The quality of pharmaceutical products starts long before the actual manufacturing process starts. It starts with the infrastructure of the facility that is actual physical structure where each equipment, machine and worker collaborates to create safe and effective pharmaceutical products.
An ideal pharmaceutical manufacturing facility has defined spaces and equipment that have been thoroughly planned and validated in order to optimize the potential for contamination to get maximum level of performance, efficiency and regulatory compliance.
This blog post provides the knowledge of effectively design of a pharmaceutical facility that meets GMPs, FDA and WHO regulations and provides a flexibility for innovation and future growth.
To this end, pharmaceutical agencies such as the FDA, EMA and WHO set forth guidelines that state that a pharmaceutical facility must have the following aspects:
- Preventing contamination and mix-ups.
- Establishing Control on the Environment.
- Establish procedures for cleaning and maintaining the facility.
- Assisting with validation, documentation and traceability.
Facility layout, movement of materials throughout the facility and the control of the environment must all work together to maintain patient safety and product integrity.
- Raw materials enter from one end.
- Manufacturing takes place in the clean area.
- Exit out through a controlled exit route.
By keeping the Clean and Dirty areas separate, you avoid having one area contaminate another.
- Temperature range: 18°C to 25°C
- Relative humidity: 30% to 60%
- Air pressure differential and direction of airflow
- Type of HEPA filter and air change rate (ACPH)
In order to control bacterial growth and particulate matter contamination in the area, these environmental conditions are strictly controlled.
- Grade A Cleanrooms (ISO 5): These areas are used for aseptic operations.
- Grade B Cleanrooms (ISO 6): These areas will provide as a background to aseptic areas.
- Grade C/D Cleanrooms (ISO 7/8): These areas are less critical for manufacturing.
The quality of the air from HVAC System and type of pressure differential for cleanliness will also differ depending on the C/D classifications.
1. Area should have access to suppliers, transportation hubs and skilled workers.
2. Location should have access to clean water, air and waste disposal.
3. Site must follow all environmental and safety laws recommended by regulatory agencies.
4. There should be proper space for additional manufacturing lines and research & development laboratories.
An ideal pharmaceutical facility location must have a balance of cost and logistics with focus on sustainability in the future.
In addition, operations which carry a high-risk level such as the handling of potent and/or cytotoxic products must be carried out in isolated, negative pressure (contained) areas with special air handling equipment.
Personnel: Personnel should use separate entry and exit points like airlocks and gowning areas to prevent cross contamination.
Materials: Materials should be transported through the use of pass boxes and dedicated ways to minimize the chance of cross contamination.
Material – are smooth, non-porous, easy to clean and stainless steel or epoxy coated.
Floors - are generally constructed using resin or epoxy to create a seamless finish.
Ceilings - should use flush panels so there are no areas for contamination to build up.
These surfaces should be resistant to chemical cleaners and should withstand routine cleaning of high frequency.
- HVAC system controls the airborne contamination level and controls the pressure zones.
- Purified water or WFI is used to clean, formulate and rinse.
- Compressed air should be dry, oil-less and filtered.
- Steam is used as a sterilizing agent and cleaning medium.
Each utility will be validated and monitored at regular intervals.
Benefits of modular construction are:
- Shorter time to complete projects.
- Less risk of contamination during construction.
- Ability to quickly change the design as per requirements.
- Ability to scale up at a more economical rate than traditional methods.
This type of flexibility is useful for the biopharmaceuticals and contract manufacturing organizations which require to respond rapidly on customer demands.
- Guided material handling systems (AMHS)
- Cleaning in place (CIP) and steam in place (SIP) systems for cleaning and sterilization of large sized equipment.
- Supervisory Control & Data Acquisition (SCADA) systems for real time monitoring of processes.
- Electronic Batch Records (EBR) for traceability of production steps.
Automation provides not only increased production but also supports compliance with data integrity under 21 CFR Part 11.
1. 21 CFR Part 210/211 of the United States (FDA): Drug Manufacturing Practices.
2. European Union's (EU) GMP Volume IV Annex 1: Sterile Manufacturing.
3. World Health Organization (WHO) TRS 1025 Annex 2: Good Manufacturing Practices for pharmaceuticals.
4. Schedule M (India): Good Manufacturing Practices (GMP) for manufacturing premises and equipment.
According to these guidelines, the design of equipment and facilities should minimize the possibility of contamination during the production and must have provision for effective cleaning, maintenance and validation activities to ensure GMP compliance.
1. Design Qualification (DQ): To confirm that the design meets the requirements of both the regulatory community and the user community.
2. Installation Qualification (IQ): To establish that equipment and utilities have been properly installed, connecting workmanship and product specifications to the production process.
3. Operational Qualification (OQ): After all equipment has been installed, it is necessary to establish whether or not the equipment functions properly under certain simulated conditions.
4. Performance Qualification (PQ): Finally the systems must perform correctly under routine operation.
Validation is performed to confirm that the facility and its equipment can consistently produce high quality pharmaceutical products.
- Energy recovery in HVAC.
- LED lighting with smart sensors.
- Water recycling.
- Minimize air changes with equivalent air quality.
Green design of manufacturing facility can reduce cost of operation and supports global efforts for sustainability and environmental responsibility.
Facilities should utilize a Quality Risk Management (QRM) process and ongoing evaluations of Corrective and Preventive Action (CAPA) to address deviations from normal and provide opportunities to continually improve facility operation. A facility created to support quality will eventually improve to meet the growing needs of the global pharmaceutical marketplace.
Pharmaceutical manufacturers need to build their plants to include as many factors related to quality, safety and efficiency as possible. Whether it is through layout or design choices, material selection or levels of automation and sustainability, design choices impact the ability of the facility to be compliant and maintain the integrity of the product.
A GMP compliant facility not only meets the regulatory requirements but also shows that company has commitment to ensuring patient safety by product quality and excellence in manufacturing process. You must review your facility design before entering into any regulatory audit.
An ideal pharmaceutical manufacturing facility has defined spaces and equipment that have been thoroughly planned and validated in order to optimize the potential for contamination to get maximum level of performance, efficiency and regulatory compliance.
The Importance of Facility Design in Pharmaceuticals
Pharmaceutical products are very sensitive and susceptible to environmental factors, cross-contamination and human mistakes. The way a facility is constructed and run affects the quality of pharmaceutical products.To this end, pharmaceutical agencies such as the FDA, EMA and WHO set forth guidelines that state that a pharmaceutical facility must have the following aspects:
- Preventing contamination and mix-ups.
- Establishing Control on the Environment.
- Establish procedures for cleaning and maintaining the facility.
- Assisting with validation, documentation and traceability.
Facility layout, movement of materials throughout the facility and the control of the environment must all work together to maintain patient safety and product integrity.
Key Principles of Effective Facility Design
The best way to develop a more effective pharmaceutical facility is to base it on and follow the guidelines for Good Manufacturing Practices (GMP). These guidelines will be focused on the design of the facility when it comes to hygiene, flow and risk-based planning.1. Flow and Layout of the Facility
Facilities should have a uni-directional flow of all materials and personnel; this method is to ensure that there is no chance of cross-contamination.- Raw materials enter from one end.
- Manufacturing takes place in the clean area.
- Exit out through a controlled exit route.
By keeping the Clean and Dirty areas separate, you avoid having one area contaminate another.
2. Controlled Environmental Conditions
Environmental control is the most important factor for the sterile or non-sterile manufacturing. These environmental controls include:- Temperature range: 18°C to 25°C
- Relative humidity: 30% to 60%
- Air pressure differential and direction of airflow
- Type of HEPA filter and air change rate (ACPH)
In order to control bacterial growth and particulate matter contamination in the area, these environmental conditions are strictly controlled.
3. Certification of Cleanroom Classifications
Cleanrooms in pharmaceuticals are classified on the basis of ISO-14644 and WHO GMP guidelines.- Grade A Cleanrooms (ISO 5): These areas are used for aseptic operations.
- Grade B Cleanrooms (ISO 6): These areas will provide as a background to aseptic areas.
- Grade C/D Cleanrooms (ISO 7/8): These areas are less critical for manufacturing.
The quality of the air from HVAC System and type of pressure differential for cleanliness will also differ depending on the C/D classifications.
Choosing the Right Location
The good location to build a pharmaceutical facility requires both strategic consideration and compliance with regulatory requirements. Site location must consider:1. Area should have access to suppliers, transportation hubs and skilled workers.
2. Location should have access to clean water, air and waste disposal.
3. Site must follow all environmental and safety laws recommended by regulatory agencies.
4. There should be proper space for additional manufacturing lines and research & development laboratories.
An ideal pharmaceutical facility location must have a balance of cost and logistics with focus on sustainability in the future.
Facility Layout and Design Considerations
1. Separation of Operations
Each operation (dispensing, production, filling, packing, storage) must be undertaken in designated areas so that the risk of cross-contamination is eliminated.In addition, operations which carry a high-risk level such as the handling of potent and/or cytotoxic products must be carried out in isolated, negative pressure (contained) areas with special air handling equipment.
2. Flow of Materials and Personnel
GMP (good manufacturing practice) facilities should be designed so that they support the one-way flow of both personnel and materials:Personnel: Personnel should use separate entry and exit points like airlocks and gowning areas to prevent cross contamination.
Materials: Materials should be transported through the use of pass boxes and dedicated ways to minimize the chance of cross contamination.
3. Surface and Finish
Surfaces of all materials used to construct GMP facilities must be:Material – are smooth, non-porous, easy to clean and stainless steel or epoxy coated.
Floors - are generally constructed using resin or epoxy to create a seamless finish.
Ceilings - should use flush panels so there are no areas for contamination to build up.
These surfaces should be resistant to chemical cleaners and should withstand routine cleaning of high frequency.
4. Utilities & Support Systems
All utilities and support systems will be designed with the expectation of continuing operations and for compliance with the applicable regulations:- HVAC system controls the airborne contamination level and controls the pressure zones.
- Purified water or WFI is used to clean, formulate and rinse.
- Compressed air should be dry, oil-less and filtered.
- Steam is used as a sterilizing agent and cleaning medium.
Each utility will be validated and monitored at regular intervals.
Modular and Flexible Design
A trend in modern pharmaceutical facilities is the use of modular construction. This type of facility is constructed using prefabricated cleanroom units. These are assembled quickly and easily expanded or modified as needed.Benefits of modular construction are:
- Shorter time to complete projects.
- Less risk of contamination during construction.
- Ability to quickly change the design as per requirements.
- Ability to scale up at a more economical rate than traditional methods.
This type of flexibility is useful for the biopharmaceuticals and contract manufacturing organizations which require to respond rapidly on customer demands.
Equipment and Automation Integration
Modern facilities include automation into their manufacturing operations to increase efficiency and decrease the chances of human error. Examples include:- Guided material handling systems (AMHS)
- Cleaning in place (CIP) and steam in place (SIP) systems for cleaning and sterilization of large sized equipment.
- Supervisory Control & Data Acquisition (SCADA) systems for real time monitoring of processes.
- Electronic Batch Records (EBR) for traceability of production steps.
Automation provides not only increased production but also supports compliance with data integrity under 21 CFR Part 11.
Ensuring Regulatory Compliance
The design of a pharmaceutical manufacturing facility is required to comply with both the national and international regulations for Good Manufacturing Practices (GMP). These regulations include:1. 21 CFR Part 210/211 of the United States (FDA): Drug Manufacturing Practices.
2. European Union's (EU) GMP Volume IV Annex 1: Sterile Manufacturing.
3. World Health Organization (WHO) TRS 1025 Annex 2: Good Manufacturing Practices for pharmaceuticals.
4. Schedule M (India): Good Manufacturing Practices (GMP) for manufacturing premises and equipment.
According to these guidelines, the design of equipment and facilities should minimize the possibility of contamination during the production and must have provision for effective cleaning, maintenance and validation activities to ensure GMP compliance.
Validation and Qualification
Before any facility can begin to be utilized, it will need to receive extensive validation to demonstrate that it is suitable for GMP production.1. Design Qualification (DQ): To confirm that the design meets the requirements of both the regulatory community and the user community.
2. Installation Qualification (IQ): To establish that equipment and utilities have been properly installed, connecting workmanship and product specifications to the production process.
3. Operational Qualification (OQ): After all equipment has been installed, it is necessary to establish whether or not the equipment functions properly under certain simulated conditions.
4. Performance Qualification (PQ): Finally the systems must perform correctly under routine operation.
Validation is performed to confirm that the facility and its equipment can consistently produce high quality pharmaceutical products.
Environmental and Energy Considerations
The design of pharmaceutical facilities is more focused on sustainability and energy efficiency these days. Some important design elements that contribute to sustainability are:- Energy recovery in HVAC.
- LED lighting with smart sensors.
- Water recycling.
- Minimize air changes with equivalent air quality.
Green design of manufacturing facility can reduce cost of operation and supports global efforts for sustainability and environmental responsibility.
Continuous Improvement and Monitoring
A facility’s construction is just the first step in developing it as an operational "entity"; after establishing a facility, constant improvements will happen. The continued follow-up with routine good manufacturing practices (GMP) audits, environmental testing and equipment calibration will also ensure continued compliance.Facilities should utilize a Quality Risk Management (QRM) process and ongoing evaluations of Corrective and Preventive Action (CAPA) to address deviations from normal and provide opportunities to continually improve facility operation. A facility created to support quality will eventually improve to meet the growing needs of the global pharmaceutical marketplace.
Pharmaceutical manufacturers need to build their plants to include as many factors related to quality, safety and efficiency as possible. Whether it is through layout or design choices, material selection or levels of automation and sustainability, design choices impact the ability of the facility to be compliant and maintain the integrity of the product.
A GMP compliant facility not only meets the regulatory requirements but also shows that company has commitment to ensuring patient safety by product quality and excellence in manufacturing process. You must review your facility design before entering into any regulatory audit.
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