Is closed processing a reality?
Somasundaram G, Senior Consultant – Asia Pacific, Global BioPharm Centre of Excellence, Process Solutions, Merck KGaAand Priyabrata Pattnaik, Director, End-to-End Solutions – Asia Pacific, Process Solutions, Merck KGaAdefine the key drivers for adopting closed processing, detail the pros and cons of closed processing and some innovations happening in this sphere
Closed processing is considered to be a logical extension of single-use and involves the use of physical barriers to separate processing fluid from the external environment, including the operators. Materials enter or leave the system via predetermined control points.
International Society for Pharmaceutical Engineering (ISPE) defines it as, “A process condition when the product, materials, critical components, or container/closure surfaces are contained and separated from the immediate process environment within closed/sealed process equipment. A process step (or system) in which the product and product contact surfaces are not exposed to the immediate room environment.” In this article, we will define the key drivers for adopting closed processing, what are the pros and cons of closed processing and how some of the innovations are happening in this direction.
Is closed processing the same as connected processing?
Biomanufacturing is steadily moving towards higher efficiency through process intensification. One of the key aspects of intensification is operational excellence through connected processing, resulting in functionally closed bioprocess. The advantages of closed processing are shorter processing time, less manual interactions in the process, reduced CAPEX, reduced resources for cleaning and validation, and reduced need for qualified manufacturing space.
Drive to go for closed processing
One of the main drivers for closed processing is to achieve Contamination Control Strategies (CCS). Closed processing, when designed and implemented correctly, mitigates the risk of contamination by adventitious agents, reduces the amount of human intervention and manipulation and protects operators. In addition to a reduced risk of contamination, closed processing offers several benefits including reducing capital expenditures, reducing the classification of cleanrooms and accelerating time to market.
What are the options available?
Critical enablers for closed connected processing are:
Closed bioreactor: Closed processing has always been mandatory in upstream processing to maintain sterility and to avoid contaminations. Also, an ecosystem of closed vessels or bags for media, feeds, glucose, antifoam, etc; have been well established. Continuous upstream processes (i.e., perfusion), have a long history in the production of unstable proteins and is therefore well-established.
Connectors: The connecting device or connection method may appear to be a small part of an overall system, however, connection and disconnection of tubing for process fluid transfer is a critical aspect of closed processing. Manufacturers need to carefully consider the available options because the connector can be the deciding factor in keeping the single use bioprocess truly aseptic.
Sampling: Sampling of biopharma process intermediates and the final product is essential for manufacturing workflows where the final product cannot be terminally sterilised. Unfortunately, “traditional” sampling methods are not closed systems and therefore do not maintain a barrier to contamination entering the process during sampling. As a result, the sampling process itself, which is critical to the success and safety of the manufacturing workflow, can lead to contamination of a unit operation and possibly an entire batch. In contrast, aseptic sampling systems are disposable, closed units that always maintain aseptic conditions and ensure the security of the process, operator, and the sample. Due to the shortcomings of traditional sampling, many biopharma companies have adopted closed, single-use sampling technologies. A closed design ensures the process sample collected from a specific point for analysis, reducing the risk of losing valuable product while maintaining the integrity of the fluid samples.
Fill finish assembly: For closed connected processes, it is important to consider the length of the tubing connecting the different unit operations carefully. It is beneficial from a contamination risk viewpoint to design the tubing length as short as possible, to make the setup easy to survey, facilitate the transfer of the liquid and minimise dead legs and losses in the tubing. This type of setup needs to be carefully planned and knowledge of the equipment used such as its appearance, size, contexture, etc., is necessary.
Potential pros and cons of closed processing
- The risk of contamination is greatly reduced, due to the physical barriers protecting the product from human contact.
- Closed systems reduce operating time by relying less on operator handling and more on pre-assembled components. Single-use products may still be used, though unnecessary for sterilisation. If implemented, these products will also reduce time in the areas of cleaning, validation, setup, and operation.
- Manufacturing operations can take place in lower classified environments (able to downgrade production area to Grade B or lower).
- Reduced operating time and cost optimisations.
- Due to the relative newness of closed operating technology, facility managers should ensure their equipment operators are capable of adjusting to the new process before adopting it. The new approach has reportedly bee