The cGMP (current Good Manufacturing Practice) regulations for pharmaceuticals are outlined in the FDA’s Title 21 of the Code of Federal Regulations (CFR) Parts 210 and 211. These regulations describe the minimum requirements for the methods, facilities, and controls used in the manufacture, processing, packaging, and storing of drug products to ensure their safety, quality, and effectiveness. They emphasize cleanroom environments to maintain sterility and prevent contamination.

The BMBL, published by the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH), is the cornerstone of biosafety practice in the United States. It provides guidelines for the safe handling and containment of biological agents in laboratories to protect workers, the public, and the environment. The BMBL version 6.0 determines specific biosafety requirements for various biological agents and activities.

Ultimately, both regulations require specific cleanroom practices, but for different reasons.

This overlap can lead to conflict – and in some cases means that separate protocols must be established for cGMP and BMBL Version 6.0 compliance.

A BSL3 and cGMP facility:

● Is equipped to handle and manufacture hazardous biological agents.

● Produces pharmaceuticals to the highest quality standards.

One area where the interrelationship between BSL and cGMP is critical is vaccine manufacturing. Infectious agents, by definition, pose a risk to human health, which means they must be handled according to BMBL standards. At the same time, the purity, potency, and safety of vaccines are critical – this is where cGMP comes in. However, there are numerous other niches where BSL3 and cGMP compliance must co-exist, and there are also numerous differences between the two standards.

BMBL and cGMP: Side-by-Side

Let’s explore some of the key differences between BMBL and cGMP standards:
Air Safety

Air filtration and air exchange rates are critical aspects of both cleanroom and biosafety requirements. While both cGMP regulations and BMBL guidelines aim to maintain a safe and controlled environment, they have different priorities and requirements in this regard.

cGMP regulates the strict control of particle and microbial contamination in cleanrooms to ensure the safety and quality of pharmaceutical products. BMBL guidelines focus on the containment of infectious agents in biosafety level (BSL) laboratories. Although air filtration and air change rates are also important in BSL laboratories, the primary concern is containment.

Depending on the cleanroom classification, cGMP air exchange requirements range from 20 to 60 air changes per hour (ACH). The BMBL, on the other hand, specifies only a minimum of 6-12 ACH.

High-Efficiency Particulate Air (HEPA) filters are a must in both cases. However, according to the cGMP, they must capture at least 99.97% of particles 0.3 microns or larger (2). The BMBL, on the other hand, emphasizes that they should be used for both supply and exhaust air. Particle capture is not regulated by the BMBL.

Finally, the cGMP guidelines emphasize the positive pressure differential between cleanroom areas to prevent contaminated air from flowing into the cleaner areas. This is in stark contrast to the BMBL, which requires negative pressure differentials.

MEP (Mechanical, Electrical, Plumbing) Systems

A BSL3, cGMP facility must meet much more stringent MEP system requirements than a non-BSL3 facility. Some specific technical requirements may include:

● HVAC (Heating, Ventilation, and Air Conditioning) clearly come first. Since they are responsible for air pressure and air exchange rates, they must be designed to release infectious agents through HEPA filters to remove particles and microorganisms.
Electrical systems must meet the facility’s power needs while providing backup power in the event of a power outage.
Plumbing systems must provide clean water to the facility and effectively dispose of wastewater while preventing cross-contamination and the spread of infectious agents.

Waste Management

As far as waste disposal in a BSL3 facility is concerned, an EDS (Engineering Controls Disinfection System) system is usually the safest and most efficient method. EDS systems inactivate and destroy agents so that the waste is no longer infectious prior to disposal.
Your EDS system must be specifically approved for use in BSL3 facilities. This means that the system can inactivate a wide range of infectious agents, but also that it is maintained according to the manufacturer’s recommendations.
Proper segregation and labeling of waste prior to entering the EDS system is essential. All waste must be disinfected – and once processed, it is considered non-infectious. Follow local regulations here. While EDS-treated waste can usually be disposed of using standard procedures, some sites mandate different procedures for waste treated in the system.
The cGMP regulations simply state that waste must be disposed of in a safe and sanitary manner.” So, for BSL3 and cGMP facilities, you should follow the BSL3 regulations.

Ultimately, both BMBL and cGMP regulations serve to identify risks and mitigate their potential consequences. Although the specific requirements may be different, the main areas of risk overlap. In this table, we compare the different risk considerations for BSL3 and cGMP facilities:

The interdependence and conflicts between BMBL and cGMP regulations can be a major challenge for biopharmaceutical companies. While setting up separate protocols and workflows can be a solution, facility design and organization must be designed from the ground up for compliance. This is where modular design can be a key aspect of compliance.

Modular design can provide a flexible and adaptable solution for biopharmaceutical facilities by allowing engineers to tailor solutions to the specific needs of the business. At Germfree, we have built several cGMP- and BSL3-compliant plants, and modular design has allowed us to do so in record time. With modular construction, the plant can be built in prefabricated modules that can be assembled on site, allowing for shorter construction times and lower costs.

Apart from the shortened deadlines and savings, the real value of a modular approach lies in its flexibility. Modular design also makes it easier to adapt the facility to specific requirements, e.g. in terms of MEP systems or biosafety features. In this way, we can create spaces that meet both cGMP and biosafety requirements without having to compromise on one or the other.
In addition, the modular design can also facilitate future expansion or modification of the facility, should that become necessary. Not only does this allow for adaptation to changing regulations or product requirements, but it also helps companies keep pace with growth – often without disrupting operations.

Ultimately, modular design is one of your best allies when it comes to managing the conflict between cGMP cleanroom and biosafety requirements. As a flexible, adaptable, and customizable solution, modular construction can meet both requirements while providing additional benefits such as time and money savings.

In summary, it can be a complex challenge for biopharmaceutical companies to manage regulations for cGMP cleanroom and biosafety requirements. From the different air filtration requirements where regulations can be completely contradictory (e.g., one regulation requires negative pressure, the other positive pressure), to specific MEP and HVAC requirements, there’s a lot to keep in mind to produce high quality products without risk to employees or the public. Modular design offers a flexible and adaptable solution that allows companies to meet both requirements without compromising on one or the other.

U.S. Food and Drug Administration. (2018). CFR – Code of Federal Regulations Title 21. Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211

Whyte, W. (2001). Cleanroom technology: fundamentals of design, testing and operation. John Wiley & Sons.

U.S. Department of Health and Human Services. (2020). Biosafety in Microbiological and Biomedical Laboratories (BMBL) (6th Edition). Retrieved from https://www.cdc.gov/labs/BMBL.html