Jeff Serle, VP of Biocontainment Solutions, Germfree, demonstrates how multimodal and modular cleanrooms can satisfy all requirements.
GermFree
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 organisations like the World Health Organisation 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.
Growing appeal of multimodal and modular cleanrooms
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 growth, coupled with increasingly complex therapies, necessitates the development of multimodal facilities capable of supporting diverse manufacturing processes.
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 personalised 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 prioritise 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 optimise 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.
Meeting regulatory challenges
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 6th 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.
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. Room classification, defined by BSLs, depends on the type of biological agent, the risk of aerosolisation 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.
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.
In an era where advanced therapies are reshaping the future of medicine, the ability to harmonise 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.