GB/T 47606-2026Pharmaceutical equipment - General technical requirements for bioreactors (English PDF)

4.1 Materials

4.1.1 All materials that come into direct contact with the materials or process media with specific requirements shall be non-toxic, corrosion-resistant, and non-shedding, and shall not come into direct contact with the materials or process media with specific requirements. The process medium undergoes a chemical reaction, adsorption, or releases substances into the material. Materials of components requiring sterilization or disinfection should be able to withstand high-temperature steam or... Sterilization and disinfection of chemical gases.

4.1.2 For all metallic materials that come into direct contact with the material or the required process medium, their quality certification documents should include, but are not limited to, material specifications. Specifications, material test reports (composition, mechanical/physical properties, etc.), manufacturing method/process documents, and certification documents for sanitary applications.

4.1.3 All polymers and other non-metallic materials that come into direct contact with the material or the required process medium should be able to fully guarantee the product or process. The purity, integrity, and potency of the fluid should be assessed, and the effects of time, temperature, etc., on material properties should be demonstrated. Quality certification documents should include, but are not limited to, these certifications. Regarding material specifications, material test reports (composition, mechanical/physical properties, biocompatibility, etc.), manufacturing method/process documents, and those used for hygiene Supporting documentation for Class A operating conditions.

4.2 Surface Quality

4.2.1 The inner surface of the bioreactor should be smooth and flat, with no blind spots for cleaning.

4.2.2 All corners of metal surfaces in direct contact with materials should have smooth transitions; their surface roughness Ra value should not exceed 0.4 µm, and should... After acid pickling and passivation or electrolytic polishing.

4.3 Appearance

4.3.1 The control components of the control cabinet should be arranged reasonably, and the wiring should be horizontal and vertical without crossing; the instruments on the control cabinet panel should have clear labels. The outer surface should be easy to clean.

4.3.2 Pipelines and valves shall be arranged neatly, and the names of media and flow directions in the pipelines shall comply with the provisions of Chapter 8 of GB 2894-2025.

4.4 Containers and Piping

4.4.1 Bioreactors equipped with in-situ cleaning (CIP) functionality for the feed pipeline during production should have appropriate measures to prevent in-situ cleaning. Cleaning (CIP) liquid contamination culture system.

4.4.2 Fittings for removable inner tubes shall use aseptic union threaded connections.

4.4.3 Gravity discharge pipelines should have a continuous slope towards the discharge point, and the slope should not be less than 1%.

4.5 Pressure Vessels and Pressure Piping

4.5.1 The pressure vessel of the bioreactor shall comply with the relevant provisions of GB/T 150 (all parts), and the heat exchanger shall comply with GB/T 150 (parts). (Some of them) and the relevant provisions of GB/T 151.

4.5.2 The pressure piping of the bioreactor shall comply with the provisions of GB/T 20801 (all parts).

4.6 Stirring Components

4.6.1 The agitator and its components in the bioreactor shall not impede the discharge of materials from the container.

4.6.2 The agitator of the bioreactor should have a debris well or other structure to prevent particulate debris from entering the bioreactor.

4.7 Intake Components

4.7.1 Flow control devices (such as rotor flow meters, mass flow controllers, and regulating control valves) should be installed outside the sterilization filter, and should It has backflow protection measures to avoid damage to the instrument during in-situ sterilization (SIP) or gas recirculation.

4.7.2 For two-stage air intake filters used in series, the air intake filter assembly closest to the bioreactor should be a sterilizing filter.

4.7.3 The air inlet filter should be installed above the liquid level in the bioreactor.

4.8 Exhaust Assembly

4.8.1 For two-stage exhaust filters used in series, the exhaust filter assembly furthest from the bioreactor should be a sterilizing filter. There should be a device for draining condensate between the filters.

4.8.2 Condensate in the bioreactor exhaust assembly should not clog the exhaust filter.

4.8.3 The tank pressure control device should be installed outside the sterilization filter.

4.9 Performance

4.9.1 The rotation speed of the agitator in the bioreactor should be adjustable within the set range, and the control error should be within ±5% of the set value.

4.9.2 The bioreactor should be able to set and control the temperature within the range of 25°C to 40°C, and the control error should be within ±0.5°C of the set value. Within the enclosure.

4.9.3 The bioreactor should be able to set and control the pH within the range of 2 to 12, and the control error should be within ±

0.2 of the set value.

4.9.4 The bioreactor should be able to set and control dissolved oxygen (DO), and the control error should be within ±10% of the set value.

4.9.5 The sealing of the connecting pipes, valves and other components of the bioreactor should be free of abnormal noise and air leakage during pressure holding.

4.9.6 Bioreactors should be capable of cleaning in place (CIP) and sterilizing in place (SIP).

4.9.7 The components inside the bioreactor tank should not impede the self-discharge of materials by gravity discharge.

4.9.8 The control software for bioreactors should have access control, account management, audit trail, electronic signature, and other features to ensure data reliability. It includes backup and restore functions.

4.9.9 The main parameters of the bioreactor control system should be controllable, displayed in real time, and recorded, and the operation process should be traceable.

Note. Key parameters include temperature, pH, dissolved oxygen (DO), pressure, liquid level, weighing, stirring speed of the stirring system, and carbon dioxide concentration.

4.9.10 When the main parameters of the control system exceed the set range during the operation of the bioreactor system, the system should immediately issue an alarm and... It can clearly display the alarm content and alarm time.

4.9.11 Under load operation, the noise of the bioreactor should meet the requirements of Table 1.

4.10 Electrical Safety The electrical safety of bioreactors shall comply with the provisions of GB/T 36035.

5.2 Surface quality test

5.2.1 Visually inspect or use an industrial endoscope to inspect the inner surface of the bioreactor.

5.2.2 Visually inspect or use an industrial endoscope to observe the surface quality of the tank interior, the stirring components, and the piping connections that are in direct contact with the culture medium. Depending on the situation, the surface roughness value of the surface in contact with the material is measured using a surface roughness meter.

5.3 Appearance Test

5.3.1 Visually inspect the control components, markings, and outer surface of the control cabinet panel.

5.3.2 Visually inspect the color and shape of the medium name and flow direction markings inside the pipeline, as well as the font of the letters and numbers and the dimensions of the arrows. Use a leather roll. Use a ruler to measure the width of the sign and the distance between two signs.

5.4 Container and Piping Testing

5.4.1 Visually inspect pollution prevention measures.

5.4.2 Visually inspect the connection type of the inner tube.

5.4.3 Use an inclinometer to measure the slope of the pipeline.

5.5 Pressure Vessel and Pressure Piping Testing

5.5.1 The inspection of pressure vessels shall be carried out in accordance with the corresponding test methods given in GB/T 150 (all parts), and the inspection of heat exchangers shall be carried out in accordance with... The corresponding test methods given in GB/T 150 (all parts) and GB/T 151 shall be followed.

5.5.2 The inspection of pressure pipelines shall be carried out in accordance with the corresponding test methods given in GB/T 20801 (all parts).

5.6 Stirring Assembly Test Visual inspection.

5.7 Intake assembly test

5.7.1 Visually inspect the installation location and protective measures of the flow control device.

5.7.2 Check the quality certification documents of the air inlet filter closest to the bioreactor.

5.7.3 Check the installation location of the air intake filter.

5.8 Exhaust Assembly Test

5.8.1 Check the quality certification documents of the exhaust filter furthest from the bioreactor, and check the condensate discharge between the two-stage filters. Device.

5.8.2 Check measures to prevent condensate from clogging the exhaust filter.

5.8.3 Check the installation location of the tank pressure control device.

5.9.1 Agitator speed test

5.9.1.1 The test conditions are as follows:

a) Ambient temperature. room temperature;

b) Relative humidity not exceeding 70%;

c) Altitude not exceeding 1000m;

d) The test medium was purified water.

5.9.1.2 The test procedure is as follows:

a) Add purified water to the bioreactor to the working volume;

b) Set the rotational speed to the midpoint of the set range and start the rotational speed control program;

c) After the process parameters reach the set values and the reactor has been running for 30 minutes, the stirring shaft of the bioreactor is measured online using a Hall effect speed sensor. Record the actual rotational speed;

d) Compare the highest and lowest speed values measured within 1 hour with the set speed values;

e) Calculate the speed control error according to equation (1). W1=(M1-S1)/S1×100% (1) In the formula. W1

--- Speed control error; M1

--- The highest or lowest measured speed, in revolutions per minute (r/min); S1

--- Speed setting value, in revolutions per minute (r/min);

5.9.2 Temperature Control Test

5.9.2.1 The test conditions are the same as those in 5.9.1.1.

5.9.2.2 The stirring speed shall be 50% of the maximum design speed.

5.9.2.3 The test procedure is as follows:

a) Add purified water to the bioreactor to the working volume;

b) Set the temperature to 37°C and start the temperature and speed control program;

c) After the process parameters reach the set value and run for 30 minutes, read the highest and lowest temperature values measured within 1 hour and compare them with the set values. Temperature value comparison;

d) Calculate the control error according to formula (2).

e) Within the allowable temperature range, arbitrarily set two more temperature values (close to the upper and lower limits of the temperature control range, other processes). (With parameters unchanged), repeat the above experiment to verify.

5.9.3 PH Control Test

5.9.3.1 The test conditions are as follows:

a) Ambient temperature. room temperature;

b) Relative humidity not exceeding 70%;

c) Altitude not exceeding 1000m;

d) The test media were phosphate buffer (pH 6.8-7.4), sodium carbonate solution (

0.2 mol/L-

0.5 mol/L), and citric acid solution. (0.5mol/L~1mol/L) or carbon dioxide.

5.9.3.2 The operating parameters are shown in Table 2.

5.9.3.3 The test procedure is as follows:

a) Add phosphate buffer (pH 6.8-7.4) to the bioreactor to the working volume, and connect sodium carbonate solution (

0.2 mol/L~

0.5 mol/L), citric acid solution (

0.5 mol/L~1 mol/L), or carbon dioxide tubing;

b) Set the pH parameter to

5.9.4 Dissolved Oxygen (DO) Control Test

5.9.4.1 The test conditions are as follows:

a) Ambient temperature. room temperature;

b) Relative humidity not exceeding 70%;

c) Altitude not exceeding 1000m;

d) The test medium is purified water or phosphate buffer (pH 6.8~7.4) and nitrogen.

5.9.4.2 See Table 3 for setting parameters.

5.9.5 Leakage Test After confirming that all pipelines, valves, and other components of the bioreactor are installed and the ends of the pipelines are closed, proceed with the flow into the bioreactor. Introduce clean compressed air at 0.1MPa~0.15MPa, listen for any abnormal noises, and check for leaks using soapy water or other leak detection solutions.

5.9.6 Clean-in-In-Situ (CIP) and Sterilize-in-Situ (SIP) Tests

5.9.6.1 Clean in In-Situ (CIP) Test The Clean In-Situ (CIP) test procedure is as follows:

0.08 g/L to

0.22 g/L riboflavin aqueous solution evenly onto the inner surface of the container, and use a wavelength of 365 nm and an intensity of [unclear - possibly "intense"]. The inner surface of the container was irradiated from all directions by a 4000 µW/cm^2 UV lamp, and the coating of the riboflavin aqueous solution was observed at a distance of approximately 38 cm. Check the condition of the lid. Initiate the in-situ cleaning (CIP) procedure for the tank. After cleaning, observe for any riboflavin residue using the same method.

b) Initiate the system in-place cleaning (CIP) program and record the water pressure and flow rate; after cleaning, use a clean measuring cup to collect the final amount of water from the drain outlet. A 500mL water sample was tested according to the purified water standard in Part IV of the Pharmacopoeia of the People's Republic of China (2025 edition).

5.9.6.2 In-situ sterilization (SIP) test Place the biological indicator at the sterilization validation port, start the system in-situ sterilization (SIP) program, and record the temperature and tank pressure. After sterilization is complete, remove... Biological indicators were produced and tested according to the sterility test method in Part IV of the Pharmacopoeia of the People's Republic of China (2025 edition).

5.9.7 Exhaustion Test The tank is discharged freely by gravity. The surfaces of all components requiring discharge are inspected. If residual droplets are found, the end face of a rubber rod is used for contact filtration. When a droplet is pressed vertically, it is considered (qualified) if the droplet disperses and does not return to its original position.

5.9.8 Access control, account management, audit trail, electronic signature, data backup and recovery test Log in to the administrator account to perform corresponding operations on the system, and check access control, account management, audit trails, electronic signatures, data backup, and more. Functions such as recovery.

5.9.9 Control, display, and recording of main parameters in experiments Log in to the administrator account, perform corresponding operations on the system, check the control, real-time display, and recording of key operating parameters, and check the audit. Tracking information display and storage status.

5.9.10 Parameter Over-Limit Alarm Test During operation, simulate situations where control parameters exceed limits, observe the system alarm status, and check the alarm records.

5.9.11 Noise Test Noise tests were conducted under the load conditions of the bioreactor, according to the method given in GB/T 17421.5.

5.10 Electrical Safety Test Electrical safety tests shall be conducted in accordance with the provisions of GB/T 36035.

6.3 Type Testing

6.3.1 Type testing conditions Type testing shall be conducted under any of the following circumstances.

a) After formal production begins, significant improvements in materials, structure, or processes may affect the performance of the bioreactor;

b) Resumption of production after a product shutdown of more than one year;

c) The factory inspection results differ significantly from the most recent type inspection results.

6.3.2 Type Test Items Type testing items include all requirements in Chapter

4.If the manufacturer does not have the testing facilities for a particular item, it may be conducted at the user's site.

6.3.3 Sampling Rules For type testing, 10% of the products that have passed factory inspection should be randomly selected as samples according to the method in GB/T 10111 (if less than 10%). At least 3 units should be randomly selected, and 1 unit should be tested.

6.3.4 Judgment Rules During type testing, if all items pass the inspection, the product is deemed a qualified product. However, if the continuity and insulation of the electrical system's protective connection circuit are not satisfactory... If either the resistance or withstand voltage fails to meet the standard, the product type test is deemed unqualified. If other items fail, testing of the sampled units is permitted. If the non-compliant items are retested twice, and they still fail, the product is deemed to have failed the type inspection.

7.1 Marking

7.1.1 Product nameplates shall conform to GB/T 13306.The nameplate shall be affixed to a prominent position and shall include at least the following information.

a) Product Name;

b) Main technical parameters;

c) Serial number and date of manufacture;

d) Name and trademark of the manufacturing unit;

e) This document number.

7.1.2 The nameplate of a pressure vessel shall include at least the following information.

a) Product Name;

b) Name of the manufacturing unit;

c) Manufacturing unit license number/license level;

d) Product standards;

e) Main materials;

f) Media name/components;

g) Design temperature;

7.3 Storage

7.3.1 Bioreactors should be stored in a dry, well-ventilated indoor or covered location free of corrosive gases.

7.3.2 Wooden packing boxes should not be stacked.