Hallie Forcinio is packing editor for Pharmaceutical Technology and Pharmaceutical Technology Europe, editorhal@sbcglobal.net.

Hallie Forcinio

	With a rising number of recalls associated with visual defects in parenteral products, and new and pending regulatory requirements, such as 

General Chapter <790> “Visible Particulates in Injections,” 

 <1790> “Visual Inspection of Injections” and 

 General Chapter <1207>, “Sterile Product Package-Integrity Evaluation,” drug makers are seeking ways to improve the inspection process (1, 2, 3, 4). Although automated inspection systems are available, the equipment may not be practical for lower volume products or lines that handle many different products (1). However, manual inspection involves repetitive motion and can cause ergonomic issues (5). Automating the movement of parenteral products for presentation for manual inspection not only improves ergonomics, but also maximizes flexibility and involves lower capital investment and qualification costs than fully automated inspection systems (5).  

	One example of automated material handling, the servo-equipped HPI-30-M machine from Luciano Packaging Technologies, transports bright (unlabeled) prefilled syringes so inspectors can check the product for particles and syringes for damaged or missing components. Designed for a major maker of parenteral products, the compact, two-station unit moves prefilled syringes so two operators can each perform a manual inspection of 100% of the product. The equipment fits in a niche between tabletop hoods or floor-standing work stations and semiautomatic systems.

	The integrated machine represents a departure from the systems currently available for handling prefilled syringes through the inspection processes. Existing systems typically consist of three separate machines-denesting, inspection (linear trunnion conveyor format), and renesting-and tend to occupy a considerable amount of floor space. “The driving motivation for this system was to accomplish these processes within a single, compact, and efficient machine configuration,” Larry Luciano, president of Luciano Packaging Technologies, told 

					Larry Luciano, president of Luciano Packaging Technologies, demonstrates the HPI-30-M automated material handling system for manual inspection of prefilled syringes at PACK EXPO East (Feb. 16-18, 2015, Philadelphia).

	On the HPI-30-M machine, a gantry picks up a nest of syringes and places it on an indexing conveyor. The nest indexes forward so an Adept robot can lift out five syringes at a time and place them in a star wheel, needle-side up. Meanwhile, the empty tub is conveyed below the indexing conveyor so it can be reunited with the nest at the conclusion of the inspection process.

	In the first inspection, a camera and infrared lighting checks the needle shield to ensure all components are present and nothing is punctured or bent. Any faulty syringes are rejected. As the star wheel rotates, syringes arrive at the first operator station and are spun as an inspector looks through a magnifier to check for particles. If particulate contamination is detected, the inspector can activate a reject. A verification system confirms the reject. Approved syringes pass to the second inspection station where the examination process is repeated. Syringes move at a rate of up to 30 per minute, the top speed of experienced inspection personnel.

	After the second inspection station, the robot removes syringes from the star wheel and passes them above the camera to inspect the flange. If the flange passes inspection, the syringe is replaced in its original space in the nest or in a discharge chute for transfer to labeling and pouching operations.

	The HPI-30-M machine features controls from Beckhoff Automation and Halcon machine vision from MVTec. 

 General Chapter <790> “Visible Particulates in Injections” (US Pharmacopeial Convention, Rockville, MD, 2014).	

 Draft Chapter <1790>, “Visual Inspection of Injections,” 

 Draft General Chapter <1207>, “Sterile Product Package-Integrity Evaluation,” 

Articles

A new machine is designed for inspection of prefilled syringes.

Automated Syringe Handling Helps Manual Inspectors

	It’s not always feasible to package products in-house. A contract packager may be the answer to moving product out the door for low-volume runs, when specialized designs such as display packaging or single-dose, private-label pouches are needed, or in situations where capacity is constrained, equipment is unavailable, or specialized equipment must be acquired.

	“Contract packagers tend to be entrepreneurial organizations and specialists in what they do,” explained Chris Nutley, president of the Contract Packaging Association (CPA), during a webinar on Jan. 20, 2015 (1). For example, a contract packager may be set up to run parenteral products, but not solid-dosage forms or vice versa. A specialist in solid-dosage forms may not be equipped to handle both blister packaging and bottle formats.

	Contract packaging services also may be offered by vertically integrated CDMOs such as Aesica, which recently received continuing FDA approval of its bulk manufacture and packaging sites in Germany. “These approvals will allow Aesica to substantially grow its contract manufacturing and packaging services for supply of pharmaceutical products to the US market,” said Dr. Werner Schick, Aesica’s general manager, Germany, in a statement (2).

	Hiring a contract packager for projects such as test runs or pilot runs “allows you to keep your focus on your core competency,” John Mazelin, executive director of the CPA, told the webinar audience. “It also increases flexibility and [shrinks] time to market,” he said.

	There are dozens, if not hundreds, of service providers and many resources to identify potential candidates including CPA’s 

. Contract packagers also may be found via referrals, trade magazines, trade shows, Internet searches, Thomas Register, and the Yellow Pages.

	Once candidates have been identified, the selection process begins with a phone interview and written vendor survey, followed by an on-site visit/audit and final evaluation. “This research can’t be outsourced,” said Mazelin. “You have to do it yourself.”

	The written survey requests information such as mission statement, organization chart, safety record, warehouse-management system, and other business details. Mazelin told the audience members to meet staff, discern who is responsible for what, and gain an understanding of operating procedures during the on-site visit.

	Considerations include location, experience, cost, communication, controls, financial strength, ethics, size, quality, years in business, and full-time staffing. But perhaps most important, the contract packager should have a compatible culture. 

	Once the decision is made, “Begin with the end in mind,” advised Mazelin. “Know what you want.”

	“Communicate the values that are important to your process,” said Nutley. The contract packager needs to understand a brand owner’s expectations regarding quality standards, volumes, deadlines, lines of communications, nondisclosure agreements, reporting, and meetings. “Determine a single point of accountability in both companies,” added Mazelin. 

	Both parties also must agree on handling/service fees, payment terms, what happens when problems occur, and certifications. “Contract packagers are open to certification,” Nutley said. But considerable time and expense is involved when a brand owner requires its own certification rather than accepting an existing certification.  “Let the contract packager be part of the process. Involve them early and keep them informed of developments as quickly as possible. It’s difficult to be strategic if not involved early,” he explained. 


	1. Institute of Packaging Professionals, “Best Practices for Using Contract Packagers,” Webinar, Jan. 20, 2015.
	2. Aesica, “Aesica secures continuing FDA approval of its bulk manufacture and packaging sites in Germany,” Press Release, Feb. 2, 2015. 

Careful selection of a contract packager should include interviews, surveys, and on-site visits.

Choosing a Contract Packager

	Protecting the shelf life of drug products can be achieved passively, actively, or as a combination of the two. The geometry of the blister also plays a role. Passive methods rely primarily on building barrier properties into the packaging material using a foil layer, a clear barrier layer, metallization, or a barrier coating. Active methods of shelf-life extension include gas flushing and insertion of a desiccant or oxygen absorber.  


	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).


	To more actively protect moisture-sensitive products, AdPack desiccant pillow packs and the newer AdCap Desiccant Capsules from Sanner are dispensed into the package prior to sealing. Compatible with standard dispensing equipment, sizes include 1, 2, and 2.5 grams. The desiccant itself consists of silica gel, molecular sieve, or a blend of the two. The capsules adsorb moisture through a cardboard disc on the top as a well as a grid structure on the side, ensuring functionality even if the capsule is lying on the cardboard side. The grid structure also provides a distinctive appearance, minimizing the chance that a patient would confuse it with a capsule or tablet product and accidentally ingest it (see 

). Additionally, good printability enhances the readability of safety instructions (7).

: Desiccant capsules adsorb moisture at the top and around the entire side wall (AdCap, Sanner). Figure is courtesy of Sanner.

	Mitsubishi Gas Chemical America, the supplier of Ageless oxygen-absorbing sachets and PharmaKeep oxygen-absorbing desiccants, also supplies oxygen-absorbing Ageless OMAC barrier film and pouches and builds oxygen-absorbing qualities into the container itself by coextruding a multilayer barrier structure. The OxyVanish bottle consists of six layers: high-density PE/adhesive/EVOH/adhesive/oxygen absorber/linear-low-density PE. Five container sizes are available: 30, 35, 40, 60, and 100 mL. For moisture-sensitive applications, Mitsubishi offers MoistVanish containers with a built-in desiccant (8).

	An active packaging option of a blister packaging standard, cold-form foil, maximizes moisture protection by replacing the traditional polyvinyl chloride layer with a PE/desiccant blend (see 

). Constantia DryFoil rollstock from Constantia Flexibles seals to a broad range of PE-based lidding materials that run on standard cold-form blister lines (9). 

: A desiccant-equipped layer maximizes moisture protection (Constantia DryFoil, Constantia Flexibles). Figure is courtesy of Constantia Flexibles.


	Selecting a barrier material and structure to meet shelf-life requirements generally requires lengthy trial-and-error testing. A marketing alliance recently established between Klöckner Pentaplast and FreeThink Technologies can shrink that time frame to as little as three weeks and eliminate the cost of line trials to forecast barrier needs for pharmaceutical products. At press time, three projects were already underway.

	The alliance optimizes both blister geometry and materials structure by creating predictive models using Klöckner Pentaplast’s Pentapharm BlisterPro blister geometry optimization technology and FreeThink’s ASAPprime accelerated stability assessment software and laboratory services. The combination of product stability and blister package models “allows drug manufacturers to narrow material choices early,” explained Michael Rashed, senior manager, Global Marketing, Pharmaceutical Films Division, Klöckner Pentaplast, in an interview with 

 at PACK EXPO International (Nov. 2–5, 2014, Chicago). Optimizing for multiple climate zones also “increases speed to market, minimizes packaging, and offers the potential for eliminating overpouches and desiccants,” he added.

	“Our accelerated stability science has allowed us to provide drug and consumer product customers a fast and accurate way to determine … product shelf-life,” said Dr. Kenneth Waterman, CEO, FreeThink Technologies, in a statement. “With Klöckner Pentaplast’s expertise and wide range of films available, we can now also provide customers with the right blister materials for stability and determine the specific blister structure and tooling design needed to optimize performance and cost. In addition, Klöckner Pentaplast has the ability to prototype and produce appropriate blister packaging for the customers to help get products to market quickly” (10).

	Although targeted primarily to pharmaceutical blister packaging, the optimization technology can be used for other packaging formats and product types. The optimization process consists of five steps:

	The ASAPprime software and laboratory services build a scientific and statistical model of a drug product’s stability and determine the barrier properties needed to achieve the desired shelf life.

	Pentapharm BlisterPro software computationally models the appropriate blister geometry for the product based on specifications and mechanical functionality.

	Combining the FreeThink ASAPprime barrier requirements for adequate product stability with BlisterPro Finite Element Analysis software allows Klöckner Pentaplast to accurately determine the appropriate barrier materials needed to balance stability needs with cost effectiveness.

	With blister geometry and barrier material optimized for the product, an electronic template is generated so prototypes can be produced on a blister machine at Klöckner Pentaplast. Resulting samples undergo performance and stability testing.

	The modeling “increases the probability of passing stability,” noted Daniel Stagnaro, director Pharmaceutical Films, Americas, Klöckner Pentaplast, during an interview at PACK EXPO. “As a result, structures don’t need to be over-engineered for launch,” he concluded.

 1. Ampac, “Ampac Introduces Flexi FoilFree HB Ultra High Barrier Film,” Press Release, Oct. 22, 2014.
	2.  Ineos, “Ineos Announces Planned Closure of Barex Plant,” Press Release, Oct. 29, 2014.
	3. Amcor Flexibles, “Amcor Flexibles Secures Three Years Supply of Barex Resins and Launches Alternative High-Performance Film,” Press Release, Nov. 4, 2014.
	4. Bemis, “Bemis Proprietary Films Provide Commercial Alternatives to Barex Resin-Based Packaging Solutions,” Press Release, Nov. 19, 2014.
	5. Rollprint Packaging Products, “Rollprint Introduces Exponent 2 Chemically Resistant, Clear Flexible Film for High-Barrier Pharmaceutical Applications,” Press Release, Oct. 31, 2014.
	6. 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.
	7. Sanner, “New AdCap® Desiccant Capsules from Sanner,” Press Release, Nov. 10, 2014.
	8. Mitsubishi Gas Chemical America, “OxyVanish (Oxygen Absorbing Bottle),” Technical Data Sheet, http://ageless.mgc-a.com/OxyVanish%20technical%20data.pdf, accessed Dec. 1, 2014.
	9. Constantia Flexibles, “Constantia Flexibles Introduces Coldform Foil Solution Offering Maximum Moisture Protection,” Press Release, Sep. 23, 2014.
	10. Klöckner Pentaplast, “Klöckner Pentaplast and FreeThink Technologies Announce Innovative Marketing Alliance,” Press Release, Nov. 2, 2014.

's Packaging Forum editor, 4708 Morningside Drive, Cleveland, OH 44109, tel. 216-351-5824, 


	Vol. 39, Issue 1
	Pages: 54-56
	Citation: When referring to this article, please cite it as H. Forcinio, "Building a Barrier in Solid-Dosage Drug Packaging," 

Better barrier materials and software modeling streamline the blister-package design process.

Extending Shelf Life through Better Blister Package Designs

	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

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

Barrier Films Protect Pharmaceuticals

New materials and software modeling streamline the blister-package design process.

	Attendees found innovations for all points in the packaging line at the inaugural Pharma EXPO and the co-located PACK EXPO International, Nov. 2-5, 2014, at McCormick Place, Chicago.  

	In preparation for filling, an Ionized Bottle Rinser from Paxton Products neutralizes static cling and uses blower-driven air, instead of more energy-intensive compressed air or water, to remove foreign material from glass or plastic containers. Rated at up to 1200 containers per minute, the unit handles sizes from 20 ounces to 3 L.

	The TE 20 tablet elevator from NJM Packaging feeds tablets, capsules, or softgels to a tablet counter or blister packaging machine at nearly double the speed (24,000 tablets per minute) of its TE 10 model. It’s also approximately 50% smaller and locates the 113-L hopper at a relatively low height for easy loading. When demand increases, the standard hopper can be replaced in the field with a larger 198-L hopper. A push of a button releases all product contact parts for tool-free removal to expedite cleaning and minimize downtime (1).

	Self-teaching optical technology in the cutting head allows the 5D Desiccant Dispenser from AZCO Corp. to run desiccant material from any supplier. Measuring 7x12x14 inches, the compact unit is rated at up to 100 cycles per minute. Cantilevered design of the self-threading, all-electric machine provides full access to the feeding process and simplifies setup. A knife cartridge cuts blade changeover time to 30 seconds without tools (2).

	Another versatile desiccant feeder, the Rx-Desiccant PLUS model from BellatRx handles either desiccant canisters or pouches (3).

	For parenteral lines, Denso Robotics introduced a cleanroom-compatible robot with an outer coating and sealed joints, which withstand hydrogen peroxide or ultraviolet light sterilization. The VS 050 six-axis robot handles 4-kg payloads and offers a maximum reach of 520 mm with accuracy of ±0.02 mm (4).

	The FXS Combi filling and closing machine from Bosch Packaging Technology handles nested syringes, vials, or cartridges. The monoblock design includes an integrated capping station. The unit may be equipped with up to six dosing heads and is suitable for peristaltic or rotary, slide-valve piston pumps as well as Bosch’s single-use PreVAS technology. It’s also compatible with isolators or restricted access barrier systems. Integration with an ATO automatic tub opener and ABO automatic bag opener, also from Bosch, results in a fully automated line (5).

	The FLR (faulty label removal) System from Newman Labelling Systems removes bad labels before application to eliminate rework of labeled containers and simplify label reconciliation and decommissioning of serialized codes. Once detected, the bad label is immediately transferred to a secure paper web, and sensors confirm this action. Being able to view each rejected label on the paper tape simplifies reconciliation. If desired, a camera can be added to automate decommissioning of serialized codes. The FLR system handles label sizes from 12x20 mm to 108x200 mm at up to 500 labels per minute. Compatible with any of Newman’s pressure-sensitive labelers, the stepper-motor-driven unit was shown mounted on the company’s S350 labeler, set up to handle vials.

	Avery Dennison can incorporate DirectLink near field communication (NFC) tags into its pressure-sensitive labels for communicating information to consumers. NFC, a form of short-range wireless communication, transforms the package into an interactive product communicator. Tapping an NFC-enabled phone against the tagged package can deliver content such as a special offer, survey, coupon, website link, or manual (6).

		NJM Packaging, “NJM Packaging Introduces the New TE 20 Tablet Elevator,” Press Release, Nov. 2, 2014.	

		AZCO Corp., “AZCO Corp.’s 5D Desiccant Dispenser,” Press Release, Nov. 2014.

		BellatRx, “BellatRx Showcasing Several Packaging Solutions at Pack Expo Booth #S-2566,” Press Release, Nov. 2014.	

		Denso Products and Services Americas, Inc., “New Denso VS-Series Aseptic Robot,” Press Release, Nov. 4, 2014.	

		Bosch Packaging Technology, “New Filling and Closing Machine FXS Combi from Bosch,” Press Release, Nov. 2014.	

		Avery Dennison, “Interactive Packaging: The Future of Labeling,” http://label.averydennison.com/en/home/lpm-products/key-label-innovations/directlink.html, accessed Nov. 24, 2014.

New pharmaceutical packaging equipment includes advances in automation and efficient systems.