Powders in their place
Containment issues for pharmaceutical filter dryers

Solids handling in filter dryers brings several problems, with several possible solutions. The guidelines presented here can equally well be applied to containment issues in other pharmaceutical solids handling equipment, including fluid-bed dryers, centrifuges and mills.

When choosing containment equipment for a new or existing high activity pharmaceutical ingredients (HAPI) plant, right at the start it is important to understand all aspects of the process, including material flow and operator access requirements. Failure to do this will result in an inappropriate containment philosophy or equipment choice, and containment performance that is not as expected.
The trend to increasingly potent drugs has brought dramatic changes in plant design and operating procedures. Ten years ago, new plants required an operator exposure level of 100 µg/m3. Five years ago the standard was 10 µg/m3, and today most new plants require 1 µg/m3. Some facilities, such as those making hormones, have operator exposure levels below 30 ng/m3.

Filter dryers are typically used to provide a closed environment for the separation and drying of pharmaceutical compounds. They eliminate the issues of solids handling, cleaning and containment associated with filtration and drying carried out in separate equipment items.
A filter dryer is typically charged with slurry from a reactor or crystallizer. The slurry is then filtered using the Nutsche principle—pressure at the top of the vessel and vacuum at the bottom—to drive the filtrate through a mesh in the bottom of the filter dryer. Depending on the process, the filter cake may then be washed and re-filtered one or more times, before drying with the aid of heat supplied by the jacket, base and agitator. At any of these steps, samples may be taken to check the water and solvent content of the cake. Once the cake is dry, it is discharged as a powder.
Discharge and sampling
There are different problem areas for solids containment in filter dryers:
-powder flow problems,
-cleaning and inspection of the discharge valve housing,
-solids discharge,
-sampling,
-changing and cleaning of the filtration media, and heel removal.
The most important of these is the cake discharge system, since it is during this process step that the largest amount of solids is moved. A number of standard solutions allow a separate container filling system to be connected to the filter dryer, without direct integration. The agitator of the filter dryer is used to discharge the cake automatically.
Technologies to facilitate container filling with automatic discharge from the filter dryer include continuous liner systems, rapid transfer ports (RTPs), inflatable seal heads and split butterfly valves (SBVs). These can achieve very high levels of containment and product protection, but they only address the issue of container filling. Issues such as sampling, changing and cleaning of the filter media, heel removal, cleaning and inspection of the discharge housing and any potential problems with solids flow still need to be considered.
An alternative arrangement is to make the solids discharge containment system fully integrated with the filter dryer. This can be done by removing the side discharge valve housing from the filter dryer and replacing it with a fully-sealed glovebox. This arrangement ensures containment down to ultra-low levels, yet provides easy access to the cake and the internals of the filter dryer—useful especially in the case of poor solids flow, and for cleaning. With this arrangement the discharge door needs to be opened and closed manually, in contrast to the pneumatic or hydraulic ram normally used to open and close the door on a standard filter dryer.
A glovebox designed for integrated solids discharge can also be used for sampling. A sample plug fitted to the discharge door allows samples to be taken, packaged, and removed from the glovebox via an RTP or continuous liner. More complex sampling systems can also be used, but this requires compromises in terms of ergonomics, cGMP and cleanability. In some cases, especially when retro-fitting a discharge glovebox to an existing filter dryer, the sampling system may need to be accommodated in a separate glovebox.
Heel removal and operator safety
The agitator in a filter dryer is designed to discharge most of the filter cake automatically, but the need to allow for thermal expansion means that there will always be a gap of 5 – 10 mm between the agitator and the surface of the filter medium. This in turn leaves a “heel” of solids—up to 5 percent of the total cake weight—that cannot be removed by the agitator.
The heel can be recovered by reslurrying it and transferring it to a smaller filter dryer. If containment is not an issue, the base of the filter dryer can also be removed and the heel scraped off by hand. An integrated discharge glovebox, however, provides access to the internals of the filter dryer without compromising containment. In this case, special tools allow up to 95 percent of the heel to be removed safely.
Filter dryers with filtration areas up to around 1 m2 require only a single access point for heel removal. Filter dryers up to 2 m2 need a second access point on the other side of the glovebox, and larger units need extra gloveboxes for this purpose as well as the one used to discharge the bulk of the cake.
Direct access to the internals of the filter dryer brings issues of operator safety. To stop operators using the glovebox when the filter dryer is not in a safe condition, the usual arrangement is to block off the gloveports using metal plates or bars, which are locked into place by a pneumatic cylinder. A series of interlocks ensures that access is not possible unless the agitator is not running, pressure is atmospheric and the vessel is at ambient temperature. The glovebox can also be equipped with other safety features including safe-change HEPA extract filters, nitrogen inerting, an extract system to maintain underpressure during operation, and a pressure control system to ensure that safe operating conditions are maintained in the glovebox. Changing and cleaning the filter medium present the biggest challenge to containment. In fact, these operations are only possible in filter dryers up to around 0.2 m2 in size because of the bulk and complexity of the equipment needed. For such applications a system qualifies in which a glovebox encloses the entire filter dryer. Unlike the other containment solutions discussed in this article, this arrangement can also provide containment for the final steps of powder dispensing and packaging, thus removing the need for the powder to be transferred to a separate dispensing station.