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

Hallie Forcinio

It's hard to predict exactly what conditions a drug will experience during the distribution process. Will delivery be delayed for a day or more by a blizzard, flood, hurricane, power outage, or holiday weekend? Will the product sit in the sun for hours before it's loaded onto a plane or clears customs?  

As air-cargo screening rules tighten, shippers fear that the frequency and length of delays will increase. Delays can be disastrous for temperature-sensitive drugs. If temperature abuse renders a drug ineffective or hazardous, it poses a danger to patients. Monetary losses can be significant, too. Because many temperature-sensitive drugs carry extremely high price tags, a single temperature-abused shipment can cost millions.  

To protect products from temperature abuse, drugmakers rely on an expanding array of tools to maintain shipments at the proper conditions. These tools also identify excursions above or below the required temperature range. 

The latest temperature-protecting packaging also qualifies as sustainable. Today's designs tend to weigh less and occupy a smaller footprint than previous containers. In addition, they are less likely to rely on dry ice. Thermal containers frequently are both reusable and recyclable, and may contain recycled content, too. Formalized reverse-logistics programs simplify container reuse, cut costs, automate replenishment, and ensure that recyclable components are reprocessed rather than consigned to landfills when they can no longer be reused.    

A prepaid shipping label expedites the return of the containers. Upon receipt, all containers are visually inspected, and any damaged components are replaced. Next, the containers are cleaned in compliance with 21 

 211.94. Before returning to service, thermal components are tracked by customer and serial number and tested to confirm that thermal performance has not degraded (AcuTemp Reusable Enviro-friendly Program Assuring Quality for AcuTemp Qualified Shippers, AcuTemp Thermal Systems). 

Another program that inspects, refurbishes, cleans, and sterilizes returned containers is supported by web-based software. The software provides continuously updated reports and alerts on container status, inventory levels, and maintenance needs and allows a user to track its shipments (Credo Encore reverse-logistics services, Minnesota Thermal Science, MTS).  

To protect temperature-sensitive shipments better, several carriers have established specialized service programs and adopted standardized temperature-control technology (Temp Control service, United Cargo, and AC Cool Chain, Air Canada Cargo).    

AcuTemp RKN Temperature Management Cargo Units for air transport of temperature-sensitive goods. (PHOTO IS COURTESY OF ACUTEMP)			

For air transport, this specialized service may include buying or leasing active temperature-controlled containers with proprietary air-movement, heating, cooling, and insulation systems that eliminate the need for dry ice. The compressor-equipped units, which are approved by the Federal Aviation Administration, the European Aviation Safety Agency (EASA), and Transport Canada, operate for more than 100 h on battery power, maintain temperatures between 4 and 25 °C in ambient conditions ranging from –30 to 49 °C, and provide payload space large enough to hold a full pallet. Longer hold times are possible if the unit can be plugged into an AC power outlet. The containers have successfully undergone operational qualification (OQ) at several pharmaceutical companies, including Pfizer. The OQ involved testing under a wide range of temperature setpoints, ambient conditions, shipping lanes, payload sizes, and transit durations (AcuTemp RKN Temperature Management Cargo Unit, CSafe).  

A large, compressor-based heating–cooling unit capable of maintaining a temperature-controlled environment for five European-sized or four US-sized pallets recently received an airworthiness certification from EASA. It maintains internal temperature between 0 and 25 °C in ambient conditions ranging from –25 to 50 °C (RAP e2 container, Envirotainer).  

The International Air Transport Association's time- and temperature-sensitive label. (PHOTO IS COURTESY OF THE INTERNATIONAL AIR TRANSPORT ASSOCIATION)			

A passive pallet-shipper system for full or half pallets provides thermal protection for more than 120 h (i.e., five days) without requiring any power. The design relies on phase-change material and vacuum-insulated panels. The reusable system provides a 48 × 40 × 52-in. space with a payload capacity of 890 L (31.4 ft

 ) or a 48 × 40 × 30-in. area that holds 406 L (14.3 ft

 ) (Credo Xtreme pallet shipper, MTS). The pallet shipper is part of a range of reusable thermal containers (Credo Cube) that are used by the largest temperature-controlled healthcare transportation provider in Canada (ATS Healthcare).  

Another passive system consists of a lockable trunklike unit that is durable, reusable, and compatible with security scanning. Capable of maintaining temperatures between 2 and 8 °C for as long as five days, the system is available with payloads of 36 L (1.27 ft

 ). An optional data logger records downloadable internal and external temperature data to show whether the internal temperature remained in spec throughout the shipment's travels (Kodiak Active Temperature Control Shipping Containers, Active CC Boxes).  

A similar reusable design with handles and a latch relies on plant-based phase-change technology and encapsulated vacuum-insulated panels to boost performance while reducing weight. The passive temperature-controlled system produces about seven times the insulating effects of common alternatives such as expanded polystyrene and polyurethane (OrcaTherm temperature-controlled packaging, Intelsius).  

For less stringent applications, a passive system maintains an 11 × 11 × 5.5-in. (0.4 ft

 ) payload area in the 2–8 °C range for 72 h. It consists of gel packs, expanded polystyrene (EPS) panels, and an outer plastic or corrugated case. The unit holds 1 to 7.5 lb of product (TimeSaver 72, Cryopak). All components of the packaging are recyclable, and the EPS insulating panels contain as much as 20% postindustrial recycled content. 

Another advantage of the design, which won a Greener Package Award in 2010 from Summit Publishing, is the energy- and time-saving nature of the phase-change material used as the core refrigerant. It freezes and thaws at 5 °C and does not need to be pre-conditioned in a refrigerator or freezer (Engineered Phase 5 phase-change material, Cryopak).  

For smaller quantities that are delivered quickly, an inflatable thermal envelope maintains the contents between 2 and 8 °C for as long as 24 hours. Patented construction blocks heat transfer and cushions the product, too. Delivered inflated, the reusable pouch features a zipper closure and dual compartments: one for product, and one for cooling-gel packs. It's available in 1-, 3-, and 5-L sizes (One Day pharmaceutical pouch, Coldpack).  

Data loggers provide a warning if the contents of an insulated package or container experienced heat or cold beyond acceptable parameters. The devices permit immediate decisions about product quality. The ability to upload temperature data from the monitor as soon as the shipment arrives eliminates delays and quarantine time associated with waiting for a monitor to be returned for analysis or a report to be faxed (Shipping Temperature Electronic Monitoring System, Almac Clinical Services). 

A specialty courier service tracks the temperature and movement of sensitive shipments in real time through a customized global positioning system (GPS)-based device. It also can provide chain-of-custody data (GPS Tracking devices, GTX, for MNX).  

Integrating a satellite network with tracking software achieves similar functionality. The two-way communication between shipping container and shipper or recipient enables real-time product tracking and management and provides an early warning if temperatures deviate beyond desired parameters (SmartLink Platform, Axeda, and satellite network, ORBCOMM). 

Yet another way to track temperatures inside shipping containers relies on an active radio-frequency identification (RFID) tag equipped with a satellite modem and GPS receiver. If an RFID reader is within range, the tag communicates with it. If not, it uses the satellite modem to upload environmental data and location coordinates (GlobalTag ST-694 and SmartChain software, Savi Networks). 

Another RFID-based data logger also relies on an RFID tag–temperature sensor combination. The semipassive tag is compatible with most Gen2 ultrahigh-frequency RFID readers and features a thin profile, easy-to-use manual interface, and 16 configurable temperature ranges between –20 and 70 °C. As many as 4000 data points can be collected. Algorithms calculate the product's remaining shelf life to provide data to support a decision to deliver or return a product that has experienced temperature abuse. Deutsche Post DHL has adopted the technology for its Smart Sensor Temperature service for temperature-controlled shipments (RT0005 easy2log Temperature Logger, CAEN RFID). 

RFID technology also is the basis for a label that records temperature information. At any point during the distribution process, a wireless reader can collect data from 30 labels located within 60 ft (20 m). Reading distances as great as 300 ft (100 meters) are possible if the line of sight between reader and label is unobstructed. Available in both the United States and Europe, the flat labels are about the size of a credit card (Ultra Wireless Label and Ultra Wireless Reader, PakSense).  

Similar capabilities are provided by high-frequency 13.56-MHz RFID tags and readers designed for humid environments (SensTag sensor, Phase VI Engineering, based on the MLX90129 sensor IC, Melexis Microelectronic Integration Systems; 13.56-MHz reader from Proxima RF).  

A temperature-control process, designed especially for clinical-trial shipments, consists of an RFID tag for recording temperature, a dedicated compartment for a mobile phone for high-speed data transmission, and a secure web-based portal. Designed to record temperatures between 5 and 35 °C at configurable intervals, the device can track more than 8000 data points and operate for nearly 60 days. If the data show that the temperature remained within specifications during shipment, the drug can be released immediately for use (RFID tag, Stora Enso; multimodal communication, MediXine Oy; Clinical Logistics Services, Parexel International).  

Several groups, including the Parenteral Drug Association, the International Safe Transit Association (ISTA), International Air Transport Association, and the US Pharmacopeia are working on tools, guidelines and regulations to support Good Distribution Practices. ISTA recently released its 

Standard 20: Design and Qualification of Insulated Shipping Containers

. It includes multiple appendices and worksheets to support the design, testing, and validation of insulated shipping containers. ISTA's new 

Standard 7E: Thermal Transport Packaging Used in Parcel Delivery Systems

With the development of Standard 20 and Standard 7E A, ISTA also established new certification categories. A handful of laboratories have completed or are working to be designated as ISTA Certified Thermal Transport Laboratories, and personnel have begun the process to earn Level I or Level II status as ISTA Certified Thermal Professionals. Laboratory certification must be renewed every two years.  

Thermal packaging, developed and tested according to the ISTA standards, is designed to simplify the sourcing process and provide confidence in its performance. "Drugmakers will be able to buy ISTA-certified thermal packaging off the shelf with all the necessary documentation and validation information," predicts Ed Church, president of ISTA. 

's Packaging Forum editor, 4708 Morningside Drive, Cleveland, OH 44109, tel. 216.351.5824, fax 216.351.5684, 

Articles

Innovations protect the quality of temperature-sensitive products.

Preventing Temperature Abuse

Sometimes it makes sense for a pharmaceutical company to outsource the packaging of one or more products. Some contract packaging firms also are contract manufacturers that can make the product as well as package it. 

Outsourcing packaging operations can expedite product launches, accommodate surges in demand or volume growth, provide access to packaging formats that are unavailable in house, locate packaging closer to the market where the product will be sold, and reduce the expenses related to installing and running a packaging line.  

Most contract packagers also provide other services, including custom designing packages that aid patient compliance, vial labeling, secondary packaging such as cartoning and kitting, cold-chain, ePedigree, and repackaging. Some firms also assemble devices such as syringes, and others offer stability testing, microbiology and chemistry laboratory testing, engineering support, and tooling design and production. Tooling frequently is dedicated to one product and often is owned by the pharmaceutical company rather than the contract packager. Tooling costs may be assumed by one company or shared by both. 

In addition to standard bottles or blisters, some contract packagers offer proprietary designs like the unit-dose Snapplicator from Tapemark. (IMAGE IS COURTESY OF TAPEMARK) 

Although outsourcing sometimes seems like an obvious solution, selecting the right partner requires considerable effort and can take time (see sidebar "Criteria for selecting a contract packager"). Companies can spend as long as 18 months on the vendor-qualification process. Because many contract packagers that serve the pharmaceutical industry specialize in specific product and package types, the first step is to identify suppliers with the capability and experience to handle the product (e.g., solid dose, liquid, parenteral, or aerosol) as well as the desired package (e.g., bottle, blister, wallet, vial, ampul, pouch, or syringe). 

Criteria for selecting a contract packager

One resource that can help identify potential suppliers is the Contract Packaging Association (Naperville, IL). Its website (

) offers advice about choosing and hiring a contract packager and provides a directory of members that's searchable by criteria such as types of products filled, packaging process, and location. 

"Quality and reliability are critical in selecting a supplier," says Aileen Ruff, group product manager for commercial packaging at Catalent Pharma Solutions (Somerset, NJ), which handles various product types and package formats. "Suppliers should also have extensive experience operating under the most stringent regulatory requirements [and] a proven record of success delivering products on time to desired specifications."  

Like pharmaceutical manufacturers, contract packagers follow current good manufacturing practices (CGMPs). They also are regularly audited by the US Food and Drug Administration, as well as by customers and other organizations. "We have standard operating procedures for everything we do," says Joe Luke, vice-president of sales and marketing at Reed-Lane (Wayne, NJ), which primarily packages solid dosage forms in bottles, travel-size vials, blisters and pouches. To maintain proper control, "all printed materials are kept in a locked area and must be reconciled as part of the final batch record," he says.  

"We can't close a master batch record or ship without a final reconciliation," agrees Paul Dupont, director of business development at Ropack (Montréal). His company specializes in stick packs and products that must be packaged in low relative humidity conditions. 

Despite stringent adherence to CGMPs, due diligence is crucial when selecting a contract packaging partner. "Visit the contract packager's operation, walk around the plant, meet the people, check out standard operating procedures. You have to feel comfortable with the people," advises Luke. 

Companies seeking a contract packager should perform a quality audit and risk assessment. The prospective supplier's history, customer references, and finances should be reviewed.  

Personnel also should examine any Form 483 citations describing CGMP compliance deficiencies that FDA inspectors have observed at a given contract packager. "Not having any [recent] 483s is definitely a positive," says Luke. However, the existence of a 483 shouldn't necessarily be a deal breaker. "It's important to know what the 483 was for and how the problem cited was addressed," he explains. 

Steve Larsen, national sales manager for Tapemark (West Saint Paul, MN), a contract manufacturer of transdermal patches, agrees that the existence of a 483 shouldn't be a disqualifier. However, "a series of 483s on the same topic should be a concern," he says. 

Once due diligence has been completed, lead times vary, but can be as little as four weeks. Project turnaround will take longer if stability tests must be performed, packaging components must be specified and ordered, tooling is needed, or the package configuration or artwork changes after the project gets underway. 

Some contract packagers offer custom designs, and several vendors have developed proprietary unit-dose delivery systems. One such system consists of a foam applicator pad backed by a small pouch, which is squeezed to break a frangible inner seal and release the product into the pad. Suitable for creams, ointments, and lotions, the system is available in 0.5- and 1-g sizes (DelPouch single-use pack, Catalent).  

Another proprietary system is a scored, four-side-sealed pouch that permits one-handed dispensing of creams, gels, pastes, or lotions. Capable of holding 0.5 to 17 mL, the pouch dispenses the product when the user pushes two of its ends together to break the score (Snap! single-use pack, Tapemark). The pouch also can be equipped with a flat or pop-up applicator pad (Snapplicator) and configured to provide a series of doses or to deliver dual-component products. 

 Custom designs for solid dosage forms include wallet-pack configurations that support patient compliance and impart child-resistant and senior-friendly features to traditional blisters (Shellpak unit-dose medication packaging, MeadWestvaco, Richmond, VA, filled by Reed-Lane). 

Contract packagers constantly upgrade their operations to meet the ever-changing requirements of their customers. One firm's strategy involves making plans to expand as soon as an existing bottling, stick pack, or blister-packaging line is running at 50% capacity. When the line reaches 75% capacity, the expansion plan is activated. "We never want to operate at higher than 75% capacity so we always have room to grow with our customers," says Dupont. "We never want to be the constraint on growth. We want to be able to take on a new project or accommodate a surge in demand," he explains.  

As a result, the company recently installed a stick-pack system that precisely fills 10 packs at a time with volumes from 180 mg to 3 g at speeds as high as 1000/min (Ropack). The equipment is installed in a Class 100,000 environment with controls that permit filling under conditions of 30% relative humidity. If needed, a nitrogen flush before sealing can reduce residual oxygen in the package headspace to less than 2%. 

Another firm recently installed two blister lines and built a secondary packaging line in Europe for nasal strips (Catalent). The lines address growing demand for these packaging formats and products. 

Another new installation involves a high-speed pouching machine that forms, fills, and seals four-side-seal pouches (Reed-Lane). It also produces multiple packs per cycle. 

Pharmaceutical companies decide not to outsource a function if it requires customized equiment or if outsourcing is perceived as risky, But brand owners considering contract packaging need to be prepared to provide the information and support needed for a successful collaboration. It's particularly important to define critical quality attributes early in the process. "Having that dialogue up front is essential," says Larsen.  

Contract packagers also need a clear description of the nature and scope of the project, product samples, drawings, Material Safety Data Sheet information, primary and secondary packaging material specifications, lot size, forecasts, and special requirements such as temperature or humidity levels. 

Luke says, "Our customer service and project management people go through a detailed checklist." This information sharing helps ensure that the project proceeds smoothly. 

Dupont concludes, "A master service agreement regulates all of our business dealings. The second document we rely on is a quality agreement that lays out in detail how we manage and report quality." 

Outsourcing packaging functions can save time and money.

Packagers for Hire

Companies that are sourcing packaging equipment shouldn't overlook used machines. These units typically cost 40–60% less than new devices and generally can be delivered more quickly, sometimes shipping the same day or the day after the order is placed. 

Because of its lower cost and shorter lead time, used equipment is a particularly good choice when budgets are tight, quick turnaround is needed, and demand for the product is uncertain or seasonal. Used equipment also scores points for sustainability because it is reused instead of being scrapped.  

However, if a project involves a unique product or package that requires highly customized equipment, it probably will require a new machine. Another situation in which a new machine might be the better choice is when advanced technology generates a lower total cost of ownership and rapid return on investment.  

Interestingly enough, today's previously owned machines frequently are "used" in name only. The used equipment currently for sale often has never run in production because of changes in product demand or company focus. Sometimes it has never been installed. 

Several companies specialize in selling used pharmaceutical packaging equipment and possess inventories of hundreds, if not thousands, of machines. Many of these dealers also sell processing equipment.  

Used packaging machines also may be found online. Options include brokers such as EquipNet (Canton, MA) that act as the middleman between buyer and seller, and a packaging-equipment section on the eBay Stores website, hosted by eBay (San Jose, CA). In addition to examining the machines under consideration, it's important for personnel to research the history, background, service, and financing options of the used-equipment dealer.  

The dealer should be reputable, established, and capable of offering various machines so that capabilities can be matched to applications without any bias toward a particular brand name or configuration. It's also helpful if the equipment is stored in a warehouse where it can be inspected and viewed in operation before it is shipped to its new home.  

Howard Newman, president of Loeb Equipment (Chicago), a fifth-generation family-owned equipment dealer, recommends asking potential suppliers, "How long have you been at your current location? Do you own your warehouse? What is your return policy? What warranty do you offer?"  

K.C. Christensen, founder of Kendell Equipment, now part of AEK Packaging Equipment, a subsidiary of Aaron Companies (Bensenville, IL), a used-equipment dealer, explains, "You want someone that can provide support if a problem arises. We have a global presence," he notes, "we can send a technician out or take the machine back." 

In addition, purchasers should take a close look at the dealer's ability to retrofit and refurbish previously owned equipment. "A lot of people claim to do refurbishing, but don't necessarily have the resources to do it," says Dave Madden, vice-president of sales at The Frain Group (Franklin Park, IL), a 30-year-old used-equipment dealer that employs 30 technicians in its mechanical shop. "A [used equipment] company also should be able to provide documented evidence of successful projects," he adds.  

Entire packaging lines sometimes are transplanted. This line from manufacturer IMA North America (Bristol, PA) was purchased by the original owner for an alcohol-based spray product that was never marketed. (IMAGE IS COURTESY OF LOEB EQUIPMENT) 

Pharmaceutical packagers sourcing used equipment should match the machines to their applications and pay attention to many of the same elements they would consider when buying a new machine (e.g., run speed, efficiency, footprint, and electrical package). "Equipment should be evaluated on the basis of the desired outcome," advises Madden.  

If the pharmaceutical packaging equipment under consideration actually ran in production, it's important to know what products and packaging materials were in contact with it. This information is crucial for primary packaging machines, but less crucial for secondary packaging machines.  

Last, but not least, Newman recommends that companies double-check a machine's control system for compatibility with the other equipment on their lines. Because many pharmaceutical packaging lines are fully integrated today, some machines are configured to be controlled by other machines and therefore possess minimal on-board control capability.  

Like Frain, AEK Packaging and Loeb Equipment dedicate a substantial amount of floor space to refurbishing. These dealers employ engineers and technicians who prepare the equipment for delivery and recondition it as necessary.  

Equipment preparation varies, but typically involves a thorough cleaning; confirmation that mechanical, electrical, and computer systems are in good working order; and replacement of wear parts, which often are sourced from the original equipment manufacturer. If necessary, controls are upgraded and change parts crafted. In fact, "We have developed a global network of suppliers for controls and change parts," reports Christensen. 

Looking a bit like a trade show, the warehouse floor at Loeb Equipment displays used packaging machines and entire packaging lines for prospective buyers' inspection. (IMAGE IS COURTESY OF LOEB EQUIPMENT) 

Machines typically are supplied with complete documentation, including manuals and schematic drawings. Transactions also may include guarantees, warranties, and right-of-return agreements. 

Some dealers provide acceptance testing, setup, and training. Line integration and aftermarket service also can be part of the vendor's package. However, postsale service typically requires a separate service agreement.  

Deciding how to pay for a machine can involve almost as much thought as determining exactly which machine to buy. Options include cash payment, leasing, and renting. Each choice presents a different degree of flexibility. Likewise, each has advantages and disadvantages.  

Cash payment results in full ownership, but it represents a capital expenditure and requires a capital budget. In most cases, accounting personnel must track depreciation for several years after the purchase. 

Many used packaging machines such as this Pharmacarton Coding System from Nutec Systems (Lawrenceville, NJ) have not seen extensive operation. (PHOTO IS COURTESY OF AARON COMPANIES) 

Leasing, either directly through the dealer or through a third-party company, spreads payments out during a specific term. At the end of the term, the equipment is returned or purchased for a price that reflects the lease payments.  

Renting does not require a commitment of more than a month or two, therefore it provides the most flexibility. In addition, rental fees are considered as expenses, so equipment can be purchased without touching the capital budget. Thus, renting is particularly well-suited to addressing seasonal spikes in demand, product introductions, and contract packaging situations.  

"Renting makes it possible to put a product on the market very fast and very economically," explains Christensen, noting that it also "provides the opportunity to test a machine before you commit." If the new product is not successful, the equipment can simply be returned. If the product succeeds, the rental can become a purchase. In that case, "we apply part of the rental [fees] to the purchase price," says Madden of Frain.  

Dealers that sell used packaging equipment are always looking to buy late-model systems that have been properly maintained. "We're probably offered 50 machines per day, but only pursue five to 10," says Christensen.  

In addition to purchasing surplus assets directly, many dealers also offer asset-redeployment services. Frain, for example, consolidates and manages surplus assets using a three-tier process that includes purchasing assets for cash, marketing them on a consignment basis, and purchasing assets for credit toward a machine or service.  

Used packaging equipment can be a cost-saving, time-saving alternative to new machines.

Used Is the New "New"

As deadlines for meeting electronic pedigree (ePedigree) requirements approach, a growing number of technology choices help deliver supporting data. The foundation of a drug ePedigree, serialization, is the application of a unique code at the item level. These unique codes can be used to authenticate products and enable tracking and tracing.   

Standards for Securing the Drug Supply Chain—Standardized Numerical Identification (SNI) for Prescription Drug Packages, 

the US Food and Drug Administration recommended that each sellable unit carry a unique serial number. In most cases, according to FDA, this identification could consist of the National Drug Code for the product plus a unique serial number with a maximum of 20 characters, printed in both machine- and human-readable forms. 

The SNI format is compatible with global standards that call for a serialized Global Trade Item Number (GTIN) for item-level identification. Normally, manufacturers would apply the SNI. If a manufacturer's package is to be broken down for sale, however, the repackager would apply an SNI to each sellable unit and link this number to the manufacturer's SNI.  

Creating an ePedigree takes item-level serialization several steps further and affects all partners in the supply chain. "It also requires a lot more integration between equipment and packaging lines and packaging lines and upper level systems," says Robb Roebles, principal product marketing manager at Cognex (Natick, MA), a supplier of machine-vision hardware and software. 

Once applied and recorded, item-level codes must be linked to the unique code applied to each bundle, carton, case, and pallet to create parent–child relationships. Serial numbers also must be captured, recorded, and certified at each stop in the supply chain, and these data must be stored in a centralized system that's accessible to all supply-chain partners.  

Serialization begins on the packaging line with the application of a two-dimensional DataMatrix code or a radio-frequency identification (RFID) tag. Since a DataMatrix code is easy and inexpensive to apply, it's now more commonly used than RFID. Many processes reproduce DataMatrix codes, including inkjet, thermal-transfer, and laser coding. 

After code printing or tag application, a camera or RFID reader and software confirm the correctness of the code and the print quality. As the product moves down the packaging line, a unique code is applied to each level of packaging. These codes are not only verified as correct and readable, but also aggregated to create parent–child relationships. With this data stored in a database, drugmakers and other supply-chain partners can determine that Product A was shipped in Carton X in Case Y on Pallet Z.  

The hardware and software associated with code capture and recording also must accommodate events on the line such as rejects or quality-assurance sampling to ensure that no discrepancies occur between the products and the data. 

Line-management software sends serialization data, including all good numbers (i.e., commissioned products), bad numbers (i.e., decommissioned products), and parent–child relationships to higher level systems. "Ultimately, this data goes into a system of record that becomes the master historian," says Joe Ringwood, chief operating officer at Systech International (Cranbury, NJ). 

Implementing serialization requires hardware such as printers and vision systems as well as software for the line, site, and historian levels. Integration is required to make everything work together. The complexity of the integration depends on what systems are already in place and the approach taken by the manufacturer. 

In general, commercial, configurable serialization software will take less time to implement than line, plant, and enterprise systems that must be customized to perform serialization functions. Choosing specific, standard devices also simplifies implementation, particularly if multiple lines or locations are involved. It's also helpful to specify device-neutral software that is compatible with virtually any brand or model of equipment. 

 "Serialization means you have to know what happens to each serialized package and requires new workflows and processes," says Ringwood. "So the better job done assessing current workflows and defining 'to-be' workflows, the smoother the implementation," he predicts. 

Ringwood also advises looking at the total cost of ownership instead of focusing solely on the expenses associated with implementation. "Many decisions have implications down the road," he explains. 

Implementing serialization requires months of planning to identify software needs, qualify vendors, perform pilot projects, and integrate hardware and software. Serialization teams should include representatives from automation, information technology, engineering, and plant-floor teams. In fact, says Roebles, the most successful implementations involve and train the plant-level personnel who work with the system daily. Actual implementation schedules vary, but vendors agree that an 18-month validation process is common. "Companies that haven't started planning better start soon or they won't be ready when FDA or a country they sell to sets [ePedigree] rules," warns Roebles. 

Implementing serialization almost inevitably requires the installation or upgrading of hardware such as printers and vision systems, which must be able to accept, capture, and transmit serialized information. Several integrated marking-verification systems are available. 

One system consists of an inkjet printer, a built-in vision system, mechanical transfer devices, and air-powered reject. Compatible with various printers and vision systems, the unit applies serialized data to cartons, verifies that the information is accurate and uploads code data to a database for ePedigree records (XMV Marking and Verification System, Mettler Toledo Hi-Speed, Ithaca, NY). A related system adds a checkweigher for additional quality assurance (CS2 MV System, Mettler Toledo Hi-Speed). 

A laser or thermal inkjet printhead prints serialized codes and other information on cartons; verifies print presence, accuracy, and quality with an onboard vision system; and records code data in an internal database. An air knife blows unreadable cartons into a reject bin equipped with a sensor that confirms that the reject has been made. A quick-change mechanism adjusts to a wide range of carton sizes. Software manages individual or multiple vision sensors, coding devices, checkweighers, and other peripherals (Pharma-Marker 450 Track and Trace System Eisai Machinery USA, Allendale, NJ, with vision technology from Cognex and Line Director software from Crest Solutions, Cork, Ireland). 

A thermal inkjet coder capable of operating at a speed of 250 feet/min combines speed with sharp print quality to eliminate the need to slow the line to apply two-dimensional DataMatrix codes. A dual processor handles serialization data input and output in real time while integrated sensors confirm code readability. Communication interfaces include RS 232, USB-B, and TCP/IP (Wolke m600 Advanced inkjet, Videojet Technologies, Wood Dale, IL). 

A serialization system capable of 360° inspection relies on six cameras to provide high-resolution images. Positioned at the infeed of bundling, case packing, or palletizing, the system reads DataMatrix codes regardless of orientation, captures serialization data from each product, and generates coded labels. Integral software aggregates serialization data from units, bundles, cases, and pallets and transmits them to an enterprise resource planning system for storage in a database. The system also can encode and read RFID tags for cases and pallets (T&T Solutions, Seidenader Vision, Harrisburg, PA). 

Software equips Cognex's In-Sight Vision Systems to perform tasks related to serialization and data capture.

Preconfigured software equips camera-based vision systems for serialization tasks such as verification of code accuracy and print quality and capture and exchange of serialization data with other systems. An easy-to-use touch screen operator interface simplifies setup and operation. The software also includes technical controls needed for 21 

Part 11 validation, including secure user authentication and automatic audit-trail generation. Because the microprocessor-equipped smart camera performs processing functions, operators do not need a personal computer or related maintenance products such as virus protection software (In-Sight Track & Trace software, Cognex).  

Line-management software plays a big role in serialization and ePedigree creation. Configurable software can expedite setup and simplify operation. Another time saver is software that is device- and data carrier-neutral and therefore works with virtually any printer, coder, scanner, or vision system and with various barcodes or RFID. Compatibility with other software, particularly high-level enterprise resource planning systems that may be in use, also streamlines implementation. 

One method that incorporates all these features looks at any physical object on the packaging line as an item and each related action as a process block. Items move through a series of linked process blocks in a stream. A group of streams make up the workflow of a packaging line. 

This architecture makes the software easy to configure and expand without writing custom code, thereby expediting implementation and reducing costs. It also ensures repeatability, simplifies reconfiguration of workflows as needs change, and minimizes revalidation. "You don't need to be a software developer to install and configure our system," says Stephen Lisa, director of technical product marketing at Systech International. The software mirrors what happens in the real world, "there's not a lot of abstract C++ or ladder logic," he explains (Item Process Stream methodology for Serialized Product Tracking software, Systech). 

A software platform from Systech uses a building block approach to map the workflow of a packaging line.  

A demonstration line helps drugmakers test the vision systems and software needed to support serialization. Compatible with either two-dimensional DataMatrix coding or RFID tags, the fully automated system includes all the inspection, line control, aggregation, and data management functions needed to successfully serialize product and capture data at each level of packaging from item to pallet (Capture and Control System, Optel Vision, Quebec City, Canada). 

Serialized identification opens doors beyond authentication and product tracking. A smartphone application not only allows field investigators and consumers to scan or input the code from a package to confirm authenticity, but also can present the product's history and prompt the delivery of promotional information or link to a chat function or customer service. 

Other possible loyalty program services include instructions about how to take the product, dose reminders, and refill reminders. The smartphone application and the associated software and services also capture sales information for brand managers and can connect physicians and pharmacists to prescribing information. Deployable in 30 days, the software requires minimal commitment from corporate information-technology personnel for implementation (Brand Loyalty and Integrity Services, Covectra, Southborough, MA).

Technology from Covectra can provide access to product information, including ePedigree records. 

Mobile-phone-based technology and serialized codes on scratch-off tags have been tested in Africa. After transmitting the code, a message confirming product authenticity arrives within a few seconds (Mobile Product Authentication technology, Sproxil, Planada, CA, mPedigree, Accra, Ghana). 

Serialized product codes serve as the foundation of ePedigree records and product traceability.

Adopting Serialization

Packaging exhibitors at Interphex, which took place April 20–22, 2010, at the Javits Convention Center in New York, concentrated on increased functionality. Examples included extremely flexible packaging machines and inspection equipment capable of performing multiple tasks.  

In a first for North America, a fully automatic machine aseptically fills and seals presterilized bags. Rated at 60 bags/min, the unit fills volumes from 50 to 1000 mL. The space-saving design features a robotic infeed and outfeed, laser printing of variable data, print-quality confirmation by a camera-based vision system, shelf-life-extending evacuation or nitrogen flushing, a clean- or sterilize-in-place product path, and fully automated changeover (BFL 854 aseptic bag filler–sealer, Plümat North America, Naperville, IL).  

A precise femtosecond laser applies tiny, two-dimensional data-matrix codes to transparent containers. The laser's ultrashort pulses do not mar the surface of the glass or plastic, but change its refractive index to mark the container without additives or emissions. Resulting codes are machine readable on full or empty vials, but only can be seen by the naked eye when illuminated at the correct angle. Codes identify the container for subsequent labeling operations and can be integrated with secondary packaging for track-and-trace requirements (TRACKinside laser coding and LineDirector software, Crest Solutions, Cork, Ireland).  

A vacuum system gently transfers solid dosage forms from bulk boxes, bag-lined drums, bags, or intermediate bulk containers (IBCs) to the hoppers of filling machines. The automated system eliminates manual handling, lifting, and climbing to reach hopper heights, as well as the need to suspend IBCs above packaging machines. The system also dedusts as it transfers, thus eliminating the need for a separate dedusting operation. For flat-bottomed drums, which are difficult to empty completely, a collar on the vacuum wand draws the bag liner inward to shift remaining product to the center for capture by the vacuum. If necessary, the system can use conditioned air or be sealed to limit operator exposure to the product (No Tip Unloader, Volkmann, Neuss, Germany).  

Linear synchronous motor technology on a modular conveyor precisely moves, positions, and tracks loads weighing as much as 2 kg with no pressure accumulation. The system can move in either direction and conveys product on small pucks at speeds of up to 2 m/s, about seven times faster than standard conveyors. As many as nine pucks can be in motion per meter. With no belts, chains, gears, wheels, or external sensors, the washdown-compatible system contains few moving parts. Software simulation and configuration tools and plug-and-play track components simplify setup and subsequent reconfigurations. Track parts include 90° and 180° curves, 180° over–under curves, 0.25-m and 1-m straight tracks, and left and right diverges (MagneMover Lite conveyor, MagneMotion, Devens, MA).  

A high degree of flexibility is built into a modular monobloc for filling and finishing rigid containers. Capable of handling round or square containers ranging in size from 10 to 1000 mL, the servo-driven system can be equipped with either a peristaltic or piston pump. An optional high-efficiency particulate air (HEPA) filtration system provides positive-pressure airflow in the filling area (Monobloc fill–finish packaging system, Filamatic, Baltimore, MD). 

The servo-driven Filamatic Monobloc fillâfinish packaging system handles round or square containers ranging in size from 10 to 1000 mL. (PHOTO IS COURTESY OF FILAMATIC.)			

Another highly flexible monobloc fills and closes microtubes or bottles and can change from one to the other in 30 min. Capable of filling volumes as great as 250 mL, the system's maximum speed is 45 containers/min. The microtube setup consists of a vibratory bowl to orient tubes, a linear filling line, and screw capping. Bottles rely on rotary turntables at the infeed and outfeed and crimp capping. Hygienic design, HEPA filtration, and compatibility with barrier systems or isolators make the system suitable for sterile products (P1520-BT monobloc, M&O Perry Industries, Corona, CA).  

Yet another monobloc fits the needs of laboratoriess, pilot plants, and clinical-trial packaging. It can fill from 1 to 100 mL at speeds as high as 45 containers/min. Capable of filling, stoppering, and crimping aluminum caps, the system enables tool-free changeover to be completed in less than 10 min. The single-operator machine is designed for cleanroom environments (Model FSAS—2205 Tabletop, Chase-Logeman, Greensboro, NC).  

Clinical trials and low-volume applications also are addressed by a highly flexible vial filler equipped with two robots. The first robot transfers a vial from the infeed and sets it on a weigh cell for filling. After the accuracy of the fill is verified, the other robot moves the vial to the stoppering station. Interchangeable filling options include piston, peristaltic, and rolling-diaphragm pumps. Personal-computer-based control ensures precise fills and minimal product waste. The unit handles as many as 60 glass or plastic containers per minute. Servo control automates changeover, which involves a minimum of change parts. A small footprint and isolator-ready construction enhance functionality (MHI vial-filling and -closing machine, Bosch Packaging Technology, Waiblingen, Germany).  

The MHI vial-filling and -closing machine from Bosch is targeted toward low-volume applications and suited for clinical-trial packaging. (PHOTO IS COURTESY OF BOSCH.)			

A syringe-assembly machine inserts the plunger rod into 1-, 2- or 5-mL syringe bodies and applies labels. The compact machine also incorporates a printer to print a lot number and expiration date on the label and a vision system to verify the information and label placement. Three models handle speeds of 100, 200, and 400 syringes/min. An inclined exit raises the syringes to the level of the thermoformer. Options include assembly of back stops and safety devices (Hasta plunger-rod inserting machine, MG America, Fairfield, NJ). The plunger-rod inserting machine can be integrated with a complete line, including a syringe denester, thermoformer, cartoner, and case packer.  

Quality control always is a prime concern, and pharmaceutical manufacturers continue to express high levels of interest in flaw-detection equipment. Particularly notable is the growing number of multifunctional systems, many capable of providing 100% inspection at line speeds.  

A low-power diode-laser system with as many as four heads checks vials of freeze-dried, liquid, or powder products for raised stoppers and headspace moisture and oxygen. Because the laser can be tuned to match the wavelength of the gas, it also can be set to detect nitrogen levels. Stand-alone or on-line configurations handle single vials or trays. Container sizes range from 1 to 200 mL. The system can check as many as 600 containers/min (high-speed headspace-inspection machine, Lighthouse Instruments, Charlottesville, VA). 

Raised stoppers also can be detected by camera-based systems. Capable of measuring variations of ±1 mm, an intermittent-motion unit holds vials steady to ensure that good images are captured. The system bolts to existing capping equipment and also analyzes headspace or checks for the presence of moisture with the addition of a laser or near-infrared module, respectively. Other options include application and verification of lot numbers (vial-inspection platform, Genesis Packaging Technologies, Exton, PA).  			

Improved operation and connectivity characterize a new leak detector for syringes and vials. Electronic vacuum control increases precision and shortens cycle time, enabling the detection of leaks as small as 0.005 cm

  per minute. To check for leaks, packages are placed in a test fixture inside a test chamber and a vacuum is pulled. If leaks or other defects are present, the equipment will register changes in absolute and differential vacuums. The nondestructive test is more sensitive than the traditional dye-ingress test (VeriPac 455 leak detector, Packaging Technologies and Inspection, Tuckahoe, NY). 

Another multifunctional system checks headspace oxygen with a laser, confirms container–closure integrity with a vacuum, and measures lyophilized-cake quality and moisture content with near-infrared technology. An integrated camera performs surface inspections and verifies two-dimensional data matrix codes. A timing screw–starwheel arrangement provides positive container handling and rejection (Wilcomat R 36 MC–LFC–V–HAS–NIR leak tester, Wilco, Wohlen, Switzerland).  

Microflow technology detects leaks as small as 0.2 μm in blister packs, pouches, vials, syringes, cartridges, and other flexible and rigid packages. Available in two designs for sterile and nonsterile products, the patented system checks for gross and fine leaks by measuring the mass of molecules in motion. Flow rate is proportional to defect size. Inline models run at speeds as high as 200 packs/min (Model ME2 packaging leak tester, ATC, Indianapolis, IN). 

ATC's ME2 microflow leak tester identifies containerâclosure integrity problems in packages of injectable products. (PHOTO IS COURTESY OF ATC)			

For solid dosage forms, a patented arrangement of mirrors and three cameras captures images that are combined to show the entire surface of the capsule, including each end. As a result, the vision system detects surface flaws and nonconforming colors, confirms the presence of the tamper-evident sealing band, and verifies print quality without rotating the capsule. Three plug-and-play change parts make it possible to inspect capsule sizes from #00 to #5. Changeover is toolless and takes less than an hour. Capable of handling 2000 capsules/min, two systems are already installed—one in India and one in Taiwan (Proditec InspeCaps 150, Symetix, Walla Walla, WA). 

The InspeCaps 150 single-file vision system inspects opaque, transparent, or translucent capsules when full or empty. (PHOTO IS COURTESY OF PRODITEC.)			

Another camera-based system provides similar inspection capabilities on slat fillers. Each camera in the multicamera system checks a 4-in area for broken, missing, and different color tablets at a speed of 7 slats/s, which is equivalent to 400 150-count bottles/min. The turnkey vision system includes lighting and brackets (Slat Counter Inspector, Optel Vision, Quebec, Canada). 

Robotic positioning with a multicamera vision system automates inspection of liquid products in ampuls, vials, cartridges, or syringes and lyophilized product in vials ranging in size from 8 to 80 mm in diameter and as tall as 200 mm. The robot picks up and rotates the liquid-filled container to check for particulates and fill level. It inspects the cake surface of lyophilized products. Optional checks include surface defects, stopper presence, aluminum-cap centering and crimping, and needle-shield condition (Mario inspection system, Dabrico, Bourbonnais, IL)  

For text and labeling inspection, an upgraded vision system centralizes management in a client–server configuration to simplify global deployment and reduce information-technology costs. The Windows-based system can compare one master with multiple samples or multiple masters with multiple samples at faster scanning and inspection speeds than its predecessors. A click of the mouse groups errors for review (Docu-Proof Enterprise Client-Server Text Inspector, Global Vision, Montreal).  

A multipage proofreading system enables batch processing of booklets, instruction manuals, and other documents to reduce proofreading time from weeks to days or minutes. Compensating for magnification differences, distortion, and ink bleed-through, the system can compare two digital files (i.e., PDFs), a digital file and a scanned document, or two scanned documents and check all aspects, including text characters, graphics, charts, and photos. Pages of different sizes may be scanned through a double-sided autofeed scanner. 

After the scan is completed, an operator reviews discrepancies the machine flags, accepts or rejects them, and may add comments about them. Review sessions can be saved, closed, and reopened as needed. A rework folder stores information about major problems like out-of-order pages. The system includes a high-quality, autofeed color scanner, software, software license and warranty, 20-in. liquid-crystal display monitor, and personal computer with Windows, Microsoft Office, and Adobe Acrobat software, plus on-site installation and training. A validation package may be purchased as an option (Avia Infinity Multi-Page proofreading system, Mnemonics, Mount Laurel, NJ).  

Serialized identification, usually undertaken for traceability and distinguishing purposes, also can support interaction with consumers and sales-generating loyalty programs. Using a smart-phone application, field investigators and consumers can scan or enter the code on a package, authenticate the product, and track its history, potentially back to the raw materials used in the batch.  

For consumers, the code scan also can prompt the delivery of promotional information or connection to a chat function or customer service. Other possible loyalty-program services include instructions about how to take the product, dose reminders, and refill alerts. The smart-phone application and the associated software and services not only provide enhanced value to the consumer, but also link brand managers directly to consumers through dashboards that show data such as who purchased the product, where the product was purchased, and what price was paid. Deployable in 30 days without a large time commitment by corporate information-technology personnel, the software also can connect physicians and pharmacists to prescribing information (Brand Loyalty and Integrity Services, Covectra, Southborough, MA). 

Scanning or inputting a code into a smart phone can authenticate product through Covectra's Brand Loyalty and Integrity Services. (PHOTO IS COURTESY OF COVECTRA)			

A staked-needle syringe with a tamper-evident closure eliminates contact between the drug and needle and offers a patient-friendly thin needle as heavy as 32 gauge. A specially designed seal keeps product from flowing into the needle until the needle shield is removed. Suitable for sensitive drugs, the syringe is free of leachables from adhesives and tungsten because the geometry of the glass barrel does not require tungsten in the glass-forming process. Domestic production is scheduled to begin before the end of 2010. The syringe is delivered with standard nests and tubs and can be filled on standard filling lines (Schott InJentle staked-needle syringe, Schott Pharmaceutical Systems, Lebanon, PA).  

Another syringe-related development features a removable label for the latest version of a safety syringe. The peel-off part of the label can be stuck to the patient chart to provide a record of the injection (Needle-Trap syringe, Schreiner Medipharm, Blauvelt, NY).  

A small, flat, four-side-sealed pouch dispenses unit doses ranging from less than 1 to 20 mL. A single dose of gel, cream, lotion, or ointment dispenses when the two ends are pressed together and the pouch snaps open along a score line. Because virtually no residue remains, overfill is not required to ensure a full dose. The structure of the pouch material varies, but it typically consists of a multilayer laminate with a layer of foil (Snap! package, Tapemark, West Saint Paul, MN). Options include a side-by-side configuration for two doses, a two-chamber setup for ingredients that can't be mixed until use and a design with a built-in applicator (Snap! Duet, Snap! Dual Chamber, and Snapplicator, Tapemark).  

A new blister-packaging option, polyester film, has been developed as a drop-in replacement to PVC. Compatible with the lidstock, equipment, and tooling used to produce PVC blisters, the polyester film offers equal or better thickness distribution, punches and perforates cleanly, and exhibits good lay-flat properties and brilliant clarity. Its tensile strength is 10% higher than that of PVC, and its elongation at break is 300% better. Its rigidity is a bit lower, and polyester blisters are expected to have a child-resistance rating at least equal to that of vinyl. A forming temperature that's about 15 °C lower than that of PVC saves energy and shortens cycle time. In addition, polyester's lower specific gravity results in higher yield. This 8% higher yield, potential for downgauging, and faster throughput offsets polyester's higher price, thus making the adoption of the chloride-free material essentially cost-neutral. Enhanced barrier properties can be achieved through lamination with Aclar or ethylene-vinyl alcohol or through coating with polyvinylidene chloride. Gauges range from 191 to 450 μm (Pentapharm kpVantage High-Performance Polyester Films, Klöckner Pentaplast, Gordonsville, VA). 

New polyester films from KlÃ¶ckner Pentaplast provide an alternative to polyvinyl chloride in blister packaging. (PHOTO IS COURTESY OF KLÃCKNER PENTAPLAST) 			

Interphex attendees found packaging machines and containers with increased functionality. This article contains online bonus material.

Even Packaging Can Multitask

The aseptic blow–fill–seal (BFS) process blow-molds unit- or multidose containers, fills sterile product, and hermetically seals the package in one highly automated machine. Because the BFS process eliminates human interventions in the filling environment, the biggest source of contamination, makers of ophthalmic, inhalation, and parenteral products such as biologics and vaccines find BFS technology appealing. 

 In fact, the US Pharmacopeia considers aseptic BFS to be an advanced aseptic process (1). "Aseptic BFS systems offer a unique combination of flexibility in packaging design, low operating cost, and a high degree of sterility assurance," explains Chuck Reed, director of sales and marketing at Weiler Engineering, (Elgin, IL), in a white paper titled "Advances in Aseptic Blow–Fill–Seal Processing of Pharmaceutical Liquids Improve Product Integrity and Patient Safety." 

The blow-molding process itself helps achieve high sterility-assurance levels because it produces a container that is free of viable micro-organisms and endotoxins. Reed's white paper cites a study that shows fractional spore-contamination levels of less than 1 × 10

  and a three-log reduction in endotoxins. The probability that the blow-molding process will create a nonsterile unit is roughly 1 in 1,000,000 (2).  

The BFS process consists of the following five completely automated steps (3–4):  

Step 1: Thermoplastic resin such as high-density polyethylene or polypropylene is melted and extruded into a tubular shape or parison. 

Step 2: When the parison reaches the proper length, the mold closes and the parison is cut. The bottom is pinched shut, the top is held in place, and the mold is positioned under the blowing and filling nozzle.

Step 3: The blow–fill nozzle descends into the mold and expands the parison with a jet of sterile compressed air or vacuum. Once the container is formed against the mold, the nozzle precisely fills sterile product into the container. 

Step 4: Separate sealing molds close to form the top and hermetically seal the container.

Step 5: The mold opens and the sealed container exits the machine for inspection, labeling, and cartoning.

To minimize the operator intervention required for cleaning and changeover, the machine's product pathway is generally steam-sterilized in place in an automated process. In the fill zone, a laminar flow of positive-pressure sterile filtered air maintains International Organization for Standardization (ISO) 5 (Class 100) conditions. "The window of opportunity to have any type of contamination is very small," says Tim Kram, general manager at Rommelag USA (Evergreen, CO), a builder of BFS equipment (Bottelpack BFS machines). In addition, carefully designed ductwork and airflow manage the particulates generated when the parison is cut off.  

Highly versatile, BFS is compatible with many products, container sizes, and packaging formats, including unit-dose containers. Virtually any viscous or suspension fluid can be accommodated, and liquid-handling systems can be configured to blend multi-ingredient formulations. 

BFS container options include vials, ampuls, bottles, plungerless syringes, and custom containers. Designs often are squeezable and may be equipped with bellows to aid dispensing. Containers also can incorporate a number of built-in features such as twist-off opening; dropper, stopper, piston, or cannula inserts; cutting-ring or self-piercing threaded closures; and Euro-Caps for infusion bottles.  

Changeover time varies. If a BFS machine is used to make a family of containers, changing mold inserts to switch between 2-, 3- or 5-mL sizes, for example, can take two to four hours. Full mold changes will take longer, probably about eight hours. However, many pharmaceutical packaging lines minimize changeover downtime by dedicating machines to a single style and size of container or by running a narrow size range so only mold inserts need to be changed.  

BFS container sizes extend from 0.1 to 10 L, although no single machine is capable of running this entire range. "BFS is especially well suited for small unit doses," says Kram, noting that it's impossible to buy a glass vial in a size smaller than 3 mL, and that prefilled syringes cost more than BFS containers. 

Output speeds depend on the machine model, number of mold cavities, container size, container weight, type of resin, and product characteristics. Smaller containers can be produced faster (i.e., at a maximum rate of 500/ min), but the run rate for the largest sizes is not likely to exceed 30/min.  

A typical automated line integrates the BFS machine with inspection equipment and, sometimes, cap welding, labeling, pouching–overwrapping, cartoning, or case packing. But inspection and secondary packaging operations are often performed off-line or even manually.  

In general, every container is inspected. A visual inspection checks for particulates, while a high-voltage or vacuum leak test verifies container integrity. Inspection systems also may check container shape and lot number or date coding. Like that of other sterile packaging processes, the validation of aseptic BFS systems includes media fills and microbial challenges.  

The servo-controlled, high-speed Bottelpack 4010M BFS machine eliminates hydraulic components and features a continuously rotating chain of molds. (IMAGE IS COURTESY OF ROMMELAG) 

Initial capital costs and a well-established base of glass packaging lines remain hurdles to the adoption of BFS technology. Installing a BFS line at a brand-new site can easily cost $10 million. Although much of this investment relates to infrastructure and space for related operations such as compounding, resin handling, and quarantine, the price tag for a BFS machine is substantial, typically in the $1.5- to $2-million range. Prices for high-speed systems approach $4 million. Other costs relate to "the quality of staffing required for qualification, validation, and continued support," says Gary L. Hanley, business director and chief executive officer of Asept Pak (Malone, NY), a packager of sterile water, saline, technical products, and medical devices and owner of four BFS machines. 

However, when one compares the overall cost of aseptic BFS with that of packaging in traditional sterile glass ampuls, vials, or bottles, BFS cuts expenses by about two-thirds because it eliminates the purchasing and storage step for containers and components, as well as handling related to cleaning, sterilizing, filling, and sealing. "If container forming, filling, and sealing can be done in one machine, you're light years ahead in labor and cost alone," explains Reed. 

The latest BFS technology focuses on controls, container geometry, minimizing particulate generation, and improving the zones of protection around container formation, filling, and sealing. Thus, many machine designs feature dark and white sides. Positioning the extruder, electrical cabinet, and mechanical systems on the dark side in an unclassified area provides easy access for operators without disturbing the white side, which is housed in an ISO 8 (Class 100,000) cleanroom.   

In the fill area of the machine, laminar air flow helps maintain ISO 5 (Class 100) conditions. In addition, some machines reduce particulate generation by replacing hot-knife parison cutting with an ultrasonic process. This change reportedly reduces particulate generate nearly 100% (KleenKut parison cutoff technology, Weiler Engineering).  

Some of the newest BFS machines are fully digital and have eliminated hydraulics. "These machines can run faster and more accurately," says Kram. In addition, self-diagnostics inside the servo drives can provide early alerts of impending problems (Bottelpack 4010M, 324M, and 362 BFS machines, Rommelag).  

Although most BFS machines are designed to produce monolayer containers, multilayer technology is available to address needs for barrier properties or product–package compatibility issues. Although three to seven layers are feasible, barrier structures typically consist of five layers with a center layer of ethylene vinyl alcohol and can eliminate the need for the foil overwrap normally used as secondary packaging for carbon-dioxide- or oxygen-sensitive products.  

When starting up a BFS operation, Reed recommends that plans include space and infrastructure for at least two machines, even if the second machine is not purchased immediately. "The flexibility that you get from having two machines soon pays for itself," he explains. 

BFS technology is particularly well-suited for small-volume parenteral ampuls. (IMAGE IS COURTESY OF WEILER ENGINEERING) 

To reduce expenses, newcomers to BFS technology sometimes purchase used equipment or request the services of a contract packager, particularly if product volumes are relatively low. Rebuilt and reconditioned machines are updated with advanced controls and meet the latest standards. "Buying rebuilt equipment offers an opportunity to enter the BFS arena at a reduced cost [typically less than $1 million for the machine]," says Bill Grabowski, president and chief executive officer of HealthStar (Braintree, MA), a contract packager of nonsterile BFS products, moldmaker, and rebuilder of Weiler BFS machines. Used machines also may be the answer to tight lead-time requirements because they typically are delivered in six or seven months. In contrast, brand new machines usually are delivered in a year or more.  

Hanley advises meeting with vendors for an in-depth introduction to the equipment. He also stresses the importance of studying the entire process when integrating up- and downstream systems, especially if multiple vendors are involved. He recommends that purchasers of BFS technology assess final product configuration, automated inspection, vacuum testing, and overwrap requirements, as well as the possibility of terminal sterilization. In addition, he says, newcomers to BFS need to understand "the amount and degree of process support needed. It's simple to just buy a machine, but very costly and time-intense to put the machine online and meet the [regulatory] requirements for doing so."  

Hal Baseman, principal and chief operating officer of ValSource (Downingtown, PA), a firm specializing in validation support, also stresses the need for up-front study to understand the process and the limitations of the line. "You want to be able to eliminate variables or at least control them," he explains, "so it's essential to determine the critical variables in the process and identify what to test." As a result, validation teams should include expertise in risk assessment as well as process development, engineering, and microbiology. 

Aseptic blow–fill–seal minimizes human intervention in the packaging process.