16-Sep-2006

Working in isolation

Abstract

Chad Ranpuria, technical manager of Powder Systems, looks at how advances in isolator technology are providing more flexible operations and faster turnaround

Within the fine chemical and pharmaceutical industry, the requirement for Class 10,000 (ISO 7) has traditionally led to use of large walk-in down flow booths and cleanrooms. While allowing considerable space for operator and equipment, the size and associated costs of these facilities can be restrictive. Large air volumes for such flow booths require large extract systems, ductwork, and associated high civil and mechanical costs. In addition, as there is no actual physical barrier present between the operator and the product, other issues and costs are incurred relating to personnel gowning, changing rooms, associated HVAC system, personnel training, HEPA filter replacement, cleaning and validation.

As the potency of pharmaceutical and fine chemical powders increases, the need for personnel protection combined with aseptic Class 10,000 condition is also increasing. Applications now typically require operator exposure levels (OELs) down to nanogramme levels less than 1microgramme/m3, based on a 1 hr operation, 8 hr time weighted average. In addition, with the rapidly moving pharmaceutical industry, the need for flexibility as well as the ability to retrofit new process equipment into existing restricted space is often a major stumbling block for the timely delivery of new technology and facility design.

Isolator technology can provide a positive alternative to down flow booths and cleanrooms. The latest isolators are compact and ergonomic for ease of operations. They use lower volumes of air and can have nitrogen purge status and offer controlled humidity conditions. Ultimately, the designs allow for work under negative or positive pressures, providing a product sterility and containment barrier at the same time.

In addition to the pharmaceutical industry delivering drugs that are far more potent than previously, the scale of operation of batches is getting smaller, thus enabling many processes to now be carried out in a smaller space. In many cases such processes can be integrated inside isolators.

The compact isolator designs allow for cleaning of just the inside of the isolator rather than a full cleanroom. This enables the cleanroom to be multipurpose and have more flexible scheduling, as other operations can be carried out, without hindrance, in the immediate vicinity.

It is now common practice to design cleanrooms that house a number of compact isolators with each isolator designed to handle a specific process, such as dispensing, milling, sieving, fluidised bed drying, granulation, vacuum tray drying, powder blending, filter drying, kilolab processing, filtration,and wet and dry chemistry steps.

contained charging

The growing biotechnology industry is also demanding more reliable methods for guaranteeing sterile operations. Companies are often required to address both containment and sterility issues in the same equipment. The need for contained charging of vessels in a sterile manner is becoming commonplace. It is always best to reduce bioburden at source and keep control of sterilisation at each point of a sterile process stream.

One weak link has been the connections for adding ingredients such as powders during processes. At these points, manual handling is required and containment and sterility can both be breached if correct procedures are not in place and followed closely.

Transfer of product under aseptic conditions requires stringent steps to avoid product contamination and to ensure containment, so that the operators are not exposed to the same product during transfer.

Recent technical advances have resulted in the introduction of new valves for the contained transfer of powders from one step of the process to another in sterile applications.

Such valves typically have an intermediate step added to the docking operation of the valve, which allows the valve to be sterilised. This can be carried out in situ and prior to any product transfer taking place. The invention also enables the intermediate step to be employed to achieve Class 100 (ISO 5) for sterile transfer of a drug. Thus the coupling up of two processes can be achieved and charging or discharging can be carried out batch wise, without introduction of bioburden or loss of sterility.

High velocity HEPA filtered air and nitrogen cleaning removes any particulate material prior to the next stage the sterilisation step which can be carried out using either clean steam, vaporised hydrogen peroxide or other suitable sterilising vapour medium.

Once the sterilisation cycle has been completed, the valve can be fully docked, which then allows the valve to open and sterile product can be transferred across safely without any sterility breach.

A common pharmaceutical requirement is for powder dispensing with Class 10,000 (ISO 7) conditions and personnel protection to below 1 microgramme/m3. Normally, such an application would revolve around down flow booth technology with HEPA inlet and extract filtration combined with open powder handling. Drums of feed material would be opened, (tilted if heavy and beyond the weight limit for manual handling and scooping of powder), to provide correct weight dispensation. Suitable working tables, scales and space for receiving containers would be provided. In addition to taking up considerable space, all surfaces are likely to get covered in dust, however carefully the manual powder transfer is done. Any spillages would also mean product losses.

A considerable amount of equipment feed containers, hoist, tables, scales and product containers then needs to be wiped to prevent cross-contamination and to ensure personnel protection. This can be cumbersome and time consuming.

In comparison, a dispensing isolator can allow for the complete process within a contained class 10,000 zone. The isolator can have an integral hoist for drum lifting, with the drum kept outside the isolator and only the liner brought inside, preventing drum contamination. Furthermore, the volume of the isolator would be considerably lower (typically 1-2 m3). This means the air flow volume for say 20 air changes would be a mere 20-40 m3/hr.

One additional advantage of the isolator is the ability to change filters safely into or within the isolator in a contained zone. This is especially important for multipurpose dispensaries needing filter changing between product changeovers. Here again, the smaller air flow volumes means extract systems are small and any spares are more affordable. The filters are also smaller (typically 150 to 300 mm) so can be easily disposed of via bag out ports in the side of isolator fabrication, and using a continuous liner to seal around the used filters.

For fast turnaround between product changeovers, the cleaning and drying steps need to be kept short. For isolators, integral clean-in-place spray balls and validated, repeatable washing and drying cycles can reduce this time to 1-3 hours. The isolator can be designed with a sloping base to a single drain point, ensuring full liquid removal and thus obviating the need for labour intensive floor and surface cleaning of a flow booth.

In a large cleanroom other isolators can be used simultaneously, providing the flexibility to plan multiple but segregated operations in the same area.

Previously open powder charging with surrounding air curtains or flow booths provided a Class 10,000 environment at the point of powder charging into the reactors. This technique enabled the bioburden to be kept low during charging operations, but the process did not maintain vessel sterility. Even the use of split butterfly valves for sealable GMP powder charging with associated personnel dust protection could not guarantee aseptic interfacing with the process vessel.

sterile docking

Recent advances with the aseptic, sterile vortex split valve system ensures that both the bioburden is reduced before charging and that the split valve can be fully sterilised in situ, between each docking, to allow for sterile transfer of product from containers to reactors.

This new, patented design allows sterile docking and product transfer between pre-sterilised reactor vessels and a number of pre-sterilised powder containers to be carried out without having to re-sterilise the vessel contents.

For product transfer where heat stability of product is critical, vaporised hydrogen peroxide (VHP) can be used to sterilise the split valve surfaces. This is achieved through the introduction of VHP into an intermediate compartment formed between the two halves of the split valve. Once sterilisation is completed, the valve discs can be fully opened up to allow sterile product to be transferred without loss of sterility.

Typically, tray driers and freeze driers have been placed with the main door opening into a confined cleanroom or final product room; the emphasis being on minimising dust dispersal within that room as opposed to powder containment at source.

One common limitation has been the dryer door opening at right angles into the room, preventing the use of an isolator in front of the door during product off-loading and dispensing. Innovative door designs now allow sideways movement of the door, keeping isolator depth (front to back) to 550 mm maximum and allowing ergonomic access to all surfaces.

Traditionally, cleanroom design has been favoured in drying operations as it allows access for maintenance, cleaning and the ability to process non-hazardous batches without the restrictions of isolators. These issues have been resolved, however, by the introduction of mobile isolators with an integral inflatable seal at the rear of the isolator, providing a gas tight seal with a relevant wall flange surrounding the static freeze-drier door housing. With this design, Class 10,000 can be achieved along with OELs of below 1 microgramme/m3.

This mobile design allows the dryer to be used with or without containment making operations easier and fit for purpose. In some sites, several dryers can be installed but with only one shared mobile isolator that fits all dryers, improving production flexibility and asset utilisation. The detachable isolator can accommodate features such as weigh scales, airlocks for contained introduction of feed materials or trays, sampling, discharge of dried product with either split valves or continuous liners or drum filling and drum weighing capabilities. The concept is that the full drying operation can be carried out under contained conditions.

The pharmaceutical industry is moving towards increasingly potent powder manufacture and, therefore, more stringent standards for operator exposure limits. Increased product protection from bioburden, more reliable sterile operations, and more flexible and rapid turnaround between batch process steps are common corporate goals. The trend in the market is to use technically advanced and ergonomic isolators. Multiple operations in large cleanrooms are becoming the norm as companies look for leaner and more efficient methods of working, with less cleaning downtime, faster turnaround and high productivity.

The demand for new solutions, such as contained transfer valves capable of being sterilised just at the stage of product transfer, is going to increase. Such solutions will deliver new cost-saving methods of processing, opening up new opportunities to companies across the industry.

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