In today's increasingly competitive pharmaceutical market, "efficiency and compliance" has become a consensus among major pharmaceutical companies. Leading global pharmaceutical companies have regarded cleanrooms as key infrastructure for improving the efficiency and quality of liquid preparation production.
1. Pfizer
In the large-scale production project of the covid-19 vaccine BNT162b2”
▶When Pfizer cooperated with BioNTech to produce vaccines, this is emphasized:
"We re-engineered our cleanroom lines to accelerate production without compromising quality."
▶The source can be traced back to Pfizer's announcement concerning the expansion of its Kalamazoo plant in Michigan, USA from the end of 2020 to the beginning of 2021.
2. Novartis
▶When talking about its global manufacturing network, Novartis mentioned:
“Modular and flexible cleanroom systems are transforming the speed at which we bring therapies to market.”
Such statements are often seen in the release of its sustainable production strategy.
3. Merck (Germany)
▶Merck Life Science:
"Advanced cleanroom environments enable consistent quality and faster scale-up in biopharmaceutical manufacturing."
4. Moderna
▶In the context of rapid launch of vaccines:
"Rapid deployment of modular cleanrooms allowed us to expand capacity quickly and meet urgent demand."
5. Lonza (provides CDMO services to many pharmaceutical giants)
▶In its annual report or industry interview, it was mentioned:
"Cleanroom technology is a key enabler for high-speed sterile manufacturing processes."
These cases all show that today, the value of cleanrooms has surpassed compliance and certification, and it is becoming the core force to speed up the entire process of pharmaceutical companies from R&D, clinical to market launch.
For the production of liquid preparations such as injections, infusions, and oral solutions, the cleanroom air flow design, differential pressure control, and rapid cleaning verification system are all guarantees for achieving efficient, continuous, and safe production.
1. What is liquid preparation?
Liquid preparations refer to a uniform or non-uniform system formed by the dispersion of drugs in a liquid medium (such as water, ethanol, oil, etc.) in the form of molecules, ions, or tiny particles, for internal or external use.
Application examples:
(1) Oral: cough syrup, antipyretic oral solution
(2) Injections: intravenous infusion (such as glucose injection, vaccine)
(3) Local medication: skin lotion, ear drops
(4) Special use: oral spray, rectal enema
2. Why is a clean room environment needed for the production of liquid preparations? How strict are the requirements for a clean environment?
(1) Liquid preparations are easily contaminated by microorganisms such as bacteria and fungi, as well as particles such as dust and fibers in the air, due to the liquid medium, which can cause the drug to deteriorate, lose its efficacy, and easily cause adverse reactions. Therefore, a clean room environment is required to ensure its safety, effectiveness, and stability. Different dosage forms have different requirements for cleanliness, but the core goal is to control microorganisms, particles, and cross-contamination while meeting strict regulatory compliance.
(2) The following is a summary of the environmental requirements for common liquid preparation clean rooms:
3. GMP Cleanroom Design Guidelines for Liquid Preparation
(1) GMP Regulatory System Applicable to Liquid Preparation Cleanrooms
China GMP "Good Manufacturing Practice for Pharmaceuticals" (revised in 2010)
"Sterile Drug Appendix" (Requirements for Sterile Liquid Preparations)
"Non-Sterile Drug Appendix" (Requirements for Non-Sterile Liquid Preparations)
US cGMP (FDA 21 CFR)
21 CFR Part 210/211 (Basic Requirements for Drug Production)
21 CFR Part 600-680 (Biological Products, such as Vaccines and Blood Products)
EU GMP (EMA/EU GMP)
EU GMP Annex 1 (Sterile Drug Production, 2022 Revised Edition)
EU GMP Part I (Basic Requirements)
WHO GMP
WHO TRS 986 (GMP Guide)
WHO TRS 961 (Sterile Drug Appendix)
(2) Functional Area Division of Liquid Preparation Cleanrooms
According to According to WHO's GMP, the floor plan of a pharmaceutical factory can be divided into the following areas:
Production area - the area directly engaged in drug production, which has cleanliness requirements.
Quality control area - equipped with quality control laboratories, inspection rooms, instrumentation rooms, etc., which have cleanliness requirements.
Storage area - where various materials and products are stored.
Materials: such as starting materials and packaging materials;
Products: such as intermediate products, materials to be packaged and finished products, products to be tested, qualified products, substandard products, reprocessed products, and recycled products. There are certain temperature, humidity and cleanliness requirements, and special attention should be paid to the special storage requirements of highly active materials, narcotics, drugs with misuse risks, and fireproof and explosion-proof items.
Weighing area - for weighing starting materials, there are certain cleanliness requirements or dust control requirements. It can be placed in the storage area.
Auxiliary area - including changing, storing, washing, washing, resting, repairing and. Except for the second change and washing, there are generally no cleanliness requirements.
(3) Cleanliness level and cleanliness requirements of different functional areas
(4) Differences in cleanroom design between sterile and non-sterile liquid preparations
(5) Principle of separation of human and material flow and design of moving lines
Principle of separation of human and material flow:
A. Completely independent channels
Human and material flow must enter the clean area through different entrances, channels and airlocks, and be physically isolated to avoid cross contamination.
Example:
Human flow: dressing room → airlock → clean area.
Material Logistics: external cleaning room → pass through/sterilizer → buffer room → clean area.
B. One-way flow
People and materials move in a single direction in the clean area (from low cleanliness to high cleanliness), and reverse or return is prohibited.
C. Gradual control
Set up transition buffer areas according to cleanliness levels (A/B/C/D), and purify step by step (such as D→C→B levels need to pass through airlock rooms).
Moving-line design
A. Personnel entry process
Non-clean area → first change room (take off outer clothes, change shoes) → second change room (wear clean clothes, hand disinfection) → airlock (pressure difference self-purification) → clean area.
Sterile preparations need to add: Class B area: sterile underwear → sterile outer clothing → gloves/mask → air shower (optional)
Reverse process when exiting to avoid contamination.
Major control
Clothing classification: Different clean level areas correspond to different changing procedures (such as separate Class C and Class B changing rooms).
Exit channel: When exiting the clean area, you must go through a dedicated exit (avoid sharing with the entry channel).
Number limit: The number of people in Class A/B areas is strictly limited to reduce intervention.
B. Material entry process
Non-clean area → outer packaging cleaning → pass through/sterilizer (such as double-door sterilizer, RTP transfer cabin) → buffer room → clean area.
High-risk materials (sterile): need to be sterilized and transferred under Class A laminar flow protection (such as vials for filling).
Key control
Sterilization measures: Sterile preparation materials need to be sterilized by moist heat, irradiation or filtration.
Transfer method:
Non-sterile: pass through with self-cleaning function (UV+laminar flow).
Sterile: Transfer within an isolator or RABS (restricted access barrier system).
Packaging removal: The outer packaging is removed in the low-level area, and the inner packaging needs to be cleaned in the high-level area before being transferred
Route design example (taking sterile injection as an example)
1. People flow
General area → First change room (change shoes, wash hands) → Second change room (C-level clean clothes) → Air lock room (pressure difference control) → C-level corridor
→ B-level changing room (sterile clothes) → air shower → B-level core area (filling under A-level laminar flow).
2. Logistics flow
Raw materials (non-clean area) → External cleaning room (remove outer boxes) → Pass through sterilizer (SIP/CIP) → C-level temporary storage
→ Transfer to filling line through A-level RABS → Finished product is transferred to the external packaging room through closed transportation.
(6) Relationship between pressure gradient and clean area layout
In the design of clean room for preparations, the relationship between pressure gradient and clean area layout is the core means to control contamination and cross-contamination. Reasonable pressure difference design can ensure that the airflow flows from the high clean area to the low clean area and prevent the reverse diffusion of pollutants. The following is a table summarizing the relationship between the pressure difference gradient and the clean area layout:
(7) Cleanroom air supply system (HVAC) design (air volume, air change rate, unidirectional flow, non-unidirectional flow application scenarios)
Air volume calculation
Unidirectional flow (Class A area):
Air volume is determined by cross-sectional wind speed:
Air volume (m³/h) = laminar flow area (m²) × 0.45 m/s × 3600
For example: 1.2m × 0.8m laminar flow hood, air volume ≈ 1555 m³/h.
Non-unidirectional flow (B/C/D level):
Air volume is calculated by air change rate × room volume, and equipment heating and personnel load corrections need to be considered
Air change times per hour (ACH): Number of clean room air change rate per unit time (times/h),
Calculation formula: ACH = clean room volume (m³) / air supply volume (m³/h)
Air change rate requirements for typical cleanliness levels (refer to ISO 14644 and GMP):
(8) Key points for air filtration system design (HEPA/ULPA filter layout, FFU or air outlet type selection)
Filter layout design
● Terminal coverage principle
A-level unidirectional flow area: High-efficiency filters fully cover the ceiling or side walls (full coverage rate ≥ 80%) to ensure uniform airflow
Example: The top of the laminar flow hood of the filling line is fully covered with ULPA filters.
B/C-level non-unidirectional flow area:
High-efficiency filters are arranged at the end of the air supply (such as ceiling FFU or diffuser), with a coverage rate of 30%-50%.
● Multi-stage filtration configuration
Typical three-stage filtration: fresh air → primary filter (G4) → medium efficiency filter (F8) → high-efficiency filter (H13/H14) → clean room
Sterile preparations: Pre-high-efficiency filters (F9-H10) need to be added after the medium efficiency filter to extend the life of HEPA.
● Layout of special areas
Dust-producing room: Install H13 filter at the return air outlet to prevent particle diffusion
Isolator/RABS: Built-in ULPA filter, independent circulating air system
FFU (fan filter unit) vs. HEPA air outlet selection comparison:
(9) Sterility assurance measures during filling and liquid preparation (laminar flow hood, RABS, isolator, filling area ISO5 environmental control strategy)
The core of sterility assurance is the comprehensive control of "environment + equipment + personnel + verification". The following is a specific summary table:
(10) Key equipment and material selection for liquid preparation cleanroom
In the production process of liquid preparations, the design of the cleanroom, equipment selection and material selection directly affect the sterility and quality stability of the product. The selection of key equipment and materials mainly follows the following principles:
1) Sterile compatibility: materials must withstand SIP/VHP sterilization without precipitation
2) Cleanability: the surface of the equipment is smooth (Ra≤0.8μm) to avoid microbial retention
3) Regulatory compliance: meet GMP, FDA 21 CFR Part 11, EU Annex 1 requirements
According to the above principles, it can be summarized into the following table:
4. How to pass GMP verification and certification for liquid preparation cleanroom (verification process DQ IQ OQ PQ, dust particles, microorganisms, pressure difference, temperature and humidity)
The liquid preparation cleanroom needs to systematically perform design confirmation (DQ), installation confirmation (IQ), operation confirmation (OQ), performance confirmation (PQ) and continuous monitoring to ensure compliance with China GMP, EU GMP Annex 1 or FDA cGMP requirements. The following are the key steps and key points for phased implementation:
▶GMP certification core process
Preliminary preparation
User Requirements Statement (URS): clarify the cleanroom function, cleanliness level (A/B/C/D), and process requirements (sterile/non-sterile).
Risk assessment (FMEA): identify critical control points (such as filling area, material transfer).
Four-stage verification (DQ→IQ→OQ→PQ)
Official inspection and certification: submit a verification report and accept on-site inspection by the drug administration (such as NMPA, FDA).
▶ Key points for phased validation implementation
● Design confirmation (DQ)
Goal: Ensure that the design meets GMP and process requirements.
Key content:
Layout rationality: personnel/logistics separation, pressure gradient (such as B-level → C-level ≥15 Pa).
HVAC system: ventilation frequency (B-level ≥40 times/h), filter grade (A-level requires ULPA).
Equipment selection: sterilizers, filling machines, etc. must meet GMP material (316L stainless steel) requirements.
Delivery documents: design drawings, URS, risk assessment report.
● Installation confirmation (IQ)
Goal: Confirm that the equipment and system are installed according to the design.
Key content:
HVAC system:
Filter integrity (PAO leak detection), air duct material
Instrument calibration (differential pressure gauge, temperature and humidity sensor)
Clean room structure:
No gaps in walls/floors (epoxy resin self-leveling), air tightness test of doors and windows.
Delivery documents: equipment list, installation record, calibration certificate.
▶ Operational Qualification (OQ)
Goal: Verify that the system operates normally under no-load conditions.
Key tests:
HVAC system:
Air velocity test (A-level laminar flow 0.45±0.1 m/s), air change rate (B-level ≥40 times/h).
Pressure gradient (adjacent area ≥10 Pa), self-cleaning time (≤20 minutes, from ISO 8→ISO 5).
Utility system:
Microbial limit of purified water/water for injection (WFI) (≤10 CFU/100ml).
Deliverables: test report, SOP draft.
▶Performance Qualification (PQ)
Goal: Simulate actual production conditions and verify that the system continues to comply with regulations.
Key tests:
Environmental monitoring (under dynamic conditions):
Suspended particles: A-level area ≥0.5μm particles ≤3520/m³ (ISO 5).
Microorganisms: settling bacteria (A-level ≤1 CFU/4h), floating bacteria (A-level ≤1 CFU/m³).
Process simulation:
Sterile preparations: culture medium simulation filling test (3 batches, full coverage of intervention actions).
Non-sterile preparations: microbial challenge test (such as preservative effectiveness verification).
Delivery documents: PQ report, environmental monitoring data, process validation report.
▶GMP certification on-site inspection focus
Document system:
Whether SOP covers all operations (such as cleaning and disinfection, dressing procedures).
Whether change control (CAPA) and deviation records are complete.
Environmental control:
Whether real-time monitoring data (pressure difference, temperature and humidity, particles) exceed the limit.
High-efficiency filter leak detection report and replacement record.
Personnel operation:
Compliance of dressing procedures (demonstration of wearing sterile clothing in Class B area).
Whether material transfer operations introduce contamination risks.
▶ Special requirements for liquid preparations
1. Sterile liquid preparations
Protection of Class A area: filling and plug exposure must be carried out in laminar flow hoods/isolators.
Sterilization verification: sterilizing filtration (0.22μm) or terminal sterilization (F0≥8).
Container sealing: vacuum decay/high voltage discharge detection.
2. Non-sterile liquid preparations
Microbiological control: validation of preservative effectiveness (USP 51).
Cleaning validation: avoid cross contamination (such as co-production risk assessment).
▶ Continuous compliance and revalidation
Regular monitoring:
Daily environmental monitoring (particles, microorganisms), annual leak detection of high efficiency filters.
Revalidation cycle:
HVAC system: every 1-2 years (or after major changes).
Sterilization process: annual culture medium filling test.
Data integrity:
Electronic data backup (audit tracking function), in compliance with FDA 21 CFR Part 11
5. Why do customers choose modular cleanrooms to produce liquid preparations? Speed, flexibility, expandable filling workshop, intelligent monitoring and compliance
Precise control, strict compliance
The modular cleanroom adopts a prefabricated structure and integrates a high-efficiency filtration system (HEPA/ULPA), which can accurately control particles, microorganisms, temperature and humidity to ensure Class C, Class D and even Class A/B cleanliness. The wall and decoration interface are designed in an integrated manner, and the joints are airtight, which meets the GMP requirements for "smooth and smooth, no particle shedding" internal surface, reducing the risk of contamination.
Flexible expansion, cost reduction and efficiency improvement
Traditional cleanroom renovation is time-consuming and labor-intensive, while modular design supports "plug and play". Through the rapid assembly of standard modules, companies can flexibly adjust production areas, such as expanding the capacity of monoclonal antibody production lines or adding cell culture areas, without stopping for reconstruction, which is more than 30% shorter than traditional construction periods.
Intelligent management, future-oriented
Integrating the Internet of Things and automation technology, modular cleanrooms can monitor parameters such as pressure difference and ventilation times in real time, and adjust airflow through intelligent air valves to reduce manual intervention. Some systems also support remote operation and maintenance and data traceability, providing dual guarantees for the compliance and traceability of drug production.
Green and sustainable, empowering industrial upgrading
The modular clean room uses energy-saving air conditioners and LED light sources, with a fresh air circulation system, which reduces energy consumption by 20%-30% compared to traditional workshops. Its prefabricated production model reduces construction waste, and the module reusability rate is as high as 98%, which is in line with the concept of green pharmaceutical manufacturing.
Airkey is committed to providing global pharmaceutical companies with fast delivery, efficient operation, and comprehensive compliance liquid preparation clean room overall solutions to help customers accelerate product launch.
