The potency of medicines and their ingredients is increasing, requiring more handling and production steps to be contained. Camille Flores-Kilfoyle, Business Development Manager, PSL, looks at integrated equipment designs that can help
Inside view of a heel removal glovebox
Pharmaceutical compounds and active ingredients developed in laboratories today have increasing potency and require additional protection for the operators and the environment. Occupational Exposure Levels (OELs) set by scientific committees and institutes are increasingly rigorous and containment performance can be set at levels as low as 10ng/m3, 8-hour Time Weighted Average (TWA). Traditional restricted access barrier systems (RABS), laminar flow cabinets or fume hoods do not provide such a strict controlled environment, but high containment technologies do.
Containment technologies such as isolators and gloveboxes can fulfil the above requirement at any scale. ISPE defines containment technology as a ‘leak tight enclosure designed to protect operators from hazardous/potent processes or protect processes from people or detrimental external environments or both.’
During the synthesis of Highly Potent Active Pharmaceutical Ingredients (HPAPIs) one of the key process steps that needs to be contained is the filtration and drying of the wet product – also called the cake. Following the reaction or crystallisation, the API then needs to be isolated and dried to be ready for the formulation stage. This step is critical as the API is more potent and requires contained handling.
Before reviewing existing high containment systems, consideration needs to be given to the process equipment that would be suitable for this synthesis process.
Agitated Nutsche Filter Dryer
The use of an Agitated Nutsche Filter Dryer (ANFD) is one of the best methods for isolating, washing, filtering and drying the product in a contained manner. There is a minimal product transfer by using the same vessel for several processes, thus reducing the risk of cross contamination and exposure. Product is transferred from the reaction vessel to the ANFD vessel where pressured filtration enables the removal of the liquid phase. Using the top lid nozzle, suitable solvents can be integrated to wash the wet cake. Finally, the drying stage is carried out without transferring the product to other process equipment, usually by circulating heating fluid within the vessel walls under vacuum.
ANFD designs vary between manufacturers and it is important to consider the following features for the best performance when producing APIs:
Minimum solvent retention under the plate: The filtration media should be fitted onto a plate that allows for good drainability to avoid the retention of solvent during the filtration and washing stage. Typically this is achieved by a suitable design of the support plate with appropriate holes or concentric grooves. Efficient drainability can be an even more critical design consideration if the filter dryer is used for aseptic processing. The mother liquor can then be collected from the bottom of the plate to be re-circulated or discarded.
Efficient agitation: The agitator of an ANFD plays an important role in each process stage. Firstly, during the filtration, the agitator can be operated to smooth the cake and squeeze out the majority of the mother liquor. Then during washing and drying, the agitator can plough the cake to maintain a constant mixing of the product for homogeneity and faster drying.
Different agitator designs are available with ANFD, but typically the agitator should have curved blades allowing bi-directional rotation to smooth or plough the cake. A good agitator design will also include blades with teeth to mix any type of cake efficiently, and create a differential velocity. The agitator should be designed in a way that allows it to be raised and lowered inside the cake and to enable bi-rotation. The seal is, therefore, an important aspect that needs to be maintained. The best performing option for such a pressured vessel is to use a double mechanical seal.
Optimum heat transfer: With ANFD technology the drying phase is performed under vacuum and the vessel walls are heated to dry the wet cake after washing and filtration. Typically, heating is achieved by circulating heating fluid throughout the jacketed wall. A full heating jacket will maximise the heat transfer as well as provide a heated filter plate. Because the wet product is located above the filtration media, heating the plate will allow for direct heat contact. Here again, the design of the plate is critical as the smaller the volume under the filtration media, the better the heat transfer.
Finally, some ANFD designs include a heated agitator where heating fluid is also circulating inside the agitator and its blades. This feature provides the most direct heat contact with the wet cake while the agitator is mixing the cake. However, careful consideration of the agitator design is necessary. It needs to be a one-piece agitator with bellows to avoid any heating fluid leakage into the product.
Cleanability: When choosing an ANFD for the filtering and drying of APIs and HPAPIs, cleaning is one of the most important features to consider. Avoiding the risk of cross contamination is crucial and operators must never be exposed to the product, even during maintenance operations. Therefore the vessel should have clean-in-place (CIP) capability, normally via a spray ball or ring fitted on the dome of the vessel. Appropriate tests (typically using riboflavin) should be carried out during the factory acceptance test (FAT) to ensure the performance of the cleaning method. With ANFD, the cleaning can be further improved by applying the reflux cleaning method. This method uses the heating capabilities of the vessel to obtain a cleaning level of typically 2.5ppm to non-detectable. Steam-in-place (SIP) should also be achievable with ANFD if used to manufacture sterile products.
To reduce the risk of cross-contamination, the design details need to be carefully considered to ensure they provide good cleaning
To reduce the risk of cross-contamination, the design details need to be carefully considered to ensure they provide good cleaning. Having a one-piece agitator without any nuts and bolts not only prevents leakage but also cuts the risk of powder cross contamination between batches. Similarly with the fitting of the filtration media, bolts and nuts should be avoided at all costs.
Contained sampling: An advantage of ANFD technology is that the process is contained. When it comes to in-process sampling, the design should include a sampling port, usually within the plug assembly on the side of the vessel. Different types of sampling methods can be used with a ball valve or sample port. For safe handling, sampling should be carried out within a glovebox fitted on the side of the vessel, or at least a flexible bag to provide containment and a controlled environment.
Because of the high potency of some APIs and pharmaceutical compounds, the offloading of the dried product is the most critical step. The fact that ANFD avoids product transfer and reduces exposure to the product during filtration, washing and drying has already been discussed, but how to maintain the containment envelope during the final product recovery and transfer still needs to be considered.
Examples of Filter Dryer contained offloading
A variety of solutions are available in the market to maintain containment during discharging and sampling operations. There are automated methods avoiding the involvement of operators but these have limitations as they do not allow for a full recovery of the product. There is often a small quantity of dried product left behind that requires manual intervention – i.e. raking of what is called the ‘heel’ of the cake. In API production these small quantities are highly valuable and need to be recovered fully to ensure an acceptable production yield.
For full product recovery, a containment method is needed to protect the product and the operator. From flexible GloveBag to glovebox and full isolator facilities, the choice depends on the product potency level or OEL, the operation ergonomics and the next process step.
Typically a high containment glovebox with two gloveports is fitted on the side of the vessel. This glovebox should: operate under negative pressure; at a controlled humidity level; and, if required, be purged with nitrogen to remove the oxygen. Because the operator will manually discharge the remaining heel, additional protection should be added to the glovebox, such as the necessary proxy, interlock and glove guards, making it impossible to use the glovebox if the agitator is running. This monocell type of glovebox features a means of transferring the products via a chute towards a container or split butterfly valve.
The glovebox can also be larger to accommodate other operations such as discharging in a drum through an additional lower cell or even an in-line milling and/or dispensing process.
The containment provider needs to evaluate the ergonomics of the ANFD discharge operations to provide a fully integrated solution
The containment provider needs to evaluate the ergonomics of the ANFD discharge operations to provide a fully integrated solution. The glovebox should be designed based on the end user requirements but also on the production room where the installation is planned. Some installations provide additional features such as a platform for the operator to reach the lid nozzles or a mobile facility to move the entire installation within the plant.
For containment equipment users, having one supplier to provide both the ANFD and high containment discharge system is ideal. The provider should be able to supply an integrated system with expertise in both types of process equipment. The discharge plug and fitting of the glovebox on the vessel are critical to a safe and efficient installation.
Powder Systems Limited (PSL), for example, has developed a Full Heel Recovery Glovebox on its Nutsche Filter Dryer. Because of the increasing potency of APIs, it has also developed a fully contained filtration and drying facility called a FilterBox. Due to the characteristics of certain products, it is necessary to open the ANFD base completely and to clean some critical areas manually in a contained manner. With the FilterBox, cleaning and maintenance procedures can be performed safely and thoroughly as the complete vessel base filtration media and discharge plug are accessed in a contained environment.
The FilterBox technology is the optimum contained filtration and drying solution for handling cytotoxic compounds as it allows the following operations to be performed in a completely contained environment:
PSL FilterBox fully-contained filtration and drying system
Scale-up from chemical development in small-scale batches to industrial volume is a complex and time intensive process requiring considerable technology risks, equipment design and process constraints. Commercial application of any technology from development requires scalable equipment to be used throughout the whole process. PSL’s lab filter dryer – the GFD – is an innovative piece of small scale synthesis/lab filtration and drying or pilot plant equipment. The GFD is a miniature version of a production filter dryer allowing lab scale filtration, washing and drying with the same reliability and benefits of the full size ANFD.
The FilterBox is available for small ANFDs, completely integrating them within a high containment isolator, providing high level containment when handling highly potent APIs or other highly active or cytotoxic powders.
The FilterBox achieves containment to nanogram levels, protecting both the product and the operator during operations including charging, sampling, filtration, drying and discharging. The cleaning procedure can be performed safely and thoroughly as the vessel base and the removable filtration basket can be easily accessed in a contained environment. Interconnecting nozzles and pipes can be dismantled without any containment breach for contained cleaning and maintenance.
The FilterBox provides a more compact design than a traditional separate ANFD and containment products, reducing the floor space requirement and impact on the plant design while the FilterBox solution is easily scalable from laboratory to industrial production.