Conflicts related to cleanroom design are elevated to a regulatory issue and require collaboration between engineers, quality professionals, regulators and researchers to resolve them. In today’s healthcare environment, the growth in Advanced Therapy Medicinal Products (ATMPs) is driving some of the largest challenges, with a critical need for high-performance manufacturing facilities. These facilities often require both biocontainment and contamination control to create an environment that can support sterile manufacturing and protect personnel and the environment from biological hazards.

Regulatory oversight for such high-performance facilities is derived from the cumulative requirements of guidelines such as ISO 14644, U.S. Food and Drug Administration Current Good Manufacturing Practice (CGMP) Regulations and European Union Good Manufacturing Practice, as well as European Union biotechnology standards and biocontainment guidelines from organizations like the World Health Organization and the U.S. Centers for Disease Control and Prevention (CDC) and National Institutes of Health. This cumulative framework, designed to protect patients and researchers alike, includes fundamental differences in requirements that lead to a risk-based, compromise-driven approach to compliance.

The need to harmonize overlapping standards in the ATMP field presents an opportunity to elevate the entire biopharmaceutical field. By adapting manufacturing platforms to align with these standards, a higher benchmark for cleanroom safety can be established, making it easier to adopt these practices across the industry.

According to the International Society of Pharmaceutical Engineers (ISPE), the global ATMP market is expected grow form approximately $8.5 billion in 2022 to over $20.5 billion by 2031. This exponential growth, coupled with increasingly complex therapies, necessitates the development of multimodal facilities capable of supporting diverse manufacturing processes. For example, gene therapies often use viral vectors such as lentiviruses and adenoviruses that require Biosafety Level 2 (BSL-2) or higher containment. Additionally, when the volume of the biological material exceeds ten liters, large-scale biosafety guidelines also come into play.

Multimodal facilities must be designed with careful consideration for strategies that ensure proper workflow separation. Activities such as cell harvesting, viral vector production and final filling require physically separated areas or cleanroom airflow pressurization strategies to prevent cross-contamination.

The evolution of ATMP manufacturing has also led to significant changes in scale and the type of process equipment used, which has further influenced facility designs. Unlike traditional large-scale biopharmaceutical manufacturing, many ATMP processes operate at smaller volumes due to the personalized nature of cell and gene therapies and the high value of individual batches. For example, therapies often involve smaller batch sizes tailored to specific patient populations or even individual patients, reducing the need for expansive cleanroom spaces.

This shift toward smaller-scale manufacturing has spurred the adoption of more compact, flexible cleanroom designs. These designs prioritize efficiency and scalability while maintaining high contamination control standards. Modular and factory-built cleanrooms have become increasingly popular, as they allow for rapid deployment of right-sized facilities that align with the smaller footprints required for ATMP processes. These innovations not only optimize the use of physical space but also reduce operational costs and time-to-market, making them a cornerstone of modern ATMP manufacturing.

In another advance, by the mid-2000’s, single-use systems (SUSs) were widely used in the manufacture of cell and gene therapies. This widespread adoption was driven by the lower cost and scalability afforded by this technology. SUSs allow for smaller, more efficient facility design requiring contamination control strategies that include less-stringent environmental controls for the cleanroom. These smaller, flexible designs promote the use of modular, factory-built cleanrooms, which reduce the time to bring new manufacturing space online. Additionally, they allow for networks of distributed manufacturing sites to be brought online worldwide.

One of the most challenging conflicts to resolve involves differing air flow requirements between contamination control and biocontainment. Traditional contamination control strategies are based on existing regulatory guidance from ISO 14644, FDA / EU GMPs and BMBL 6^th edition. These strategies include cleanrooms designed to protect the products from environmental contamination. A typical design employs an outward cascade of directional airflow, though each anteroom, step by step.

ISO 14644 defines air cleanliness by ISO classes (or EU Grades) where lower numbers denote cleaner or less particle laden the air. GMPs require high-risk processes to occur in primary containment devices, such as isolators or restricted access barrier systems (RABS), with unidirectional ISO Class 5 (Grade A) environments. The surrounding rooms are classified as ISO 7 (Grade B) or ISO 8 (Grade C) depending on the type of primary containment. Entry and exit to these spaces require a series of clean anterooms with ISO 8 and controlled not classified (CNC or Grade D) air preceding or following, before reaching uncontrolled areas of the building. (See figure 1)

Conversely, the CDC’s Biosafety in Microbiological and Biomedical Laboratories (BMBL) biocontainment guidelines require inward cascading airflow, directing air from less-contaminated areas toward spaces with higher contamination potential. (See Figure 2) Room classification, defined by BSLs, depends on the type of biological agent, the risk of aerosolization during processes and the volume of biological material handled.

BSLs range from 1 to 4, with higher levels indicating greater hazard potential. Most ATMP manufacturing processes typically require BSL-2 environments. In these settings, primary engineering controls (PECs) include negative-pressure containment devices, such as Class II biological safety cabinets or Class III gloveboxes. These airflow strategies are designed to ensure environmental protection from hazardous biological materials handled within the cleanroom.

However, when processes like the production of viral vectors require adherence to both the GMPs and BSL-2, conflict between the guidelines becomes apparent. A purely cascading airflow design cannot satisfy both guidelines simultaneously.

The compromise lies in airflow design strategies known as “sinks” or “bubbles,” where air flows into or out of the anteroom from both sides rather than cascading through it. For example, in a viral vector process requiring ISO 7 and BSL-2, designers might add an additional anteroom sink to satisfy both the GMP and BSL requirements. The cleanroom/BSL-2 laboratory is protected by series of three anterooms, with air cascading from the cleanroom through two anterooms, into the unclassified sink anteroom.

This element of the design would satisfy the GMP requirement for stepwise entry to the cleanroom with outward cascading airflow. Furthermore, the BSL-2 lab requirement of inward directional airflow would be satisfied, as the surrounding corridor air flows into the first sink anteroom. (See figure 3)

The level of conflict in regulatory guidance is further enhanced when a process needs BSL-3 containment, which requires two doors with inward directional airflow.

Trying to satisfy the cumulative GMPs and BSL requirements not only complicates designs, it also adds operational steps to cleanroom operations. This will increase both startup and operational cost.

In an era where advanced therapies are reshaping the future of medicine, the ability to harmonize regulatory requirements for cleanroom and biocontainment designs is critical. By embracing innovative solutions like multimodal modular cleanrooms, the industry can overcome these complex challenges, ensuring patient safety, operator protection and operational efficiency. Collaboration among engineers, quality professionals, regulators and researchers will drive the development of flexible, high-performance facilities that set new standards for biopharmaceutical manufacturing. These efforts not only address today’s regulatory conflicts but also create a foundation for transformative breakthroughs, enabling the biopharma industry to deliver life-changing therapies to patients worldwide.

Check out this case study to see how Germfree can deliver BSL-2/ GMP Compliance using our modular cleanroom platform. 

In early 2024, Germfree, a company specializing in the design and manufacture of modular cleanrooms, approached E Tech Group to collaborate on modernizing their building management and critical monitoring systems. The goal of the partnership was two-fold: first, to meet current regulatory standards for environmental monitoring and data integrity, specifically complying with FDA’s 21 CFR Part 11 regulations governing electronic records and electronic signatures. Additionally, Germfree wanted their cleanrooms to employ advanced data storage and aggregation technologies so clients can readily use data analytics for manufacturing intelligence initiatives to optimize their process.

Germfree’s modular cleanrooms are typically employed for specialized applications including:

• Cell and gene therapy production
• Decentralized, on-demand pharmaceutical manufacturing
• Early and preclinical stage drug manufacturing
• Biopharmaceutical research and production
• Specialized production of customized medication (hospitals and compounding pharmacies)

The modular cleanroom design incorporates several critical features required by this clientele. These include strict environmental control and monitoring capabilities to ensure the safety, efficacy, and compliance of the therapies produced. Each cleanroom can be customized to meet a client’s specific regulatory requirements including USP 795, 797, and 800 for pharmacies, biosafety levels 1 through 4, European grades B, C, and D environments for gene and cell therapies, as well as all relevant ISO standards. In addition, the cleanrooms can be customized to meet a client’s specific layout, materials, and integrated technology requirements.

Figure 2: Germfree’s modular cleanrooms are designed for compliance with all regulatory requirements and are built with durable construction materials.

Overview of FDA’s 21 CFR Part 11 Regulation

The 21 CFR Part 11 regulation by the U.S. Food and Drug Administration (FDA) sets the standards for electronic records and electronic signatures in FDA-regulated industries. It establishes the criteria under which electronic records and signatures are considered trustworthy, reliable, and equivalent to paper records and handwritten signatures. The regulation ensures that electronic systems used in manufacturing processes maintain data integrity, security, and compliance so that the production of pharmaceutical products is safe and effective.

E Tech Group’s environmental monitoring system (EMS) provides precise control, continuous monitoring, and recording of environmental conditions to meet compliance requirements. The system was designed and implemented with the following fundamental priorities:

• Full adaptability to comply with all relevant regulations and standards
• Adherence to the 21 CFR Part 11 protocol
• Full system scalability, ensuring seamless integration of any future additions to the cleanroom module
• An intuitive user interface, such that new users can operate it without significant training
• Maintaining cost-competitive pricing of the cleanroom

E Tech Group’s building management system (BMS) design fully controls all environmental equipment, including air handlers, exhaust fans, fan filter units and variable air volume (VAV) systems to maintain the desired conditions within the cleanroom. It not only provides trend data visualization for real-time system performance insights but also maintains a complete record of environmental conditions.

The critical monitoring system (CMS) implemented by E Tech Group provides verification and documentation that the cleanroom conditions remain within specified limits, as required for compliance with regulatory standards and supporting quality assurance. In compliance with 21 CFR Part 11 regulations, the CMS incorporates secure login processes, electronic signature capabilities, and detailed audit trails, so that every action is traceable, securely recorded, and verifiable. This level of monitoring and record keeping is important for maintaining the integrity of critical environments where precise control over environmental parameters like temperature, absolute and differential pressure, humidity, and particle count is necessary for sensitive processes.

Additionally, the CMS monitors and records environmental conditions within relevant process equipment such as autoclaves and incubators. This provides a comprehensive record that products are manufactured and stored under the ideal conditions required by regulatory standards, including current Good Manufacturing Practice (cGMP) regulations.

E Tech Group designed the user interface to be highly intuitive, allowing new users to operate it without significant training, while also maintaining cost-competitiveness. The interface is built using Ignition (by Inductive Automation), allowing users web browser access to easily make adjustments to temperature, pressure, humidity, and other environmental parameters.

Germfree’s engineering team possesses extensive knowledge and expertise to advise clients on the regulatory requirements relevant to their particular application. Their engineers determine necessary air changes, room classifications, pressure cascades, and other specifications.

Clients can focus on their core science while relying on Germfree expertise for cleanroom design, and the cleanroom’s capabilities to maintain compliance and product integrity during production.

What is Manufacturing Intelligence?

The field of manufacturing intelligence integrates aspects of computer science, data analytics, and systems engineering to optimize manufacturing processes, and it is one of E Tech Group’s core capabilities. At a high level, its goal is to collect and aggregate data from diverse sources within the manufacturing process, including equipment performance metrics, environmental data, sensors, production lines, and product quality results into a singular platform. Advanced analytics, machine learning, and data visualization tools can then readily analyze this data, providing valuable insights that can increase productivity, optimize and predict maintenance needs, improve product quality, and reduce costs.

E Tech Group incorporated a singular data aggregation platform into the cleanroom’s design so that clients can readily employ data analytics and other manufacturing intelligence initiatives to optimize their process.

Cleanrooms typically employ different vendors’ specialized process equipment including, but not limited to spectrometers, bioreactors, and chromatographs.  It is common for each piece of equipment to utilize differing communication protocols and data formats, which made full data integration a challenging endeavor.

E Tech Group collaborated with equipment vendors to standardize communication protocols, encouraging their adoption of the industry-standard OPC UA to simplify data transfer to a single data aggregation platform within the cleanroom. In addition, E Tech Group identified equipment-specific datasets that are particularly valuable for end-user analytics and collaborated with vendors to extract this needed data.

Figure 3: E Tech Group incorporated a data aggregation platform into their design, providing clients the capability of employing manufacturing intelligence initiatives to their process.

A powerful example illustrating the benefits of manufacturing intelligence involves golden batch analysis. When an ideal production batch (the “golden batch”) is created, all critical process parameters are trended that led to its creation. This set of parameters then serves as the gold standard for optimal production conditions of the batch.

With these parameters known, every subsequent batch in production can be monitored in real time to see how it’s trending in comparison to the golden batch parameters. Manufacturing intelligence uses data analytics and machine learning to compare real-time production data against the golden batch, identifying deviations and even suggesting real-time process parameter adjustments. The result is better product quality and consistency, reduced waste, and therefore improved efficiency.

To balance cutting edge capability with cost-effectiveness, the modular cleanroom design incorporates the following platforms:

• PLC: A Rockwell Automation PLC was selected to automate and integrate the control of all critical systems, ensuring robust operation and compliance with regulations including 21 CFR Part 11.
• User Interface: The system’s user interface was implemented using Inductive Automation’s Ignition to support the project’s budgetary goals while also providing easy accessibility via web browser.
• Historian: A Canary Labs historian was selected based on its high level of functionality and cost-effectiveness.
• Isolator (Optional Addition): The cleanroom’s isolator is integrated with AST’s (Advanced Sterilization Technologies) automated fill-finish systems for sterile manufacturing.
• Smarthood (Optional Addition): Designed by Germfree, the Smarthood incorporates label printing and weighing scales that enhance IV compounding efficiency.

At Germfree and E Tech Group, we take great pride in our contribution to therapy research, and supporting the accessibility of rare and novel drugs for those who need them most. We deeply understand the significance of this effort and have diligently worked to align our solutions with clients’ budget constraints so that vital research and treatment can continue.

The collaboration between Germfree and E Tech Group has significantly advanced modular cleanroom technology. By integrating modern building management and critical monitoring systems tailored to meet the stringent demands of the pharmaceutical and biotechnological industries, clients can be confident that the necessary conditions for producing safe and effective therapies are met.