Differential pressure control involves maintaining specific pressure differentials between different areas within a pharmaceutical facility. It is used to control the flow of air and prevent cross-contamination between areas of varying cleanliness requirements. Positive pressure differentials are employed in cleanrooms and aseptic manufacturing areas to prevent the entry of contaminants from less clean areas. Negative pressure differentials are used in containment areas handling potent compounds or hazardous materials to ensure containment and protect personnel and the surrounding environment.
Differential Pressure between Change Room, Buffer, and Production area.
The difference in differential pressure between the change room, buffer room, and production area depends on the type and classification of the products and processes involved, as well as the standards and regulations that apply. But it always will be in a sequence from High to low or Low to high.
ISO guideline for Differential Pressure GMP Area
ISO 14644-16, which provides recommendations for energy efficiency in cleanrooms and separative devices. These standard states that “the pressure difference between two adjacent rooms should be sufficient to prevent ingress of contamination from the surrounding area into the cleanroom or clean zone”. It also suggests that “a pressure difference of 5 Pa to 15 Pa is normally adequate for most applications“1.
WHO guideline for Differential Pressure in GMP Area
WHO Guidelines on heating, ventilation, and air-conditioning systems for non-sterile pharmaceutical products, which provide recommendations for good manufacturing practices (GMP) for HVAC systems for non-sterile products.
These guidelines state that “the pressure differential between adjacent rooms should be at least 10 Pa to prevent cross-contamination”. They also provide some examples of acceptable pressure differentials for different types of non-sterile products, such as oral solid dosage forms, liquids and creams, and APIs. For example, for oral solid dosage forms, the guidelines suggest a pressure differential of 15 Pa between the production area and the buffer room and a pressure differential of 10 Pa between the buffer room and the change room2.
USP Guidelines for Differential Pressure in GMP Area
USP Guidelines for Compounding Facilities, which provide recommendations for safety and quality standards for compounding sterile and non-sterile preparations. These guidelines state that “a pressure gauge or velocity meter shall be installed to monitor the pressure differential or airflow between the buffer area and ante-area, and the ante-area and the general environment outside the compounding area“. They also specify that “0.02 to 0.05 in w.c. is the recommended differential pressure to be maintained between two areas” in USP <797> for sterile compounding, and “negative pressure rooms to be maintained between 0.01 to 0.03 in w.c.” in USP <800> for hazardous drugs compounding 3.
Positive and negative differential pressure are commonly used in pharmaceutical Good Manufacturing Practice (GMP) facilities for specific areas to control airflows and minimize the risk of contamination.
Note: The selection of positive or negative differential pressure depends on the intended purpose and the requirements of the specific area. Here are some recommendations for when and why positive and negative differential pressure is used in pharma GMP:
Tolerance Ranges of Differential Pressure:
The pressure differential should be of sufficient magnitude to ensure containment and prevention of flow reversal, but should not be so high as to create turbulence problems. It is suggested that pressure differentials of between 5 Pa and 20 Pa be considered. Where the design pressure differential is too low and tolerances are at opposite extremities, a flow reversal can take place. There should be no risk of overlap in the acceptable operating range, for example, 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting in failure of the pressure cascade (for examples, see Fig. A2.10). The upper and lower limits for pressure differentials between areas in a facility should be defined by the manufacturer. Where there are interleading rooms, the limits should be appropriate to ensure that there is no overlap in actual values, as this may result in a loss in pressure differential between areas and even a reversal of airflow2.
List of Positive Differential Pressure GMP Areas:
Liquid Dosage Forms (Solutions, Suspensions, Emulsions, Syrups, Elixirs): Liquid Dosage Forms (Solutions, Suspensions, Emulsions, Syrups, Elixirs): Positive differential pressure may be used in areas involved in the manufacturing, filling, and packaging of liquid dosage forms. By maintaining positive pressure, these areas are protected from the ingress of contaminants, such as airborne particles or microorganisms. It helps ensure the integrity and quality of the liquid formulations by minimizing the risk of contamination during critical processing steps.
Cleanrooms and Aseptic Processing Areas: Cleanrooms and Aseptic Processing Areas: Positive differential pressure is often maintained in cleanrooms and aseptic processing areas. The higher pressure inside these areas prevents the entry of contaminants from surrounding spaces. This helps protect the product and maintain the desired cleanliness levels. Positive pressure also aids in controlling the dispersion of airborne particles generated within the cleanroom, preventing them from spreading to adjacent areas.
Buffer zones/Barrier Areas: Buffer zones/Barrier Areas: Positive differential pressure is employed in Buffer zones, such as gowning rooms and airlocks. It ensures that air flows out of these areas and into adjacent spaces, preventing contamination from entering the controlled areas. This helps maintain the cleanliness and integrity of the controlled environments.
Bubble Airlock: Higher Pressure inside the airlock and lower pressure on both sides.
Packaging and Filling Areas: Packaging and Filling Areas: Positive differential pressure may be utilized in packaging and filling areas to prevent the ingress of contaminants from the surrounding environment. By maintaining positive pressure, these areas remain protected, reducing the risk of product contamination from foreign particles during the critical packaging and filling processes.
Parenteral Dosage Forms (liquid Injectables, Infusions,) in the Parenteral DOsage form area the fresh air is supplied continuously from HVAC, and filling is performed in highly pressure class with airlocks outside this zone to prevent cross contaminations.
Harms of Reversal of Positive Differential Pressure:
Reversing the intended positive or negative differential pressure in pharmaceutical GMP facilities can have detrimental effects on product quality, safety, and personnel well-being. If positive differential pressure is reversed, meaning that the pressure becomes negative or equalizes with the surrounding areas, it can lead to the following issues:
Reversal of positive pressure can allow contaminants, such as airborne particles or microorganisms, to enter the controlled areas. This can compromise the cleanliness and sterility of the pharmaceutical products. Contamination can occur from adjacent spaces or even from non-controlled areas, leading to cross-contamination risks, compromising the containment of hazardous substances or microorganisms, and posing risks to personnel and the environment. Airborne contaminants may escape from containment areas, leading to potential exposure and spreading of hazardous materials.
In both cases, it is crucial to promptly identify and address any pressure reversal issues to minimize potential risks. Routine preventive maintenance, calibration, and validation of HVAC systems, including pressure sensors and controls, are vital to ensure the reliable and consistent operation of the differential pressure systems.
It is important to note that any pressure reversal issues should be thoroughly investigated to identify the root cause and implement appropriate corrective actions. Engaging qualified professionals and adhering to regulatory requirements and industry best practices are essential to maintain a safe and compliant manufacturing environment in pharmaceutical GMP facilities.
List of Negative Differential Pressure GMP Areas:
Solid Dosage Forms (Tablets, Capsules, Powders, Granules, Sachets): Solid Dosage Forms (Tablets, Capsules, Powders, Granules, Sachets): Negative differential pressure is often maintained in areas where solid dosage forms are handled or processed. This helps prevent the exit of contaminants, such as dust or particulate matter, into surrounding areas. Negative pressure ensures that the air flows inwards from these areas, minimizing the risk of cross-contamination and maintaining the cleanliness of the adjacent area and person. In the tablet section, the pressure difference is kept negative from its adjacent area. Usually, the airlock is recommended outside the tablet section. This slight difference in both areas prevents dust particles from the tablet section to other areas. This logic can be applied in the same as other dosage forms. Just to prevent the cross-contamination of powder/dust particles from one area to another or adjacent areas, e.g. corridors or airlocks.
Inhalation Dosage Forms (Metered Dose Inhalers, Dry Powder Inhalers): Negative differential pressure is employed in areas dedicated to the manufacturing and filling of inhalation dosage forms. This helps contain airborne particles generated during the production process, ensuring they are properly captured and exhausted through the appropriate ventilation system. Negative pressure prevents the dispersion of potentially harmful particles and protects personnel from inhalation exposure.
Transdermal Dosage Forms (Patches): Negative differential pressure may be utilized in areas involved in the manufacturing and packaging of transdermal patches. It helps ensure the containment of volatile compounds or adhesive-related particles, preventing their release into the surrounding environment. Negative pressure aids in capturing and venting any potential contaminants generated during patch manufacturing, maintaining a controlled and safe working environment.
Containment Areas: Negative differential pressure is commonly used in containment areas where hazardous substances or potent compounds are handled, such as areas for manufacturing cytotoxic drugs or handling infectious agents. Negative pressure prevents the escape of airborne contaminants from these areas into surrounding spaces. This protects personnel, the environment, and adjacent manufacturing areas from exposure to potentially harmful substances.
Isolation Rooms: Negative differential pressure is employed in isolation rooms, such as quarantine areas or rooms used for handling highly infectious materials. The negative pressure helps contain airborne contaminants within the isolated area, reducing the risk of spreading infectious agents to the external environment.
HVAC & fume Hood Exhaust Systems: Negative differential pressure may be utilized in HVAC exhaust systems to ensure the proper extraction of air from specific areas, such as fume hoods or equipment enclosures. This prevents the release of hazardous substances or volatile compounds into the surrounding environment, maintaining a safe working environment.
Area-to-area: there is always a negative Pressure buffer zone between two different areas. for example between two tablet sections, between syrup and tablet sections. or any other dosage form area within the same premises. Or it can be reversed if the case of negative pressure areas adjacent to it. The only reason behind this is to prevent cross-contamination between two different areas within the same premises.
Coating Area: Negative pressure differentials are commonly utilized in extraction systems or containment booths within the coating area. These systems effectively capture and remove any volatile compounds, fumes, or particulates generated during the coating process, preventing their dispersion into the surrounding environment. By applying negative pressure differentials, the release of harmful substances can be contained, promoting a safe working environment and protecting operators from potential health hazards.
Sink Air Lock: Lower pressure inside the airlock and higher pressure on both sides
Differential Pressure in Coating Area:
Differential pressure plays a crucial role in the coating area of industrial processes, significantly impacting the quality, efficiency, and overall performance of coating applications. In this context, differential pressure refers to the controlled pressure difference maintained between different zones within the coating area.
Purpose of Negative Pressure in coating area: One of the primary purposes of maintaining differential pressure in the coating area is to ensure the proper airflow and containment of airborne particles. By establishing positive pressure differentials, clean air can be supplied to critical zones, preventing the entry of contaminants from surrounding areas. This helps maintain a clean and controlled environment, minimizing the risk of defects or imperfections in the coating process.
Negative pressure differentials are commonly utilized in extraction systems or containment booths within the coating area. These systems effectively capture and remove any volatile compounds, fumes, or particulates generated during the coating process, preventing their dispersion into the surrounding environment. By applying negative pressure differentials, the release of harmful substances can be contained, promoting a safe working environment and protecting operators from potential health hazards.
In addition to contamination control, differential pressure also influences the airflow patterns within the coating area. Proper airflow management, facilitated by appropriate pressure differentials, ensures an even and consistent distribution of coating materials. This helps to achieve uniform coating thickness, reduce overspray, and optimize the overall coating quality.
It is essential to design the coating area with careful consideration of the required pressure differentials, airflow velocities, and control mechanisms. Regular monitoring and adjustment of differential pressure levels are necessary to maintain optimal conditions and ensure the effective functioning of the coating process.
By effectively managing and controlling differential pressure in the coating area, manufacturers can achieve improved coating quality, reduced rework, increased operational efficiency, and enhanced worker safety. Implementing industry best practices and complying with relevant standards and regulations are key to successfully harnessing the benefits of differential pressure in the coating area of industrial processes.
Note: It is important to note that the selection and implementation of positive or negative differential pressure should be based on a thorough risk assessment, considering factors such as the nature of the materials handled, the desired level of containment, and regulatory requirements. Regular monitoring and maintenance of the differential pressure systems are necessary to ensure their effectiveness in maintaining appropriate airflow control and preventing contamination risks.
Harms of reversal of Negative Pressure
Here are some potential harms associated with the reversal of negative pressure:
Contamination Risk: Reversal of negative pressure can lead to the escape of airborne contaminants from the controlled area. This can result in the contamination of adjacent areas, equipment, products, or personnel. Contaminants may include hazardous substances, volatile chemicals, allergens, or microorganisms, which can compromise product integrity and pose risks to personnel and the surrounding environment.
Cross-Contamination: Negative pressure is often employed to contain hazardous substances or microorganisms within a specific area. Reversing the negative pressure can break the containment, allowing these contaminants to spread and cross-contaminate other areas. This can result in the contamination of products, raw materials, or equipment, jeopardizing their quality and safety.
Occupational Exposure: Negative pressure is utilized to protect personnel by preventing the dispersion of harmful substances or microorganisms into the surrounding environment. If negative pressure is reversed, it can lead to an increased risk of occupational exposure to hazardous materials. This can have adverse health effects on workers, ranging from respiratory issues to systemic toxicity, depending on the nature of the contaminants.
Regulatory Compliance: Many industries, including pharmaceuticals, biotechnology, and healthcare, have specific regulations and guidelines in place to ensure proper containment and protection from hazardous substances. Reversal of negative pressure violates these requirements and can lead to non-compliance with regulatory standards. This may result in legal consequences, fines, or the suspension of operations until corrective measures are taken.
Product Quality and Safety: Negative pressure plays a crucial role in maintaining product quality and safety in controlled environments. This can lead to product degradation, reduced efficacy, compromised sterility, or increased risk of adverse reactions in patients or end-users.
Note: To mitigate the harms of negative pressure reversal, it is essential to implement robust monitoring systems, routine maintenance, and regular inspections of HVAC systems. Real-time monitoring of pressure differentials, alarms, and automated controls can help promptly identify and address pressure deviations. Personnel should receive proper training on the importance of negative pressure containment and the procedures to follow in case of pressure reversal
3 types of airlocks are common in Pharma Premises
Cascade Airlock: High Pressure on One side of the airlock and lower pressure on the other side
Sink Air Lock: Lower pressure inside the airlock and higher pressure on both sides
Bubble Airlock: Higher Pressure inside the airlock and lower pressure on both sides.
selection of airlock depends upon need and area of working nature. The following 2 are explained for better understanding.
Personnel Airlocks: Personnel airlocks are designed to control the entry and exit of personnel into cleanrooms. They are equipped with interlocking doors to ensure that both doors are never open simultaneously, thereby maintaining a pressure differential that prevents unfiltered air from entering the cleanroom. Personnel airlocks often have features like air showers or gowning stations to help personnel change into appropriate cleanroom attire and remove particulate contaminants before entering the critical environment.
Material Airlocks: Material airlocks, also known as goods transfer airlocks, are used for the smooth transfer of materials, equipment, and components into and out of cleanrooms. These airlocks ensure that any external contaminants are removed from materials before they enter the cleanroom and prevent cleanroom contaminants from escaping during the transfer process. Material airlocks are typically equipped with mechanisms like pass-through chambers, UV germicidal lamps, and High-Efficiency Particulate Air (HEPA) filters to maintain the required cleanliness levels.
In conclusion, positive and negative pressure differentials are vital elements in pharmaceutical Good Manufacturing Practice (GMP) areas. Positive pressure helps maintain cleanliness by preventing contamination from entering critical zones, while negative pressure ensures the containment of hazardous materials. By implementing appropriate pressure differentials and adhering to industry standards, pharmaceutical facilities can enhance product integrity, protect personnel, and maintain a safe manufacturing environment.