be created by the supplier and the end user. Key needs for formulation include:

		Efficient component introduction for both solids and liquids

		Robust and operationally appropriate mixing

		Minimization or elimination of bioburden

		Representative sampling with ability to perform an aseptic disconnect

		Effective filter flushing and/or wetting

		Well-characterized materials of construction

		Ability to perform a pre-use post-sterilization integrity test (if required)

		Ability for single or redundant filter design, as dictated by the end user

		Filter placement inside or outside of the isolator, as dictated by the end user.

		Ability to make a sterile connection between the outlet of the final sterilizing-grade filter and the filling assembly

		Optimized header bag and manifold design

	By creating a sound initial design together, fit for intended use will not be based solely upon verification after installation but will be designed into each assembly.
	
	


	With a thorough evaluation of the assembly design process, manufacture, and use, risks associated with single-use assemblies for final sterile filling can be identified and mitigated. By mitigating these risks, single-use assemblies can be successfully implemented in all process steps including formulation, filtration, and filling operations.


	Sue Walker is global product manager for Mobius Final Fill at EMD Millipore, 80 Ashby Road, Bedford, MA 01730, Sue.Walker@emdmillipore.com. 

Troubleshooting

Careful design of a single-use assembly by both the supplier and end user together can mitigate risks and create fitness for the intended use.

Designing Single-Use Assemblies for Sterile Filling

	
	Bosch Packaging Technology's Sigpack HCUL horizontal flow wrapper packages up to 300 single blow-fill-seal (BFS) vials per minute. The machine ensures hermetic packages even at high speed using long-dwell, cross-sealing technology.

	Primary packaging units, delivered as BFS cards, are fed into the Sigpack HCUL with the aid of a Sigpack LDF Delta robot or other intelligent loading solution. Before being packaged in the flow wrapper, the vials are separated by the feeding system's separation unit.

	The long-dwell sealing system has a cross-sealing unit that allows the sealing jaws to close more gently and in a more controlled manner than other flow wrappers currently available, even at high speeds. This long-dwell sealing ensures longer sealing times to produce hermetic packages. The balcony design of the cross-sealing unit with individually mounted heating elements allows fast changeovers. Depending on application requirements, the station has the flexibility to be equipped with either ultrasonic or heat-sealing technology. Also available are hybrid machines that use ultrasonic sealing technology on the longitudinal sealing unit and heat sealing on the cross seam. Because thermo-sensitive products can be damaged when exposed to heat, usually occurring when transported over the longitudinal sealing unit, this hybrid configuration provides a high-speed solution for these products.

	The machine's control system monitors the alignment of the products as well as the information printed on the packaging, such as the barcode. By making sure that packages which do not meet the specifications are automatically rejected, only hermetically sealed packages leave the machine.

	The Sigpack HCUL is expandable to accommodate modified atmosphere packaging (MAP). In the Real Time (RT) MAP system, the gas supply for the RT-MAP and the sensor for measuring residual oxygen content are integrated in the longitudinal sealing unit. As a result, this provides real-time measurement of residual oxygen content in the package, rejecting those that have excessive residual oxygen. The amount of gas supplied or extracted is precisely controlled so that only the necessary amount is released. The RT MAP system has improved measuring accuracy and reduces production costs.

A horizontal flow wrapper separates vials and individually packs them at high speed using a long-dwell sealing system with ultrasonic or heat-sealing technology.

Horizontal Flow Wrapper Packages Single Blow-Fill-Seal Vials

	
	Pre-sterilized, nested syringes are an alternative to bulk syringes that must be sterilized at the filling line. As the injectables market grows globally, there is growing use of pre-sterilized syringes because they are "off-the-shelf" systems, comments Kevin Wrigley, product and service manager at Vetter. Bulk syringes, which offer more flexibility, remain in high demand for products with specific primary packaging requirements. "Pre-sterilized syringes offer standardized systems and are often easier to handle because of the tubs they are nested in," says Wrigley. "Bulk syringes on the other hand, offer a wider range of choices for product-specific processes or primary packaging material like closure components. Ultimately, the decision regarding the drug-delivery system will depend on the specific filling requirements of the product, market volume, and the business strategy of the pharma/biotech company when launching a product." Choosing the most suitable packaging should begin in the earliest clinical stages, adds Wrigley. "Once a drug manufacturer has decided on a pre-sterilized system, process adjustments or format changes might be limited because of the pre-set packaging and tub characteristics."

	Advantages of pre-sterilized syringes include lower investment costs and smaller-footprint equipment for filling and closing. Fewer processing steps and less handling help reduce damage. "Since syringes are even more prone to damage and much more difficult to transport than other glass containers, they were the first packaging type to be offered as pre-sterilized solution in nests," notes Klaus Ullherr, product manager at Bosch Packaging Technology.


	Pre-sterilized vials or cartridges are now also available, and, to date, are typically used in smaller batches, such as in formulation and development laboratories, according to Markus Hörsch, sales and marketing director at Bausch+Ströbel. The company's SFM 5110 filling system is designed for these applications and processes all pre-sterilized containers (vials, cartridges, or syringes) in nests inside tubs.

	Schott's adaptiQ system for ready-to-use pharmaceutical vials consists of a patented nest that securely holds up to 100 clean and sterile vials in an industry-standard tub. It is suitable for both small and large batches, and is advantageous for smaller batches because it minimizes setup time for packaging changes. Besides simplifying the process, the nested packaging protects the glass containers from scratches caused by vial-to-vial and vial-to-machine contact, which reduces the reject rate and also preserves the cosmetic quality of the vials, noted the company in a press release. Schott is advancing to full-scale production at its US facility, the company announced in a Jan. 12, 2015 

	Bosch recently launched a filling and closing machine for pre-sterilized nested syringes, vials, and cartridges. "The FXS Combi is the first machine of its kind with an integrated capping station for vials and cartridges," says Ullherr. "The capping of vials and cartridges takes place directly after the stopper insertion. This ensures the highest pharmaceutical safety, as the container is immediately and safely closed after filling."

	A challenge in setting up a line for pre-sterilized syringes is how to transfer the sterile syringes to the point of filling without compromising sterility. Syringes, nested in tubs, are sealed with a plastic layer and also protected by a bag. Combining the filling and closing machine with an upstream tub and bag opener eliminates contamination risk, notes Ullher.

	Although most syringes are glass, plastic syringes are also available pre-sterilized. Some small adjustments might need to be made to filling and closing machines to handle plastic syringes. "Depending on the plastic material, plastic can be more delicate and requires a gentler handling," notes Ullherr. "Plastic syringes might require a centering plate made of plastic instead of metal, and they can also have a slightly different diameter than glass syringes."


	For changing from one product to another in filling equipment, manufacturers can choose from clean-in-place/sterilize-in-place (CIP/SIP) systems and single-use, disposable systems. "The use of CIP/SIP is recommended for the production of large batches and toxic products, while contract manufacturers and smaller batches will work with single-use systems, as they can eliminate the loss of capacity resulting from lengthy cleaning validation as well as the risk of contamination between batch runs," comments Ullherr. In 2014, Bosch expanded its PreVAS prevalidated, pre-assembled, and pre-sterilized single-use filling systems, which the company developed in cooperation with Sartorius Stedim Biotech. For example, a new mobile filling station can be combined with existing filling lines. In this version, the product bag is situated outside of the isolator, and the filling tubes are guided through the isolator wall using a newly developed multi-tubing port, before being connected to the filling station, Bosch said in a 

Production Trends

Pre-sterilized, nested syringes and vials are seeing increased use in sterile filling.

Equipment and Processing Report-01-21-2015

Barrier Films Protect Pharmaceuticals

Blow-Fill-Seal Equipment Can Be Installed in Cleanroom

Designing Single-Use Assemblies for Sterile Filling

Horizontal Flow Wrapper Packages Single Blow-Fill-Seal Vials

Filling Pre-sterilized Containers