Cleanroom HVAC and pressure cascade

The heating, ventilation and air-conditioning system supplies filtered air to each room so that it "maintains a positive pressure and/or an airflow relative to the background environment of a lower grade under all operational conditions and should flush the area effectively" (Annex 1, 4.14). Air moves from cleaner to less clean areas, never the other way.

Annex 1 sets four grades, A to D (4.4), and gives a guidance value of "a minimum of 10 Pascals" between adjacent rooms of different grades (4.14). Where unidirectional airflow protects exposed product, it gives a guidance air speed range at the working position and asks for airflow visualisation to correlate with it (4.30).

Where it sits: Around every controlled space: airlocks and change rooms, preparation, filling, and the background rooms of RABS and isolators.

• —Sterile manufacturing suites
• —Aseptic filling rooms and their backgrounds
• —Change rooms and airlocks
• —Sterility testing laboratories

In the reference facility: Plant utilities, HVAC & energy centre, Processing & formulation suite, Aseptic filling & isolator line, Personnel gowning & change, Material staging, weighing & dispensing

Not covered on this page: Containment design for potent, pathogenic or radioactive materials, where Annex 1 4.14 allows modified pressure regimes; Non-sterile manufacturing areas.

• 01Air handling units (fans, coils, humidifiers). Condition and move the air: temperature, humidity and volume.
• 02Pre-filters and terminal HEPA filters. Clean the supply air; the terminal filter is the last barrier before the room. See the HEPA filtration page.
• 03Supply and return ductwork, diffusers and low-level returns. Set the airflow pattern in the room.
• 04Pressure control dampers. Hold each room at its pressure relative to its neighbours.
• 05Airlocks and pass-through hatches. Separate grades; Annex 1 asks for interlocked doors on airlocks into grade A and B (4.13).
• 06Building management or environmental monitoring system. Displays pressure differences and raises alarms (Annex 1, 4.16).

Connects to: Isolators, RABS and unidirectional airflow units in the room; Chilled water, steam and power; Environmental monitoring programme; Gowning and material flow procedures.

• 01Differential pressure transmitter. Pressure differences between rooms and grades, fitted as indicators between cleanrooms (Annex 1, 4.16). Watch for: ports connected the wrong way round, reversing the sign.
• 02Airflow velocity probe (anemometer). Air speed at the working position under unidirectional airflow. Watch for: readings taken at a different height from the one qualified.
• 03Optical particle counter. Total particles ≥0.5 µm and ≥5 µm for classification and monitoring. Watch for: sample tubing long or bent enough to lose large particles.
• 04Active air sampler and settle plates. Viable contamination in air and on surfaces. Watch for: media dried out over long exposures.
• 05Temperature sensor (RTD or thermocouple). Room temperature. Watch for: sensor not at the location that matters (cold spot, load centre).
• 06Humidity sensor. Room humidity. Watch for: condensation or peroxide exposure shifting the sensor.

• 01Pressure differential (limit, Pa). Between adjacent rooms of different grades; Annex 1 guidance value of at least 10 Pa (4.14), with the site’s own limits set in qualification.
• 02Airflow velocity (measured, m/s). At the working position under unidirectional airflow; Annex 1 guidance range 0.36–0.54 m/s unless scientifically justified in the CCS (4.30).
• 03Airborne particle concentration (limit, particles/m³ per size channel). By grade and state, for classification against Annex 1 Table 1 in qualification; the site sets its monitoring limits in a separate programme (4.24).
• 04Viable airborne contamination (limit, CFU/m³ or CFU/plate per exposure). By grade during qualification, against Annex 1 Table 2 (4.31).
• 05Recovery (clean-up) time (measured, min). Determined in qualification; guidance value under 20 minutes (Annex 1, 4.29).
• 06Supply airflow volume (measured, m³/h). At each supply filter, part of qualification and requalification (4.25, 4.32).

SPEQ publishes no universal alarm or acceptance values: they depend on the process, the product and the site’s own qualification.

• 01Control loop: Room pressure control. Adjusts supply or exhaust to hold each room’s differential.
• 02Alarm: Pressure difference out of range. Warns operators at once of a supply failure or a critical difference below its limit; it is not overridden without assessment, and any alarm delay is justified in the CCS (Annex 1, 4.16).
• 03Interlock: Airlock door interlocks. Stop both doors of an airlock into grade A or B opening at once (Annex 1, 4.13).
• 04Procedure: Requalification schedule. Grade A and B at most every 6 months, grade C and D at most every 12 months, and after significant change (Annex 1, 4.32).

An alarm asks for a response; an interlock stops an action; a safety function protects people and has its own risk basis.

• 01Design. User requirements by grade; Airflow and pressure cascade design; Contamination control strategy (CCS) input.
• 02Qualification (Annex 15; Annex 1, 4.25). Installed filter leakage and integrity; Airflow volume and velocity; Pressure difference; Airflow direction and visualisation; Microbial contamination; Temperature and humidity; Recovery.
• 03Classification (Annex 1, 4.26–4.29). Particles ≥0.5 and ≥5 µm, at rest and in simulated operation; Sampling locations per ISO 14644-1, plus critical points such as the point of fill.
• 04Routine. Pressure difference records and alarms; Environmental monitoring results and trends.
• 05Requalification and change. Periodic requalification to Annex 1, 4.32; Requalification after remedial action or significant change.

• 01EU GMP Annex 1: Manufacture of Sterile Medicinal Products — European Commission (EudraLex Volume 4), 2022 revision, in operation 25 August 2023. EU / EEA; revised jointly with the PIC/S Committee; in force. Supports: Grades (4.4); filtered supply and the 10 Pa guidance (4.14); airflow visualisation (4.15); pressure indicators (4.16); qualification tests (4.25); classification (4.26–4.29); air speed guidance (4.30); microbial limits (4.31); requalification intervals (4.32).
• 02EU GMP Annex 15: Qualification and Validation — European Commission (EudraLex Volume 4), 2015. EU / EEA; in force. Supports: The qualification approach Annex 1 applies to cleanrooms (4.24).
• 03ISO 14644-1: Cleanrooms and associated controlled environments — Part 1: Classification of air cleanliness by particle concentration — ISO (TC 209), 2015 (Edition 2). International; consensus standard. Supports: Classification and sampling locations (Annex 1, 4.28).
• 04ISO 14644-3: Cleanrooms and associated controlled environments — Part 3: Test methods — ISO (TC 209), 2019 (Edition 2). International; consensus standard. Supports: Test methods for the qualification tests.
• 05Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice — US FDA, September 2004. United States; guidance. Supports: FDA’s expectations for clean areas supporting aseptic processing in the United States.