As pharmaceutical manufacturers strive to find green production methods, many companies are discovering that sustainable strategies also can improve efficiency and reduce costs. One such strategy is 

 the process of injecting a sanitary, solid, silicone rubber projectile into a safe, closed-loop sanitary system to clean out the pipeline between batches (see Figure 1). The projectile, or pig, is forced through a pipeline by compressed air, carbon dioxide, nitrogen, water, or the next product. The pigs generally are made of medical-grade silicone that complies with 21 

 Section 177.2600 and is approved by the US Food and Drug Administration.  

A unit called a pig detector helps ensure that a pig is not lost. A pig detector also automates the pigging system so that operators can send it back and forth in a pipeline accurately (see Figure 2). Some of pigging’s advantages for the pharmaceutical processing industry include the following:  

	A 30% reduction in cleaning-chemical consumption. 

Because they rely on expensive ingredients and manufacture valuable finished products, pharmaceutical processors have long sought ways to increase product recovery. Companies typically have addressed the problem by limiting the size of their pipelines because small pipelines are easier to clean than large ones.  

But manufacturers do not have to limit pipeline size, which can also reduce productivity. Introducing a sanitary pig into a pipeline effectively pushes usable material into a filler, storage tank, tanker, or a final package for product recovery. Operators also can clean challenging areas such as 90° elbows fully with a pig. Pigging can recover product at a rate higher than 99%. As the value of the recovered product increases, the time required to achieve a return on the investment in the pigging system is shortened.  

As more material is recovered and converted into finished product, the scrap volume is decreased, and batch yields rise. Pigging technology is equally effective on pipelines with large diameters, thus pharmaceutical manufacturers can achieve significant increases in production by using 2-in. pipelines rather than the 1-in. models that are currently the standard. Pigs are available in sizes from 0.5 to 8 in.  

Improved product recovery increases efficiency, lowers the cost of individual items, and increases a production line’s profitability. A reduction in the scrap rate translates directly into decreased waste-handling and -hauling fees. If scrap liquid product is discharged into the sewer, a lower scrap rate can mean reduced surcharges, especially for high biochemical-oxygen-demand materials.  

Many of the pharmaceutical industry’s processes rely on batch manufacturing and produce several batches per day or shift. Time is valuable in such a production environment. Because batch-to-batch consistency and cleanliness are vitally important, the cleaning process must be rigorous. A long cleaning cycle—including a water flush, the introduction of clean-in-place (CIP) chemicals, and another water flush—usually is necessary.  

Injecting a sanitary pig into the pipeline, however, can eliminate the need for the initial water flush and the time associated with it. Because pigging cleans the pipeline so effectively, it reduces cross-contamination concerns and quickens the cleaning process. The pig’s effectiveness comes from the fact that it is slightly oversized and pushes out the product like a squeegee.  

Pigging typically reduces cleaning cycle time by half, thus enabling more batches to be produced with the same equipment per day or per shift. When pipelines with large diameters are used, these production increases and efficiency gains are compounded. Pigging systems can be used before cleaning validation or integrated into cleaning-validation procedures.  

For companies that are looking for ways to reduce their environmental footprint, pigging could be a way to reduce water consumption because it eliminates the need for an initial water flush during CIP. The technique could be especially valuable in areas that experience drought conditions.  

Companies that switched from traditional CIP systems to pigging systems have reported a water savings of roughly 50% and a chemical savings of about 30%. This reduced use of resources not only saves the cost of water itself, but also the cost of water treatment and sewerage costs. Depending upon the particular circumstances of a production line, this saving can improve the return on the investment in the pigging system.  

Reduced cycle times, reduced water and chemical consumption, and greatly increased product recovery and production rates are important reasons that pharmaceutical manufacturers are becoming interested in pigging. This technology helps pharmaceutical manufactures establish sustainable processes on the plant floor and can help them improve their bottom lines. 

Neil O’Connor is president of Process Pigging Systems, 1776 Mentor Ave., Cincinnati, OH 45212, tel. 513.731.6005, 

Articles

In the Mixer

Pigging is a sustainable strategy that can aid in cleaning and product recovery and improve a manufacturing line's efficiency and throughput.

Pigging Can Improve Efficiency and Sustainability

Although continuous processing is applied in other manufacturing industries, it is not widely used in the pharmaceutical industry, which relies on batch manufacturing. But the US Food and Drug Administration’s quality-by-design initiative and the possibility of improving production economics and process control are encouraging companies to consider continuous processing in pharmaceutical manufacturing. Microreactors, which are based on flow chemistry, can be used to apply continuous processing to the manufacture of active pharmaceutical ingredients. Recent technological advances in microreactor technology are improving the application and scale at which the technology can be applied.  

One notable change relates to the equipment’s functionality. At first, various types of microreactors were designed for specific reactions, and chemists had to choose the best microreactor accordingly. During the past several years, however, multipurpose microreactors have emerged that are applicable to a bigger portfolio of reactions than before, says Gregor Wille, specialist for microreactor technology at Sigma Aldrich (St. Louis, MO). A large part of chemists’ work is in multipurpose applications, and the development of multipurpose microreactors represents a paradigm shift, says Wille.  

This shift has occurred thanks to a change in the plates within the microreactors. In the past, each mircoreactor had individual plates for mixing, reaction residence time, or temperature control, but newer microreactors use plates that integrate several functions. These new machines are gaining widespread acceptance in the pharmaceutical industry, says Sergio Pissavini, business director of Corning Reaction Technologies (Corning, NY).  

Multifunctional plate reactors can be reconfigured easily to suit various reaction requirements, says Martin Jönsson, sales and marketing manager for Alfa Laval Reactor Technology (Lund, Sweden). These devices can be used for liquid–liquid reactions and two-phase liquid reactions. Multifunctional plate reactors also allow operators to determine the ideal equipment parameters during process development.  

The types of unit operations that microreactors can perform have also expanded. New machines can isolate and purify the chemical products of reaction mixtures by performing tasks such as phase separations and distillations, according to Peter Poechlauer, principal scientist of DSM (Heerlen, The Netherlands). For example, the inner surfaces of new microreactors combine hydrophilic and lipophilic domains that enable the units to separate phases.  

Traditionally, microreactors’ yields have been limited by the size of the machines’ tubes, which affects the flow of ingredients. Operators have tried 

 strategies to improve yields, including wrapping small pieces of tubing around a heating or cooling exchanger and stacking grooved reactor plates. But equipment manufacturers such as Corning now offer larger units with wider tubing than before. The larger flow-chemistry reactors still have good surface-to-volume ratios, but offer a flow path with a larger diameter to help improve throughput and yield, says Jeffrey W. Sherman, head of advanced technology development at Mettler-Toledo (Columbus, OH).  

Technological improvements have enabled some pharmaceutical companies to begin using microreactors for commercial-scale production. In a joint project, Corning and DSM developed equipment and a production process that safely and cost-efficiently produces the nitrated intermediate required to make naproxcinod. First, the partners successfully achieved current good manufacturing practice standards and then accomplished pilot-scale production. This year, Corning provided DSM with a large-scale reactor that can produce more than 100 tons of product annually, says Pissavini. Corning is now developing reactors for several major companies whose names cannot be disclosed because of customer agreements.  

Still, the promise of efficient scale-up of microreactors with consistent, predictable results has not yet been realized, Sherman says. Pharmaceutical companies question whether parallel synthesis (i.e., stacking several microreactors to make large quantities) is pragmatic. The technique requires manufacturers to buy and maintain a lot of equipment. Although parallel synthesis might reduce safety and scale-up problems, it introduces problems such as equipment validation and real-time control. “People are wary of saying that microreactors are the answer,” says Sherman.  

Hope for the technology’s future seems justified, however, considering how much technological advances have improved the equipment. And companies such as sanofi aventis (Paris) and Schering-Plough (Kenilworth, NJ) have publicly recognized that microreactors can produce high-quality chemicals cost efficiently and with a low environmental impact, says Pissavini.  

A desire to improve product quality, a need for greater process control, and FDA’s promotion of continuous processing may spur greater industry adoption of microreactors. “I think flow chemistry is here to stay and will increasingly play a role alongside batch reactors,” says Sherman. 

Production Lines

Recent advances in microreactor technology are improving the application and scale at which the technology can be applied.

Are Microreactors Practical for Large-Scale Production?

Enercon Industries
 Sealer enhances productivity


 The Super Seal Touch induction cap sealer from Enercon Industries (Menomonee Falls, WI) provides as much as 20% more induction-sealing power than the company’s previous devices. This increase in power is designed to boost productivity.

The unit’s redesigned cap-inspection system is integrated electrically and mechanically with the sealer to reduce setup time. In addition, the system includes recipe-management capabilities. Operators can store parameters for various products by name and perform product changeover easily. Users also can block other operators from adjusting the system. 

The sealer’s touchscreen improves operator control and allows the unit to provide data about the sealing system. The touchscreen displays faults in descriptive text instead of codes and also supports several languages. The sealer also provides network connectivity, thus allowing packagers to control and monitor cap sealing data remotely from a central location.

Schreiner MediPharm
 Hologram seal makes counterfeiting difficult


Schreiner MediPharm’s (Oberschleißheim, Germany) Transparent-Hologram-Seal is intended to provide reliable evidence of tampering and counterfeiting and ensure that patients receive pharmaceutical products intact. The seal is fixed to the package with a strong adhesive so that an attempt to peel it off would damage the packaging surface. In addition, the seal’s 2D single-image design and holographic effects are designed to make counterfeiting especially difficult and thus ensure the safety of packaged pharmaceuticals.

The seal is transparent so that variable data on the package such as batch information is legible and intact. The Transparent-Hologram-Seal is appropriate for small- and large-volume production. Schreiner MediPharma and its sister company Schreiner ProSecure codeveloped the seal. Schreiner ProSecure specializes in authentication, tamper-protection, and track-and-trace solutions. 

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the November 2009 edition from Enercon and Schreiner.

Equipment and Processing Report-11-18-2009

Pigging Can Improve Efficiency and Sustainability

Are Microreactors Practical for Large-Scale Production?

November 2009 Editor's Picks: Products from Enercon Industries and Schreiner MediPharm