Process manufacturing: No transfer required

As the pharmaceutical industry has matured, concerns about the safe handling of drug compounds during the manufacturing process have increased. To meet exposure limits and protect batches from any kind of contamination, the industry’s need for improved containment has increased.

By Diane Dierking

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As the pharmaceutical industry has matured, concerns about the safe handling of drug compounds during the manufacturing process have increased. To meet exposure limits and protect batches from any kind of contamination, the industry’s need for improved containment has increased. Vendors have responded by providing glove boxes, better seals, more robust dust-collection systems and improved vessel design.

One such piece of equipment that incorporates many of these improvements is the agitated filter dryer, which Rosenmund Guedu, Liestal, Switzerland, invented in 1971. “The agitated filter dryer is a unique piece of processing equipment to separate solids from liquid in a single vessel,” says Todd Peterson, manager of filters and dryers for De Dietrich Process Systems Inc., Charlotte, N.C., which acquired Rosenmund in 1999.

The filter dryer typically is designed to provide a closed environment for separating, washing and drying in a single vessel, and is continually evolving to meet manufacturers’ needs. Vendors have taken various approaches to address contained powder discharge, including glove boxes, continuous liner technology and specially designed valves and scrapers, promising product recovery upward of 99%.

Although generally used for pharmaceutical applications, chemical producers such as Eastman Chemical Co., Kingsport, Tenn., also are making use of the technology. “It’s easier to justify the cost for pharmaceuticals,” says Bryan Suggs, business analyst for Eastman. “But we also use filter dryers for general chemicals production.”

Machines that multi-task
Depending on the application, the agitated filter dryer might use either cloth (generally polyethylene or polypropylene) or metal mesh media; a manufacturer might even alternate between the two. The filter media can be held in place by bolts or clamps, and the metal mesh has the added option of being welded. Most advanced designs now use a boltless mechanism to secure the filter media by simply clamping it between the two halves of the filter dryer. This also provides a sterile design, says Chad Ranpuria, process manager for Powder Systems Ltd. (PSL), Liverpool, England. Cloth filter media is more likely to be used when processing specialty chemicals. Although many pharmaceutical manufacturers prefer metal mesh since product can more easily be recovered, cloth is ideal when used for single runs. The types and pore sizes of filter media that are available are continually expanding, while the cost is relatively stable, Ranpuria says.

Agitated filter dryer vessels separate into two pieces to allow access to the vessel internals, mainly for changing or repairing filter media. The two parts are generally sealed with an O-ring and can be held together with bolts, C-clamps or a bayonet closure (Figure 1); these last two are easier to assemble.

Once the vessel is charged with slurry, pressure is either applied from the top of the filter dryer using a gas, such as nitrogen or compressed air, or a vacuum is pulled from beneath the filter media, thereby forcing or pulling liquid through the cloth or mesh. Low pressures are generally used (1 barg to 2 barg) to keep the cake from becoming so compressed that the crystals fuse together. The liquid exits at the bottom of the vessel where it might be recycled or reused in another part of the process.

While the crystals are collecting on the filter media, the smooth edge of the agitator acts to smooth the surface of the cake so there are no crevices. The other edge of the agitator, which can rotate in both directions, might have teeth for digging into the cake to help break it up and remove it from the filter media (Figure 2). The cake might be broken up and washed several times to remove all trace solvents or impurities.

The powder is then dried by applying heat to the vessel. “Heating has become more sophisticated and efficient,” Ranpuria says. Not only are PSL’s filter dryer vessels fitted with jackets on the walls and top dome, but the agitator shaft and blades are also heated, providing direct contact with the powder. Several vendors’ designs also supply heat to the bottom filter plate.

Lewis Fabricius, P.E., manager of reactor systems for Pfaudler Inc., Rochester, N.Y., says the company’s design speeds drying by using an internal heating grid that directly conducts heat to the product. The company also offers an optional heated nitrogen distribution system, which can fluidize the cake, thereby reducing drying times.

Vendors now can provide programmable logic controllers (PLCs) that integrate with a site’s distributed control system (DCS), as well as an interlock system. “If the unit is under pressure or vacuum, you don’t want someone to open the side-discharge valve,” Ranpuria says. “So you add a pressure sensor and an interlock system so the valve can’t be opened until the vessel is at atmospheric pressure.”

Customized control systems can be used to set the nitrogen purge, temperature and pressure cycles, Ranpuria says. “It also makes it possible to dry to a specific end point which is a great benefit for processes that need to be repeatable.”

For smaller, lab-scale units, however, it probably doesn’t pay to automate units, says Lawrenzo Heit, New Brunswick, N.J.-based group leader for Bristol-Myers Squibb Co.

The final step is to remove the finished product from the filter dryer vessel.

PSL’s approach is to attach a glove box directly to the side of the vessel so no powder can escape. Operators then discharge the dried product using the agitator controls and transfer the loose powder from the vessel to containers, such as drums or bottles. Since the agitator is designed so that it can’t damage the filter media, there is always some product left on it, which is called the heel. This can be removed through the glove box with a specially designed rake, Ranpuria says.

De Dietrich’s Peterson says there are various methods to remove the heel; the best one depends on the customer’s needs, but that there is “no perfect solution at the moment.” Smaller units come equipped with a glove box and might also have a pusher port, which is mounted opposite the side-discharge valve, and allows powder to be manually pushed out of the vessel. Larger filter dryers use the agitator to push the powder out the side-discharge valve, and might combine a nitrogen purge to help sweep product off the filter plate. Vessels up to 4 m² (filter surface area) can also be tilted, which requires additional mechanical equipment in addition to flexible connections (Figure 3).

Pfaudler started offering filter dryers in 2003 after entering into a partnership with Delta Costruzioni Meccaniche (DCM), Misinto, Italy, which has been building filter dryers for 30 years. Fabricius says the company’s filter dryer can be equipped with any of three features to aid in heel removal: The vessel tilts and has retractable nitrogen side-sprayers in addition to the nitrogen distribution system.

Contain yourself
An agitated filter dryer might supplant several different pieces of equipment on the plant floor: Eli Lilly and Co., Indianapolis, is gradually replacing several centrifuge/dryer combinations where appropriate, says Kumar Abhinava, Ph.D., engineering consultant for the company, whereas Eastman prefers the filter dryers to the open-top nutsche filter/dryers they used to have, Suggs says.

“In the past, the filtration and drying steps would have been carried out in separate pieces of process equipment -- typically a centrifuge and tray dryer combination,” Ranpuria says. “This required lengthy solids handling steps when transferring from centrifuge to tray dryers with all the associated containment and cleaning issues, together with any product losses due to the transfer step.”

This equipment is being taken offline not only to reduce the potential for employee exposure when material is manually transferred, but today’s agitated filter dryer provides a high degree of containment and also meets cGMP standards. As an added benefit, the filter dryer takes up less floor space than the equipment it replaces, Abhinava says.

In the past, pharmaceutical manufacturers might have had to meet occupational exposure limits (OELs) of 100 μg/m³ to protect personnel – now many OELs are as low as 1 μg/m³, and in some cases are less than 100 ng/m³. “Many drugs are becoming more and more potent,” Ranpuria says. “The efficacy is increasing, so manufacturers are producing less and they need higher containment.” Abhinava concurs, saying containment figures prominently when selecting technology and that filter dryers usually are chosen for products requiring a high level of containment.

 “Some of these drugs are lethal,” De Detrich’s Peterson says. The degree of containment provided by the agitated filter dryer also reduces the costs associated with personal protective equipment (PPE) and can make it unnecessary to make certain drugs in cleanrooms, which are expensive to build and maintain, Peterson says.

To meet cGMP standards, vendors provide a clean-in-place (CIP) system, as well as a steam connection and drain so the vessel can be sterilized by steam-in-place (SIP). “The standards for GMP keep changing and becoming more rigorous,” says Bristol-Myers’ Heit. “The newer filter dryers have fewer problems meeting our cleaning standards.”

Many vendors now test the efficiency of the CIP system with riboflavin (vitamin B2), low levels of which will fluoresce in UV light. CIP systems generally consist of some arrangement of sprayers or a ring with nozzles. Vendors set the direction of the sprayers or nozzles so all of the internal parts are adequately cleaned, especially in places where material might get trapped, as proved by riboflavin testing.

When several batches are processed in a single campaign, the metal mesh filter media can become less efficient as particles become wedged between the fine wires. Ranpuria says PSL’s filter dryers are equipped with a reflux cleaning system. This allows manufacturers to heat and recirculate solvent or some other liquid at pressure or under vacuum. The bottom plate of the vessel is designed such that the amount of solvent needed to cover the filter media is minimized. After the procedure, the mesh is returned to like-new efficiency and a polishing filter recovers any product in the exiting liquid, Ranpuria says.

The high level of containment that can be achieved with the filter dryer certainly is one of its most attractive features. Another is the ability to filter and dry in the same vessel so operators don’t have to manually remove material from one vessel and transfer it to another. Processing the material in one vessel is safer and reduces potential loss of material. “You don’t want to handle material twice,” Ranpuria says. “Each time you lose product.”

Other benefits of using the filter dryer are reduced capital cost, including erection costs, and reduced maintenance, Abhinava says. The lower capital costs are a direct result of the smaller footprint of the filter dryers, whereas maintenance costs are diminished because “there are fewer things that can go wrong with one piece of equipment,” Abhinava says.

Another benefit to using an agitated filter dryer is that an entire lot can be processed at one time, whereas a lot likely has to be processed batch wise in a centrifuge, Abhinava says. “This is a ‘quality’ advantage that is important to pharmaceutical manufacturers.”

De Dietrich’s Peterson estimates about half of the filter dryers the company sells are a standard design, with the remaining being designed on a per-customer basis. PSL’s Ranpuria and Pfaudler’s Fabricius both say their companies sell more custom vessels than standard. The high percentage of custom design is due, in part, to the control and interlock systems that can be sold with the filter dryer.

Although more units are being sold, Peterson and Ranpuria say the average size of the vessels has decreased as drug compounds become more active. However, the need for control systems, containment and cleaning, for example, has increased.

Suit your application
The agitated filter dryer is not suitable for every application, however. “Amorphous products are hard to deal with in any filter,” Fabricius says.

Those who use the equipment also say it has a couple shortcomings. For the most part, they indicate they can get around such issues once they are identified.

Gary Hedden, Palo Alto, Calif.-based group leader of process development for Roche Pharmaceuticals, says there are two small filter dryers in his lab: a Rosenmund machine, purchased circa 1993, and another from PSL, vintage 1999. Both are used for developing pharmaceuticals and are rarely used to process the same thing twice. “After CIP, we always have to take the filter dryer apart to get the last bit of material that is stuck in the filter media and in the O-ring groove,” Hedden says.
Eastman’s Suggs says they used to have problems with material getting lodged around the O-ring at the side-discharge valve; he now specifies a higher-grade O-ring that provides a better seal to avoid such problems. Since 1998, Eastman has purchased four agitated filter dryers from Rosenmund/De Dietrich that range in size from 6 m² to 12 m²; these larger vessels do not have CIP systems. “Since we often process the same chemical for several runs, it’s sufficient to manually wash the bottom filter plate with a hose,” he says.

Bristol-Myers Squibb’s Heit and colleague Tom Mitchell, a senior research scientist, have seven filter dryers in their care. The company has six vessels from Rosenmund that range in size from 0.03 m² to 1.5 m², as well as a 0.28 m² unit from Pfaudler (another unit from the company is on the way). Heit says the vessels are used in the pilot plants for process development and producing drugs for clinical trials. Since the filter dryers are used for a different product every time, “we spend as much time cleaning as we do processing,” Heit says, even with the CIP systems.

“The filter dryer can become a bottleneck since you are combining two unit operations into one unit,” Lilly’s Abhinava says. “We usually use it when filtration and drying rates are sufficiently fast in order for the filter dryer not to be a bottleneck.”

Ranpuria says that although the filter dryer might limit throughput, “it is more cost effective as one single unit, thereby simplifying manufacture and removing complexity while minimizing product handling steps, reducing potential cross-contamination during handling, and saving analytical time.”

Heit and Mitchell say they would like for filter dryer vendors to offer a more complete package that includes glove boxes or other systems for removing the product, adding that PSL is leading in such offerings. “The mechanisms for getting material in and out, and for cleaning the vessel should be resolved at the vendor level, not onsite,” Heit says.

Fabricius says Pfaudler is making progress toward offering such a package: The company is working with outside vendors to provide isolators, such as gloveboxes, as well as other technologies to ease product handling.

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