How to build a GMP-compliant production workshop: The question of how to build a GMP-compliant production workshop is quite complex, because there are many types of extraction products, and the production process requirements are different. Based on industrial production practice, the following aspects should be considered.

1. Design principles and precautions for GMP production plants

Cleanliness level ≥0.5μm 100 level 10000 level 100000 level ≤3500 ≤350000 ≤3500000 dust particles/m³ live microorganisms/m³ ≥5μm ≤0 ≤2000 ≤20000 ≤5 ≤100 ≤500

1.1. Process design of the plant The process layout is determined according to the product's process flow. The process layout should be reasonably connected in the order of the processes to avoid cross-overs and the mixing of personnel and materials. Personnel and materials should have their own entrances and exits, and personnel flow and material flow should be separated as much as possible. Cleanroom plants should be reasonably laid out according to the cleanliness level. Processes with high cleanliness levels should be located in the center, and corresponding auxiliary measures should be set up, including cleaning and changing rooms.

1.2. Architectural design Architectural design first considers the type of plant design, i.e., single-story or multi-story plants. Generally, single-story, large-span plants are preferred. The advantages are: the process layout of a single-story plant is easier to be reasonable than that of a multi-story plant; it is more flexible and easier to update product types and modify the workshop when the process flow changes; it is easier to install equipment and public pipelines.

1.3. Key points in the design of clean plants The cleanliness level of clean plants is based on the "Clean Plant Design Standard" GB73-84 currently implemented in China. In principle, the air cleanliness levels of industrial cleanrooms commonly used in most countries are adopted, and the cleanliness levels are divided into three levels.

Issues to be noted in the design of the above three levels:

① Airflow organization Generally, grade 100 uses vertical laminar flow and horizontal laminar flow, while grade 10,000 and grade 100,000 use turbulent flow (generally top air supply and bottom wall return air).

② Pressure difference Areas with high cleanliness levels are positively pressurized relative to adjacent areas with lower cleanliness levels.

③ Air supply volume Air supply volume is an important factor in achieving the purification requirements of clean plants. A certain coefficient should be reserved during design according to the actual situation.

④ Fresh air volume Fresh air volume generally accounts for 70% of the air supply volume. Air supply volume category Cleanliness level Airflow organization Vertical laminar flow Laminar flow work surface Grade 100 Horizontal laminar flow Turbulent flow Cleanroom Grade 10,000 Turbulent flow Air changes 24 15 Grade 100,000 Cross-sectional wind speed (v) m/sec 0.25 0.35

1.4. Issues to be noted in the design of clean plants:

① The clean area and auxiliary area should be divided on the floor plan. Personnel entering the clean area must first pass through the auxiliary buffer area. The auxiliary buffer area includes a changing room and a buffer room. The flow of personnel should be from the area with low cleanliness level to the area with high cleanliness level.

② In order to save energy, the space in the clean area should not be too large, and the height should be reduced as much as possible, provided that production requirements are met.

③ Dust prevention facilities, such as airlocks and pass-through windows, should be installed at the junctions between cleanrooms of different cleanliness levels.

④ The windows separating the clean area and the non-clean area are double-layer sealed windows, and the doors should be airtight.

2. Issues during construction To ensure that the newly built plant meets GMP requirements, quality control during plant construction is crucial:

① Wall requirements The walls should be flat and smooth, dust-free and easy to clean, so the walls are generally painted with high-quality waterproof coatings. For clean plants with high cleanliness levels, the walls can be clad with color-coated steel plates, and the junctions between the inner walls and the ceiling should be rounded.

② Partition materials Generally, aluminum alloy materials and polystyrene color-coated steel plate materials are used. In particular, plants with cleanliness levels generally use color-coated steel plate materials. The advantages of this material are its light weight, smooth and bright surface, easy cleaning, simple construction, and easy modification of the workshop when the production process changes.

③ Floor material requirements The floor material should have high strength, be wear-resistant, smooth, and easy to clean. Generally, it is a cast-in-place terrazzo floor. For plants with high cleanliness requirements, epoxy resin floors are generally used. Floor drainage: Ordinary plants use ordinary floor drains, plants with cleanliness levels should use clean floor drains, and plants with high cleanliness levels should not have floor drains.

④ Windows Generally, steel windows and aluminum alloy windows are used. The junctions between the windows and the walls should be chamfered. Windows with high cleanliness levels should be fixed windows, and the window glass and walls should be flush to prevent dust accumulation on the windowsills and make them easy to clean.

II. Production equipment Production equipment plays an important role in extraction production, and the quality of the product largely depends on the degree of equipment perfection.

Equipment must meet the requirements of the production process and national standards. The following aspects should be considered for equipment:

1. Selection of purification equipment

① Equipment should be suitable for the process requirements of the product, and its capacity should be suitable for batch production capacity.

② The equipment structure should be simple, easy to operate, easy to disassemble, clean, sterilize and maintain.

③ The transmission parts of the equipment should be well sealed to prevent product contamination.

④ Crushing, sieving, and mixing equipment should be equipped with effective dust collection devices.

⑤ The applicable range and accuracy of various metering and detection control instruments of the equipment should meet the production requirements and reach the national metering standards.

2. Equipment materials The contact surfaces of equipment and processed items should be smooth, easy to clean and disinfect, have high chemical corrosion resistance, and not react with processed items to change their composition or content.

3. Equipment layout

① Equipment should be reasonably laid out according to the process flow, so that the processed materials flow in the same direction, avoiding repeated back and forth.

② Equipment should have sufficient operating space and reasonable floor area. Some equipment can be installed in a mobile or semi-fixed manner for easy cleaning and maintenance. To prevent cross-contamination, equipment in clean areas should be installed separately, one machine per room. Measures should be taken for equipment spanning different cleanliness levels to prevent contamination of areas with high cleanliness levels.

③ Fixed pipelines should be sprayed with different colors according to the "Color Code for Pharmaceutical Equipment and Pipelines," and should have flow direction markers. In cleanroom facilities, pipelines should be installed within technical mezzanines and shafts to avoid and reduce exposure.

4. Equipment Validation: Equipment at critical control points of the production process, such as special equipment and equipment for aseptic filling, should be validated after installation, and a validation cycle should be established for regular validation, in addition to ensuring that its selection, installation, and use are suitable for the production process.

III. Completion Acceptance of Cleanrooms: Cleanroom acceptance should include multiple aspects, including personnel, facilities (equipment), hygiene, production management, and quality assurance. In terms of building construction alone, it can be summarized as follows:

① Completion acceptance should be conducted sequentially, starting from the plant layout, then building and decoration, and finally production equipment.

② Building and decoration should be accepted according to product production process requirements.

③ Cleanrooms should be accepted in accordance with the national industry standard JGJ71-90 "Cleanroom Construction and Acceptance Standard." First, the project completion acceptance is conducted, followed by a comprehensive performance evaluation. Both must include performance testing of the cleanroom.

1. Project Completion Acceptance: This involves visual inspection of each part of the project, single-unit trial operation, and system joint trial operation. The performance of the cleanroom should be tested and adjusted under no-load or static conditions, and relevant construction inspection records should be reviewed. Visual inspection items include: whether the installation of various pipelines, ducts, and purification air conditioning equipment is correct and tight; whether the installation and sealing of high-efficiency and medium-efficiency filters are reasonable; and whether the walls, floors, and ceilings of the cleanroom are smooth and flat, and whether doors and windows are tight. Single-unit trial operation refers to the separate trial operation of air conditioners (refrigeration and heating systems), local purification equipment, and other equipment requiring trial operation, to check whether they meet the relevant technical regulations. System joint trial operation is carried out after the single-unit trial operation is qualified, to check whether the interlinked operation of various equipment components meets the technical requirements.

2. Comprehensive Performance Evaluation: The methods and evaluation standards for comprehensive performance testing should comply with JGJ71-90 "Cleanroom Construction and Acceptance Standard." The tests include: cleanliness level, air supply volume, exhaust volume, cross-sectional air velocity, airborne and settled bacteria, temperature, and humidity.

3. Documents to be submitted during completion acceptance:

a. Design change negotiations and as-built drawings.

b. Factory certificates and inspection documents for major materials, equipment, and instruments. Major building materials should also have inspection documents from the local construction engineering quality supervision station.

c. Unit project and sub-project quality inspection and evaluation reports, concealed project records (including photos).

d. Equipment trial operation records, pipeline pressure test records. After the completion acceptance of the plant is qualified, the construction party and the construction party should sign a construction project warranty contract.