A Step Closer to Closure in Bioprocessing

cleanroom contamination control – Technical cleanliness and clean room | Image Credit: © Josef - Stock.adobe.com

Within the biopharmaceutical industry, the term “closed processing” refers to manufacturing performed using systems operating in a contained, segregated way. The reduction of interactions between biological products and sources of contamination opens up substantial possibilities for facility designs.

This article provides a brief history of closed processing, highlighting the progress made, future developments, benefits, challenges, and anticipated gains. It reviews regulatory context and emerging guidance, concluding with innovations in facility design using closed process components, shaping the “Facility of the Future” in biopharmaceutical manufacturing.

Vocabulary and definitions

Below are definitions of the terms related to closed processing as generally spelled out.

More than a decade ago, the International Society for Pharmaceutical Engineering (ISPE) defined “closed processing” 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).

BioPhorum defines closed process as, “a scheme in which all manufacturing systems used in process are closed” (2). This is complemented by the definition of a “closed system” as, “A system that isolates the process zone from its manufacturing environment and prevents ingress of environmental contaminants during product contact. The process zone is limited by equipment […]” (2).

The following three criteria were identified by ISPE to define a closed system (3):

• bioburden: quantity of viable microorganisms present and able to grow
• initial cleanliness of materials: level of chemical residues or nonviable particles in the product pathway
• equipment integrity: system’s ability to prevent physical barriers from being breached and penetration of microorganisms through components before and during the process.

The allowed limits for each product would determine the acceptable levels of residual bioburden and material cleanliness.

Closure at the system level can be achieved in two ways. A system is said to be functionally closed when it can be opened punctually (e.g., to install a filter or make a connection) and brought back to a closed state through disinfection or sterilization prior to use for product processing. A system is said to be fully closed when never exposed to the environment and when all elements introduced undergo an additional step avoiding contact with the environment (e.g., a pre-sterilized, single-use bag with transfer lines with aseptic connectors).

BioPhorum doesn’t make this distinction; it focuses on the closed end state, achieved by meeting the following two conditions (2):

1. “removal of latent contaminants in the process zone to a level commensurate with the process requirements, whether aseptic or low bioburden, prior to process contact.
2. prevention of ingress of environmental contaminants during process contact.”

Neither of those definitions implies sterile conditions; they describe achieving a state that can be qualified as bacteriostatic. For drug product manufacturing and final formulation, filtration, and filling, the capability to assure sterility must be verified, as mentioned in Annex 1 of the European Union’s good manufacturing practice (GMP) guideline (4). This would include the use of closed systems, when implemented.

Trends, benefits, and challenges

Market studies were performed, confirming a pronounced interest for closed systems across all geographic areas and professional functions surveyed (number of respondents N=42). The following is a summary of the findings.

The main motivations for the adoption of closed systems include:

• reducing the risk of contamination
• decreasing cleanroom requirements
• minimizing the risk of cross-contamination of products, especially when multiple products are manufactured in the same area.

It is perceived to be applicable for all types of biopharmaceutical products, and particularly beneficial for products that require a high classification cleanroom such as Grade A.

The consensus is that downstream steps would benefit the most from a closed mode of operation. This goes hand in hand with the opinion that they would be the easiest to convert—in particular, bioburden reduction and virus removal filtrations.

Nevertheless, the study highlights the challenges associated with the implementation of closed systems. The greatest obstacles are gaps in technology and facility design, such as connection solutions, to maintain closure, for transfer between different equipment; process monitoring and analytical tools management in closed mode; ready-to-use consumables to eliminate preparation or decontamination (difficult to run in a closed mode); and integrity testing solutions to identify breach of closed systems.

Furthermore, the market study shows a balance between implementation in new and existing facilities. However, the latter are often dedicated to a single or limited number of products and may require costly modifications.

Read the article in the Manufacturing and Facilities 2024 eBook.

About the authors

Sarah Le Merdy, senior strategic marketing manager mAb and ADC, Merck KGaA, Darmstadt, Germany; Christophe Dufossé, senior strategic marketing manager Next-Gen Bioprocessing, Merck KGaA, Darmstadt, Germany

Article details

BioPharm International®
eBook: Manufacturing and Facilities
November 2024
Pages: 4–10

Citation

When referring to this article, please cite it as Le Merdy, S. and Dufossé, C. A Step Closer to Closure in Bioprocessing. BioPharm International Manufacturing and Facilities eBook. 2024 November.