Solid protection

The awareness of the need for contamination control and personnel safety now extends beyond the confines of the pharmaceutical industry. Industries such as food, beverage and, more recently, bioengineering and nanotechnology have been focusing on isolators to overcome issues of potent-product containment.

Traditional methods of process containment and operator protection used a 'low-tech' combination of cleanroom and personal protective equipment (PPE).

Isolation technology, on the other hand, offers enhanced product handling capabilities without constrictive gowning regimes and minimises potential for human error through incorrect procedures. Considering these performance advantages, the potential for innovative isolator development in these 'new' industries becomes apparent.

Established isolator technologies exist for, among others, the subdivision of bulk powders, drum or process vessel charging, product dispensing, sampling, milling, filling and weighing, as well as liquid decanting. These offer acceptable, achievable, validatable control of potent substance handling with measurable protection levels for people and environments.

However, where glove boxes or isolation chambers were once built around a single 'process', the trend now is for the integrated design of complete contained systems. These often now incorporate unique, integrated processing equipment such as dryers and mills within isolators.

For example, a totally contained, space-saving micronising system, developed by Hosokawa Micron in conjunction with AstraZeneca, involved the design of the mill to fit into an isolator. This was also of an innovative design to take into consideration the noise and vibration resulting from the high classifier rotor speeds within a confined space, as well as the overall weight (600kg) of the monobloc designed mill.

As isolator technology and contained processing becomes more commonplace across a range of industries, design changes will be needed. What are the catalysts for change in isolator technology and how will those demands be met? The main drivers for design changes are:

1. increased potency/value of products

2. increased demands for operator protection

3. exacting standards of validation for processes and containment levels

4. single-line multi-processing requirements

5. biotechnology development.

The increase in potency of active ingredients in pharmaceuticals is already pushing the boundaries of system design for the protection of the product, the protection of the person and the total recovery of expensive ingredients.

Fully contained systems achieving 8-hour OELs (operator exposure levels) below 0.01mg/m3 with purpose-designed processing equipment will continue to be developed with increasing use of monobloc and crevice-free mill designs that facilitate product discharge.

Easy clean CIP/SIP (clean-in-place, sterilise-in-place) systems will also become the standard. As less and less human intervention is deemed appropriate, design and production protocols will focus on automatic and remote operation and cleaning options.

The demand from manufacturers for validated processes and guaranteed operator exposure levels will also greatly influence future isolator technology. Investigation and interrogation of process protocols and operator procedures will determine strict operational parameters.

There will be design integration of semi-automated systems, alleviating the potential for human error. Improvements in in-line sampling and real-time analysis display may also be incorporated into isolator design.

Modern pharmaceutical manufacturing systems are moving away from dedicated single product facilities, which are now often regarded as something of a luxury. The ideal now is to have a highly flexible multi-purpose plant, which can process several high value products in one fully validated production unit.

With these design criteria in mind, Hosokawa Micron collaborated with a leading pharmaceutical manufacturer to produce a highly flexible, ultra-fine grinding/micronising suite with high containment isolation. The suite has been tested and validated to meet all of the manufacturer's current and predicted future micronising needs.

Working closely with the client's engineers, Hosokawa Micron designed an integrated milling system with high containment Stott isolator units situated in a multi-storey process area. System controls were integrated into existing control systems at the client's site, enabling monitoring of all critical process parameters for historic trend analysis. The containment philosophy attains operator exposure levels of 10µg/m3 and full isolation achieving containment levels below 5µg/m3.

Moving from pharmaceuticals to the biotechnology industry, the Stott flexible isolator, for example, has been developed in response to R&D and biotechnology client demands for a low-cost, lightweight, compact isolator that still offers high levels of product and personnel protection.

The Stott isolator comprises a standard, stainless steel, base section suitable for bench mounting, or with an optional base frame. To this base can be fitted a range of upper sections complete with glove ports. These include an FDA-compliant flexible antistatic polyethylene canopy or a rigid Perspex cover, or even a stainless steel canopy complete with windows.

This design ensures the units can be offered at cost-effective prices, making them ideal for companies wanting to do trial batches before scaling up to full production facilities, and looking for the flexibility of a contained, small scale R&D unit - yet one that has the same high level protection and performance levels of production units.

Getting the solids-liquid mix just right

The process of adding a liquid to a powder is a tricky balancing act — too much liquid and the mixture can become doughy, pasty and sticky; too little, and the mixture is not evenly moistened and consistency is lumpy.

Hosokawa Micron has now come up with an answer to this problem in the shape of the Schugi Flexomix, a mixer-agglomerator that is said to make adding liquids to powders simple. The Flexomix can simultaneously mix and agglomerate several liquids and solids, resulting in mixtures or aggregates that exhibit a constant grain structure and homogeneity.

The machine consists of a vertical cylindrical chamber enclosing a vertical, fast rotating shaft. Several protruding knives are fastened to the shaft, which rotates at adjustable, high speeds between 1000 and 3500rpm. This creates an intensive turbulent stream inside the mixing chamber, into which liquid is introduced through atomising nozzles mounted in the upper portion of the chamber, just above the upper mixing blades.

Powder is fed into the unit via top inlets and is brought into a highly turbulent, circular flow to create an aero suspension. The surfaces of the solid particles are evenly wetted by the dispersion of the atomised water. By increasing the amounts of liquid, wetted particles grow in size by clustering together in aero suspension.

If significant amounts of liquid are injected, however, the product has a tendency to adhere to the chamber wall. The Flexomix overcomes this build-up with a self-cleaning design. This consists of a flexible mixing chamber that is continuously deformed by rollers moving vertically along the chamber, which consequently stays almost clean.

A typical application is the rehumidification of wheat flour.

Here, flour with moisture content of 8% is dosed into the mixer at a constant rate. The addition of water is controlled by a dosing pump set at a constant defined rate. The dosing system is carefully selected to meet the properties of the wheat flour feed and the required homogeneity and moisture accuracy of the rehumidified wheat flour.

The variation in water-to-powder ratio is defined by the accuracy of the dosing systems and therefore a gravimetric powder dosing system is used. The Flexomix itself ensures the homogeneity of the end product, which has a humidity of 13%, making the flour ready for further processing, storage or packing.

Bev Antrobus is with Hosokawa Micron.