The aseptic production process is one of the major process validations in the preparation of aseptic bulk drugs. Since many raw materials cannot be sterilized, the raw materials must be filtered, dried, pulverized, and packaged. It is possible to avoid contamination by microorganisms. There are quite a number of factors that affect the sterility of the product, such as the design of the production and its equipment layout, the production environment, the pollution of all production-related equipment and materials, personnel operations and health conditions, etc. Quality is important. In order to ensure the sterility reliability and adaptability of the aseptic manufacturing process system, a series of validations will be required to ensure product sterility.
Aseptic process verification needs to solve many problems, such as the choice of simulated media, the requirements of aseptic process validation, the sterilization of equipment, how to achieve the purpose of full culture, the assurance of aseptic organization and the analysis of final results. If the item is not handled well, it will affect the final result of zui.
1 Selection of simulated media Aseptic bulk drugs are critical to the selection of simulated media. The selected simulated media should have the following characteristics:
(1) There is no bacteriostatic effect. If the simulated medium has a bacteriostatic effect, it will inhibit the growth of bacteria in the production system, so that the bacteria cannot be cultured, and false results are produced. The simulated medium has a role in promoting bacterial growth. Protection against the production environment is particularly important if solid culture media that promote bacterial growth are selected for verification. Because if some operations are to expose the medium, the dust particles of the medium will drift to some places that are difficult to clean, such as the air supply and air return of the air conditioning system, which will create conditions for the bacteria to breed there. There are measures to protect dead corners that are not easy to clean from contamination by media.
(2) The simulated medium should also have good solubility. Because if the solubility is not good, the simulated medium suspended in the medium causes the medium to turbid, which affects the judgment of the result.
(3) After the simulated medium is added to the medium, the quality of the medium should not be affected, and the pH does not change greatly to accommodate the growth of most bacteria.
(4) It is not corrosive to the equipment, harmless to the human body, and does not pollute the environment.
The choice of simulated media depends on the specific conditions of each company. Currently, most manufacturers use media filling tests to prove the reliability of their aseptic process. The medium used should have good solubility and high nutrient level to meet the growth of various microorganisms. It is generally verified by a growth promotion test. If the production process is under anaerobic conditions, the medium selected should be capable of growing anaerobic microorganisms.
2 Relevant requirements for aseptic process verification 2.1 Preparation before verification 2.1.1 Design and confirmation of production facilities The production facilities shall be designed to reduce potential pollution to a small size. For example, production facilities should be easy to clean and disinfect, air with products or materials must have certain quality requirements, temperature and humidity control should be appropriate, operators wearing sterile clothing should feel comfortable, prevent pollution and cross-contamination, etc. Wait. Emphasis should be placed on design details and sources of contamination to ensure that aseptic production is implemented. Aseptic process validation is one of the more difficult validations performed, and participants should be fully aware of the design and validation of the facility, which is a major factor in the success of the validation.
2.1.2 Confirmation of public works Public works (such as steam, compressed air, heating, refrigeration, water systems, etc.) that affect product quality should be confirmed.
Utility engineering is one of the guarantees that production can be implemented normally. If any one of the systems fails, it will cause potential or serious pollution of the product. The maintenance plan of the public works should be carried out and executed according to the plan. The purpose is to prevent the system from malfunctioning and ensure the smooth progress of the production, instead of repairing after the failure, the public works that are often repaired and failed to ensure the aseptic production. .
2.1.3 Equipment and Process Validation All equipment, aseptic environments, computer control systems, and production processes should be validated prior to verification. Product exposure is one of the main reasons for the failure of the aseptic process to verify the occurrence of contamination. To prevent or reduce the probability of contamination, it is very important to provide a laminar flow hood or isolator for laminar air to exposed products. It is also essential that the sterilized items are transported from the sterilizer to the production line and protected before entering the production line through necessary manual operations. Personnel should be avoided to contact the equipment or materials. These should be verified.
2.1.4 Cleaning and Sterilization of Equipment The surface of equipment that is exposed to simulated media prior to aseptic process verification shall be cleaned and sterilized to prevent recontamination after sterilization. If the produced drug has antibacterial or bactericidal properties, such cleaning is particularly important, and it is confirmed that the microorganism is not bacteriostatic after washing, or the bacteriostatic property can be effectively eliminated. If the cleaning or sterilization is not complete, the residual drug may cause the simulated medium to be contaminated or the microorganisms on the surface of the device may cause the simulated medium to be infected and the verification fails. This cleaning and sterilization process should be verified to ensure thorough cleaning and successful sterilization.
Equipment sterilization is a key part of aseptic process validation. All process-related equipment must be sterilized. First, the equipment should be sterilized by sterilization, including the determination of the cold spot, temperature distribution and heat penetration. The challenge of biological indicators, Zui finally determines the temperature, time and exhaust point of sterilization. The biological indicator used should confirm its type, source, concentration of the species and D value.
3 Aseptic maintenance of organizational assurance In order to ensure the smooth implementation of aseptic process verification, the establishment of the Aseptic Process Validation Implementation Team aims to: (1) provide human, financial and material support for verification work; (2) final decision verification The handling of various matters during the period; (3) approval of the verification plan and plan and verification report; (4) responsibility for the work of each sub-group.
The requirements of the security assurance group: All the inspections of the group need to be confirmed in writing and the records are kept; all groups and all personnel must report the abnormal situation in time; all the team leaders are on duty throughout the verification period.
4 Aseptic process verification process Aseptic process verification design should fully reflect the concept of QbD (quality comes from design), as far as possible in line with the process, zui to ensure the quality of the product to a large extent.
4.1 Confirmation of Standard Operating Procedures and Staff Training Standard Operating Procedures (SOPs) are written procedures that guide the operator in performing an operation, are the operating standards of the operator, and are the key to the success of the production operation. Standard operating procedures should provide sufficient guidance to the operator to complete this operation.
The standard operating procedures should be prepared by the technical staff, reviewed by the department head, and approved by the head of the quality assurance department. The approved standard operating procedures are used to train the operator to make them truly understandable and proficient. The original and training records of the standard operating procedures are stored in the data management department, and copies are stored at the operation site. Before verification, it should be confirmed that there is a standard for each operation, so as to avoid management loopholes, and confirm that this operation has been trained, and the operator is already proficient.
All operations and quality management personnel should be trained and verified before the verification (according to the verification plan and SOP) to avoid the personnel in the verification process do not understand or even know how to do it, to ensure the smooth implementation of the verification. If more than 20% of the aseptic operators are newly added or exchanged in the production workshop, the aseptic process verification should be repeated to ensure that the aseptic operation can be carried out smoothly.
4.2 Meter Calibration Meter calibration shall be carried out by qualified personnel or units in accordance with company-approved SOPs and in accordance with nationally traceable standards. The calibration frequency of the instrument is at least in accordance with national regulations, and is adjusted according to the frequency of use and is strictly in accordance with this standard. The higher the frequency of use, the more worn the meter is, and the higher the correction frequency should be. The resulting data is invalid due to the use of uncalibrated meters.
4.3 Process conditions The production process of aseptic bulk drugs has its own characteristics: many types of equipment, complicated equipment, long pipelines, and different production processes have different characteristics, and solid or liquid simulation media are selected according to their respective characteristics. Although the internal exposure of the equipment has been minimized and the exposure of the material products has been minimized, there are inevitably some equipment that communicates with the external environment or that the materials are exposed to the environment. There should be a respirator or a hundred-layer laminar flow at these openings. Air protection is better protected with an isolator. When verifying, there should be an operation that simulates the exposure of these materials.
Some production processes have crystallization operations, which makes the simulation process somewhat difficult, because there is a phase change in the crystallization process, and it should be considered whether this change will affect the growth of microorganisms. A good way to choose zui is to select two simulated media that react in the crystallization process to form another simulated medium. The choice of such a medium can be very difficult. For the sake of simplicity, the same liquid simulation medium can be used to simulate the crystallization process flowing through all the lines to the crystallization tank. If the crystallization process has a seeding operation, this should also be done during the simulation. The seed crystal can be replaced by a simulated medium. In order to make the crystal grain size uniform, some crystallization processes have a cooling process, and should not be cooled during the simulation because the microorganisms are not easy to grow at low temperatures.
The temperature during the drying process generally inhibits the growth of microorganisms and even kills the microorganisms. The room temperature should be kept during the simulation to avoid the temperature being too high to kill the bacteria and the verification fails. It is also useful to freeze the moisture to remove moisture, and the choice of simulated freeze-drying parameters should not inhibit bacterial growth.
In short, in the verification process, the process parameters are as close as possible to the actual situation, but in order to make the microorganisms grow well, the selected process parameters are allowed to be inconsistent with the actual conditions, but these parameters should not be significantly different from the production process. The dispensing dose of the aseptic bulk drug is generally large. In this case, the dispensing speed should be slowed during the dispensing process to increase the possibility of product exposure, and the operation is poor.
In the verification, the zui difference condition should be set according to the abnormal situation that has occurred in the production process or the possible abnormal conditions that can be expected to investigate whether the sterility of the product will be affected when the abnormality occurs during the production process.
4.4 Operation time limit In the production of APIs, each operation should have an operation time limit to ensure that the sterilized articles are protected from microbial contamination or product degradation. The longer the operating time limit, the greater the chance that the product will be contaminated.
In the aseptic process verification, the operating time limit should be adjusted to be large and operate under the condition of zui. If the verification result is reliable at this time, the operation performed at less than this time is of course reliable. In particular, the storage time of sterilized items from sterilization to use is more important. At the time of verification, the sterilized items should be placed at least for the specified storage time, which is more convincing.
Aseptic process verification needs to solve many problems, such as the choice of simulated media, the requirements of aseptic process validation, the sterilization of equipment, how to achieve the purpose of full culture, the assurance of aseptic organization and the analysis of final results. If the item is not handled well, it will affect the final result of zui.
1 Selection of simulated media Aseptic bulk drugs are critical to the selection of simulated media. The selected simulated media should have the following characteristics:
(1) There is no bacteriostatic effect. If the simulated medium has a bacteriostatic effect, it will inhibit the growth of bacteria in the production system, so that the bacteria cannot be cultured, and false results are produced. The simulated medium has a role in promoting bacterial growth. Protection against the production environment is particularly important if solid culture media that promote bacterial growth are selected for verification. Because if some operations are to expose the medium, the dust particles of the medium will drift to some places that are difficult to clean, such as the air supply and air return of the air conditioning system, which will create conditions for the bacteria to breed there. There are measures to protect dead corners that are not easy to clean from contamination by media.
(2) The simulated medium should also have good solubility. Because if the solubility is not good, the simulated medium suspended in the medium causes the medium to turbid, which affects the judgment of the result.
(3) After the simulated medium is added to the medium, the quality of the medium should not be affected, and the pH does not change greatly to accommodate the growth of most bacteria.
(4) It is not corrosive to the equipment, harmless to the human body, and does not pollute the environment.
The choice of simulated media depends on the specific conditions of each company. Currently, most manufacturers use media filling tests to prove the reliability of their aseptic process. The medium used should have good solubility and high nutrient level to meet the growth of various microorganisms. It is generally verified by a growth promotion test. If the production process is under anaerobic conditions, the medium selected should be capable of growing anaerobic microorganisms.
2 Relevant requirements for aseptic process verification 2.1 Preparation before verification 2.1.1 Design and confirmation of production facilities The production facilities shall be designed to reduce potential pollution to a small size. For example, production facilities should be easy to clean and disinfect, air with products or materials must have certain quality requirements, temperature and humidity control should be appropriate, operators wearing sterile clothing should feel comfortable, prevent pollution and cross-contamination, etc. Wait. Emphasis should be placed on design details and sources of contamination to ensure that aseptic production is implemented. Aseptic process validation is one of the more difficult validations performed, and participants should be fully aware of the design and validation of the facility, which is a major factor in the success of the validation.
2.1.2 Confirmation of public works Public works (such as steam, compressed air, heating, refrigeration, water systems, etc.) that affect product quality should be confirmed.
Utility engineering is one of the guarantees that production can be implemented normally. If any one of the systems fails, it will cause potential or serious pollution of the product. The maintenance plan of the public works should be carried out and executed according to the plan. The purpose is to prevent the system from malfunctioning and ensure the smooth progress of the production, instead of repairing after the failure, the public works that are often repaired and failed to ensure the aseptic production. .
2.1.3 Equipment and Process Validation All equipment, aseptic environments, computer control systems, and production processes should be validated prior to verification. Product exposure is one of the main reasons for the failure of the aseptic process to verify the occurrence of contamination. To prevent or reduce the probability of contamination, it is very important to provide a laminar flow hood or isolator for laminar air to exposed products. It is also essential that the sterilized items are transported from the sterilizer to the production line and protected before entering the production line through necessary manual operations. Personnel should be avoided to contact the equipment or materials. These should be verified.
2.1.4 Cleaning and Sterilization of Equipment The surface of equipment that is exposed to simulated media prior to aseptic process verification shall be cleaned and sterilized to prevent recontamination after sterilization. If the produced drug has antibacterial or bactericidal properties, such cleaning is particularly important, and it is confirmed that the microorganism is not bacteriostatic after washing, or the bacteriostatic property can be effectively eliminated. If the cleaning or sterilization is not complete, the residual drug may cause the simulated medium to be contaminated or the microorganisms on the surface of the device may cause the simulated medium to be infected and the verification fails. This cleaning and sterilization process should be verified to ensure thorough cleaning and successful sterilization.
Equipment sterilization is a key part of aseptic process validation. All process-related equipment must be sterilized. First, the equipment should be sterilized by sterilization, including the determination of the cold spot, temperature distribution and heat penetration. The challenge of biological indicators, Zui finally determines the temperature, time and exhaust point of sterilization. The biological indicator used should confirm its type, source, concentration of the species and D value.
3 Aseptic maintenance of organizational assurance In order to ensure the smooth implementation of aseptic process verification, the establishment of the Aseptic Process Validation Implementation Team aims to: (1) provide human, financial and material support for verification work; (2) final decision verification The handling of various matters during the period; (3) approval of the verification plan and plan and verification report; (4) responsibility for the work of each sub-group.
The requirements of the security assurance group: All the inspections of the group need to be confirmed in writing and the records are kept; all groups and all personnel must report the abnormal situation in time; all the team leaders are on duty throughout the verification period.
4 Aseptic process verification process Aseptic process verification design should fully reflect the concept of QbD (quality comes from design), as far as possible in line with the process, zui to ensure the quality of the product to a large extent.
4.1 Confirmation of Standard Operating Procedures and Staff Training Standard Operating Procedures (SOPs) are written procedures that guide the operator in performing an operation, are the operating standards of the operator, and are the key to the success of the production operation. Standard operating procedures should provide sufficient guidance to the operator to complete this operation.
The standard operating procedures should be prepared by the technical staff, reviewed by the department head, and approved by the head of the quality assurance department. The approved standard operating procedures are used to train the operator to make them truly understandable and proficient. The original and training records of the standard operating procedures are stored in the data management department, and copies are stored at the operation site. Before verification, it should be confirmed that there is a standard for each operation, so as to avoid management loopholes, and confirm that this operation has been trained, and the operator is already proficient.
All operations and quality management personnel should be trained and verified before the verification (according to the verification plan and SOP) to avoid the personnel in the verification process do not understand or even know how to do it, to ensure the smooth implementation of the verification. If more than 20% of the aseptic operators are newly added or exchanged in the production workshop, the aseptic process verification should be repeated to ensure that the aseptic operation can be carried out smoothly.
4.2 Meter Calibration Meter calibration shall be carried out by qualified personnel or units in accordance with company-approved SOPs and in accordance with nationally traceable standards. The calibration frequency of the instrument is at least in accordance with national regulations, and is adjusted according to the frequency of use and is strictly in accordance with this standard. The higher the frequency of use, the more worn the meter is, and the higher the correction frequency should be. The resulting data is invalid due to the use of uncalibrated meters.
4.3 Process conditions The production process of aseptic bulk drugs has its own characteristics: many types of equipment, complicated equipment, long pipelines, and different production processes have different characteristics, and solid or liquid simulation media are selected according to their respective characteristics. Although the internal exposure of the equipment has been minimized and the exposure of the material products has been minimized, there are inevitably some equipment that communicates with the external environment or that the materials are exposed to the environment. There should be a respirator or a hundred-layer laminar flow at these openings. Air protection is better protected with an isolator. When verifying, there should be an operation that simulates the exposure of these materials.
Some production processes have crystallization operations, which makes the simulation process somewhat difficult, because there is a phase change in the crystallization process, and it should be considered whether this change will affect the growth of microorganisms. A good way to choose zui is to select two simulated media that react in the crystallization process to form another simulated medium. The choice of such a medium can be very difficult. For the sake of simplicity, the same liquid simulation medium can be used to simulate the crystallization process flowing through all the lines to the crystallization tank. If the crystallization process has a seeding operation, this should also be done during the simulation. The seed crystal can be replaced by a simulated medium. In order to make the crystal grain size uniform, some crystallization processes have a cooling process, and should not be cooled during the simulation because the microorganisms are not easy to grow at low temperatures.
The temperature during the drying process generally inhibits the growth of microorganisms and even kills the microorganisms. The room temperature should be kept during the simulation to avoid the temperature being too high to kill the bacteria and the verification fails. It is also useful to freeze the moisture to remove moisture, and the choice of simulated freeze-drying parameters should not inhibit bacterial growth.
In short, in the verification process, the process parameters are as close as possible to the actual situation, but in order to make the microorganisms grow well, the selected process parameters are allowed to be inconsistent with the actual conditions, but these parameters should not be significantly different from the production process. The dispensing dose of the aseptic bulk drug is generally large. In this case, the dispensing speed should be slowed during the dispensing process to increase the possibility of product exposure, and the operation is poor.
In the verification, the zui difference condition should be set according to the abnormal situation that has occurred in the production process or the possible abnormal conditions that can be expected to investigate whether the sterility of the product will be affected when the abnormality occurs during the production process.
4.4 Operation time limit In the production of APIs, each operation should have an operation time limit to ensure that the sterilized articles are protected from microbial contamination or product degradation. The longer the operating time limit, the greater the chance that the product will be contaminated.
In the aseptic process verification, the operating time limit should be adjusted to be large and operate under the condition of zui. If the verification result is reliable at this time, the operation performed at less than this time is of course reliable. In particular, the storage time of sterilized items from sterilization to use is more important. At the time of verification, the sterilized items should be placed at least for the specified storage time, which is more convincing.
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