	Blister packaging, a common format for solid-dosage forms, also serves as secondary packaging for ampules, syringes, vials, cartridges, and bottles. Many recent equipment introductions integrate blister form, fill, and seal (FFS) with cartoning to create more compact, easier-to-use systems that are serialization-ready and accommodate the latest anticounterfeiting technology.

	One integrated system, the robot-equipped Integra 520V blister line from Marchesini Group, operates at up to 520 blisters/500 cartons per minute. Introduced at Achema 2015 (June 15–19, 2015), the integrated FFS/cartoning system measures 10 m in length. However, if needed, the two sections can be separated by a wall so that the blister thermoformer and cartoner can be installed in rooms with different classifications.

	The flexible system accommodates different product feeders and handles a variety of blister materials and carton formats including tuck-in, alternated (even) flap, and fourth flap. New pushers, a drum-type carton opener, leaflet pick-and-place system, and Cinquecento carton-loading mechanism maximize cartoning efficiency. A balcony design separates the product feeding area from the electrical and mechanical area to help minimize downtime related to cleaning and changeover. Other downtime-reduction features include tool-less changeover using quick-release parts and automatic splicing tables for forming and lidding materials to simplify reel replacement. 

	The blister is formed three ways, depending on the material type: compressed air for polyvinyl chloride, polyvinylidene choride, and poly-chloro-tri-fluoro-ethylene (e.g., Aclar from Honeywell); air-and-plug assist for difficult-to-shape plastic; or mechanical forming dies for aluminum. Locating the forming station at the back of the machine reduces its overall footprint and protects operators from forming-material fumes. Separating the forming-material loading area and the machine feeding station minimizes the area requiring modified atmosphere and lowers costs.

	Multiple cameras confirm product presence inside the blister and web pull through each station. Blisters are coded by cold punches and cut in the same station. Once cut, the blisters are picked up and placed directly onto the conveyor belt of the Robocombi robot. The three-axis robot feeds the blisters into the bucket belt of the cartoner and can be programmed for different stacking heights, based on the preset blister count. Software synchronizes the transfer, tracking, and stacking system. A manual loading station allows missing blisters to be replaced on the toothed belt.

	The carton magazine is located below the product conveyor to minimize dust above the blisters and make it easier to load the carton blanks. On the carton conveyor, pairs of pushing and guiding fingers hold the cartons securely. The leaflet-feeding unit is enclosed by guards to minimize noise and positioned lower than on previous models to improve loading ergonomics. The integrated pusher and blade of the Cinquecento carton-loading mechanism precisely insert blisters into cartons and raise automatically when the machine is cleaned or serviced (1).

	Another integrated line, the Noack 960 blister machine and Promatic PC 4000 continuous-motion cartoner from Romaco North America, was shown for the first time at Pharma EXPO (Sept. 28­–30, 2015). The Noack 960 blister machine features anticounterfeiting technology developed by NANO 4 U for banknote authentication. Applied online by a heatable coding tool without the use of additional materials or impact on line speed, the technology offers unique primary packaging identification, meets requirements of the European Union Falsified Medicine Directive 2011/62/EU, and can be integrated on any blister machine with a coding station.

	Individual blister packs are coded with overt and/or covert security features, such as holograms with company logos or combinations of letters and digits. Invisible codes that can be verified quickly and easily also can be incorporated into holograms. All that is needed for verification of a hidden logo or DataMatrix code is a simple laser pointer. The system is rated at 700 blisters/420 cartons per minute (2).

	For secondary packaging of liquid-dosage products, Uhlmann Packaging Systems has introduced the BLU 400 blister machine. Capable of producing and filling 400 blisters per minute, the machine operates with 300-mm-wide material, divided in up to eight lanes, with a maximum forming depth of 42 mm.

	A rotary feeder and four-axis robot places products in the blisters lengthwise or crosswise. Before being pressed into place in the clamp-pack, a mechanical check ensures correct positioning. The two-step, press-in function minimizes the force needed to seat the products and the risk of product damage. Other features include single-cycle handling, versatile feeders, and a rotary table at the end of the machine, which turns the filled blisters 180 or 270 degrees so they are properly oriented to be pushed into cartons (3).

		Marchesini Group, “Integra 520V, the New Robotized Integrated Blister Line Able to Package 520 Blisters and 500 Cartons Per Minute,” News Release, July 23, 2015.	

		Romaco, “Romaco North America to Exhibit Three Technologically Advanced Solutions at Pharma EXPO Las Vegas,” News Release, July 29, 2015.  	

		Uhlmann Packaging Systems, “Uhlmann Introduces BLU 400 Blister Machine for Liquid Dose Products,” News Release, Sept. 3, 2015.

Articles

Packaging

Integrated pharmaceutical blister-packaging equipment systems strengthen serialization and brand protection capabilities.

New Equipment Improves Blister Packaging

	Shear cell testing was developed in the 1960s specifically to deliver design parameters for hopper specification (1). Its introduction marked a major step forward in powder testing, and the associated hopper design methodologies were the first to bring a mathematical approach to powder handling equipment specification. They remain in widespread use, but issues with hopper performance are still commonplace, highlighting the limitations of relying solely on shear cell analysis to design and optimize this crucial unit operation. Dynamic powder testing and the measurement of bulk powder properties can complement shear cell testing, especially when shear cell testing fails to reveal the causes of poor hopper performance, such as erratic discharge and inconsistent flow.


	The design methodologies developed by Jenike for hopper specification center on identifying the flow/no flow condition that marks the boundary between acceptable and unacceptable hopper discharge (1). Similarly, shear cell analysis involves measurement of the force required to shear one pre-consolidated powder plane relative to another to induce the transition from stasis to flow. 

 shows three common configurations of shear cells. The differences in physical geometry and configuration of the apparatus will influence aspects such as accuracy, repeatability, and applicability, but essentially, all shear cells are intended to measure similar properties of the sample.

Shear cell data is thus most relevant when investigating the performance of powders at the onset of flow, under moderate to high stress. This situation would occur in a large hopper in which the powder is stored under its own considerable weight. However, shear cell testing has a number of limitations that are problematic in developing a broader understanding of powder behavior, including:

		Declining accuracy for non-cohesive powders.

		Less relevance for powders in a low stress, unconsolidated state

		Limited scope to investigate the impact of parameters such as the extent of aeration.

	These limitations mean that the behavior of many powders, in a variety of unit operations (including small hoppers) can be quite different from what might be predicted on the basis of shear cell data. If a powder is free-flowing or prone to aeration, for example, it may flood from a hopper, flowing far more easily than shear cell data might predict. On the other hand, if a powder is particularly sensitive to the impact of moisture, hopper discharge may cease far more readily than shear cell analysis would indicate, if the processing environment is poorly controlled.


	Dynamic powder testing was developed in the 1990s to meet the need to measure powder flowability under process-relevant conditions (2). It involves measurement of the torque and force acting on a helical blade at it rotates through a powder sample along a defined path, as shown in 

As the blade traverses through the powder, force and torque, with respect to height, are recorded. These two measurements are used to determine the energy gradient (i.e., work done per mm of travel) as shown in 

. Total flow energy is the area under the energy gradient curve.

	Well-defined methodologies are in place for a range of dynamic properties, including the following:

		Basic flowability energy (BFE) is measured as the blade descends and exerts a bulldozing action on the powder; it reflects how a powder will flow under forced conditions.

		Specific energy (SE) is measured using an upward traverse of the blade to impose a gentle lifting action; SE quantifies flow behavior in a low stress, unconfined environment.

	Other parameters characterize how powders behave in a consolidated, conditioned, aerated, or even fluidized state, all of which can be investigated directly using dynamic methods. Dynamic testing, therefore, has strengths that directly address the limitations of shear cell analysis.


	Dynamic testing can be used to measure flowability under low stress conditions to simulate the conditions in smaller hoppers. Furthermore, dynamic testing can be deployed to systematically investigate the impact on powder flow behavior of a wide range of parameters, including aeration and moisture, even for relatively free-flowing powders. Such information can be valuable in troubleshooting poor hopper performance.

	In addition, there are bulk powder properties that are not routinely measured but have been demonstrated to significantly influence hopper flow. Permeability, for example, is a measure of how readily a powder transmits air through its bed. Poor permeability is known to contribute to low and/or pulsatile flow (3).

	In summary, shear, bulk, and dynamic properties are all relevant for the design and operation of hoppers. While shear cell data remains useful for generating fundamental parameters for large-scale hopper design, dynamic testing and permeability measurements can be valuable for optimizing the design and performance of hoppers, particularly smaller vessels routinely used in the pharmaceutical industry. Using these techniques in tandem allows comprehensive hopper optimization.

		A.W. Jenike, “Storage and flow of solids

Bulletin of the Utah Engineering Experiment Station, 123, University of Utah (Salt Lake City, Utah, 1964; revised 1980).	

		G. Carlson and B. Hancock, “Development of a Material Sparing Method to Determine Powder Permeability to Air,” poster presented at AAPS (Atlanta, GA, 2008). 


	Jamie Clayton is operations director at Freeman Technology, 1 Miller Court, Severn Drive, Tewkesbury, Gloucestershire, GL20 8DN, tel: +44 (0) 1684 851551, 

. For further information, read Jamie’s article in 

Identifying Powder Properties that Define Process Performance

Troubleshooting

Dynamic powder testing and measurement of bulk powder properties can complement shear cell testing to identify the causes of poor hopper performance in solid-dosage drug manufacturing.

Best Practices for Optimizing Hopper Performance

	As medicine spending continues to increase, there is a lot of expectation and pressure on the pharmaceutical industry not just to develop new drugs but also to ensure the quality of their products. But challenges such as patent expiries and the death of blockbuster drugs in an increasingly cost-constrained marketplace mean that players both big and small have to adapt with the changing trends if they want to survive and thrive. 

Biotech boom, niche markets, and a smaller batch size

	One of the biggest trends is the move towards biotechnology and personalized medicine, notes Christian Treitel, head of pharma business development and product management at Bosch Packaging Technology. Small-molecule drugs that are chemically synthesized using predictable processes are being replaced by larger, more complex biologics that are produced in living cells and often consist of heterogeneous mixtures. The structure of a chemical API is independent of the manufacturing process but biologics, on the other hand, are defined by the exact manufacturing process, which can be difficult to control from the starting material to the final drug product.

	“While this shift opens up new possibilities in medical diagnosis and therapy, we see batch sizes becoming smaller, derived from the need to treat orphan diseases that affect only a small population of patients worldwide,” says Treitel. FDA has played a crucial role in facilitating the development of orphan drugs through its fast-track program. As a result, the industry is moving away from the one-size-fits-all model and investing more into the development of targeted therapies and finding cures for niche diseases. “The researchers embrace it,” says Treitel, “because there are many areas where you can tap on the potential of targeted therapies; however, for the manufacturers, the complexities of production can be a challenge.”

	Smaller lots mean more frequent changes, Treitel points out, and changeover takes time. “You have to clean your equipment,” he says, “and then, there is also the additional task of documentation because it is important to make sure that everything is properly documented.”

	According to Treitel, customers are now looking for solutions to manage the complexities of modern drug manufacturing, including fast changeovers. “The aim is to make changeover times shorter,” he says. “Basically, you want it to be faster and more convenient for the operators, which is very important.” The new Manesty TPR tablet presses-TPR 200 (for small to medium batches) and TPR 700 (for high production volumes)-from Bosch, for example, have been designed for fast product changeovers, easy cleaning, and simple operation. 

High potency drug manufacturing, isolators, and containment systems

	Another key trend is the rapid growth of high potency APIs, which require specialized containment to ensure that both operators and the environment are protected from exposure, observes Treitel. “You want to really make sure that the product is safe and that the operator is safe.”

	There has been major breakthrough in isolator and containment systems and pharmaceutical manufacturers recognize the advantages of these technologies (e.g., improved aseptic environments and lower operational costs) compared with conventional clean rooms. “Liquid filling lines are becoming more complex and require integration of the filling machine with an isolator and subsequent machines [such as a freeze dryer or an overseal capping machine],” says Treitel. The challenge is to ensure safe functioning of the interfaces, but at the same time, keep the overall controls system simple and be able to easily operate the individual components. Bosch offers everything from a single source, according Treitel.

	For an industry that is highly regulated, quality remains a top priority. “FDA is getting stricter and really checking on pharmaceutical facilities. You often hear of warning letters being issued,” says Treitel. “This means pharmaceutical manufacturers have to work on their quality procedures, and they are looking for support from us-for example, if you are looking to replace your equipment and want certain things to be automated so that manual intervention and human errors can be reduced.”

	The relationship between supplier and the pharmaceutical industry is changing, observes Treitel. “As a supplier, it is no longer about supplying single machines but helping the customer to integrate the different pieces of equipment and providing support in implementing projects.” 

Production Trends

The biotech boom, niche markets, smaller batch sizes, and high potency manufacturing are among the key trends shaping the pharmaceutical industry, and equipment must keep up with features such as fast changeovers and automation.

Equipment and Processing Report-11-18-2015

New Equipment Improves Blister Packaging

Best Practices for Optimizing Hopper Performance

Pharma Equipment Keeps Up with Trends