admin@hepacleanroomfilter.com
The 2010 revision of GMP does not provide detailed descriptions of cleanliness level classification. It only states in Article 48 that: Exposed process areas for the production of non-sterile preparations such as oral liquids, solid preparations, topical preparations (including rectal preparations), and epidermal external drugs, as well as exposed process areas for the final processing of packaging materials in direct contact with drugs, shall be set up with reference to the requirements for Grade D clean areas in the Annex to Sterile Drugs.
Annex 2: API
Article 3: Exposed environments for refining, drying, crushing, packaging and other production operations of non-sterile APIs shall be set up in accordance with the requirements for Grade D clean areas.
Annex 3: Biological Products
Article 14:
• Grade D: Pooling of raw plasma, component separation, pasteurization before filling; closed fermentation system environment for oral preparations; preparation, filling, drying and inner packaging of in vitro immunological reagents such as ELISA kits.
• Grade C: Filling of positive serum, antigens and antibodies for in vitro immunological reagents.
• Grade B + A: Processes specified for non-terminal sterilized products in sterile drugs; preparation and pooling of products without sterile filtration before filling.
Annex 4: Blood Products
Article 14: Processes such as bag breaking, pooling, separation, extraction of raw plasma, and pasteurization before filling shall be carried out at least in Grade D clean areas.
Annex 5: Traditional Chinese Medicine Preparations
Article 11: For extraction, concentration and paste collection in closed systems, the operating environment may be non-clean; for open production, the operating environment shall match the cleanliness level of the preparation area.
Article 14: Refining processes before concentrated preparation of TCM injections shall be completed at least in Grade D clean areas.
Article 15: External TCM preparations for non-traumatic surfaces and other special TCM preparations may be produced in non-clean workshops.
For the classification and application of cleanliness levels in pharmaceutical facilities, greater reference should be made to Annex 1: Sterile Drugs, Chapter 3: Cleanliness Levels and Monitoring. Selection of cleanliness levels for production environments mainly refers to Article 13.
I. Application of Grade B + A Environment
1. Filling, sub-packaging, stoppering, capping of non-terminal sterilized products (in incompletely sealed state).
2. Preparation of liquid or product that cannot be sterile-filtered before filling (suspensions, emulsions, implants, surgical/traumatic ointments, powders, aerosols, etc., excluding terminally sterilizable products).
3. Assembly, transfer and storage of packaging materials and utensils in direct contact with drugs after sterilization in incompletely sealed state.
4. Crushing, sieving, mixing and sub-packaging of sterile APIs.
5. Exposed operations such as refining, crystallization and drying of liquid medicine that cannot be sterile-filtered before drying of non-terminal sterilized sterile APIs.
II. Application of Grade B Environment
1. Transfer of incompletely sealed non-terminal sterilized products in fully sealed containers.
2. Transfer of packaging materials and utensils in direct contact with drugs after sterilization in fully sealed containers.
III. Application of Grade C + A Environment
1. Filling of terminally sterilized products with high contamination risk.
2. Current trend: Filling of all terminally sterilized products under C + laminar flow protection, regardless of contamination risk, to minimize contamination.
IV. Application of Grade C Environment
1. Preparation of liquid or product that can be sterile-filtered before filling for non-terminal sterilized products.
2. Closed sterile filtration of liquid medicine for non-terminal sterilized products.
3. Filling of terminally sterilized products with low contamination risk.
4. Preparation and filtration of terminally sterilized products with high contamination risk.
5. Preparation and filling of terminally sterilized ophthalmic preparations, sterile ointments and sterile suspensions.
6. Final treatment of packaging materials and utensils in direct contact with terminally sterilized drugs after final washing.
V. Application of Grade D Environment
1. Final washing, assembly, packaging and sterilization of packaging materials and utensils in direct contact with non-terminal sterilized drugs.
2. Capping of terminally sterilized products.
3. Material preparation (weighing, sub-packaging) before filling of terminally sterilized products.
4. Concentrated preparation or closed preparation and filtration of terminally sterilized products.
5. Final washing of packaging materials and utensils in direct contact with terminally sterilized drugs.
6. Exposed environment for refining, drying, crushing and packaging of non-sterile APIs.
7. Plasma pooling, separation, pasteurization for biological products; closed fermentation for oral preparations; preparation, filling, drying and inner packaging of in vitro reagents.
8. Plasma bag breaking, pooling, separation, extraction and pasteurization for blood products.
9. Open extraction, concentration and paste collection of TCM shall match the cleanliness of preparation area.
10. Refining before concentrated preparation of TCM injections shall be at least in Grade D clean areas.
VI. Recommendations for Zoning Design
(1) Personnel Flow Design
1. Entrance hall; toilets outside general changing; locker for personal belongings; negative pressure shoe-changing room.
2. Personnel entrances concentrated for easy management.
3. Separate entrances for Grade D, C, B; separate exit for Grade B.
4. Avoid re-changing after entering lower-grade areas.
5. Combined changing for D/C, separate for B if possible.
6. Male/female separated changing.
7. Standard changing sequence: shoe change → hand wash → outerwear removal → clean gown → hand disinfection.
8. Pressure gradient and interlocking doors.
9. Ventilated storage for gowns and shoes.
10. Positive pressure to outside, negative pressure inside for shoe rooms.
11. Negative pressure for highly sensitizing workshops.
(2) Material Flow Design
1. Separate material/personnel entrances; near freight elevators.
2. Buffer rooms or pass-through boxes for material transfer.
3. Cleaning → disinfection → sterilization for D → C → B.
4. Interlocked transfer hatches; pressure difference monitoring.
5. Separate or time-staged transfer for raw materials, packaging, utensils.
6. Dedicated waste exit.
7. Separate in/out for clean/used utensils.
8. Sealed connections for conveyor lines between grades.
(3) Material Storage and Cleaning Area Design
1. Cleaned materials stored in Grade D.
2. Weighing in Grade D under weighing booth, sealed transfer to C.
3. Final washing in Grade D; no washing rooms in C/B.
4. Treated utensils transferred to C/B for storage.
5. Centralized laundry.
6. Disinfectant prepared in D, filtered to C/B.
7. Separate dirty/clean zones.
(4) Main Production Area Design
1. Core zones: preparation, filtration, filling, lyophilization, capping, refining, crystallization, drying, crushing, mixing, tableting, encapsulation, etc.
2. Logical material flow from warehouse to warehouse.
3. Key clean zones (B, C) placed centrally, surrounded by D or general areas to reduce contamination.
4. Avoid high-risk equipment near external walls.
5. No weighing/washing/storage in C/B unless properly treated.
6. Minimize floor drains; no drains in B/C, preferably none in D.
7. Avoid activated carbon in formulation production.
8. Integrated capping with laminar flow to control particles.
9. Promote automated lines to reduce human intervention and contamination.
