Written by:
Jordi Gibert Amat, head of the biotechnology business unit at Klinea Biotech & Pharma Engineering.
Núria Nieto Nicolau, Head of Advanced Therapies at Klinea Biotech & Pharma Engineering.
Leonardo Guasco, sales manager at Litek Pharma.
Advanced therapies (ATMPs) offer personalized treatments capable of addressing diseases that were previously incurable. However, their manufacture poses significant challenges, including the high energy footprint of cleanrooms, which require constant laminar airflow, high air exchange rates, and precise climate control to maintain temperature and humidity within strict ranges. It is estimated that a typical cleanroom may require between 30 and 50 times more energy than a similar building without these environmental requirements [3]. This impact takes on special relevance in the current context of decarbonization, driven by regulators such as the EMA and AEMPS [2] and by frameworks such as the European Union’s climate neutrality goals [5], Spain’s RITE [6], and the GMP guidelines for ATMPs [4].
In this scenario, isolators emerge as a key solution: they reduce the critical area subject to Grade A conditions, alleviate the load on HVAC systems, minimize the risk of contamination, and simplify validation [3]. Furthermore, the ongoing revision of Part IV of the GMP [4] reinforces the role of closed systems as the preferred option in the manufacture of ATMPs. Thus, isolators not only meet a regulatory requirement but also provide a competitive advantage by reducing energy demand, containing operating costs, and improving the facility’s total cost of ownership.
Overview of Insulators: Fundamentals and Advantages
The isolator is a closed system with a continuous physical barrier between the operator and the product. This ensures Class Aconditions (ISO 5 according to EN ISO 14644-1)[7] within the isolator by recirculating the internal air and subjecting it to HEPA filtration to maintain the sterility of the environment. Thus, this equipment can be installed in areas of at least Class D, as established in Annex 1 of EU GMP (2022) [8], since the critical environment is maintained within the closed isolator itself. However, for higher-risk sterile processes—such as frequent handling or a high microbiological load—a Grade C background environment may be required, always in accordance with the Contamination Control Strategy (CCS).
Its key components include automated decontamination systems capable of performing complete cycles using hydrogen peroxide (H₂O₂) vapor or other sterilizing agents, eliminating the need for direct human intervention in the disinfection of the critical area. It also features integrated gloves that allow materials to be handled without compromising the sterile barrier, as well as high-efficiency filtration mechanisms that protect both the product and the operator. Loading and unloading chambers with airlocks or RTPs (Rapid Transfer Ports) ensure that materials can be introduced and removed without compromising the integrity of the sterile environment.
The use of isolators, as opposed to open systems in cleanrooms, offers clear operational and economic advantages (Table 1). An open system requires a Grade A environment within a Grade B environment[8], which entails high energy consumption, very high air change rates, and a continuous load on the HVAC system. In contrast, an isolator confines these critical conditions to its interior space, reducing the volume of air that needs to be treated and, consequently, lowering energy consumption and operating costs. Furthermore, the physical barrier drastically reduces the risk of contamination from human intervention and simplifies compliance with environmental monitoring and validation requirements[3]. It provides an additional layer of biosafety for the operator, reducing exposure to biological materials handled in the manufacture of ATMPs, such as cells or non-replicating viral vectors.
Isolators are ideal for ATMP manufacturing processes that require prolonged aseptic handling or the handling of high-risk products. Examples include the production of TIL cells for immunotherapy, allogeneic dendritic cells for personalized vaccines, or certain gene therapy processes involving viral vectors that are susceptible to cross-contamination.
In ATMPs, isolators are enclosed, airtight separation devices capable of maintaining a Grade A internal environment, isolated by a rigid barrier, gloves, and safe transfer systems.
This solution is particularly well-suited for processes involving prolonged aseptic handling, live cells, or viral vectors, where there is no terminal sterilization and sterility is ensured through comprehensive process control. Litek Pharma offers modular isolators for ATMPs featuring a polished AISI 316L stainless steel chamber, laminar flow, integrated VHP/H₂O₂ biodecontamination, PLC/HMI automation, dual HEPA H14 filtration options, environmental monitoring, and the ability to integrate centrifuges, incubators, microscopes, genetic modification equipment, and fill-and-finish solutions. They also incorporate airlocks, RTPs, and safe waste disposal systems, which facilitate material transfer and reduce the risk of cross-contamination. [9]
An increasingly blurred boundary between sectors
The convergence between cosmetics, biotechnology and pharmaceuticals is not only conceptual. At the technological level, many tools, knowledge and methodologies are shared, although the regulatory frameworks are different.
This convergence creates opportunities, but it also requires sound judgment. It is not a matter of “copying” pharmaceutical models, but rather of adapting biotechnological solutions to the cosmetics industry, striking the right balance between technical rigor, agility, and economic viability.
The companies that best manage this frontier are those capable of translating scientific complexity into understandable, safe and competitive products.
Energy Sustainability Analysis
The published comparison between an open system (A in B) and a closed system with isolators (A in D) for the production of ATMPs demonstrated a marked reduction in HVAC consumption and total energy use, as well as an approximate 50% decrease in greenhouse gas emissions, attributable primarily to the lower environmental classification of the sump and the lower volume of air subjected to intensive treatment, which sets the sump of a closed isolator at Grade D, always subject to justification in the CCS. The analysis not only highlights the savings but also their environmental impact: lower electricity consumption means fewer emissions and reduced cooling demand, which translates to reduced water use, in line with the European Green Deal.
Ultimately, switching to an insulator doesn’t just save money—it’s a strategic decision that combines sustainability, efficiency, and regulatory compliance[3].
Economic Analysis: CAPEX, OPEX, Depreciation
The implementation of isolators affects the cost structure, both in terms of initial investment (CAPEX) and annual operating expenses (OPEX). While an open system in a Class B room requires more complex infrastructure (construction of high-classification rooms, high-capacity HVAC systems, and additional access points), an isolator in a Class D room reduces these requirements, although it adds the cost of the equipment itself.
With OPEX, the difference is even greater: the open system involves high energy consumption and recurring costs for validation, maintenance, monitoring, and consumables (especially protective clothing); the isolator reduces the need for a critical-grade environment and simplifies environmental control. Thus, the additional initial investment is offset by operational savings that yield a return on investment within two to five years, depending on the process and the intensity of use of the facility.
Reducing operating costs can substantially improve the project’s profitability over its useful life, although the exact payback period must be evaluated on a case-by-case basis depending on the type of process, usage intensity, plant design, and local operating costs.
Regulatory Compliance and Quality
The use of closed systems such as isolators is clearly supported by regulations governing the production of sterile drugs. Annex 1 of the EU GMP, revised in 2022, states that, where feasible, aseptic processes should be carried out in closed systems to minimize the risk of microbial and particulate contamination[9]. In the case of ATMPs, Part IV of the GMP specifies that this Annex applies only to operations involving sterilization, referring to it for guidance [10].
Although its application in this area is limited, the principle of favoring closed systems over open ones strengthens the technical and regulatory justification for isolators in ATMPs.
The isolators ensure a Grade A environment independent of the room, stabilizing critical parameters (temperature, humidity, airflow) and reducing viable and nonviable particles. This simplifies monitoring, minimizes deviations, and streamlines inter-batch validations. In addition, this strict control mitigates cross-contamination, accelerates product release, and facilitates inspections by the EMA, AEMPS, or FDA [10].
The use of isolators is integrated with the risk analyses required by GMP regulations[9]. By reducing uncontrolled environmental factors and manual intervention, the overall risk to the product is minimized, which directly impacts final quality and batch-to-batch consistency. This stricter control not only facilitates regulatory compliance but also provides operational benefits: fewer revalidations, a lower risk of cross-contamination, and a positive impact on product release times and costs.
Beyond ATMPS: The Versatility and Scalability of the Technology
They enable the scaling of processes under reproducible and validated conditions[12]. This ability to maintain critical environments consistently across different scales makes them a strategic tool for the industrialization of complex processes, such as the manufacture of ATMPs.
Looking ahead, the ongoing revision of Part IV of the GMPs specific to ATMPs is expected to further strengthen this role. In its Concept Paper, the EMA highlights the need to update the design requirements for production areas, aligning them with Annex 1 and promoting the use of closed technologies as the standard[4]. If this approach is confirmed, isolators will go from being a recommendation to the preferred solution for meeting regulatory requirements and ensuring environmental control in ATMPs, with the new requirements expected to take effect.
Conclusions
We’ll skip the metaphor and the lengthy introduction to get straight to the point: the isolator integrates environmental sustainability, economic efficiency, and operational excellence without compromising the quality of the final product. Environmentally, it reduces energy consumption and the carbon footprint by minimizing the critical cleaning area. Economically, it substantially reduces operating costs and facilitates a rapid return on the initial investment. Operationally, it stabilizes critical process conditions, reduces variability, and simplifies validation and environmental monitoring tasks.
Furthermore, its versatility and scalability allow the same technology to be applied to everything from the production of advanced therapies to other sterile medications, without sacrificing efficacy or compromising quality. With the upcoming revision of Part IV of the GMPs for ATMPs, it will establish itself as the strategic solution for facilities seeking to combine regulatory compliance, competitiveness, and sustainability in the manufacture of ATMPs.
Bibliography
[2] https://www.amrindustryalliance.org/mediaroom/pressure-mounts-on-pharma-to-act-on-environmental-targets/
[3] Pinnetta G, Adamini A, Severina F, Fagioli F, Zanini C, Ferrero I. Evaluating Ecological Impact and Sustainability in the Manufacturing of Advanced Therapies: Comparative Analysis of Greenhouse Gas Emissions in the Production of ATMPs in Open and Closed Systems. Bioengineering (Basel). September 6, 2023;10(9):1047. doi: 10.3390/bioengineering10091047. PMID: 37760149; PMCID: PMC10525939.
[4]https://www.ema.europa.eu/en/documents/scientific-guideline/concept-paper-revision-part-iv-guidelines-good-manufacturing-practice-specific-advanced-therapy-medicinal-products_en.pdf
[5] https://www.consilium.europa.eu/en/topics/climate/
[6] https://www.miteco.gob.es/es/energia/eficiencia/rite.html
[7] https://www.iso.org/standard/53394.html
[8] https://litek-pharma.com/en/products/atmp-isolator-advanced-therapies/
[9] https://www.gmp-compliance.org/files/guidemgr/20220825_gmp-an1_en_0.pdf
[10]https://www.fda.gov/files/drugs/published/Sterile-Drug-Products-Produced-by-Aseptic-Processing-%E2%80%94-Current-Good-Manufacturing-Practice.pdf
[11]https://ispe.org/pharmaceutical-engineering/november-december-2020/flexible-facility-design-multiple-cell-therapy