Benedikt Simons, of Rosenmund VTA, describes a single system designed to both filter and dry lab or pilot scale ingredients, avoiding the difficulties of wet cake handling
Once pharmaceutical products have been developed in a lab, suitable processes must be developed to manufacture the product on a commercial scale. Development departments therefore require mini versions of the production systems under consideration that are accurate in detail.
Only if these provide reproducible results can the process be scaled up to industrial dimensions. It must also be possible, however, to manufacture small batches economically with these pilot-scale systems, typically for clinical trials or to provide product samples.
Many industrial products are in powder form. Following their manufacture by wet chemical processes, they are precipitated or crystallised out from the solvent. The subsequent steps are usually filtration or separation, drying and milling, each operation being carried out in a separate special-ised unit.
As long as the product is still in liquid form, it is relatively easy to transfer from one individual unit to the next. The user can face a virtually insurmountable problem, however, when needing to transfer filter cake - product in a form not readily capable of flowing - to the dryer.
If it is essential to avoid a manual operation to protect the operator, it is a logical step to combine the filtration and drying processes in one unit. In practice, a filter/dryer represents the most cost-effective solution. The slurry is filtered, the filter cake smoothed over, often washed several times and finally dried, all in the same vessel (Figure 1).
The product is fed to the filter/dryer as a slurry. It takes only a few seconds before the filter cake forms on the level filter media and acts as a filter aid (cake filtration), so that even the fine material is then held back completely, although it may make the filtrate slightly turbid at first. If all of the product needs to be retained, this initial filtrate can be returned to the slurry and filtered again.
As a rule, the filtration process is accelerated by pressurising the slurry, which often enables a residual moisture content of 20% or less to be achieved in the cake.
Frequent product changes necessitate simple maintenance concepts. The filter base of the laboratory filter/dryer can be lowered for inspection and replacement of the filter media. A specially adapted retaining system enables all commonly used types of filter media, such as single- or multilayer metal meshes or filter cloths of various porosities, to be fitted into the one unit without needing to modify it.
easy mobility
In contrast to production systems, the vessel flange on the laboratory filter/dryer is not at the level of the filter plate but at that of the cake. This enables the base filled with product to be lowered and wheeled on its castors to another section of the plant for further processing. The main filter/dryer unit itself is also on castors, so that it can be moved around easily by one person for use anywhere on the site. It is only a question of connecting utilities - electrical power, compressed air, heating and process media - and the unit is ready to process the next batch.
The adjustable-height, S-shaped agitator has proved to be suitable for carrying out a variety of tasks, such as slurry agitation, cake smoothing, product discharge and heat transfer. In the course of the process, its functions change with its direction of rotation. The operator can observe the process through an illuminated sight glass and can intervene directly by adjusting the agitator shaft speed or position.
The agitator is raised and lowered from outside the vessel by a pneumatic actuator, the shaft being hermetically sealed by means of etal bellows to prevent the ingress of product, bacterial contamination or even cross-contamination by residues from previous batches.
Residual moisture is evaporated off, the necessary heating energy being supplied through heat transfer surfaces. In addition to the base and walls of the vessel, a heated agitator is also a very effective means of transferring the energy.
absolute pressure
Drawing a vacuum in the vessel reduces the boiling point of the liquid and hence the process temperature. If the absolute pressure is reduced too rapidly, however, this can prove disadvantageous, as too much evaporation in the initial phase can result in pores closing up as particles contract, thus trapping the residual moisture. For such instances, Rosenmund has developed special processes in which the absolute pressure is reduced in stages while keeping a constant rate of evaporation. This results in shorter drying times with considerably less residual moisture than with conventional methods.
A dust filter in the cover retains the product fines entrained in the offgas stream. These form a dry filter cake, which is then detached from the filter surface by gas pulse jets that blow it back into the vessel.
To prevent the temperature in the vessel falling below the dew point, the cover, agitator and dust filter of laboratory units can also be constructed as heated versions. A film of condensate could otherwise form on unheated surfaces, and in the worse case scenario droplets falling from this film could moisten the product again.
product removal
Laboratory units must often be completely cleaned after each batch, particularly if the product changes frequently. This means that the residual product, which is usually valuable, is lost. The S-shaped agitator is lowered to only a few millimetres above the base of the vessel to discharge the product, and this technique, together with the side discharge valve, is used to reduce the residual product (filter heel) to a very thin layer at the bottom. To help discharge this layer, Rosenmund has developed the GasKnife, a system of jets integrated in the agitator. The jets of gas blow away the heel from the vessel bottom, and the residual product is completely removed through the side discharge valve.
In addition, the company has developed the CleanSeal system to remove residual product from the side discharge valve. The special geo-metry of the sealing surfaces means that any product build-up there can be virtually excluded (see Fig. 3). An additional system of jets assists this function with its self-cleaning action on the valve seat, thus ensuring sustainable shut-off for this valve.
discharge option
Some development departments prefer to remove the product manually via an isolator. A universal adaptor can be used to replace the side discharge valve to fit a glove box and fill the product into containers under strict containment conditions.
The subsequent WIP (wash-in-place) cleaning process is carried out using spray nozzles (Fig. 4). These nozzles are arranged so that all surfaces are completely wetted, a prerequisite for being able to remove all traces of the product. A Riboflavin test is carried out to confirm the correct positioning of the cleaning nozzles. Riboflavin can be detected by fluorescence even when present in only minute quantities. The equipment item to be tested is wetted with a Riboflavin solution, and then after sufficient residence time has elapsed, it is rinsed with the nozzle system. If no fluorescence can be detected when radiated with UV light, the test has been successful.
Modern development centres are equipped to handle flammable liquids and dusts, and therefore need ATEX certified explosion-proof equipment. Mobile lab filter/dryers must also comply with these requirements. Switching devices and operator controls are installed in a flameproof enclosure mounted on the unit and do not require additional wiring or external barriers.
RoLab, with its new generation of mobile filter/dryers, has been designed primarily for use in laboratories and for pilot-scale operation. It enables filtration and drying tests to be carried out efficiently and is the key to reliable system scale-up. However, this multipurpose unit can also be integrated into a regular production line for small quantities of APIs or intermediates.
The system's simple concept makes it particularly user-friendly, while its high degree of standardisation keeps it cost effective. Rosenmund also offers rental units in all sizes for test purposes.