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1. General Principles
1.1.
This specification applies to the ventilation, air conditioning, and air purification (HVAC) air system design for clean areas and auxiliary areas in biopharmaceutical plant rooms.
1.2.
System design shall ensure the production environment continuously meets Good Manufacturing Practice (GMP) requirements, provides the necessary environmental parameters for core processes, including but not limited to air cleanliness, temperature, humidity, pressure differential, and airflow pattern, and possesses appropriate redundancy and energy efficiency.
1.3.
All materials, equipment, and construction installation must comply with relevant national and industry standards, and meet international general guidelines such as cGMP and ISO 14644.
2. Design Standards and Parameters
2.1. Air Cleanliness Grades:
Grade A Area (ISO 5): Unidirectional airflow, recommended air velocity 0.36-0.54 m/s (guideline value, requires validation), uniform airflow must be maintained above operating points.
Grade B Area (ISO 5): Serves as the background environment for Grade A areas.
Grade C Area (ISO 7).
Grade D Area (ISO 8).
2.2. Environmental Control Parameters:
Temperature: Typically controlled within the range of 20°C to 24°C, accuracy ±2°C. For special process areas, determine according to process requirements, accuracy can reach ±0.5°C.
Relative Humidity: Typically controlled within the range of 45% to 60%, accuracy ±5% RH. Stricter control is required for hygroscopic products or special processes.
Room Pressure Differential: Minimum pressure differential gradient between adjacent rooms of different cleanliness grades shall be ≥10 Pa (typically 10-15 Pa). Minimum pressure differential from clean area to non-clean area shall be ≥15 Pa. High-risk areas maintain relative positive or negative pressure (e.g., toxic operation areas).
Air Changes Per Hour: Grade C area ≥25 ACH, Grade D area ≥15 ACH. Actual value must be determined comprehensively by calculating cooling/heating loads, humidity loads, and cleanliness requirements, and requires validation.
2.3. Fresh Air Volume:
Shall be the greater of the following two values:
a) The sum of air volume required to compensate for indoor exhaust air and maintain indoor positive pressure.
b) The fresh air volume required to ensure indoor personnel hygiene requirements, ≥40 m³ per person per hour.
3. Air Handling System Design
3.1. System Zoning Principles:
Independent systems shall be zoned according to cleanliness grade, temperature and humidity requirements, functional areas, operational shifts, and product contamination risk level.
Penicillin products, high-activity, high-toxicity, and high-sensitizing drugs must use independent, dedicated air conditioning systems.
Production areas for different product types, dust-generating rooms in solid dosage forms, and areas with severe pollutants should have independent systems.
3.2. Air Handling Unit (AHU):
The unit should adopt a modular structure including hydrophilic membrane type heat recovery section, primary filtration section, pre-heating section (optional), cooling coil section, re-heating section, steam humidification section, fan section, intermediate filtration section, and discharge section.
The unit casing should feature thermal insulation and anti-cooling bridge design, with interior panels made of stainless steel.
Fans should be equipped with standby motors or adopt a dual-fan configuration to ensure uninterrupted system operation. Motors should use Variable Frequency Drive (VFD) for air volume regulation and pressure differential control.
All components and panels contacting humid air need to use corrosion-resistant materials.
3.3. Filtration System:
Primary Filter: G4/F5 efficiency, located after the fresh air and return air mixing section.
Intermediate Filter: F7/F8 efficiency, located after the unit's supply fan.
Terminal Filter: High Efficiency Particulate Air (HEPA) filter.
Grade A/B Areas: Install H14 grade (99.995% @ 0.3μm MPPS) or higher efficiency liquid trough type or zero-leakage frame HEPA filters.
Grade C/D Areas: Install H13 grade (99.95% @ 0.3μm MPPS) and above efficiency HEPA filters.
All HEPA filters require on-site PAO/DOP scan leak testing and shall be equipped with final resistance monitoring devices.
4. Air Duct System
4.1.
Duct material should use high-quality low-carbon galvanized steel plate, with smooth, clean, and corrosion-resistant inner and outer surfaces. Ducts within clean areas should be made of stainless steel plate.
4.2.
Duct fabrication and installation must comply with cleanroom specifications, using咬口 connections, all seams require sealing treatment. Ducts must be kept clean, require degreasing before installation, and require blowing, cleaning, and sealing after installation is complete.
4.3.
Necessary cleaning openings and measurement ports should be set on ducts. Main ducts should have inspection ports for measuring air volume and pressure differential.
4.4.
Duct insulation material should be non-combustible, non-dusting, and resistant to bacterial growth (such as closed-cell rubber foam or phenolic foam), covered with a dust-proof protective layer.
5. Airflow Organization and Air Supply/Return
5.1. Air Supply:
Grade A Area: Must use unidirectional airflow supply ceiling (FFU or diffuser panels), covering the entire key process operation area, ensuring the airflow pattern is not disturbed.
Grade B/C/D Areas: Use ceiling-mounted HEPA filter supply air outlets. Layout should prioritize protecting key process points and operators.
5.2. Return/Exhaust Air:
Grade A/B Areas: Use low-level return air outlets arranged on both side walls, the lower edge of the outlet should ideally be 100-300mm from the floor.
Grade C/D Areas: Can use side wall low-level returns or corridor returns.
Dust/Moisture generating rooms: Should have independent exhaust systems and maintain relative negative pressure indoors. Exhaust outlets should be close to the dust/moisture generation points.
All return/exhaust air outlets should be equipped with easily removable and cleanable filter screens (e.g., primary G4) or check valves.
6. Pressure Differential Control
6.1.
An orderly pressure differential gradient between cleanrooms and adjacent spaces, and between areas of different cleanliness grades, must be established and maintained.
6.2.
An automatic pressure differential control system should be used, maintaining the set pressure differential by adjusting automatic dampers on supply air, return air, or exhaust air volumes.
6.3.
Install visual pressure differential gauges at the entrance of each critical room, the range should be suitable for the actual pressure differential. Also, transmit pressure differential signals remotely to the Building Automation System (BAS) for centralized monitoring and alarm.
7. Control System and Monitoring (BAS/BMS)
7.1.
The HVAC system should be integrated into the Building Management System (BMS) or an independent automatic control system to achieve automatic control, recording, alarm, and energy management.
7.2.
The system should continuously monitor and record the following key parameters: Supply/return/exhaust fan start/stop, fault status; VFD frequency; Primary/intermediate filter pressure differential; HEPA filter final resistance; Temperature and humidity in various areas; Pressure differentials in key rooms.
7.3.
Different operational mode scenarios should be set (e.g., production mode, standby mode, disinfection mode) to save energy.
7.4.
System alarms should be managed by priority level. Critical parameter deviations (e.g., pressure differential reversal, temperature exceedance) should immediately trigger audible/visual alarms and be recorded.
8. Validation and Testing
8.1.
After system installation is complete, comprehensive Qualification and Validation (IQ/OQ/PQ) must be performed, including but not limited to:
Airflow balance testing and adjustment (ensuring supply, return, exhaust, fresh air volumes and air change rates per room conform to design).
HEPA filter leak test (PAO/DOP scan).
Cleanliness test (particle counting).
Pressure differential test.
Temperature and humidity stability test.
Airflow pattern test and visualization (Grade A/B areas).
Recovery test (self-cleaning time test).
Noise and illumination level test (if applicable).
8.2.
All test reports must be archived as the basis for system release for use. A periodic revalidation plan should be established.
