At Interpack 2014, held from the 8th to the 14th of May in Germany, companies presented their latest innovations and concepts in packaging and processing technologies. For the pharmaceutical industry, key topics that dominated this year’s event were serialization and track-and-trace solutions as organizations make preparations to comply with global legislations that safeguard against medicine falsification.

 Domino launched the F220i fiber-scribing laser for precision marking on a wide range of surfaces, including plastics and metals. The properties of the laser beam can be adjusted to provide a sharper color contrast. Integration of the system into production lines is easy because of its compact size. F220i can be used for static or “on the fly” marking. The flexible i-Tech scan head can be rotated to mark in any direction, in any orientation, in a variety of font sizes, and in both low and high production line speeds. Additional benefits of F220i include its low maintenance, high uptime, high reliability, and a laser lifespan of up to 100,000 hours.

Domino also showcased its BK652 black ink, which dries in less than half a second. The ink has been specially developed for use with Domino’s thermal ink jet (TIJ) G-Series range to print high-definition, machine-readable traceability codes without slowing down the speed of production lines. More importantly, the code is durable throughout the product lifespan from manufacture to distribution, storage, and dispensation.

Videojet’s new code-detection system checks for the presence of a printed code on products and packaging. The automated inspection system uses a combination of hardware and software to verify that the ink-jet printed codes contain sufficient contrast in the marking area. An alert is issued when a coding error is identified, such as a missing, mispositioned, or clipped code. Operators can set a threshold for a code to be considered unacceptable and a limit for the number of bad codes that can be detected before a fault is indicated. The system can be configured to take a variety of actions upon detecting a coding error. It can, for example, send an alert signal to eject the product or stop the packaging line. The bad code images are stored on the system, which means that operators will be able to quickly identify the root cause of the coding errors and implement measures to prevent recurrence.

Optel Vision’s Flying CartonTracker, on the other hand, is a stand-alone unit that handles the printing and verification of cartons to ensure accurate serialization identification. The system is easily adapted to any table or conveyor in an existing line and can handle a wide range of carton sizes with speeds up to 400 cartons per minute. It can be integrated just after a cartoner or at the end of the production line and can be fed automatically or manually by operators. Cartons are held from the top. The printing and inspection are performed in a continuous motion without stopping the item. A camera ensures that the printed information meets quality requirements. Faulty cartons are rejected on the fly. The addition of other inspections, such as dimensional measurement of the item, verification of pre-printed information, or barcode grading, is also possible.

Mettler-Toledo’s new launch, the XS2 MV TE, integrates four technologies-marking, vision verification, tamper-evident sealing, and checkweighing-into one fully enclosed unit with a small machine footprint. Its components include an ink-jet printing system, high-resolution verification cameras, mechanical transfer units, sorting devices, and an accurate weigh-cell technology. Product codes printed onto the packages are verified by the camera system for accuracy and legibility. The data are saved in an internal database. The weight of each product is checked to ensure completeness of the product. Products that do not hit the target weight, for example due to a missing information leaflet, will be removed. The new tamper-evident feature of the XS2 MV TE is supported by sensor verification and consists of a small sealing module. Wrongly marked or sealed, askew, or incomplete boxes are separated out into reject bins during sorting. The open software interface eases communication with various standard data protocols and network systems using simple upgrade procedures for track-and-trace requirements.

The Traceable Quality System (TQS) by OCS Checkweighers is a track-and-trace solution that combines serialization and aggregation of pharmaceutical products to enable a traceable product flow from the manufacturer, through the distribution chain, to the patient. The fully integrated single software product manages the operation of three functional units-product handling, coding, and camera inspection-across all levels of aggregation. TQS-SP (single pack) offers a user-friendly solution for the serialization of individual folded boxes. An integrated layout editor sends the print data to the printer and an image of the imprint to the camera. Each operation is fed into central software, which means that the same user interface provides access to all components of the system. A sophisticated, continuously variable and optimally synchronized top and bottom conveyor picks up the folded boxes from the cartoner upstream or from a manual in-feed system. The matrix codes may either be printed on the flaps or on the top of the boxes. The TQS-BP (bundle pack), designed for the first stage of aggregation, compiles the serial numbers of several individual packages and uses them to create a serial number unique to the bundle. It has a format-independent conveyor system that takes over bundles directly from the bundle-packaging machine.

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Packaging

Equipment solutions for printing and verifying codes and combining serialization with aggregation and checkweighing were shown at Interpack 2014.

Serialization at Interpack 2014

In blow-fill-seal (BFS) technology, which is a form of advanced aseptic manufacturing, the container is formed, filled, and sealed in one continuous, automated system.  A primary advantage of this technology is reducing human intervention, which reduces the risk of microbial contamination and foreign particulates. BFS has long been used in liquid pharmaceutical applications, including small containers, such as ophthalmic and respiratory drug ampoules, as well as larger volume containers, such as saline or dextrose solutions. More recently, BFS technology has been expanding into injectables and into biologics, including vaccines and monoclonal antibodies (mAbs). 


  Catalent, which has used BFS for more than thirty years, recently launched ADVASEPT, a new technology for "glass-free delivery" of injectable drugs, using BFS technology.  The aseptically filled polymeric containers reduce or eliminate many of the concerns associated with traditional glass vials, including the potential for glass-particulate contamination and accidental breakage, the company noted in a press release.  Because the technology involves a new container closure, the stability of the drug needed to be measured in the polymer container to identify any concerns with permeation or extractables and leachables. Catalent's analytical group developed test methods for determining an extractables and leachables profile, and a two-year stability study comparing plastic and glass containers for biologics is underway, said Bill Hartzel, director of strategic execution, Sterile Technologies, at Catalent, in an interview with 

. After nine months, the data continues to be positive and shows comparability of the mAb in a glass vial to an ADVASEPT vial. 

"BFS technology embraces quality-by-design principles," adds Hartzel. "It simplifies the manufacturing process by reducing variables and removing human intervention and is heavily based on automation. We have challenged the system and identified the critical control parameters to provide enhanced sterility assurance. This proprietary filling technology is designed to drastically reduce the level of foreign particulates in the vial compared to traditional glass vial manufacturing." 


  BFS technology is beneficial for biologics, which typically cannot withstand terminal sterilization and must be processed aseptically. Although there have been concerns that the container is at an elevated temperature during the filling process, much development work has been done to control the impact of heat exposure. Tightly controlling the process is crucial in heat-sensitive applications, noted Chuck Reed, director of sales and marketing at BFS-equipment manufacturer Weiler Engineering, in an interview with 

Weiler's system controls process parameters, such as incoming product temperature and mold temperature, and has been successfully used for heat-sensitive materials for more than 20 years, says Reed. 

Catalent has been supplying a commercial biologic using BFS technology for nearly 20 years. "A challenge with large molecule products is the difficulty in extrapolating the data across molecules, and it is important to understand the process to evaluate whether the biologic is suitable in BFS," explains Hartzel. "Through its understanding of the process, Catalent has proven experience with filling commercial biologics using BFS and continues to provide additional testing on mAbs to provide confidence that this technology is suitable for biologics."  


  To enable aseptic processing, BFS equipment is operated within a cleanroom. In addition to product characteristics, container design, and equipment parameters, the production environment in the cleanroom, including controlled room temperature and humidity, is important to consider, notes Josef Trapl, technology manager for the LifeScience segment at engineering and construction firm M+W Group. For producing biologics, both GMP and biosafety requirements must be considered, and an interdisciplinary engineering approach should be used for correct integration of the equipment in the cleanroom and safe operation of the facility, says Trapl.

Inside the cleanroom, the product-contact path of a BFS system is typically sterilized in place using steam. In addition, the fill area of the system is a crucial section for maintaining sterility. The fill area has traditionally been manually sanitized. Weiler, however, recently introduced a patent-pending, automated system using nitrogen dioxide (NO

) sterilization to both sterilize and depyrogenate the fill area, which provides additional assurance of sterility. NO

 sterilization has low residual sterilant and is thus particularly suited to biologics, which can be sensitive to residual sterilant in the fill area, notes Reed. Noxilizer's NO

-based NOX FLEX Rapid Biodecontamination system is now an option on new Weiler ASEP-TECH Blow/Fill/Seal machines. Noxilizer and Weiler presented results of a study using the new system in a poster, "

Decontamination and Depyrogenation of an ASEP-TECH Blow/Fill/Seal System

," at the 2014 PDA Annual Meeting in San Antonio, Texas, and the July issue of 

 will include an interview with the companies. 

Production Trends

New advanced aseptic manufacturing technologies are available for filling liquid pharmaceuticals, including biologics.

Blow-fill-seal Technology Advances in Aseptic Filling Applications

Reliable systems to transfer bioprocess samples directly from bioreactors to analytical devices while maintaining process sterility are crucial for biopharmaceutical companies to effectively take advantage of process analytical technology (PAT) and gain a more fundamental understanding of what is happening within bioreactors.  
   
  Bend Research (part of Capsugel Dosage Form Solutions) has collaborated with major biopharmaceutical companies, including Pfizer, Eli Lilly, and Boehringer Ingelheim, to develop the Modular Automated Sampling Technology (MAST) platform. MAST consists of a sterile sampling system, a sample scheduler and navigator for automated sampling and delivery of samples to various analytical instruments, and a data-management system for collecting and analyzing the results, and if desired, providing feedback to the bioreactor for direct adjustment of reaction conditions.

The MAST platform includes the Sample Pilot, a sterile sampling unit that consists of a sampling module and an associated programmable logic controller (PLC). The SP100 Sample Pilot modules collects 50-mL samples for monitoring of pilot- and commercial-scale manufacturing operations, and the SP200 takes incremental 5-mL samples for analysis of development-scale reactions and reactions that run in smaller laboratory-scale bioreactors and pilot-scale, single-use bioreactors. Each sample assembly consists of proprietary valves and a pump and is designed to draw samples from the bioreactor and push them out to user-defined destinations, according to Clint Pepper, a director at Bend Research. "Because we use positive displacement, rather than pulling the samples out with a vacuum, it is possible to deliver even viscous culture samples with high cell densities to analytical instruments more than 50 feet away."

To maximize the potential of sterile biopharmaceutical sampling, the MAST platform design includes software systems for managing sample scheduling, delivery of the samples, processing of the analytical results, and adjustment of bioreactor parameters if desired. The MAST Sample Scheduler and Navigator modules will work together to facilitate sample collection from bioreactors and transfer to analytical testing systems. 


  The steam-sterilized SP100 module has been successfully demonstrated in five different bioreactors in three different facilities. "During recent development runs on pilot-scale bioreactors, the MAST platform and SP100 successfully delivered more than 480 samples without contamination, including more than 200 cumulative days of successful operation at the 30-L to 500-L scales in both cell culture and microbial applications," reports Pepper. "The sanitant-sterilized SP200 module has been deployed in five different facilities ranging in scale from bench reactors to large-scale, single-use bioreactors. The SP200 units have collected over 2000 samples in more than 240 accumulative days of operation with no contamination or loss of sample integrity."   MAST systems have been placed in nine client facilities (15 total units installed) with more than 2400 sterile samples collected without loss of sterility.  "The major MAST product modules have moved out of the beta testing stage and are being sold to early adopters as precommercial products," says Pepper. 

The MAST platform offers biopharmaceutical manufacturers several advantages, according to Pepper, including the ability to collect reproducible samples more frequently and automatically without operator involvement, which reduces the risk of contamination and operator exposure. The ability to integrate analytical results from numerous sources provides more insight into cell behavior and the impact of process parameters, enabling the use of more sophisticated process-control strategies.  

Cynthia Challener, PhD, is a contributing editor to 

This article was excerpted from an article that will appear in the July issue of 

The Modular Automated Sampling Technology platform takes online samples from bioreactors and transfers them directly to analytical devices.

Advances in Real-Time Bioreactor Sampling

Xylem's 2900M Online Monitoring and Control System includes an online sampler, analyzer, and controller for laboratory bioreactors. The YSI Sitini Online Sampler from Xylem can be set up to automatically draw fluids from

 the bioreactor, delivering samples directly to the 2900 biochemistry analyzer for testing. Sampling is done aseptically with no risk of contamination, as lines are flushed and antiseptic is kept in them after each drawing.

The analyzer measures glucose, glutamine, glutamate, lactate, and other analytes, with accurate results in less than one minute. The components of the 2900M system are autoclavable. The analyzer and the Sitini Sampler can also connect to process management instruments via RS232, ethernet, or OPen Connectivity (OPC) to incorporate into existing applications, and the searchable database allows for quick access to stored results. 

The YSI Sitini Online Sampler draws fluids from a bioreactor and delivers the samples to an analyzer.

Xylem Laboratory System Enables Online Monitoring and Control of Bioreactors

label-and-cap combination features a first-opening indication that prevents the illegal reuse of medicine containers under the guise of being unopened, original products. Flexi-Cap comprises a label combined with a cap that gives a clear and irreversible indication that a primary container has been opened. The technology is similar to the cover for wine bottles but adapted to the specific requirements of the pharmaceutical industry. 

To use Flexi-Cap, the film cap is positioned over the closed container, and the label is applied without covering the peel-open tab of the opening strip. Once the strip is opened, the bottom part of the cap, together with the label, remains attached to the container. Attempting to remove the rest of the cap destroys the label, thus eliminating the possibility of unnoticed illegal reuse.

Flexi-Cap enables flexible use with different container types, forms, and sizes. In contrast to shrink-wrap solutions, the label construction can be applied without using heat, making the solution viable for temperature-sensitive medicines. The pharmaceutical manufacturer's label and brand design remain unchanged, due to the combination of label and cap. In addition, the top of the cap allows space for bar code printing or chip integration for electronic tracking. 

The Flexi-Cap features a first-opening indication as an anticounterfeiting solution.

Equipment and Processing Report-06-18-2014

Serialization at Interpack 2014

Blow-fill-seal Technology Advances in Aseptic Filling Applications

Advances in Real-Time Bioreactor Sampling

Xylem Laboratory System Enables Online Monitoring and Control of Bioreactors

Label–Cap Combination From Schreiner MediPharm Prevents Counterfeiting