Designing a GMP Cleanroom for a Pharma Plant: Filter Stages and Air Cleanliness Grades

Vietnam is seeing a strong wave of investment in domestic pharmaceutical manufacturing — from generic drugs and OTC tablets to vaccines and biologics. The journey from "ordinary production room" to "cleanroom meeting GMP-WHO/EU" is the toughest challenge for every plant. This article rounds up what you need to know about filter stages and air cleanliness grades before investing.

1. Why must a pharma plant have a cleanroom?

Pharmaceuticals contact the body directly — orally, by injection, inhalation, or topically. A speck of dust or a bacterium in the final product can cause:

• Poisoning for IV drugs.
• Loss of potency due to interaction with impurities.
• Outbreaks if bacteria grow inside the vial.

That is why every pharmaceutical regulator (US FDA, EMA, Vietnam's Drug Administration, WHO PreQual) requires producers to follow Good Manufacturing Practice (GMP) — of which cleanrooms are the foundation.

2. GMP classification for pharma plants

GMP-WHO and EU GMP Annex 1 split production into 4 grades: A, B, C, D.

Grade A — High-risk operations

• Sterile compounding and vial filling (vaccines, injectables).
• Cell-culture handling, biologics.
• Sealing injectable vials before terminal sterilisation.

Requirement: ISO 5 both at rest and in operation; laminar velocity of 0.36-0.54 m/s at the working plane.

Grade B — Background to Grade A

• The area around Grade A; typically the same room but outside the LAF box.

Requirement: ISO 5 at rest, ISO 7 in operation.

Grade C — Non-sterile compounding

• Tablet, capsule, and syrup compounding.
• Intermediate steps in biologics production.

Requirement: ISO 7 at rest, ISO 8 in operation.

Grade D — Peripheral areas

• Secondary packaging (cartons).
• Raw-material and finished-goods warehouses.
• Anterooms and support corridors.

Requirement: ISO 8 at rest.

3. Filter train by GMP grade

This is the core of pharma-plant HVAC design:

Grade D

Pre G4 → Medium F8 → HEPA H13 (at ceiling terminal box).

• ACH: 20 per hour.
• Differential pressure: +15 Pa vs. the surrounding technical area.

Grade C

Pre G4 → Medium F8/F9 → HEPA H14 (terminal box).

• ACH: 30 per hour.
• Differential pressure: +15 Pa vs. D.

Grade B (Background)

Pre G4 → Medium F9 → HEPA H14 (AHU/MAU) → ULPA U15 (FFU).

• ACH: 40 per hour.
• Differential pressure: +15 Pa vs. C.

Grade A (LAF box)

Pre G4 → Medium F9 → HEPA H14 (AHU/MAU) → ULPA U15/U17 (LAF/FFU) under laminar flow.

• ACH: 60 per hour (or higher, to reach 0.45 m/s ±20% laminar velocity).
• Differential pressure: +15 Pa vs. B.

Overall pressure cascade

Technical area (~0 Pa) → Common corridor (+5 Pa) → Grade D (+15 Pa) → Grade C (+30 Pa) → Grade B (+45 Pa) → Grade A (+60 Pa).

4. A typical layout

A GMP-WHO injectable pharma plant typically has 4 zones:

1. Zone D (raw-material warehouse, secondary packaging, clean corridors).
2. Zone C (compounding, dissolution, coarse filtration).
3. Zone B (filling, 0.22 µm sterile final filtration — inside a sealed room with LAF).
4. LAF/Grade A (the work zone for direct sterile product — sitting inside B).

Rooms connect via airlocks or pass boxes for material/product transfer without breaking the pressure cascade.

5. AHU/MAU for the pharma plant

The central air-handling system is the "heart" of the pharma cleanroom:

• 100% fresh-air AHU (MAU) for sterile zones — no recirculation to avoid cross-contamination.
• Recirculating AHU with 80-90% recirculation + 10-20% fresh air for standard compounding — energy-efficient.
• Two-stage cooling coil for deep dehumidification (30-55% RH depending on product).
• Clean-steam injection humidifier — no chemicals, no chilled mist (which causes microbial contamination).
• VAV controller adjusts airflow to demand — saving 20-40% electricity vs. fixed CAV.

6. Special design considerations

a. Cytotoxic / hazardous-actives rooms

• Need negative pressure so pathogens/actives do not escape.
• HEPA H14 on both supply and exhaust.
• Dedicated HVAC, no recirculation with other areas.

b. Tablet rooms with high powder load

• Heavy dust load — Pre and Medium need shorter replacement cycles (1-2 months).
• Cyclone + Cartridge filter on exhaust before discharge to atmosphere.

c. Vaccine vial-filling rooms

• Class A LAF box placed directly over the filling machine.
• Laminar velocity 0.45 m/s ±20% — measured every 6 months with an anemometer.
• Annual smoke (visualisation) test to prove the laminar flow is genuinely uniform.

7. Validation and maintenance

GMP validation of the HVAC / cleanroom is mandatory:

DQ (Design Qualification)

• Approve design drawings, URS, FRS.

IQ (Installation Qualification)

• Verify installation against spec — model, serial, filter location, power, pressure.

OQ (Operational Qualification)

• Test ACH, differential pressure, temperature, humidity, at-rest particle counts.

PQ (Performance Qualification)

• Test in operation (with people and machines running) over 3 consecutive shifts.

Periodic maintenance

• Daily: check differential pressure, temperature, humidity.
• Weekly: clean ceilings, floors, walls.
• Monthly: check ΔP across each filter.
• Every 6 months: DOP/PAO test HEPA and ULPA.
• Annually: re-qualification, full particle counting, airflow visualisation.
• Every 3-5 years: replace HEPA (H14 and above need an integrity test prior to replacement).

8. Real-world cases in Vietnam

Major Vietnamese pharma plants — Sanofi (Đông Anh), Hau Giang Pharma, Imexpharm, Pymepharco, Vingroup VinBioCare, AstraZeneca (in-house tolling) — all use the 4-grade GMP-WHO architecture with the full Pre + Medium + HEPA/ULPA chain. Cleanroom investment makes up 25-40% of total facility capex — reflecting how central the system is.

Conclusion

A GMP cleanroom for a pharma plant is not just a "premium room" — it is an integrated system of architecture, HVAC, filtration, and validation. Understanding the filter chain for each grade A/B/C/D, investing in the right HEPA/ULPA, and maintaining discipline are the keys to passing GMP-WHO and EU audits and exporting into the toughest markets.

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About Green Filter

Green Filter supplies the full range of filters for every GMP A/B/C/D grade: Pre, Medium F8/F9, HEPA H13/H14, ULPA U15/U17 and 304 stainless-steel FFUs for pharma and biological cleanrooms. Green Filter's team has experience advising on IQ/OQ/PQ validation and providing on-site HEPA/ULPA scan testing.

📞 Contact Green Filter for filter consulting for your pharma plant: [insert hotline / email / website]

See also: How to choose HEPA/ULPA by cleanroom class · HEPA/ULPA validation and replacement · What is a cleanroom?.