Containment in the production of solid formulations With these containment solutions you are on the safe side
Although modern containment systems are state-of-the-art technology in the production of solid pharmaceutical formulations, the interfaces to the surroundings and the cleaning processes still represent critical aspects. These need to be managed with a great deal of know-how.
The number of highly effective drugs in OSD production has risen dramatically in recent years. As a consequence, containment is becoming an ever more important issue in the production of solid formulations. Any endangering of staff, surroundings, and the environment due to escaping substances or because of inadequate cleaning can have fatal consequences. Increasingly stringent legal requirements and regulations and the rising complexity of manufacturing methods further underline the necessity of high-quality containment solutions. This is why there is now a wide range of different approaches and concepts depending on the toxicity level of the active ingredient being processed.
In this article, we present the special requirements of containment in OSD production using two very different granulating lines as examples in order to highlight the great range of design options on offer. What all these options share is the now common horizontal construction method with predominantly pneumatic conveying systems within a close system. Differences can be found among other things in the interfaces to the surroundings and in terms of the cleaning processes used – but both are explained in more detail in the article.
Containment valves (split butterfly valves) are used to optimize the interfaces for the inflow and outflow of materials. In the initial design, it is very important to coordinate the makes and sizes of these valves with the operating company, because they need to be compatible with the latter’s containers and must be designed for the required containment level.
For optimized handling and quick and easy cleaning, liner systems are often used at sampling points.
In addition to the use of primary filters within the line, the exhaust air from the mixer, from the fluidized bed, and from the pneumatic conveying equipment is also passed through a redundant backup filter and/or dedusters. These ensure that the exhaust air is free of particles, and they are equipped with bag-in-bag-out (BiBo) systems for contamination-free filter changes and dust discharge.
As a minimum, the cleaning concept must ensure that all dust is bound with moisture before the line is opened. The first-run rinsing water is collected separately. These minimum requirements are relatively easy to implement, but are generally not sufficient for larger lines or production setups with more stringent requirements. This is why our two examples also differ in terms of these details.
Small batches up to OEB 4
With the aid of the Diosna Compact Granulation System CGS 150 with WIP system it is possible to manufacture batches of up to 70 kg (launch plant). The system can be used up to OEB 4 and contains an integrated mixer that is charged under vacuum and is thus inherently safe. A pressure shock-proof design of 12 bar is provided.
This system is used to produce ready-to-compress granules in a production room with limited floor space (Figure 2). For charging of the mixer, the raw materials are sucked in through a docking station with split butterfly valves. The dry mill is interchangeable. The conical mill can be substituted with an oscillating mill. So that the screen insert can be inspected/replaced under containment conditions if required, it is possible to install a soft isolator via an additionally attached collar.
The integrated blender performs two roles: It docks the container on the active part of the split butterfly valves and takes care of final mixing with the external phase for the tableting process. The blender is integrated in the line control system and is therefore also integrated in the batch reporting. Cleaning is performed using a WIP system without recirculation. The WIP station is only equipped with a pressure boost pump, a heater, and two detergent dosing pumps. Cleaning nozzles are positioned at various points in the line, to ensure proper cleaning of the plant. For some components (e.g. vacuum conveying hoses, product filters of mixer and dryer) a wet down with subsequent dismantling is more efficient and hence the procedure of choice. The advantage is, that the dismantling of these components shortens considerably the cleaning downtime by simplifying the internal geometries of the process equipment and parallel off-line cleaning of parts. Cleaning adapters are coupled by hand to the active split butterfly valves. Thanks to the large integrated operator platform, all components of the system are very easily accessible for dismantling and inspection after cleaning.
Production batches up to OEB 5
Batches up to 300 kg can be manufactured using the Diosna Compact Granulation System CGS 800 (Figure 1). The mixer is charged under gravity, and there is a CIP system that also cleans the air supply and exhaust air lines. The complete system is suitable for use under OEB 5 conditions (OEB = Occupational Exposure Band). The complete system is suitable for use under OEB 5 conditions (OEB = Occupational Exposure Band). Here again, a pressure shock-proof design of 12 bar is provided to ensure absolute safety also for the unlikely event of an explosion inside of the equipment in this system, charging of the mixer is performed using a lift/swivel post hoist.
The container is docked above the mixer on the active part of the containment valve on the lid of the mixer. Since containers will always display certain tolerances, flexible installation of the active split butterfly valves is generally required. Before the two halves of the valves are interlocked with each other and the valves are opened, the correct position is checked automatically.
All product filters in the system are designed as stainless steel filters suitable for CIP. They are rinsed intensively from the inside and outside and drained at the same time. The large cartridges of the dryer rotate during cleaning while being simultaneously lowered and raised again. They can be lowered to operator height for inspection. All surfaces that come into contact with product, all pipes that carry product, and the binder containers are cleaned automatically. The air supply and exhaust air lines are also included in the cleaning process from time to time. To do this, CIP-appropriate quick-acting valves and cleaning nozzles are installed in the lines. All cleaning valves are equipped with position feedback systems. The CIP station in the technical zone is equipped with a buffer container, a centrifugal pump, a heater, and three dosing pumps. The flow rate, pressure, temperature, and concentration of the cleaning medium are measured. A centrifugal pump at the lowest point of the system sends the cleaning medium back to the CIP station when cleaning is running in recirculating mode.
After the CIP cleaning, with the exception of the binder tank the system is dried using hot air from the supply part of the fluidized bed. The cleaning adapters for the containment valves on the mixer and under the dry mill are equipped with large connections for the drying air for this purpose. Due to their sizes and weights, the cleaning adapters are installed in stainless steel frames and are docked/undocked with the aid of the lifting columns.
Scope for alternatives
The two examples show how differently production lines for containment applications- can be designed. The smaller one of the two systems operates with around 20 valves and six cleaning nozzles, while the 800-liter plant is equipped with 120 valves and 30 cleaning nozzles. In between there is, of course, plenty of scope for other alternatives, and this is something users definitely take advantage of. The start of a project must therefore always involve a thorough analysis of the requirements of the product and process – ranging from the batch size to the requirements for qualification and documentation. The URS specifications generally do not go down to a detailed level in terms of how the system needs to be designed. It is up to the supplier to highlight the different options and explain their impact as part of a comprehensive consultation process.
WIP or CIP?
In terms of cleaning, we should not restrict ourselves to just thinking about the terms WIP or CIP. Some parts of a plant can be cleaned very easily using fully-automated systems, while partial automation or manual cleaning may make more sense for other areas in the same line. It is also important to not forget about the characteristic properties of the product. These may permit CIP for the line in some cases, or only WIP in others.
Very extensive CIP with recirculation of the cleaning media is chosen in particular for larger lines and lines with particularly stringent containment requirements (example 2). This is very safe and reliable and opens up many options for optimizing the cleaning process, including for more challenging cleaning tasks. High flow rates with corresponding flow speeds, high cleaning agent concentration, and high temperatures can be achieved in this way. Nonetheless, recirculating the cleaning medium means that less water, steam, and cleaning agent is required. An inspection after cleaning is not necessarily required. Despite this, the line should always be designed in such a way that all parts of the line are easily accessible and can be easily inspected, e.g. the shaft seals of the mixer.
In the case of lines where the cleaning medium is recirculated, it is important to consider that significantly more pipes are required and that they will be contaminated with product and cleaning agents by the recirculated medium, so they must also be cleaned and rinsed accordingly afterwards. The final rinse of the system with demineralized water thus requires more of the medium than a simple system without recirculation.
When weighing up alternatives, it should also be taken into account that highly complex WIP or CIP cleaning also requires a large number of valves, nozzles (see above), tubes, hoses, pneumatic lines, and cables. All of this takes a great deal of time and effort to install, control, qualify, and look after throughout the entire service life of the equipment. The more highly automated the cleaning system, the more hoses, valves, and cables may be required in the cleanroom – this may be perceived as disruptive in some cases.
Every process is different
Since every process presents different containment challenges, each one requires an individual design based on the plant/line size, available space, toxicity of the products, and the requirements relating to product and operator safety. In addition, it is also important to take into account the individual attitudes of operating companies and operating personnel to the topics outlined above to ensure that a satisfactory outcome is achieved for everyone involved.