Tablet sticking, in which material adheres to the surface of a tablet-punch face, is a perennial problem that causes defects in pharmaceutical tablets, reduces output, and results in press downtime. Tableting experts have developed an understanding of the causes of sticking and have an array of solutions, but finding the best solution can be a time-consuming process. Experts are currently working on further increasing the fundamental understanding of the underlying causes of sticking. This understanding can be used to develop predictive models to more quickly find solutions to specific sticking problems. 

Tooling supplier I Holland's Tableting Science Anti-Stick Research (TSAR) program, in collaboration with the University of Nottingham’s School of Pharmacy and experts from the Laboratory of Biophysics and Surface Analysis in the UK, is developing a predictive tool to identify the best punch or die-coating solution to prevent sticking in a given formulation. "Each sticking problem is unique and a specific solution must be found for each formulation," notes Rob Blanchard, research, development, and quality systems manager at I Holland. He explains that, currently, the performance of each coating is field tested against a problematic formulation, and offsite testing is used to identify the best solution. This process, however, is costly and time consuming for the customer. The predictive tool developed through the TSAR project will eliminate these problems by providing quick guidance without time-consuming tests. In the first year of the two-year TSAR program, researchers used analytical techniques (e.g., atomic force microscopy and time-of-flight secondary ion mass spectrometry) to perform adhesion mapping, which chemically analyzes the particles adhering to a punch tip to better understand the interactions that cause sticking. These data are now being used to develop the predictive tool. Researchers also compressed tablets with various formulations using different punch-tip coatings; these experiments will be used to validate the predictive tool at the end of the process in the coming months. 

The Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers, the State University of New Jersey, has developed mechano-chemical models and computational methods that predict the evolution of micro-structure and interparticle forces during powder compaction (1). Powders with sticking and picking tendency show adhesion of powder to die walls and tool surfaces. “This can be explained by a competition mechanism between inter-particle bonding and particle-wall adhesion,” says Alberto Cuitino, a C-SOPS researcher and Rutgers professor. He explains that, during ejection of the tablet from the die, the weaker links will naturally break first, resulting in either sticking/picking (if particle-wall adhesion is stronger than inter-particle bonding), internal cracks (if particle-wall adhesion is weaker than most inter-particle bonds), or no defectology (if enough bonding strength was developed during compaction). “These competing effects can be quantified if the network of particle-particle and particle-wall forces are known, which is unfortunately not possible with current experimental techniques,” says Cuitino. The computational models developed at C-SOPS can be used as cost-effective tools to understand and predict the impact of manufacturing process variables on product performance. 

Tooling supplier Natoli, a member of the C-SOPS consortium, has already used some of the fundamental information developed at C-SOPS on the role of surface energy in the compaction process and optimal tablet shapes to help solve sticking problems, says Charles Kettler, director at Natoli. Last year, Natoli announced the creation of the Natoli Institute of Industrial Pharmacy Development and Research, in partnership with Long Island University's Arnold and Marie Schwartz College of Pharmacy, to further develop fundamental understanding of tableting problems and formulation studies. Laboratory facilities for the Institute are currently being constructed at the university, and are expected to open late this year with fully qualified equipment. One of the Institute's projects will use a unique screening method developed by Pfizer (2) to screen for the sticking tendency of formulations at or prior to the clinical scale. “This method is a way to test small amounts of API with a given tablet design and tool steel and coating for propensity to sticking for a given API and formulation,” explains Kettler. 

M. Mullarney, B. MacDonald, and A. Hutchins, 

Articles

Production Trends

Experts, including researchers at I Holland, Natoli, and Rutgers Universityâ€™s Engineering Research Center for Structured Organic Particulate Systems, are seeking a greater understanding of the fundamental causes of tablet sticking and are developing predictive models to more quickly find solutions to specific sticking problems.

Researchers Seek Solutions to Tablet Sticking

The restricted access barrier system (RABS) offers an effective approach to impact cleanliness in the manufacture of aseptic products. RABS provides a level of separation between the operator and product that affords product protection superior to traditional systems. However, to operate a RABS cleanroom successfully, several best practices must be followed.     


During the operation, the barriers may not be compromised; lifting the separation can lead to contamination and increased risk to the product. Therefore, when aseptic operations are carried out in a RABS, it is the intent to fully eliminate the need to open RABS doors. If the filling is interrupted with an open-door intervention, a complete cleaning and line clearance must be carried out, and the batch is eliminated. 

During the line set-up stage, all machine parts and formats must be installed with the barrier closed by using a special glove-portal system. Thorough mock-up studies when designing a machine are essential. Such studies allow a well thought-through configuration of the machine and the barrier around it that allows the operator to reach all areas within the machine using the gloves. The mock-up studies simulate all routine operations and potential interventions on the machine. Operators of different departments (e.g., engineering and quality assurance) join forces to ensure the mock-up studies are as effective as possible.


Disinfection after each production batch must be completed. Once the filling process and the monitoring of the microbiological environment have been completed, the barriers are opened for cleaning. This is followed by a high-level disinfection with a sporicidal agent (e.g., peroxide suspension), which generates oxygen radicals to avoid build-up of resistance. 


  Following production, all gloves must be tested for integrity and sterilized. Using a pressure-decay test, the gloves are removed and tested for even the smallest damage that could compromise the system. If the gloves are found to be airtight, they can be cleaned, steam-sterilized, and remounted back into the glove ports for use in the next production batch. 

Aseptic transfer systems for zone transition


  Materials and formats are only carried into the ISO 5 area using aseptic transfer systems. Any parts used in the production, including any raw materials such as syringes and stoppers, are sterilized in steam or dry heat and doubly packed. The outer packaging is sprayed with a sterilizing agent containing alcohol before being transferred to the ISO 5 area through a lock, and the outer packaging is removed. All steps are performed using the glove portal system. Packaging materials are also put into sterilized bags and placed in special containers. The containers are sprayed down prior to introduction so when they are opened inside the barrier, the content is exposed to ISO 5 conditions only.


  A RABS process is safe and secure with both a cleanroom design and aseptic safety comparable to an isolator, but with a higher degree of flexibility. Automation of the system reduces the variability of operators while it also makes the entire process reproducible. At Vetter’s Ravensburg South production facility, for example, approximately four million media-fill units were filled over seven years in three different cleanrooms with RABS units with no resulting contaminated units. RABS is one of the most effective and efficient responses to current and future challenges in the manufacturing of aseptic products.

Joerg Zimmermann is director of Process Development and Implementation at Vetter (

Troubleshooting

RABS is a flexible barrier system that maximizes product control but minimizes operator interaction when best practices are followed.

Best Practices for Restricted Access Barrier Systems in Aseptic Manufacturing

Eltherm
     Electronic temperature controllers are designed for demanding applications and high loads.

Netzsch
 Disperser targets forces to separate agglomerated particles.

Featured products from Pharmaceutical Technology's monthly newsletter, Equipment & Processing Report

August 2013 Editor's Picks: Products from Eltherm and Netzsch

 (Las Vegas Convention Center; Sept. 23-25), pharmaceutical manufacturers will find a range of packaging technologies, from syringe fillers and capping equipment to labelers and vision inspection systems, and support for market trends shaping their businesses. A sampling of exhibitors sheds light on several of these trends and the resources suppliers and equipment manufacturers have in place to help drug manufacturers address them.


The pharmaceutical industry is gearing up for California’s E-Pedigree Law, which is scheduled to take effect in 2015. Alioscia Bassani, president of 

 (Booth 3905), says the new regulation is one of the most important drivers in production-line monitoring technologies for pharmaceutical packaging. Capmatic specializes in the manufacturing and integration of turn-key liquid and tablet packaging-line systems for middle-tier pharmaceutical companies, ranging from bottle unscrambling, filling, capping, and weighing to advanced labeling systems. “We’re getting all of our equipment upgraded to accommodate the new requirements; once California adopts the new regulations we know the rest of the states will follow,” Bassani says. Recently Capmatic built a new filling system with peristaltic pumps that can be integrated directly to a PLC and controlled through the human-machine interface on the machine. “We offer a unique hybrid approach to equipment design and integration, creating multiple applications under one system,” Bassani says.

Pharmaceutical lines, which are handling significant increases in stock-keeping units (SKUs), require greater flexibility. “The likelihood that new SKUs will be run in the lifetime of a pharmaceutical line is very high,” says Geoffroy Bretzner, managing director for 

 (Booth 1209). In addition to providing end-of-line case packing, shrink wrapping, and palletizing for pharmaceutical manufacturers, Cermex/Sidel has developed serialization expertise in pharmaceutical applications based on the anti-counterfeiting technologies it has developed for other markets. “There’s a high demand for serialization technology,” Bretzner adds. “New packaging lines need to be serialization-ready, while existing lines need to be retrofitted to allow for serialization.” 

“The global trend is the slow, irregularly paced, but nonetheless consistent move to adopt serialization in national markets,” says Jonathan Ludlow, machine-vision promoter at 

 (Booth 7455). He adds that verification systems are moving from PC-based to smart camera-based systems because of lower cost, ease of installation, and improvements in integration. Smart cameras have a dedicated processor in each unit and operate independently for more precise verification along the line of production. Ludlow notes that the pharmaceutical industry is constrained by the need to track and “mistake-proof” product assembly and packaging and to ensure the legibility of critical information such as date and lot codes. 

 (Booth 1300), a critical trend in pharmaceutical line inspection is integrating checkweighing equipment with code printing and verification. The company’s Versa RxV platform integrates high-speed carton inspection with alpha-numeric and machine-readable code printing and verification.  “We are also developing applications in which human and machine-readable information can be printed and then verified on the bottom of bottles as they travel from a customer’s conveyor to our checkweigher-infeed conveyor,” says Kevin Zarnick, sales manager. Thermo Fisher Scientific’s booth will highlight the Versa RxV checkweigher with a single HMI for integrated printing, code recognition, and verification, along with its APEX 500 metal detector for contaminant detection after induction sealing.

Product inspection technologies will also show up in full force at PACK EXPO Las Vegas. X-ray systems for contaminant, missing product, and mass detection are core technologies for exhibitor 

 (Booth 4506). Novus’ imaging technology is based on the QNX platform. “This is the same software platform used in satellite communications. It’s more reliable than Windows-based systems, and it’s designed with inherent networking capabilities to provide remote control and monitoring as well as process feedback control,” says company president David DiPrato. Novus also plans to show a new line of low-pressure and high-pressure washdown systems for pharmaceutical applications.

Contaminant detection continues to be a top demand for pharmaceutical manufacturers. 

 (Booth 4903) employs laser absorption spectroscopy to measure oxygen content within vacuum-closed or nitrogen-flushed containers. The company specializes in leak-detection and inspection equipment, offering stand-alone or combined systems. “Our technology enables detection of 10-micron leaks in liquid-filled containers with very low fills as well as maximum fills with no head space,” says Patrick Schlatter, area sales manager for Wilco, adding that the company’s detection technologies are nondestructive and designed for highly sensitive products. Recently Wilco launched a new laser technology to detect propellant gases on aerosol products.

Greener pharmaceutical manufacturing practices are being implemented by 

 (Booth 3520). Serac specializes in weight-filling equipment and offers container tare and product-weight recording all in one filling machine, while storing this information in accordance with 21 

 Part 11 standards. Serac has developed clean- and steam-in-place systems with closed-loop, high-pressure chambers that enable quicker cleaning with fewer chemicals, thus reducing energy and chemical use while minimizing downtime. Widely used in dairy production, Serac notes these systems are especially useful for pharmaceutical liquid products such as specialty mouthwashes, anti-bacterial gels, and cough syrups. “We also offer pneumatic and servo-controlled capping technology that traces capping torques and verifies accurate sealing,” says Dan Waldron, regional sales manager for Serac.

 (Booth 5935), says there are a plethora of new medical products entering the market that require specialized and flexible packaging solutions-combination packs with multiple products in one pack, medical devices combined with active products, new personalized medicines, and products that are especially sensitive to heat and oxygen. “Multivac has developed clean and flexible thermoforming equipment specifically tailored to new medical devices and pharmaceutical products,” says Van de Vel. Multivac recently launched a new thermoformer designed to handle combination packs with large and deep forming requirements and to package sensitive products.

New labeling technologies will also be on display at the show. 

 (Booth 5712) notes a significant spike in interest for clear labeling. Tri-Tronics manufactures photoelectric sensors to print date and lot codes on products at high speeds without deviating from print areas or migrating out of drop zones when line speeds change. Recently Tri-Tronics released an ultrasonic, clear label sensor that detects clear, paper, mylar, or metallic labels on most web backing materials. “The demand for clear labeled products is growing across all areas of packaging,” says Tim Kelley, vice president of marketing at Tri-Tronics. “Our Ultrasonic Clear Label Sensor gives customers the confidence to walk away from setup without needing to attend to the sensor until the next changeover.” 

PACK EXPO Las Vegas is a great place to find unique resources and opportunities in the pharmaceutical industry. The Pharmaceutical Pavilion showcases innovative solutions to secure, protect, and dispense medical devices and pharmaceuticals, and the Rx Lounge is a forum where professionals can network and exchange ideas within the industry. The Rx Lounge’s Ask-the-Expert resource will be staffed and waiting to give technical advice. Registration is open at 

PMMI (the Association for Packaging and Processing Technologies

), which organizes the PACK EXPO family of trade shows,

is a trade association representing more than 600 packaging and processing supply chain companies that provide a full range of packaging and processing machinery, materials, components and containers.

Packaging

Companies exhibit developments for pharmaceutical packaging to meet needs, such as e-pedigree and inspection requirements.

Equipment and Processing Report-08-21-2013

Researchers Seek Solutions to Tablet Sticking

Best Practices for Restricted Access Barrier Systems in Aseptic Manufacturing

August 2013 Editor's Picks: Products from Eltherm and Netzsch

PACK EXPO Showcases Solutions for Inspection and Serialization