closed systems

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Using a closure analysis method to reduce CGT contamination risks

Many cell therapy manufacturing processes use open unit manipulations. As a result, they are at risk of potential contamination that can result in manufacturing batch failure. The processes therefore rely on end-to-end aseptic processing to ensure the final drug product is safe and free of potentially harmful contamination. Addressing these risks has led BioPhorum to publish Cell and gene therapy closed systems – closure analysis of a mock...

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Closure analysis of a mock autologous cell therapy process

In its current state, cell therapy manufacturing comprises several open and manual operations which increase the risk of contamination. Members of BioPhorum’s Cell & Gene Therapy Commercialization workstream have generated a ‘mock’ process detailing the manufacture of a generic autologous CAR-T product operated through a series of process steps combining some open and some closed system elements. The mock process has undergone an end-to-end closure analysis to identify those operations that pose the highest contamination risks, and to provide suggested mitigation solutions to minimize such risks. Suggestions include options that are currently available, as well as potential future ‘desired state’ options. This paper details the full process and summarizes potential risks and possible mitigations. The primary aim of this paper is to demonstrate systematic application of a closure analysis method on an ex vivo gene therapy (also known as gene-modified cell therapy) process so that organizations can apply similar analyses to their own processes. The secondary aim is to propose process closure solutions that companies could implement in their own operations.

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Formulation team sweeps away barriers to sharing

Biopharmaceutical formulations often present as complex mixtures that can be sensitive to heat, light, and many other factors, all of which must be monitored and assessed. However, until recently, developers worked mostly independently, with only their own resources and expertize to develop those assessments and set acceptable parameters. Within BioPhorum, competing companies can work together and benefit from sharing information that...

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The Spontaneous Infection: Did you leave the back door to your cultivation suite open?

In Shared clean-in-place systems: To share or not to share? and How much harm can a single droplet do? Considerations for a viral inactivation step, BioPhorum’s Drug Substance Closed Systems in CNC workstream addressed viral segregation of manufacturing steps relating to the purification process. In this follow-up paper, published by BioProcess International, the workstream looks more closely at viral contamination risks related to perhaps the...

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How to appropriately classify your cleanroom at early-stage design

BioPhorum Drug Substance Closed Systems in Controlled Non-Classified Workstream has recently published its room classification model article in the July/August 2021 edition of the PDA (Parenteral Drug Association) journal.  The paper outlines an assessment process to assist biopharmaceutical companies in assigning an appropriate grade of cleanroom during the early stage of design (e.g., concept design phase) in drug substance manufacturing...

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Shared clean-in-place systems: to share or not to share

This paper discusses design challenges such as how biomanufacturers often use extreme measures to segregate a post-nanofiltration operation from a cell-culture operation – but use a common glass washer or clean-in-place (CIP) skid for cleaning and sanitizing components from the two operations. The article looks at this apparent contradiction by using a mathematical model to evaluate the potential carryover/crossover risk.It aims to simplify production facilities so that a manufacturer doesn’t have multiple systems performing the same task. This means lower costs and complexity and facilities that are quicker to build and operate.

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Shared clean-in-place systems: to share or not to share?

The risk of viral contamination is acknowledged when developing biopharmaceutical products derived from mammalian-cell culture. And viral clearance and appropriate viral segregation are important factors in the manufacturing process and facility design. Good manufacturing practice guidelines from the US FDA and the EMA emphasize that appropriate segregation of process operations is a regulatory expectation. However, the word ‘appropriate’ is...

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Modular and mobile: Improving the biomanufacturing facility lifecycle using a standardized, modular design and construction approach

Traditionally, biopharmaceutical facilities can take up to three to five years from design through qualification before they are ready for full operation. Such facilities are often product dedicated, requiring significant and costly modification to accommodate additional products once the original product lifecycle has ended. This inherent inflexibility has become a major concern for the industry, especially given the increasing pressure to reduce costs and quicken the speed to market. To address these concerns this paper proposes a standardized design approach around an example facility solution for 2,000L-scale mAb application. The example facility focuses on demonstrating how a modular design approach may be realized using various construction methods – including traditional stick-built, prefabricated and skid assemblies, as well as modular cleanrooms or complete modular building units – without requiring major reconfiguration. At the core of this investigation is the intent to align the biopharmaceutical industry around a common understanding and approach to the design and construction of manufacturing facilities that makes the capital project process more predictable by, reducing schedule durations, improving project cost certainty, increasing facility design repeatability and ensuring greater regulatory compliance.

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Closed systems: Data driven equipment and facility design case study

Moving low bioburden drug substance manufacture from inflexible operations in a grade C environment to a modern, flexible multi-product facility in a CNC environment will result in significant reduction in costs for the industry. Such designs provide superior benefits like energy conservation, reduced facility capital and operating cost, shorter facility construction and qualification times, enhanced facility throughput and operational flexibility, reduced cost of goods and speed to market; all while maintaining the highest product quality standards. Capital costs may reduce by 45 per cent and operational costs by between 50 per cent (energy) to 100 per cent (Environmental Monitoring). This document reports on the learnings from bioburden reduction studies on hybrid (stainless steel and disposable) functionally closed bioprocessing systems developed over three years in collaboration with the Biomanufacturing Training and Education Center (BTEC) at NC State University that support these developments. The study concluded that measures as simple as flushing with WFI may be successfully employed to effectively mitigate the risk of assembling and operating a modern hybrid closed bioprocessing system in a controlled, non-classified environment, and are more effective at preventing bioburden contamination than making an open connection in a classified cleanroom without a subsequent cleaning step.

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Biomanufacturing technology roadmap: 5. Modular and mobile

This chapter of the first edition biomanufacturing technology roadmap published in 2017, describes the vision, scope and benefits that could be gained in the biopharmaceutical manufacturing industry from the development and use of a modular and mobile approach to facility design and creating. To help the industry achieve this future state it describes the scenarios considered, the future needs, challenges and potential solutions as well as the linkages and dependencies on other parts of the roadmap. It considers the contribution that disruptive and emerging technologies can play and regulatory considerations before finalizing with conclusions and recommendations.

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