How close are we to closed processing?

[Author’s Note: This article presents the authors’ views on benefits, considerations, current technologies available and gaps that the industry is facing for closed processing.]

Closed processing, considered to be a logical extension of single-use systems, 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.

Closed processing has been defined 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’’ (1).

The aspiration of the biopharmaceutical industry is to move to fully integrated closed processing in a batch, semi-continuous, or continuous mode of operation. The intention is to remove aseptic manipulations that pose a risk of contamination to bioprocessing, to increase process efficiency and, ultimately, to achieve a higher state of patient safety.

Is closed processing the same as connected processing?

Biomanufacturing is steadily moving toward high-efficiency throughput process intensification. One of the key aspects of intensification is operational excellence through connected processing combined with barrier isolation, which results in a functionally closed bioprocess.

The advantages of closed processing are:

• Shorter processing time
• Fewer manual interactions in the process
• Reduced capital expenditure
• Fewer resources for cleaning and validation
• Smaller qualified manufacturing spaces

Drivers for Closed Processing

One of the main drivers for closed processing is to achieve contamination control strategies. 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 that includes reducing capital expenditures, reducing the classification of cleanrooms, and accelerating time to market.

What are the available options?

Critical enablers for closed connected processing are:

(a) Closed Bioreactor

Closed processing has always been mandatory in upstream processing to maintain sterility and avoid contamination. Also, an ecosystem of closed vessels or bags for media, feeds, glucose, and antifoam, for example, have been well established. Continuous upstream processes (i.e., perfusion) has a long history in the production of unstable proteins and is therefore well-established (2).

(b) 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.

(c) Sampling

Sampling of biopharmaceutical process intermediates and the final product is essential for manufacturing workflows where the final product cannot be terminally sterilized. 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 biopharmaceutical 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.

(d) Fill Finish Assembly

For closed connected processes, the length of the tubing that connects the different unit operations should be considered carefully. From a contamination risk viewpoint, it is beneficial to design the tubing length as short as possible, to make the setup easy to survey, and to facilitate the transfer of the liquid and minimize dead legs and losses in the tubing. This type of setup needs to be carefully planned, thus having a strong knowledge of the equipment used (e.g., its appearance, size, contexture) is necessary.

What are the potential pros and cons of closed processing?

Pros

• Risk of contamination is greatly reduced, due to the physical barriers protecting the product from human contact.
• Reduced operating time by relying less on operator-handling and more on preassembled components. Single-use products may still be used, though it is not necessary for sterilization. If implemented, these products will also reduce the amount of time in the areas of cleaning, validation, setup, and operation.
• Closed systems can be operated in a lower classification environment (production area in Grade B or lower).
• Operating time is reduced, and costs are optimized.

Cons

• Relative newness of closed operating technology should prompt facility managers to ensure equipment operators can adapt to the new process before adopting it. The new approach has reportedly been met with uncertainty by many engineers who preferred the more traditional process.
• Operating is at high risk.
• Large amount of Grade A space is used.
• Operational costs are increased.

Future Perspective

Though we aspire to achieve fully integrated, completely closed bioprocessing, we are not there yet.

There is general confusion about how we define connected processing with closed processing and continuous/contiguous processing. Closed processing is the idea that the flow path of product and materials could be operated as a closed system, reducing or eliminating the dependence on a controlled cleanroom environment to prevent environmental contamination and ensure quality. Whereas, closed processing necessitates a connected processing and should not be confused with continuous processing.

Summary

The benefits of closed processing are compelling, and regulatory agencies have encouraged this approach to mitigate risk of adventitious agent contamination (3). As regulations continue to crystallize, biopharmaceutical manufacturers are increasingly exploring their options about evolving from open to hybrid to closed processing. While widespread adoption of these regulations may be several years away, the recent COVID-19 pandemic resulted in the rushed implementation of single-use and closed processing to increase the production capacity for SARS-CoV-2 vaccines and therapeutics. The pandemic has likely accelerated the pace of consideration and integration.

Many technologies are available today to facilitate closed processing including bioreactors, single-use systems, automated equipment, sterile connectors, and in-process sampling. Use of these technologies not only minimize the risk of contamination today but will also reduce the cost of facilities in the future, enable greater flexibility in manufacturing, accelerate workflows and help ensure high product quality.

References

1. ISPE Baseline Guide for Biopharmaceuticals Facilities, Second Edition, November 2013.
2. Mobius^® Single-Use Bioreactors: A scalable ergonomic system designed to optimize your fed batch and perfusion process. MerckMillipore Data Sheet DS3377EN00, Ver. 8.0; 01/2020. https://www.merckmillipore.com/Web-SG-Site/en_US/-/SGD/ShowDocument-Pronet?id=201306.10928. (PDF Download)
3. EU GMP Annex 1 Revision: Manufacture of Sterile Medicinal Products (Draft), Section 8.116, EU Commission. https://www.gmp-compliance.org/files/guidemgr/2020_annex1ps_sterile_medicinal_products_en.pdf. (PDF Download)