Munters
 Air handlers feature double-wall panel construction


 Integrated Custom Air handlers (ICA) from Munters (Amesbury, MA) are designed to help integrate desiccant dehumidifiers into other air-conditioning components. The devices feature double-wall panel construction and an 0.75-in. thermal break that prevents exterior condensation. Models are available with 2.5- and 4-in. wall thickness. The ICA units also include Triple Slope stainless drain pans to eliminate standing water in the cooling sections. The ICA units are available with Galvalume, aluminum, and stainless-steel interiors and exteriors. The devices are suitable for protecting hygroscopic powders during tablet operations such as weighing, mixing, blending, and compressing.

A Siemens programmable logic control enables personnel to operate the dehumidifier and the integrated system. The control is intended to ensure consistent equipment performance and maximize energy efficiency. The air handlers include Munters’s PowerPurge energy-optimization package, which reduces the amount of energy required to reactivate the units by as much as 40%. 

NETZSCH Fine Particle Technology 
 Mills accommodate various grinding media


The updated Mini and Micro series agitator bead mills from NETZSCH Fine Particle Technology (Exton, PA) have a smaller footprint than earlier versions of the machines. The mills’ seal-flush systems and cooling-water hoses are integrated into their machine frames, thus providing installations that are neater and easier to clean than before, according to John Hill, the company’s application and process advisor.

The devices can use grinding media between 50 µm and 2 mm in size, thus allowing operators to grind particles to a size of 25 nm. The units accommodate zirconium-oxide, stainless-steel, and polyurethane grinding chambers for specific applications. The mills perform wet grinding of 0.05–1.5-L batches and yield particles as small as 10 nm. In addition, the mills let users adjust the pump speed and mill agitator speed separately, thus providing complete control over the grinding process, says Hill.

Articles

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the March 2010 edition from Munters and NETZSCH.

March 2010 Editor's Picks: Products from Munters and NETZSCH

Last month, the US Food and Drug Administration approved Novartis’s (Basel) meningitis vaccine Menveo, and Health Canada approved Merck’s (Whitehouse Station, NJ) Gardasil vaccine for human papillomavirus. These developments demonstrate recent advances in biologicals and indicate the drugs’ importance for the industry’s future. Most biopharmaceuticals are liquid products delivered through injections. To find out about the process of manufacturing prefilled syringes, and to learn about innovations in filling lines, 

 talked to Thomas Otto, managing director of Vetter (Ravensburg, Germany), a company that specializes in aseptically prefilled syringe systems, cartridges, and vials.

EPR: What are the advantages of prefilled syringes?  

Otto: The advantage is that prefilled syringes are ready for injection. The product is inside the container in the right volume and the right dosage. The user only has to open the syringe and initiate the injection. He or she doesn’t have to prepare a vial or take the product out into a syringe system—everything is prepared in place. Prefilled syringes support active-ingredient yield and correct dosage.  

Prefilled systems have a big advantage for freeze-dried products. If you have a freeze-dried vial, you have the solvent, for example, in a separate syringe. If you have a dual-chamber syringe, this enables less overfilling. So costs clearly can be reduced, especially when it comes to the high-value substances.  

EPR: Are prefilled syringes limited to certain types of products?  

Otto: In principle, there is no limitation to prefilled syringes. We at Vetter fill various types of product. It doesn’t matter whether it’s a biotechnology product, a vaccine, or anything else. Only a few products such as high-viscosity products can’t be filled into a prefilled syringe. Some products are not stable in liquid form over a long time. You can freeze dry them and keep the active drug and the solvent separately in dual-chamber syringes.  

EPR: What processing options do drugmakers have if they want to present their products in prefilled syringes?  

Otto: They have two main concepts. The first concept is bulk processing—the firm that’s doing the filling gets all the packaging components and prepares them itself for filling. This includes washing, siliconization, and sterilization. This technology requires a lot of knowhow and capital investment on one hand, but it gives the pharmaceutical manufacturer control of the process. Bulk processing is fully scalable and available for high-speed and high-volume filling, as well as small-scale clinical production. It gives the manufacturer flexibility, but it’s a complex process.  

The other process uses presterilized systems such as the Sterile Clean Fill system from BD (Franklin Lakes, NJ). In this system, syringes and stoppers arrive at the filling site already prepared and sterilized. The advantage is that the filler does not have to prepare the packaging components, but only to fill the product. On the other hand, if you control the preparation process, you’re much more flexible because you can use the right amount of silicone and the right stopper treatment for your product. The presterilized parts are treated by chemical sterilization processes such as ethylene oxide. Rubber stoppers are gamma irradiated, which might cause a particle problem. If you have the preparation process in house, you can perform heat sterilization or other methods.  

EPR: Does Vetter use bulk processing or presterilized systems?  

Otto: We have both processes here in house. We understand the advantages of both systems.  

EPR: Has Vetter incorporated robots into its operations?  

Otto: Vetter has been using robots for transferring components for many years. Vetter’s experience with robots is excellent because they remove all need for manual processes. We have highly automated bulk lines; all manual transfers have been removed all the way from the detraying of the untreated syringes to the filled syringes and delivery trays.  

EPR: Does Vetter use disposable components in its processes?  

Otto: Vetter has designed a new filling line for preclinical, Phase I, and Phase II in our new plant in Skokie, Illinois, where we use a lot of disposable technology such as vessels, preparation tanks, and filling needles. Stainless-steel vessels cost a tremendous amount of money and takes a lot of time, therefore, disposable technology is interesting.  

EPR: Is disposable technology more popular in clinical phases than it is in manufacturing?  

Otto: Today, yes. If you’re thinking about high-volume production and you’re doing the production every day, it makes a lot of sense to use stainless-steel containers and filling needles. But if you need a component one time or only a few times, then it makes a lot of sense to use disposable technology. I’m sure that both technologies will have their place in the biopharmaceutical industry, but disposable technology is growing in popularity.

In the Mixer

Recent developments demonstrate the importance of biologicals, which usually are delivered through injections, for the drug industry's future. To find out about the process of manufacturing prefilled syringes, and to learn about innovations in filling lines, Equipment and Processing Report talked to Thomas Otto, managing director of Vetter.

Filling Now for the Future

Continuous manufacturing is a relatively new concept for the pharmaceutical industry, although other industries have been pursuing it for years. The strategy entails feeding a constant stream of raw materials into a process that runs continuously at a steady state. Material flows from one step to the next without interruption until a final dosage form is created. A continuous process is not meant to be stopped and restarted, but kept running for an extended period.  

This manufacturing strategy could bring the pharmaceutical industry advantages such as consistent and improved product quality, reduced waste, lower inventory and equipment costs, easy scale-up, flexibility, and short cycle times. Continuous manufacturing also could enable chemical reactions that are difficult in batch operations (e.g., those with exceptionally high temperatures or pressures) and, ultimately, real-time release of finished products.  

The technology required for continuous manufacturing comes mainly from the oil, gas, and food industries, says Malcolm Berry, head of continuous-processing projects at GlaxoSmithKline Research and Development (London). Plug-flow reactors, heat exchangers, continuously stirred tanks, and distillation columns have long been available for large-scale operations. At first, it was difficult for drugmakers to find models of these machines that were appropriate for small-scale processes, particularly for laboratory processes. Recently, more walk-up laboratory-scale continuous equipment has been introduced.  

New developments in reactor technology are encouraging manufacturers to pursue continuous manufacturing. Typically, companies adapt a new process to an existing batch manufacturing plant and often accept suboptimal performance as a result, says Peter McDonnell, senior technical director of Genzyme UK (Haverhill). More pharmaceutical companies began adopting continuous reactors when commercially available packages emerged in recent years such as oscillating baffled reactors from Nitech, mesoscale plate reactors by Corning, and Alfa-Laval’s reactors, which are based on their heat exchangers.  

Novartis (Basel) is collaborating with scientists from the Massachusetts Institute of Technology (MIT) to develop new continuous-processing equipment. MIT scientists have developed a new alternative to current granulation processing that combines microscale quantities of active ingredients and excipients to produce a thin film, says Tom Van Laar, head of global technical operations at Novartis. Operators can convert the film into nearly any dosage form. For example, layers of thin film could be combined to form a tablet.  

Many pharmaceutical manufacturing sites are reluctant to switch to continuous processing because they have large quantities of batch manufacturing equipment that is underused. But some batch equipment could still be needed to serve as feed tanks, buffer pots, makeup vessels, and waste-handling units. In addition, buffer capacity in a continuous process allows a manufacturer to keep a small inventory of intermediates to allow for on-line maintenance and troubleshooting. Batch equipment also would be needed for long continuous processes such as crystallizations based in continually stirred tank reactors.  

Some pharmaceutical companies are intrigued by the potential benefits of continuous manufacturing, but are uncertain about how to convert to it from their existing batch operations. Making the switch requires great understanding of the process, the critical process parameters, and associated critical quality attributes, say Rick McCabe, senior technical project manager of global manufacturing services, and Alex Chueh, director of technology, science, and operations of global manufacturing services, both of Pfizer (New York). A key goal of the transition would be to develop a fully integrated system with robust, high-level control and automation capabilities.  

The strategy for converting to a continuous process depends on the number of processing stages a manufacturer requires and the problem being addressed. The more stages a company puts together, the greater the level of process understanding required to ensure that the quality of the end product is fit for its purpose. “For example, many batch processes have an isolation, intermediate purification, or change of solvent in them. It’s very difficult to do that continuously, by definition,” says Berry. Such steps would need to be eliminated from the process if possible by redesigning the entire process at the outset.  

The journey toward fully continuous manufacturing typically starts with a single unit operation. A company might introduce continuous reactors or separators, for example, into an existing plant. This strategy is wise until the manufacturer gains confidence in the reliability of the equipment and the process, says McDonnell.  

It is also sensible to identify individual operations that could halt the whole production process if they failed. Personnel could either engineer these operations out of the process or provide redundancy by, for example, having one piece of equipment in service and another on standby. Manufacturers also must design the continuous operation to accommodate routine servicing such as water sanitization. Introducing buffer steps could allow parts of the plant to keep running while other parts are closed for maintenance.  

One approach to the transition would be to develop a manufacturing-scale continuous process during research and development, then ship the equipment directly to the factory to avoid scale-up and technology transfer. Although the idea may seem cost-effective, a manufacturer would need to pay close attention to installation costs during equipment design. Installing equipment into a new building can be expensive, sometimes more costly than the equipment itself, says Berry. GSK is considering this strategy but has not yet decided to adopt it, he adds.  

The industry is going to adopt continuous processing eventually because of its great advantages, and Novartis hopes to be part of the vanguard, says VanLaar. The company began developing continuous technology with MIT in 2007 and plans the first semipilot scale-up of part of the manufacturing process later in 2010. The next milestone will be in 2013, when a segment of the process will be ready for commercialization at close to commercial scale. Novartis intends to market a broad range of products created through continuous manufacturing by 2015. After that, it will take five to 10 more years for the company to switch from its current asset base and product portfolio to the new ones, says Van Laar.  

It’s worth the time and effort to convert to continuous manufacturing because the approach is “transformational” and its advantages “huge,” says Van Laar. Patent expirations, generic competition, and economic considerations might lead the industry to reconsider its traditional aversion to risk and new processes. If drugmakers become convinced that continuous manufacturing can help them create products of higher quality than before, in less time and at lower cost than before, it could well become the new industry standard. 

Production Lines

Continuous manufacturing could bring the pharmaceutical industry advantages such as improved product quality, easy scale-up, flexibility, and short cycle times. But how can a company switch from batch to continuous manufacturing?

Equipment and Processing Report-03-17-2010

March 2010 Editor's Picks: Products from Munters and NETZSCH

Filling Now for the Future

The Continuous Quest for Process Improvement