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In order to achieve a stable cleaning effect for online cleaning of equipment in the biopharmaceutical industry and ensure that the concentration of the cleaning agent prepared during online CIP cleaning is stable and reliable, a study was conducted on how to accurately prepare the alkali cleaning agent used for online CIP cleaning of equipment used in production. A method for accurately controlling the actual alkali amount and alkali concentration of the cleaning target based on an automatic control system was introduced.
In the biopharmaceutical industry, the Clean In Place (CIP) process is an indispensable part of the entire product production process and is directly related to the safety, stability and consistency of drug quality. The alkali cleaning step in the cleaning process is a key link in the CIP process and plays an irreplaceable role in effectively removing dirt and microorganisms on the surface of the product in contact with the medium. Therefore, whether the alkali concentration is prepared properly directly determines the effect of alkali cleaning and disinfection.
Part.01
Problems with the preparation of CIP cleaning alkali solution:
Currently, in the biopharmaceutical industry, the online CIP cleaning process of production equipment generally adopts the typical "five-step cleaning method". The cleaning process is: purified water (step 1) → hot alkali solution (step 2) → purified water (step 3) → injection water (step 4) → clean compressed air drying (step 5) → end [2]. In the alkali solution preparation process, a mainstream method is to add alkali solution mother liquor to a certain amount of purified water, use a CIP water outlet pump to circulate and mix, and continuously circulate and heat through a plate heat exchanger. At the same time, the online conductivity meter detects its conductivity value in real time. When the alkali solution temperature process value and the conductivity process value in the preparation tank reach the target set value, the alkali solution preparation is completed, and accurate alkali solution preparation is not achieved. Through a survey of some biopharmaceutical companies, it was found that in the previous online CIP cleaning process of production equipment in the company, the alkali solution concentration was usually unable to be accurately controlled due to the incomplete alkali solution preparation process and the lag of detection instruments. In order to achieve the cleaning effect, the problem is often solved by increasing the concentration of alkali solution. However, this will not only lead to a waste of alkali solution, but also greatly increase the amount of water used for the subsequent two steps of purified water and injection water cleaning due to the increase in alkali solution concentration, which increases the cleaning cost. Therefore, it is particularly important to ensure that the concentration of the cleaning agent alkali solution required for online cleaning is accurately controlled while ensuring the cleaning effect.
Part.02
Accurate preparation method for CIP cleaning alkali solution:
2.1 Alkali preparation principle Add a certain concentration of concentrated alkali mother liquor to a certain amount of purified water, mix and heat it in a circulating manner, and use an online conductivity meter to detect its conductivity value. When the conductivity and temperature reach the target set values, the alkali solution preparation is completed.
2.2 Alkali solution preparation parameter indicators Concentrated alkali mother liquor: NaOH solution of a certain concentration. Target concentration after preparation: This article uses 0.07~0.08 mol/L as the reference value. Alkali solution temperature after preparation: the temperature required for cleaning verification.
2.3 Hardware composition of the CIP station alkali solution preparation process pipe tank module The hardware of the CIP station alkali solution preparation mainly consists of tank liquid preparation tank, alkali dosing pump, CIP circulation pump, heat exchanger, pipeline, valve and detection instrument.
2.4 Description of the CIP alkali solution preparation process A certain amount of purified water is added to the alkali solution preparation tank of the CIP station through the purified water circulation distribution system, the alkali preparation circulation pump is started and the industrial steam heat exchange passage is opened to circulate the solution in the tank until the target temperature is reached. At the same time, a certain concentration of NaOH solution is added to the alkali solution preparation circulation pipeline through the alkali addition metering pump for circulation and mixing. After the mixing is completed, the conductivity is tested online. When the conductivity is less than the set value, alkali is added according to the alkali addition setting time and then the conductivity is tested. If it is still lower than the set value, alkali is added for the second time and the conductivity is tested. This cycle is repeated. When the alkali solution conductivity reaches the set value within the specified number of alkali additions, the alkali solution preparation is completed. When the alkali addition times reach the set times, the circulation conductivity is still lower than the set value, the alkali preparation process is stopped, and a message is issued to indicate that the alkali solution preparation has failed.
2.5 The amount of CIP alkali solution to be prepared is determined by taking the bottom valve of the alkali preparation tank of the CIP station as the starting point, and returning to the top of the alkali preparation tank after reaching the farthest cleaning point of the station as the minimum amount of alkali preparation. The maximum inner diameter of the pipeline is used for calculation during the calculation process, and the final calculated amount plus 15% of the tank volume is used as the alkali solution preparation amount. The calculation formula is as follows: V=π×(D/2)2×L+V1×0.15 (1) Where: V is the target amount of alkali solution preparation; D is the inner diameter of the pipeline; L is the length of the pipeline; V1 is the volume of the cleaning target tank. 2.6 The flow measurement of the CIP alkali solution metering pump is based on the technical indicator manual of the CIP station alkali metering pump manufacturer as a guide to conduct actual flow test verification. Consult the technical indicator manual of the metering pump and set the target flow value on the metering pump according to the flow chart. Manually open the alkali dosing pump, inject the concentrated alkali mother liquor into the pre-prepared container through the outlet pipe of the dosing pump, and record the alkali dosing time. Calculate the alkali dosing pump flow rate according to the weight of the alkali in the container. Repeat the above operation 3 times, and take the average value as the actual flow setting value (Q1) of the dosing pump.
2.7 Determination of CIP alkali dosing time Use a certain concentration of concentrated alkali mother liquor to prepare the target concentration of alkali. According to the determined current actual flow value of the alkali dosing pump and the target alkali volume to be prepared, the calculation formula of the alkali dosing time is as follows: t1=(V×ρ1/ρ2)/Q1 (2) Where: t1 is the alkali dosing time; V is the alkali preparation amount; ρ1 is the target alkali concentration; ρ2 is the alkali mother liquor concentration; Q1 is the alkali dosing pump flow rate. 2.8 Determination of the full circulation time at the maximum preparation amount of the CIP station According to the maximum alkali preparation amount of the target pipe tank to be cleaned as needed, the cycle time is calculated according to the determined alkali preparation circulation passage flow. The calculation formula is as follows: t2=Vmax/Q2 (3) Wherein: t2 is the circulation detection time; Vmax is the maximum demand for alkali solution preparation; Q2 is the circulation pump flow rate.
Part.03
Automation control design for accurate preparation of CIP alkali solution
3.1 Parameter setting for preparation of CIP alkali solution
Part.04
Verification of CIP alkali solution preparation function
4.1 Verification method
The CIP station is used as the verification platform for the precise alkali solution preparation function. The terminal equipment at the farthest point in the cleaning target is selected as the cleaning target. The target alkali solution preparation amount, concentrated alkali mother solution addition time and alkali solution circulation detection time are calculated. The above parameters are input into the automatic program parameter setting window in the control system, and the alkali solution preparation program is started. After the preparation program is completed normally, the alkali solution is sampled and tested [4]. The above alkali solution preparation process is repeated three times, and the sample numbers are 1#, 2#, and 3# respectively.
4.2 Acceptable standard
The concentration of alkali solution after three consecutive preparations is between 0.07 and 0.08 mol/L.
4.3 Parameter confirmation
1) Fixed parameters of CIP station and target equipment to be cleaned
2) Determine the target alkali solution preparation amount V. The pipe diameter D of the path to be cleaned is 0.04 m. By mapping the process P&ID diagram, the total length of the pipeline in this path is L=60.7 m. The alkali solution preparation amount V can be calculated by the formula in Section 2.5 above: V=3.14×(0.04/2)2×60.7×1 000+800×0.15≈196 L3) Determine the time t1 for adding concentrated alkali mother solution. Here, 50% NaOH solution is used as the concentrated alkali mother solution. From the above, we know that Q1=13.3 g/s, V=196 L; the molecular weight of NaOH is 40 g/mol, so the amount of target alkali solution with a concentration of 0.1 mol is ρ1=0.1 mol×40 g/mol=4 g. The addition time t1 of concentrated alkali mother solution can be calculated by the formula in Section 2.7 above: t1=（196×4/0.5）/13.3≈118 s4) Determine the alkali solution circulation detection time t2. It is known that the maximum alkali solution preparation tank volume of CIP station No. 1 is Vmax=V=196 L, Q2=2.8 L/s. The cycle detection time t2 can be obtained by the formula in Section 2.8 above: t2=196/2.8=70 s4.4 Alkali solution preparation verification results Sample test results: The molar concentration of sample 1# is 0.07 mol/L, the molar concentration of sample 2# is 0.08 mol/L, and the molar concentration of sample 3# is 0.08 mol/L.
Verification conclusion: The concentration range of the three alkali solution preparations is between 0.07 and 0.08 mol/L. 4.5 Verification summary Through the above verification, it can be confirmed that the method of automatic and precise preparation of alkali solution can make the CIP alkali solution preparation meet the requirements of precise alkali concentration. At the same time, good online CIP alkali solution concentration precision preparation provides strong support for the quantitative cleaning of purified water and water for injection in the two steps after online CIP. By adopting the above-mentioned precise alkali solution preparation method, while meeting the cleaning effect, the amount of purified water and concentrated alkali mother liquor required for each alkali preparation step is reduced by 34.7% compared with before, and the amount of industrial steam is reduced by 29% compared with before, thereby reducing the raw material cost and energy consumption cost of the process, which has a significant effect on improving the quality and efficiency of the enterprise.
Part.05
Conclusion:
This paper proposes an effective solution for accurate alkali solution preparation through innovative research on the automated control process of CIP alkali solution preparation in biopharmaceutical companies. Through verification and evaluation, the automated alkali solution preparation method operates stably and can achieve precise control of the target process parameters. At the same time, it also provides a stable demand basis for the amount of water used for alkali solution preparation, the amount of concentrated alkali mother liquor, the amount of injection water for flushing, and the amount of industrial steam.
In the future, further research can be conducted on how to achieve precise control of the optimal amount of water used for cleaning while achieving the cleaning effect, so as to achieve the best cost control and form the most economical and effective online CIP cleaning method.
