Designing a biologics facility involves creating a layout and process flow that ensures biologic products’ safe, efficient, and compliant production. The design of such a facility should adhere to Good Manufacturing Practices (GxP) to ensure the safety, quality, and efficacy of biological products. Here are some key considerations and components to focus on when designing a biologics facility:

1. Facility Layout Design

A biologics facility layout should prioritize the following elements:

1. Zoning in the Facility Layout

Zoning involves creating separate, defined areas within the facility for distinct purposes. This segmentation is essential for maintaining contamination control and ensuring each area operates under the necessary environmental conditions.

Key Zones to Consider:

1. Raw Material Storage Area:
   • Sterile vs. Non-Sterile Materials: To avoid cross-contamination, the storage area should have separate spaces for sterile and non-sterile materials. Sterile materials might include media, reagents, or cells, while non-sterile materials could include packaging components and other supplies.
   • Controlled Storage Conditions: Depending on the material type, the storage area may need to be temperature-controlled or humidity-controlled.
   • Key Feature: Segregation of materials, clear labelling, and tracking systems for raw materials.
2. Cleanrooms/Production Areas:
   • Cell Culture & Fermentation Suites: This is where the biological product is produced. These areas should have stringent environmental control (temperature, humidity, air cleanliness) to ensure cell growth and fermentation conditions.
   • Downstream Processing Areas include filtration, purification, and final product formulation. These areas may include chromatography columns, centrifuges, and other purification technologies.
   • High Standards for Cleanliness: Cleanrooms are categorized into different grades (e.g., ISO Class 5, Class 7, etc.) depending on the level of contamination control required.
   • Key Feature: Unidirectional flow from raw material entry to product output. Clean areas should be isolated to prevent product contamination.
3. Quality Control/Quality Assurance (QC/QA) Labs:
   • Testing: These labs conduct the necessary analyses on raw materials, in-process materials, and final products to ensure they meet regulatory and quality standards.
   • Separation from Production: These areas should be separated from the manufacturing zones to minimize contamination risks.
   • Key Feature: Sterile environments and rigorous cleaning and testing protocols for contaminants.
4. Packaging/Labeling Areas:
   • Controlled Environment: Packaging and labelling should occur in controlled or clean environments to prevent contamination of the final product.
   • Automation: Automated lines may fill, seal, and label products.
   • Key Feature: Security and traceability, ensuring only approved products are correctly packaged and labelled.
5. Warehouses:
   • Finished Goods Warehouse: This area stores finished products that are ready for shipping. It must be segregated from production areas and may require specific storage conditions (e.g., refrigerated or frozen).
   • Packaging Materials Warehouse: This is where raw materials used for packaging (e.g., bottles, vials, labels) are stored.
   • Key Feature: Inventory control systems and segregation of different product types.
6. Employee and Visitor Areas:
   • Offices and Administrative Spaces: For the management, technical, and regulatory staff.
   • Break Rooms and Meeting Rooms: Staff can rest and hold meetings without contaminating production or controlled areas.
   • Key Feature: These areas should be isolated from clean zones to prevent contamination.
7. Utilities Rooms:
   • HVAC: Heating, ventilation, and air conditioning systems are crucial for maintaining environmental controls in cleanrooms and other production areas.
   • Water Systems: Water for Injection (WFI), purified water (PW), and other utility services should be readily available.
   • Power Systems: Backup power to ensure continuity of operations.
   • Key Feature: Efficiency and reliability of critical systems to maintain production uptime.

Commissioning of HVAC Systems

2. Materials Flow

The flow of materials is critical to the efficiency of a biologics facility. Materials should move in a unidirectional and logical sequence to reduce contamination risks and prevent errors.

Unidirectional Material Flow:

1. Raw Materials → Manufacturing → Quality Control → Packaging → Storage → Shipping
   • The movement should avoid backtracking or mixing of different product stages. Raw materials should enter the facility and be transferred directly to the production area.
   • As the product moves through the manufacturing and QC processes, it should not be handled in reverse order, ensuring that only finished goods are shipped.
2. Separation of Product Types:
   • Incoming materials: Clean, segregated delivery points and direct routing to storage areas.
   • In-process materials: Transported in dedicated, clean trolleys or carts to avoid contamination.
   • Finished products: After final processing, they should be carefully moved to packaging and labelling.
3. Waste Flow:
   • Waste should be disposed of at specific points segregated from the product flow. This prevents waste from contaminating production areas.
   • Hazardous, biological, and chemical waste should follow strict protocols for storage and disposal.
4. Logistical Considerations:
   • The layout should support smooth and efficient movement, reducing unnecessary travel distances or bottlenecks.
   • Automated material handling (e.g., conveyors or robotic systems) may be employed to optimize flow.

3. Employee Movement and Access Control

Employee movement should be carefully planned to minimize cross-contamination, particularly in cleanrooms and other controlled environments.

Key Features for Managing Employee Flow:

1. Gowning/De-Gowning Areas:
   • Employees must gown before entering clean or sterile areas and de-gown afterward. The gowning area should be located at the cleanroom’s entry to ensure no contamination occurs before entering production areas.
   • Separate de-gowning areas are essential to ensure no contamination is carried out of controlled spaces.
2. Personnel Entry and Exit:
   • Airlocks act as transitional zones where airflow is controlled to prevent contamination.
   • Controlled Entry: Employees should enter the critical zones (cleanrooms) through secure, monitored access points, which may include access control systems (e.g., card readers and biometrics).
   • Movement within Zones: Once inside the clean areas, personnel should follow specific routes to reduce contamination risk. For example, walking paths in clean areas should be clearly defined to minimize foot traffic in sensitive zones.
3. Minimize Foot Traffic:
   • Foot traffic should be minimized in the cleanroom and critical areas. This can be done by designing production zones with clear pathways and access routes to prevent unnecessary movements through sterile zones.
4. Separate Access for Visitors:
   • Visitors should be kept to a minimum in sensitive areas. When they need to enter, they should be adequately trained in gowning procedures and restricted to non-production areas.

2. Process Flow Design

A Process Flow Design is a key part of any biologics facility layout, as it ensures that materials, personnel, and waste move efficiently, safely, and competently. A well-designed process flow will prevent contamination, optimize production efficiency, and ensure the facility meets regulatory requirements such as GxP standards. Below is a breakdown of key flows for personnel, materials, and waste within a biologics facility:

1. Personnel Flow (Men)

Efficient personnel flow is crucial to maintaining sterile environments, minimizing contamination risks, and ensuring regulatory compliance.

Entry/Exit Procedures:

1. Gowning and De-Gowning Areas:
   • Entry: Employees must pass through gowning areas before entering cleanrooms or controlled areas. These areas should include airlocks, where airflow is controlled to prevent contamination.
     • Design Features: Each zone has separate gowning and de-gowning areas (e.g., separate areas for clean and non-clean spaces). Gowning kits include gloves, lab coats, shoes, and head coverings.
     • Airlocks: Airlocks act as transitional spaces between clean and non-clean zones. The air inside clean areas should flow into these airlocks to prevent contamination.
   • De-Gowning: After leaving a clean area, personnel should de-gown in a designated area. This ensures that contaminants are not carried outside of controlled zones.
   • Hygiene Stations: Hygiene stations with handwashing facilities, alcohol-based hand sanitizers, and other cleaning agents should be available at all entry and exit points.

Workflow Management:

1. Training and Awareness:
   • All employees should be trained on the flow paths for handling raw materials, equipment, and products throughout biologics production.
   • Training ensures personnel do not inadvertently mix or contaminate different materials during handling.
   • Employees should also be familiar with the access control systems and know where they can and cannot enter, especially in restricted or clean areas.
   • A clear signage system should guide personnel through the facility, indicating restricted zones, clean areas, and emergency exits.

2. Material Flow

Efficient material flow is critical for production efficiency, preventing bottlenecks and ensuring compliance with regulatory requirements.

Raw Materials:

1. Reception and Storage:
   • Separate Storage for Sterile and Non-Sterile Materials: Raw materials should be segregated upon arrival based on their classification (sterile/non-sterile) and stored in labelled controlled areas.
   • Controlled Storage Conditions: Some materials, such as certain biologic reagents or cell cultures, may require specific environmental conditions (e.g., temperature, humidity, or light) and should be stored accordingly.
     • Design Features: Temperature-controlled rooms or cold storage for sensitive materials (e.g., raw materials for cell culture or biologic reagents).

Process Materials:

1. Material Movement Through Production Stages:
   • Cell Culture and Fermentation: Materials are transferred to the cell culture or fermentation suites, where cell lines are grown, or bacteria/fungi are fermented.
   • Filtration and Purification: After cell culture, materials move through filtration units (e.g., to remove cellular debris) and purification steps (e.g., chromatography).
     • Critical Monitoring Points: During production, key monitoring stations should be located where product quality and sterility are regularly tested to ensure compliance. These points could include sampling areas for sterility testing, pH checks, or protein assays.
     • Process Flow Management: Materials should flow in a unidirectional path (raw materials → production → QC, → packaging) with clear separation of each step to prevent contamination between stages.

Finished Goods:

1. Packaging and Labeling:
   • Controlled Packaging Areas: After successful production, biological products move to the packaging and labelling areas, filling, sealed, and labelled under sterile conditions.
     • Environmental Control: These areas should be controlled for environmental parameters (e.g., cleanrooms with HEPA-filtered air, temperature, and humidity controls).
   • Segregated Storage: Finished goods are stored separately from production areas in a warehouse. Careful inventory management prevents stockouts or errors.

3. Waste Flow

Waste management is critical in biologics production to prevent contamination, reduce environmental impact, and comply with health and safety regulations.

Types of Waste:

1. Non-Hazardous Waste:
   • This includes general waste such as packaging materials, paper, plastics, and office waste. It should be stored in segregated bins or rooms away from production and clean areas.
   • Recycling Options: Depending on the facility’s waste management strategy, certain materials (e.g., plastic containers, and paper) could be recycled.
2. Hazardous Waste:
   • Includes chemicals, expired reagents, solvents, or any material that poses a risk to health and the environment.
   • Proper Segregation: Hazardous waste should be segregated into bins or storage rooms, with warning signs and restricted access.
   • Disposal Methods: Hazardous waste must be disposed of following local, state, and federal regulations, with options for neutralization or incineration.
3. Biological Waste:
   • Includes items contaminated with biological material, such as used filters, contaminated equipment, or waste from cell cultures.
   • Containment: Biological waste should be stored in separate, labelled containers to prevent leaks or spills.
   • Disposal: The facility may need to use specialized methods, such as autoclaving (steam sterilization) or incineration, to destroy biological material before disposal.

Proper Disposal:

1. Waste Storage and Disposal Routes:
   • Waste storage must be segregated from clean or production areas, clearly labelled, and restricted access.
   • Designated waste handling routes should lead directly from production areas to waste disposal or treatment facilities to prevent cross-contamination.
   • A centralized waste management system can help streamline waste segregation and disposal across the facility.

Environmental Controls:

1. Waste Treatment:
   • Waste treatment facilities should be integrated into the facility to treat hazardous and biological waste. Incineration or biological neutralization (e.g., using autoclaves) should occur on-site.
   • Emissions from waste treatment processes should be monitored and controlled to ensure compliance with environmental regulations (e.g., air filters and emission controls).
   • The incineration facility or biological waste neutralization areas should be separated from clean production zones.

3. Prime Components for Each Process

When designing a biologics production facility, each process—cell culture/fermentation, downstream processing, quality control (QC)/quality assurance (QA), and packaging/labelling—requires a set of specialized components to ensure the process is efficient, compliant, and meets quality standards. Below is a breakdown of the prime components for each process:

1. Cell Culture/Fermentation

This stage involves growing cells or microorganisms in controlled conditions to produce biologics, such as proteins, antibodies, or other therapeutic products.

Prime Components:

1. Bioreactors:
   • Function: Bioreactors are essential for culturing cells or microorganisms. They provide the controlled environment needed for growth and product formation.
   • Types: Depending on the process, these could be stirred-tank bioreactors, bubble-column reactors, or airlift reactors.
   • Key Features: Temperature, pH, and oxygen levels are tightly controlled, and bioreactors are typically designed to handle different production sizes, from small-scale research to large-scale manufacturing.
2. Media Preparation Equipment:
   • Function: Media is essential for cell growth, containing all the nutrients, growth factors, and salts needed.
   • Types include sterile filtration units, media mixing tanks, and sterilizers for creating liquid or solid media.
   • Key Features: Automated mixing systems, temperature control, and sterile environments for preparing the culture medium.
3. Incubators:
   • Function: Incubators maintain the necessary environmental conditions for cell growth, such as temperature, CO₂ concentration, and humidity.
   • Key Features: CO₂ incubators maintain proper gas concentration for cell cultures, and temperature-controlled incubators ensure constant growth conditions.
4. Air Filtration Systems:
   • Function: Air filtration systems (e.g., HEPA filters) are essential to ensure a sterile environment by preventing contamination from airborne particles or microorganisms.
   • Key Features: Laminar flow hoods and air handling units (AHUs) with HEPA or ULPA filters ensure that the air within the production environment remains free from contamination.

2. Downstream Processing

This phase involves extracting, purifying, and finalizing the biological product from the cultured cells or microorganisms.

Prime Components:

1. Centrifuges and Filtration Systems:
   • Function: Centrifuges separate cells, debris, and other particulate matter from the product, and filtration systems further purify it.
   • Key Features:
     • High-speed centrifuges for cell separation.
     • Tangential flow filtration (TFF) or cross-flow filtration for separating proteins or other biomolecules.
2. Chromatography Columns:
   • Function: Chromatography purifies the target product by separating molecules based on size, charge, or affinity.
   • Types:
     • Ion exchange chromatography for charge-based separation.
     • Affinity chromatography is used to bind specific biomolecules to a stationary phase.
     • Size exclusion chromatography (SEC) separates molecules based on size.
   • Key Features: Columns are packed with specific resins or beads that selectively bind and purify molecules of interest.
3. Tanks and Mixing Vessels:
   • Function: For intermediate storage and mixing of solutions during the purification process.
   • Key Features:
     • Stainless steel mixing vessels equipped with agitators or stirrers.
     • Storage tanks for holding buffers, solvents, or purified products.
     • Automated control systems for monitoring levels, temperature, and pressure.

3. Quality Control (QC) and Quality Assurance (QA)

QC/QA is critical to ensure the biological product meets the required identity, purity, potency, and safety standards.

Prime Components:

1. Analytical Equipment:
   • Function: Analytical instruments test and verify biologics’ quality, identity, and purity at various production stages.
   • Types:
     • High-performance liquid chromatography (HPLC) for separation and quantification of biomolecules.
     • Polymerase chain reaction (PCR) verifies genetic material and ensures sterility.
     • Mass spectrometry is used to identify molecular weight and structure.
     • Spectrophotometers are used to measure protein concentration and other biomolecular characteristics.
   • Key Features: These instruments are critical for batch release testing and regulatory compliance.
2. Cleanrooms and Laboratories:
   • Function: Cleanrooms provide controlled environments to prevent contamination during testing, inspection, and sampling. Laboratories carry out various analytical and microbiological tests.
   • Key Features:
     • ISO-rated cleanrooms to prevent contamination.
     • Contamination control systems such as HEPA filtration, airlocks, and gowning procedures to maintain sterility.
     • Biological safety cabinets (e.g., Class II biosafety cabinets) prevent cross-contamination while handling samples.

4. Packaging and Labeling

Once the biologic product is purified and undergoes QA/QC, it is ready for packaging and labelling for distribution.

Prime Components:

1. Packaging Lines:
   • Function: Packaging lines fill, seal, and label the final product, ensuring it is safely enclosed and ready for transport.
   • Types:
     • Automatic filling machines: For precisely filling vials, syringes, or bottles.
     • Sealing machines: To ensure the product is securely closed.
     • Labeling machines: These are used to affix labels onto the packaging.
   • Key Features: The packaging line should be integrated with sterility protocols, ensuring the product remains contamination-free throughout all packaging stages.
2. Barcode Scanning Systems:
   • Function: Barcode scanning is crucial for tracking and ensuring labelling is applied to the correct product batch.
   • Key Features: Integration with an inventory management system ensures product traceability and compliance with regulatory tracking requirements.
3. Storage and Transport Packaging:
   • Function: Biological products require special storage and transport packaging after packaging to maintain stability and ensure they remain in good condition during shipping.
   • Types:
     • Cold storage: For temperature-sensitive products (e.g., refrigerated packaging for biologics that require cold chain management).
     • Insulated shipping boxes: These are used to maintain the temperature during transit.
   • Key Features: Packaging should be designed to protect the product from light, temperature fluctuations, and physical damage.

4. GxP Expertise for Biologics Facility Design

GxP (Good Manufacturing Practice) regulations ensure product safety, quality, and consistency throughout biologics manufacturing. A biologics facility must be designed to meet rigorous standards set by health authorities such as the FDA (U.S. Food and Drug Administration) or the EMA (European Medicines Agency). Expertise in GxP compliance is essential, and companies like GxP Cellators specialize in ensuring that biologics facilities adhere to these strict guidelines.

Here are some key considerations for GxP expertise in biologics facility design:

1. Compliance with GxP Guidelines

Adhering to GxP standards is the foundation of any biologics facility design. GxP guidelines govern everything from the equipment used to the processes in place to ensure product quality and safety.

Key Components:

1. Regulatory Compliance:
   • FDA, EMA, and Health Authority Standards: The facility must be designed to comply with local and international health authority regulations, including the FDA’s 21 CFR Part 210/211 and EMA’s guidelines for biologics manufacturing.
   • The design must meet requirements such as:
     • Quality Assurance: Ensuring the facility and processes support consistent, high-quality product production.
     • Control of Facilities and Equipment: Proper equipment cleaning, maintenance, and operation requirements.
     • Environmental Control: Cleanroom standards, HVAC requirements, and controlled environments to minimize contamination risk.
2. Validation:
   • Process and Equipment Validation: All systems, equipment, and processes must be validated to produce biological products consistently according to predefined quality standards. Validation must cover:
     • Installation Qualification (IQ): Ensuring equipment is installed properly.
     • Operational Qualification (OQ): Confirming that the equipment works as expected under normal operating conditions.
     • Performance Qualification (PQ): Verifying that equipment and systems perform consistently and produce the desired results.
3. Documentation:
   • Record Keeping: Every stage of the facility design and build, including any changes or upgrades, must be thoroughly documented. This ensures:
     • Compliance audits: Maintaining detailed records that demonstrate ongoing compliance during facility operation.
     • Change Control: Document any modifications made during design or operation to maintain compliance throughout the facility’s lifecycle.

2. Environmental Control Systems

Environmental controls are essential to prevent contamination, maintain product quality, and ensure compliance with GxP standards.

Key Components:

1. HVAC (Heating, Ventilation, and Air Conditioning) Systems:
   • Design for Cleanrooms: HVAC systems must be specifically designed to control temperature, humidity, and airflow to meet the sterility requirements for cleanrooms and other controlled environments.
   • Airflow Management ensures the airflow is unidirectional and contamination-free (e.g., positive pressure systems to prevent outside contaminants from entering).
   • Monitoring and Control: HVAC systems should have automated controls that continuously monitor and adjust parameters like temperature, humidity, and particle count in real time. This is essential for environmental monitoring in cleanrooms.
2. Water Systems:
   • Purified Water (PW): Systems for producing purified water used in cleaning, media preparation, and some process steps.
   • Water for Injection (WFI): Water for Injection systems must meet the highest standards of purity and sterility, which are essential for use in biologics production.
   • Design Considerations: The water system should be designed to prevent microbial growth, with features like reverse osmosis (RO), distillation, and sterilization systems. Compliance with standards like USP (United States Pharmacopeia) and EP (European Pharmacopoeia) is required for WFI systems.

Clean Utilities | GMP Manufacturing Sites | GMP Facility

 

3. Risk Assessment and Safety

Effective risk management is essential to ensure that biologics facilities operate safely and minimize risks associated with contamination, personnel safety, and environmental hazards.

Key Components:

1. Contamination Control:
   • Preventive Measures: Designing the facility to minimize the risk of cross-contamination (e.g., through airlocks, cleanroom zones, and unidirectional workflow).
   • Cleaning Protocols: Clear procedures for the cleaning and disinfection of all surfaces, equipment, and rooms to ensure that microorganisms, chemicals, or previous product residues do not contaminate biologics products.
   • Microbial Control: Implementing measures to prevent microbial growth, especially in areas where sterile conditions are required (e.g., sterile filtration, UV sterilization, and environmental monitoring).
2. Personnel Safety:
   • Gowning Procedures: Proper gowning protocols to ensure that personnel do not introduce contaminants into clean areas.
   • Training: Employees must undergo regular training on GxP compliance, contamination control, safety procedures, and emergency protocols.
   • Protective Equipment: Design facilities with appropriate protective equipment, such as biosafety cabinets, glove boxes, and personal protective equipment (PPE), to safeguard personnel from exposure to hazardous materials or products.
3. Emergency Systems:
   • Fire Suppression: Facilities must have reliable fire suppression systems, including sprinklers and clean agent fire extinguishers, mainly where hazardous materials are used or stored.
   • Emergency Shutdown Protocols: Automated systems to shut down equipment or isolate areas in case of a critical failure or contamination event.

4. Modular Design for Flexibility and Scalability

A modular design provides flexibility and scalability, allowing the facility to be expanded as the production volume grows or new products are developed.

Key Components:

1. Modular Components:
   • Pre-fabricated Modules: Sections of the facility, such as cleanrooms or utility areas, can be pre-fabricated in modular units that can be assembled on-site. This allows for faster construction and easier upgrades.
   • Flexibility: Modular components can be reconfigured as needed, allowing for quick adaptation to new production demands or regulatory changes.
   • Scalable Utilities: Utility systems (e.g., HVAC, water, and power systems) can be designed to accommodate future expansions with minimal disruption to existing operations.
2. Future Proofing:
   • Capacity for Expansion: The facility should have provisions for increasing capacity in response to growing product demand or evolving regulatory requirements.
   • Adaptable Systems: Systems like bioreactors, fermentation tanks, or cleanrooms can be designed to accommodate future product lines or larger-scale production by adding more modules or expanding existing units.

Contact Us

Finalize Your Biologics Facility Layouts with GxP Cellators

If you’re ready to finalize your biologics facility layouts and ensure they meet GxP (Good Manufacturing Practice) standards, GxP Cellators is the ideal partner. With a proven track record of designing GMP-compliant biologics facilities, our expert consultants will guide you through every phase of the design and build process.

Our Expertise Includes:

• Facility Layout Design: We ensure that materials, personnel, and waste flow efficiently and safely while minimizing the risk of contamination.
• Process Flow Design: We streamline workflows to ensure compliance with regulatory guidelines for materials handling, personnel movement, and waste disposal.
• GxP Compliance: We ensure that your facility meets the stringent requirements of health authorities such as the FDA, EMA, and other regulatory bodies.
• Risk Management and Safety: We provide robust systems to prevent contamination, ensure personnel safety, and maintain effective environmental monitoring.

Whether you need support with cleanroom design, validation processes, or modular facility design for scalability, our team is ready to ensure your biologics facility is compliant, efficient, and safe.

Get Started Today:

To take the next step, contact GxP Cellators today. Our consultants will help you finalize your facility’s design, optimizing it to meet the highest industry standards for quality, safety, and compliance.