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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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.

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