Sterilization process of sugar-containing double-chamber bag blood filtration replacement liquid

Abstract

The invention provides a sterilization process of a glucose-containing double-chamber bag blood filtration replacement liquid, a to-be-sterilized product is a filled and sealed blood filtration replacement liquid, the sterilization adopts a moist heat sterilization process, the sterilization temperature is 121 DEG C, the heating time is 1500-3800 s, the sterilization time is 25-30 min, and the cooling time is greater than or equal to 2000 s. The sterilization process is simple and easy to operate, the method is stable, and it is ensured that the content of 5-hydroxymethylfurfural in a blood filtration replacement liquid A chamber is at a low level after sterilization; b, a chamber sterilization exposure stage: 121 DEG C is greater than 12min; the sterile standard level of the obtained glucose-containing double-chamber bag blood filtration replacement liquid reaches the standard within 18 months, the validity period reaches 18 months, and the glucose-containing double-chamber bag blood filtration replacement liquid has very good market circulation and clinical use values.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical manufacturing technology, specifically relating to a sterilization process for a glucose-containing dual-chamber bag blood filtration replacement solution. Background Technology

[0002] Hemofiltration replacement fluid is a specialized replacement drug used in hemofiltration therapy to replace water and electrolytes in the patient's body, thus replacing some of the kidney's function. Because the replacement fluid is composed of electrolytes similar to blood plasma and is directly infused into the patient's vein, a large volume is required per administration. There are no internal barriers (such as liver detoxification) to filter out harmful substances. This "direct and large-volume" administration method dictates that its quality must meet the highest standards of sterility and pyrogen-free as injectable medications. Any minute microbial or pyrogen (endotoxin) contamination will be directly "infused" into the patient's body with the fluid, with potentially disastrous consequences.

[0003] The double-chamber bag is a packaging form, specifically a three-layer co-extruded double-chamber bag (I) for injection, consisting of chamber A and chamber B, with a filling ratio of 1:19 between chamber A and chamber B. Chamber A contains the active ingredient anhydrous glucose and electrolyte salts, including but not limited to calcium chloride, magnesium chloride, and lactic acid. Chamber B contains the active ingredient electrolyte salts, including but not limited to sodium chloride, potassium chloride, and sodium bicarbonate, for use in sterile preparations for hemodialysis.

[0004] According to the decision tree in the sterilization guidelines, terminal sterilization is the preferred method for sterile preparations. Because this product has two chambers, A and B, with a significant difference in their contents, chamber A may be over-sterilized if the sterilization exposure period of chamber B (121℃ > 12min, standard sterilization time F0) is met. The content of 5-hydroxymethylfurfural (5-HMF) is a key quality attribute and a "signal" for glucose-containing injection products. Glucose in chamber A is prone to degradation under prolonged high-temperature conditions, producing 5-HMF. Since 5-HMF continuously increases during storage, if the 5-HMF content in a 0-day sample is too high, it will exceed the standard requirements during stability testing, resulting in a shorter product shelf life (<12 months) and hindering market circulation. Summary of the Invention

[0005] To address the problems existing in the prior art, the applicant investigated the key parameter of heating time in the moist heat sterilization process and screened a suitable sterilization temperature, time and heating time that can meet the requirements of 121℃>12min for the sterilization exposure stage of chamber B, and also meet the requirements of a low 5-hydroxymethylfurfural content in chamber A, and meet the requirements for sterilization of glucose-containing dual-chamber bag blood filtration replacement solution within the shelf life of 18 months.

[0006] The purpose of this application is to provide a sterilization process for a dual-chamber bag blood filtration replacement solution, wherein the blood filtration replacement solution is a glucose-containing blood filtration replacement solution, the volume ratio of the two chambers of the dual-chamber bag blood filtration replacement solution is 1:19, the sterilization is carried out by moist heat sterilization, the sterilization temperature is 121℃, the sterilization time is 25-30 min, the heating time is 1500-3800 s, and the cooling time is ≥2000 s.

[0007] Furthermore, the sterilization pressure of the moist heat sterilization is ≥150kPa.

[0008] Preferably, the heating rate during sterilization is ≤10℃ / min.

[0009] Preferably, the sterilization time is 27 minutes, the heating time is 1800-3600 seconds, and the cooling time is 2400 seconds.

[0010] In some preferred embodiments, the specific operating steps of the sterilization process are as follows:

[0011] 1) Set the drainage pressure value and the indoor drainage level value;

[0012] 2) Place the glucose-containing blood filtration replacement solution double-chamber bag to be sterilized on the sterilization cart, load it according to the verified loading method, align it with the track, push it into the sterilization cabinet and close the cabinet door tightly.

[0013] 3) Sterilize according to the set process parameters;

[0014] 4) Exhaust and cool the sterilizer according to the set exhaust time.

[0015] Preferably, in the above sterilization process, the volume ratio of the two chambers of the double-chamber bag is 1:19.

[0016] Preferably, in step 1), the water level in the inner chamber is set to 520 mm and the water level in the inner chamber is set to 100 mm.

[0017] Preferably, in step 2), the glucose-containing blood filtration replacement fluid double-chamber bag is fully loaded.

[0018] Preferably, in step 3), the sterilization temperature is 121℃, the sterilization time is 27min, the heating time is 1800-3600s, the cooling time is 2400s, the heating rate is ≤10℃ / min, and the sterilization pressure is ≥150kPa.

[0019] Preferably, in step 4), the sterilizer is opened slowly when the temperature display inside the sterilizer is less than 50°C and the pressure gauge reads 0 MPa.

[0020] The sterilization process described in this application can meet the requirements of 121℃ for 12 min during the sterilization exposure stage of chamber B, and also ensure that the 5-hydroxymethylfurfural content in chamber A is at a low level. The resulting glucose-containing double-chamber bag blood filtration replacement fluid meets the sterility standard within 18 months, and the blood filtration replacement fluid has a shelf life of 18 months, which has good market circulation and clinical use value. Detailed Implementation

[0021] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions in the embodiments of this application will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this application.

[0022] Specifically, in this embodiment of the application, sodium bicarbonate blood filtration replacement solution is used as an example. The volume of chamber A is 250 ml, and the active ingredients are magnesium chloride, anhydrous glucose, calcium chloride, and lactic acid; the volume of chamber B is 4750 ml, and the active ingredients are sodium chloride, potassium chloride, and sodium bicarbonate.

[0023] Preparation Example 1: Preparation of Sugar-Containing Two-Chamber Bag Blood Filtration Replacement Fluid

[0024] S1: Weighing

[0025] Weigh out the prescribed amounts of magnesium chloride, anhydrous glucose, calcium chloride, lactic acid, potassium chloride, sodium chloride, and sodium bicarbonate.

[0026] S2: Solution preparation

[0027] A chamber preparation solution

[0028] 1) Solution preparation

[0029] Add a certain amount of water for injection to the mixing tank. When the temperature is ≤80℃, add the weighed magnesium chloride, calcium chloride, anhydrous glucose, and lactic acid to the mixing tank. After adding the materials, start stirring for at least 10 minutes to ensure complete dissolution. Then add water for injection to the mixing tank until the prepared volume is reached. After circulating and stirring for at least 10 minutes, take samples to test the properties, pH value, content (lactic acid, total chlorine), and microbial load.

[0030] 2) Filtration

[0031] The drug solution undergoes two-stage filtration: the first stage uses three 0.45μm polypropylene filters, and the filtered drug solution is sent to the filling process; after filtration through three 0.22μm polyethersulfone filters at the end, the solution is filled, and the temperature of the filtered drug solution is ≤60℃.

[0032] Solution preparation in chamber B

[0033] 1) Solution preparation

[0034] Add a certain amount of water for injection to the mixing tank. When the temperature is ≤50℃, add the weighed sodium chloride and potassium chloride to the dilution tank, followed by sodium bicarbonate. After adding the materials, stir for at least 10 minutes to ensure complete dissolution. Then add water for injection to the mixing tank to the prepared volume. While stirring, introduce an appropriate amount of carbon dioxide to adjust the pH of the solution to 7.3–8.0. Then, stir and circulate for at least 10 minutes. Subsequently, take samples to test the properties, pH value, content (bicarbonate, total chloride), and microbial load.

[0035] 2) Filtration

[0036] The drug solution undergoes three-stage filtration: the first stage uses three 0.45μm polypropylene filters, the second stage uses three 0.22μm polypropylene filters, and then the drug solution is sent to the filling process; after being filtered by three 0.22μm polyethersulfone filters at the end, it is filled, and the temperature of the filtered drug solution is ≤50℃.

[0037] S3 filling and packaging

[0038] Take the three-layer co-extruded double-chamber bag (I) for injection, fill the A and B chambers with the drug solution according to the following parameter range, seal it, fold the A chamber back to the back, put it into the sterile high-barrier infusion outer packaging bag, seal it and vacuum it.

[0039] category A chamber Chamber B Theoretical filling volume (ml) 260 4940 Filling range (ml) 255～265 4915～4965

[0040] Preparation Example 2A: Preparation of a chamber containing only glucose replacement solution

[0041] S1: Weighing

[0042] Weigh out the prescribed amounts of anhydrous glucose, sodium chloride, potassium chloride, and sodium bicarbonate.

[0043] S2: Solution preparation

[0044] A chamber preparation solution

[0045] 1) Solution preparation

[0046] Add a certain amount of water for injection to the mixing tank. When the temperature is ≤80℃, add the weighed anhydrous glucose to the mixing tank. After adding the materials, start stirring for more than 10 minutes to ensure complete dissolution. Then add water for injection to the mixing tank to the prepared volume. If necessary, adjust the pH of the solution to 2.0-5.5 with hydrochloric acid. Stir and circulate for at least 10 minutes. Take samples to test the properties, pH value, content, and microbial load.

[0047] 2) Filtration

[0048] The drug solution undergoes two-stage filtration: the first stage uses three 0.45μm polypropylene filters, and the filtered drug solution is sent to the filling process; after filtration through three 0.22μm polyethersulfone filters at the end, the solution is filled, and the temperature of the filtered drug solution is ≤60℃.

[0049] Preparation of solution in chamber B: Same as in preparation example 1.

[0050] S3 filling and packaging: Same as preparation example 1.

[0051] Preparation Example 3: Preparation of Sugar-Free Two-Chamber Bag Blood Filtration Replacement Solution

[0052] S1: Weighing

[0053] Weigh out the prescribed amounts of magnesium chloride, calcium chloride, lactic acid, sodium chloride, potassium chloride, and sodium bicarbonate.

[0054] S2: Solution preparation

[0055] A chamber preparation solution

[0056] 1) Solution preparation

[0057] Add a certain amount of water for injection to the mixing tank. When the temperature is ≤80℃, add the weighed magnesium chloride, calcium chloride, and lactic acid to the mixing tank. After adding the materials, start stirring for at least 10 minutes to ensure complete dissolution. Then add water for injection to the mixing tank to the prepared volume. If necessary, adjust the pH of the solution to 2.0–5.5 with hydrochloric acid. After circulating and stirring for at least 10 minutes, take samples to test the properties, pH value, content (lactic acid, total chlorine), and microbial load.

[0058] 2) Filtration

[0059] The drug solution undergoes two-stage filtration: the first stage uses three 0.45μm polypropylene filters, and the filtered drug solution is sent to the filling process; after filtration through three 0.22μm polyethersulfone filters at the end, the solution is filled, and the temperature of the filtered drug solution is ≤60℃.

[0060] Preparation of solution in chamber B: Same as in preparation example 1.

[0061] S3: Filling and packaging: Same as preparation example 1.

[0062] Experimental Example 1: Sterilization Process

[0063] Take the packaged sodium bicarbonate blood filtration replacement solution from Preparation Example 1, place it on the sterilization cart as required, load it according to the prescribed loading method, and push it into the sterilization cabinet. Close the sterilization cabinet. Insert the control probe into the circulating water of the sterilization cabinet and set the sterilization parameters: sterilization temperature 121℃, sterilization time 27min, sterilization pressure ≥150Kpa, F0 ≥12, heating rate ≤10℃ / min, heating time 1800s, cooling time 2400s, cooling temperature 50℃, and sterilization is complete.

[0064] After sterilization, samples were tested for their appearance, pH value, 5-hydroxymethylfurfural content, and other parameters. All test indicators met the standard requirements, and the 5-hydroxymethylfurfural content was 0.02%, far below the standard limit. Data from the validation probe during sterilization was processed. During the sterilization exposure phase in both chambers A and B, the temperature reached 121℃ for more than 12 minutes at all points, and the F0 value during sterilization was greater than 12. The sterility level of the sterilized product was tested, and the results all met the standard requirements. Stability studies were conducted on this batch of products according to the Chinese Pharmacopoeia. The results showed that after accelerated sterilization (6 months) and long-term sterilization (6 months), all indicators met the standard requirements.

[0065] Table 1. Results of long-term test on sterilized samples

[0066]

[0067]

[0068] Table 2 Results of accelerated testing of samples after sterilization

[0069]

[0070] Table 3 Results of the sterilization full-load heat penetration test

[0071] chamber A chamber Chamber B Sterilization process parameters 121℃×27min 121℃×27min Maximum temperature during sterilization exposure (°C) 122.44 122.24 Duration (min) during the sterilization exposure phase when the temperature at all points reaches 121℃. 15.6 12.1 <![CDATA[Lowest F0 throughout the process]]> 31.68 30.34 <![CDATA[Highest F0 throughout the process]]> 40.99 33.92 <![CDATA[Full-process average F0]]> 36.81 31.92

[0072] Experimental Example 2: Sterilization Process

[0073] Take the packaged sodium bicarbonate blood filtration replacement solution from Preparation Example 1, place it on the sterilization cart as required, load it according to the prescribed loading method, and push it into the sterilization cabinet. Close the sterilization cabinet. Insert the control probe into the circulating water of the sterilization cabinet and set the sterilization parameters: sterilization temperature 121℃, sterilization time 27min, sterilization pressure ≥150Kpa, F0 ≥12, heating rate ≤10℃ / min, heating time 2700s, cooling time 2400s, cooling temperature 50℃, and sterilization is complete.

[0074] After sterilization, samples were tested for their appearance, pH value, 5-hydroxymethylfurfural content, and other parameters. All test indicators met the standard requirements, and the 5-hydroxymethylfurfural content was 0.02%, far below the standard limit. Data from the validation probe during sterilization was processed. During the sterilization exposure phase in both chambers A and B, the temperature reached 121℃ for more than 12 minutes at all points, and the F0 value during sterilization was greater than 12. The sterility level of the sterilized product was tested, and the results all met the standard requirements. Stability studies were conducted on this batch of products according to the Chinese Pharmacopoeia. The results showed that after accelerated sterilization (6 months) and long-term sterilization (6 months), all indicators met the standard requirements.

[0075] Table 4. Results of long-term test on sterilized samples

[0076]

[0077]

[0078] Table 5. Results of accelerated testing of samples after sterilization

[0079]

[0080] Table 6 Results of the full-load heat penetration test for sterilization

[0081]

[0082]

[0083] Experimental Example 3: Sterilization Process

[0084] Take the packaged sodium bicarbonate blood filtration replacement solution from Preparation Example 1, place it on the sterilization cart as required, load it according to the prescribed loading method, and push it into the sterilization cabinet. Close the sterilization cabinet. Insert the control probe into the circulating water of the sterilization cabinet and set the sterilization parameters: sterilization temperature 121℃, sterilization time 27min, sterilization pressure ≥150Kpa, F0 ≥12, heating rate ≤10℃ / min, heating time: 3600s, cooling time: 2400s, cooling temperature 50℃, then sterilization is complete.

[0085] After sterilization, samples were tested for their appearance, pH value, 5-hydroxymethylfurfural content, and other parameters. All test indicators met the standard requirements, and the 5-hydroxymethylfurfural content was 0.03%, far below the standard limit. Data from the validation probe during sterilization was processed. During the sterilization exposure phase in both chambers A and B, the temperature reached 121℃ for more than 12 minutes at all points, and the F0 value during sterilization was greater than 12. The sterility level of the sterilized products was tested, and the results all met the standard requirements.

[0086] Table 7. Results of long-term test on sterilized samples.

[0087]

[0088]

[0089] Table 8 Results of accelerated testing of samples after sterilization

[0090]

[0091] Table 9 Results of the full-load heat penetration test for sterilization

[0092]

[0093] Experimental Example 4: Sterilization Process

[0094] Take the packaged sodium bicarbonate blood filtration replacement solution from Preparation Example 1, place it on the sterilization cart as required, load it according to the prescribed loading method, and push it into the sterilization cabinet. Close the sterilization cabinet. Insert the control probe into the circulating water of the sterilization cabinet and set the sterilization parameters: sterilization temperature 121℃, sterilization time 27min, sterilization pressure ≥150Kpa, F0 ≥12, heating rate ≤10℃ / min, heating time: 4000s, cooling time: 2400s, cooling temperature 50℃, then sterilization is complete.

[0095] After sterilization, samples were tested for appearance, pH value, 5-hydroxymethylfurfural (5-HMF), and content. All test indicators met the standard requirements. While the 5-HMF content of 0.05% met the standard, it showed an increasing trend during stability testing, and will not meet the standard requirements after 18 months of stability testing.

[0096] Table 10 Results of long-term test on sterilized samples

[0097]

[0098] Table 11 Results of accelerated test on samples after sterilization

[0099]

[0100]

[0101] Table 12 Results of the full-load heat penetration test for sterilization

[0102]

[0103] Experimental Example 5: Sterilization Process

[0104] Take the packaged sodium bicarbonate blood filtration replacement solution from Preparation Example 1, place it on the sterilization cart as required, load it according to the prescribed loading method, and push it into the sterilization cabinet. Close the sterilization cabinet. Insert the control probe into the circulating water of the sterilization cabinet and set the sterilization parameters: sterilization temperature 121℃, sterilization time 27min, sterilization pressure ≥150Kpa, F0 ≥12, heating rate ≤10℃ / min, heating time: 1200s, cooling time: 2400s, cooling temperature 50℃, then sterilization is complete.

[0105] The data from the verification probe during the sterilization process were processed. In chamber A, the temperature reached 121°C for more than 12 minutes. However, in chamber B, the temperature reached 121°C for 11.4 minutes (less than 12 minutes) during the sterilization exposure phase, which did not meet the audit requirements.

[0106] Table 13 Results of the full-load heat penetration test for sterilization

[0107]

[0108]

[0109] Experimental Example 6: Sterilization Process

[0110] Take the packaged sodium bicarbonate blood filtration replacement solution from Preparation Example 2, place it on the sterilization cart as required, load it according to the prescribed loading method, and push it into the sterilization cabinet. Close the sterilization cabinet. Insert the control probe into the circulating water of the sterilization cabinet and set the sterilization parameters: sterilization temperature 121℃, sterilization time 27min, sterilization pressure ≥150Kpa, F0 ≥12, heating rate ≤10℃ / min, heating time: 3600s, cooling time: 2400s, cooling temperature 50℃, then sterilization is complete.

[0111] After sterilization, samples were tested for their appearance, pH value, 5-hydroxymethylfurfural content, and other parameters. All test indicators met the standard requirements, and the 5-hydroxymethylfurfural content was 0.03%, far below the standard limit. Data from the validation probe during sterilization was processed. During the sterilization exposure phase in both chambers A and B, the temperature reached 121℃ for more than 12 minutes at all points, and the F0 value during sterilization was greater than 12. The sterility level of the sterilized products was tested, and the results all met the standard requirements.

[0112] Table 14 Results of long-term test on sterilized samples

[0113]

[0114]

[0115] Table 15 Results of accelerated test on samples after sterilization

[0116]

[0117] Table 16 Results of the Sterilization Full Load Heat Penetration Test

[0118] chamber A chamber Chamber B Sterilization process parameters 121℃×27min 121℃×27min Maximum temperature during sterilization exposure (°C) 122.39 122.27 Duration (min) during the sterilization exposure phase when the temperature at all points reaches 121℃. 18.2 13.0 The lowest F0 throughout the entire process 36.01 32.70 The highest F0 throughout the entire process 42.10 34.98 The average F0 over the entire process 38.71 33.78

[0119] Experimental Example 7 Sterilization Process

[0120] Take the packaged sodium bicarbonate blood filtration replacement solution from Preparation Example 2, place it on the sterilization cart as required, load it according to the prescribed loading method, and push it into the sterilization cabinet. Close the sterilization cabinet. Insert the control probe into the circulating water of the sterilization cabinet and set the sterilization parameters: sterilization temperature 121℃, sterilization time 27min, sterilization pressure ≥150Kpa, F0 ≥12, heating rate ≤10℃ / min, heating time: 4000s, cooling time: 2400s, cooling temperature 50℃, then sterilization is complete.

[0121] After sterilization, samples were tested for their appearance, pH value, 5-hydroxymethylfurfural (5-HMF) content, and other properties. All test indicators met the standard requirements, and the 5-HMF content was 0.06%, which, although within the standard, showed an increasing trend during stability testing. Therefore, the 5-HMF content will not meet the standard requirements after 18 months of stability testing.

[0122] Table 17 Results of long-term test on sterilized samples

[0123]

[0124] Table 18 Results of accelerated test on samples after sterilization

[0125]

[0126] Table 19 Results of the Sterilization Full Load Heat Penetration Test

[0127] chamber A chamber Chamber B Sterilization process parameters 121℃×27min 121℃×27min Maximum temperature during sterilization exposure (°C) 122.46 122.31 Duration (min) during the sterilization exposure phase when the temperature at all points reaches 121℃. 18.8 13.9 The lowest F0 throughout the entire process 38.00 34.05 The highest F0 throughout the entire process 44.11 36.80 The average F0 over the entire process 42.10 35.58

[0128] Experimental Example 8: Sterilization Process

[0129] Take the packaged sodium bicarbonate blood filtration replacement solution from Preparation Example 3, place it on the sterilization cart as required, load it according to the prescribed loading method, and push it into the sterilization cabinet. Close the sterilization cabinet. Insert the control probe into the circulating water of the sterilization cabinet and set the sterilization parameters: sterilization temperature 121℃, sterilization time 27min, sterilization pressure ≥150Kpa, F0 ≥12, heating rate ≤10℃ / min, heating time: 4000s, cooling time: 2400s, cooling temperature 50℃, then sterilization is complete.

[0130] After sterilization, samples were tested for their appearance, pH value, 5-hydroxymethylfurfural content, and other properties. All test indicators met the standard requirements.

[0131] Table 20 Results of long-term test on sterilized samples

[0132]

[0133]

[0134] Table 21 Results of accelerated test on samples after sterilization

[0135]

[0136] Table 22 Results of the full-load heat penetration test for sterilization

[0137]

Claims

1. A sterilization process for a dual-chamber bag blood filtration replacement solution, wherein the blood filtration replacement solution is a glucose-containing blood filtration replacement solution, characterized in that: The sterilization is performed using moist heat sterilization at a temperature of 121°C for 25-30 minutes, with a heating time of 1500-3800 seconds and a cooling time of ≥2000 seconds.

2. The sterilization process as described in claim 1, characterized in that, The sterilization pressure for moist heat sterilization is ≥150 kPa.

3. The sterilization process as described in claim 1, characterized in that, The sterilization heating rate is ≤10℃ / min.

4. The sterilization process as described in claim 3, characterized in that, The sterilization time is 27 minutes, the heating time is 1800-3600 seconds, and the cooling time is 2400 seconds.

5. The sterilization process as described in claim 4, characterized in that, The volume ratio of the two chambers of the dual-chamber bag blood filtration replacement fluid is 1:

19.

6. The sterilization process according to any one of claims 1-5, characterized in that, The specific operating steps of the sterilization process are as follows: 1) Set the water level for the inner chamber and the water level for the inner chamber drainage; 2) Place the glucose-containing double-chamber bag blood filtration replacement solution to be sterilized on the sterilization cart, load it according to the verified loading method, align it with the track, push it into the sterilization cabinet and close the cabinet door tightly. 3) Sterilize according to the set process parameters; 4) Exhaust and cool the sterilizer according to the set exhaust time.

7. The sterilization process according to claim 1, characterized in that, The volume ratio of the two chambers of the dual-chamber bag is 1:

19.

8. The sterilization process according to claim 6, characterized in that, In step 1), the water level in the inner chamber is set to 520 mm and the water level in the inner chamber is set to 100 mm. In step 2), the blood filtration replacement fluid double-chamber bag containing glucose is fully loaded.

9. The sterilization process according to claim 6, characterized in that, In step 4), the sterilizer is opened slowly when the temperature display inside the sterilizer is less than 50°C and the pressure gauge shows 0 MPa.

10. The sterilization process according to claim 6, characterized in that, In step 3), the sterilization temperature is 121℃, the sterilization time is 27min, the heating time is 1800-3600s, the cooling time is 2400s, the heating rate is ≤10℃ / min, and the sterilization pressure is ≥150kPa.

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