Isolator or Single-Use Equipment Containment Strategies in the Development of Oral Solid Dosage (OSD) Forms
No-one who deals with highly active substances in OSD development can avoid the issue of containment. However, the smaller scale places different demands on equipment compared to the equivalent steps in production. What do developers need to look out for, and what practical solutions are available? We look for clues between the laboratory and the plant.
Even during the development phase of high-potency oral drugs, the same requirements apply in terms of employee and product protection as during production. However, different containment solutions are usually applied at the smaller scale than later on in production processes. Two practical examples highlight the technical requirements in relation to process equipment. The focus here is on granulation and drying.
In the area of development, the choice of containment solution depends on various factors, with a key aspect being the size of the batches. For smaller batches up to around 5 kg, experience has shown that a successful approach is to install the process equipment inside the isolator — though larger capacities can certainly also be handled in this way. The reason is simple: thanks to their small dimensions at this scale of production, pumps, mixers, dryers and mills are easy to operate within the isolator. The size and weight of the individual components allows comfortable handling of materials and equipment, even with safety gloves. Another reason is safety: isolators are very safe. Despite the fact that the processes are performed manually, the possibility of active ingredients being released is almost entirely ruled out. Another important advantage in using an isolator during the development phase is the fact that the setup is highly flexible. Processes can be easily stopped or changed, and the apparatus can be opened at almost any time to check products or take samples. In this way, developers get a very good feel for how their recipes perform.
The isolators and their equipment items are often individually adapted to the product in question.
Mixers and fluidized beds are supplemented with balances, pumps, and mills as required. Different lock systems can be needed for transfer into and out of the isolator, and in these cases a mock-up study should be carried out beforehand. In such a study, every aspect of the handling is simulated in a wooden model of the isolator, ideally using original process components (so as to get a feel for their weight, for instance), and the study should also cover cleaning and disassembly of the equipment.
Inward and outward transfer of active ingredients and excipients (in bags or plastic bottles) takes place through “alpha-beta” ports (these are also known as rapid transfer ports, RTP). Alpha-beta ports are locks that enable contamination-free transfer into and out of the isolator. Liner packages and split butterfly valves are also used for the outward transfer.
It is a prerequisite for implementing containment via isolators that the process equipment is designed and arranged appropriately. Today, high-shear mixers are used not only for wet granulation for tabletting mixtures, but also very often for the dry mixing of inhalable drugs (Dry Powder Inhaler, DPI), since the high-shear forces allow for perfect homogeneity even for smallest drug contents. For installation inside an isolator, mixers ranging in size from 0.25 to 20 l can be equipped with interchangeable bowls.
The location of the mixer drive is an important aspect. This should always be outside the isolator, to facilitate cleaning and general handling. The shaft seals for both the main drive (through the base of the isolator) and the chopper (through the rear wall) are gas-tight and liquid-tight. The mixer lids are made of glass to make it easy to observe the mixing process.
Fluidized bed dryers are also known for their flexibility. Fluidized bed dryers that have been optimized for isolator operation can be equipped with interchangeable containers that range in size from 100 ml to 20 l. Only the parts that come into contact with the product are located inside the isolator itself. With suitable designs, a variety of fluidized bed processes — such as top and tangential spray granulation, and pellet coating — can be performed within the same container. An interesting alternative to granulating lines under containment conditions are single-pot systems. Mixers can be designed as single-pot units for drying the granules under vacuum. To do this, the mixing containers have double walls and feature special shaft seals for vacuum operation. The vacuum pumps and heating/cooling devices are located in the technical area.
All in one solution
In an example production plant (see photos, below and on next page, showing a rectangular layout), the material flows from right to left through a rapid transfer port into the mixer. Bags are used to transfer excipients and active ingredients into the isolator. A peristaltic pump in the rear wall supplies binder to both the mixer and the fluidized bed. The wet or dry mill is arranged between the mixer and the fluidized bed. To the left of this is the fluidized bed apparatus. This area has an angled, L-shaped layout. The material container and the filter housing can be swiveled and tilted to the side. Police filters for the process exhaust air are integrated into the rear wall, where they can be swapped without risk of contamination. With this design, granulation is completed within a short space of time and with minimum effort. This makes it superior to alternatives such as an isolator with two or three mobile, interchangeable process inserts for the mixer and the fluidized bed. On the other hand, the cleaning requirements are slightly higher with this solution if only part of the line is used, for instance in fluidized bed granulation. Cleaning is performed with the aid of spray nozzles in the filter housing of the dryer, and with manually operated spray guns.
The alternative …
An isolator is not always necessary, however. Anyone who only works occasionally with highly active substances, or just wishes to be prepared in advance, will usually shy away from the comparatively high investment costs of an isolator. For this reason, the use of foil bags in combination with containment valves made of plastic is becoming increasingly popular. While the bags themselves are disposed of after a single use, the containment valves can be reused multiple times, for example for an entire campaign. The valves and bags are attached to the apparatus with sturdy fixings. Plastic split butterfly valves that are compatible with stainless steel half flaps are another interesting option. The active (heavy) half made of stainless steel is installed on the mixer, dryer, or mill, while the passive half made of plastic is installed on the containers.
… single-use bags
On a line for the production of batches up to 9 kg, foil bags were used for material transfer and for containment valves made of plastic. This achieves the required containment for the process steps of wet granulation in the mixer, drying, and various spray processes in the fluidized bed. The key reason why single-use equipment was chosen was the fact that in this case working under containment conditions is only required occasionally.
The system is designed so that the bags with the solids are suspended and docked above the mixing container. The valve can then be used more often before it is finally disposed of. A similar approach is adopted for emptying the mixer and for all further steps in the process, such as drying and calibration (grinding). The exhaust air from all system components, particularly from the dryer, also passes through HEPA filters in addition to the primary filters before it is discharged. Cleaning of the system is largely performed while it is closed. This is done manually and via wash-in-place (WIP) nozzles in the fluidized bed. All dust is bound before the apparatus is opened.
Operation is safe thanks to extensive training of the operating personnel and the preparation of corresponding standard operating procedures (SOPs). In special cases, personal protective equipment can also be worn. Handling of the components was perceived as comfortable, particularly in comparison with the operation of similar apparatus through the gloves of an isolator. The low weight of the materials, including the foil bags, also made a positive impression on the operators.
The valves are easy to open and close manually, thanks to their design and the small diameter. However, automation and safety functions such as limit switches are not possible. The containment components are not pressure-resistant or vacuum-tight, and only offer limited watertightness. The latter needs to be taken into account during cleaning, among other operations. Similarly, during manual cleaning, without additional measures the wastewater is not collected automatically, as it is in the isolator. Compared to placing equipment inside an isolator, therefore, this solution is less costly but is no match in terms of operational safety, comfort, or flexibility.
These two examples show two major technologies for manufacturing solid formulations in the research and development phases. Whether to choose enclosure in an isolator or in bags will depend entirely on the application.