1、How do biotech cleanrooms meet the production needs of vaccines, cell and gene therapy products?
A.Hardware facilities
Cleanroom Surface Requirements
The surfaces inside the cleanroom (area) (walls, floors, ceilings, etc.) should be flat and smooth, without cracks, tight joints, no particles falling off, and able to withstand cleaning and disinfection, no dust accumulation, and no mold growth. This is extremely important for preventing contamination in the production of vaccines, cells, and gene therapy products, because these products are very sensitive to tiny particles and microorganisms in the environment. Once particles fall off or microorganisms grow, it may affect product quality.
Pipeline setup requirements
The water, electricity, steam and building pipelines in the cleanroom (area) must be concealed. This can reduce the possibility of dust accumulation and microbial adhesion on the surface of the pipeline, avoid pollution to the production environment, and ensure that vaccines, cells and gene therapy products are produced in a clean environment.
Cleanliness level classification and requirements on air
Number of dust particles and microorganisms in the air: The production plant must be divided into different cleanliness levels according to the production process and product quality requirements. The number of dust particles and microorganisms in the cleanroom (area) must comply with the regulations, and the results must be recorded. Different production links of vaccines, cells and gene therapy products may require different cleanliness levels to meet their specific production needs. For example, gene therapy products are highly sensitive and highly active, and are more prone to cross-contamination or activity changes between batches. Therefore, the production environment requirements are more stringent, and the control standards for dust particles and microorganisms are higher.
Examples of cleanliness levels for different products
Class 100: For products that are not sterilized and filtered before filling (such as some vaccines), the preparation, merging, filling, freeze-drying, and sample addition may require a Class 100 clean environment. In such an environment, the risk of contamination of products by microorganisms and particles can be minimized to ensure the safety and effectiveness of the product.
Class 10,000: The preparation, merging, refining, and addition of products that need to be sterilized and filtered before filling may require a Class 10,000 cleanroom.
Class 100,000: Processes such as the merging of raw plasma, non-low-temperature extraction, pasteurization before packaging, capping, and the closed system environment for fermentation and cultivation of oral preparations (exposed parts require sterile operation); packaging, preparation, packaging, and drying of enzyme-linked immunosorbent assay reagents; colloidal gold reagents, polymerase chain reaction reagents and other in vitro immune reagents may be produced in a Class 100,000 clean environment.
B.Production workshop layout
Strict separation from other workshops
Biological production workshops must be strictly separated from production workshops for penicillins, cephalosporins, hormones, anti-tumor chemicals, and isotope drug. The production of vaccines, cell and gene therapy products requires dedicated, independent production spaces to prevent cross-contamination during the production of different types of drugs, because these products have complex production processes and high environmental requirements. If contaminated by other chemicals, they may change the properties of the products or introduce harmful substances.
Production plant requirements for special products
Isotope biological agents: The production plants of isotope biological agents must comply with the national requirements for radiation protection and obtain an isotope use license to ensure radiation safety during the production process, avoid harm to products and operators, and ensure that qualified products are produced in an environment that meets the requirements.
BCG and tuberculin: BCG production plants and tuberculin production plants must be strictly separated from other product production plants, and their production equipment must be dedicated. This is due to the particularity of BCG and tuberculin. Dedicated plants and equipment can prevent cross contamination with other products and ensure the stability and reliability of product quality.
Clostridium botulinum and Clostridium tetani products: These two types of products must be produced in corresponding dedicated facilities. These dedicated facilities are designed to meet their special production processes and prevent contamination requirements to avoid adverse effects on other products or the production environment.
Isolation requirements for production of different types of products
The processing or filling of biological products such as production strains of bacteria and viruses and non-production strains of bacteria and viruses, production cells and non-production cells, strong toxins and weak toxins, dead toxins and live toxins, before and after detoxification, products containing bovine serum and those not containing bovine serum, live vaccines and inactivated vaccines, human blood products, and preventive products shall not be carried out in the same production plant at the same time, and their storage must be strictly separated. Different types and adjacent areas should maintain a relatively negative pressure and have independent air purification systems. This strict isolation measure is to avoid mutual interference and cross-contamination between products of different natures, to ensure the quality and safety of each product, and to meet the high-quality production needs of vaccines, cells, and gene therapy products.
C.Equipment
Basic requirements on equipment
Equipment that comes into direct contact with products must have a smooth, flat surface, be easy to clean, be corrosion-resistant, and not undergo chemical changes with or adsorb the products being processed. For vaccines, cell and gene therapy products, these characteristics of the equipment help maintain product stability and purity. For example, in the production process of cell therapy products, if the surface of the equipment is not smooth and difficult to clean, impurities or microorganisms may remain, which may contaminate the cell products; if the equipment undergoes chemical changes with the product or adsorbs the product, it will change the composition and content of the product, affecting the therapeutic effect of the product.
Requirements on specific equipment
Purified water and water for injection production equipment: Purified water and water for injection production equipment must ensure water quality. Water storage tanks, input pipes, pipe fittings and valves must be made of non-toxic, corrosion-resistant materials. The water storage tanks are airtight, and the vents must be sterilized with non-shedding fiber hydrophobicity. The water pipelines can prevent stagnation and be easy to disassemble, clean and disinfect. In the production of vaccines, cells and gene therapy products, the quality of water is directly related to the quality of the product. For example, high-quality water is required in the dilution of vaccine production and the preparation of solutions in the cell culture process. These requirements ensure the safety and purity of production water.
Sterilization equipment: The internal working conditions of the sterilization equipment are monitored by instruments, which are calibrated regularly and fully recorded. For the production of vaccines, cells and gene therapy products that require a sterile environment, the normal operation and accurate monitoring of sterilization equipment are crucial. It can ensure that the product meets the sterility requirements during the production process, prevent microbial contamination of the product, and ensure the safety and effectiveness of the product.
D.Production process
Bacteria, viruses, and cell management
The bacterial and viral strains and cells used in the production of biological products must be established in accordance with the requirements of the "China Biological Products Regulations", with a clear history, traceability, clear lineage, and records. There are comprehensive inspection records of bacterial and viral strains and cells, and the quantities entering and leaving the warehouse are consistent with the registered numbers, and they are stored in separate warehouses under appropriate conditions. For the production of biological products such as vaccines and cell therapy products that use bacterial and viral strains or cells as starting materials, good bacterial and viral strain and cell management can ensure the consistency and stability of product quality, and strong traceability helps to find the causes and take measures in a timely manner when problems arise.
Material storage
Materials must not be stored in such a way that they are exposed to moisture, deterioration, contamination or have any error. In the production of vaccines, cell and gene therapy products, proper storage of various materials such as raw materials, excipients, packaging materials, etc. is an important part of ensuring product quality. For example, if the active ingredients of vaccines are exposed to moisture or deteriorate, they will lose their immunogenicity. If the raw materials of cell therapy products are contaminated, it will affect the activity and function of the cells.
2、How to meet the strict requirements of specific biological processes on temperature and humidity and monitor data changes in real time?
Methods to meet specific bioprocess temperature and humidity requirements
Determine temperature and humidity requirements
First, we need to clarify the precise requirements of temperature and humidity for a specific biological process. For example, in some special processes in the biomedical purification workshop, such as cell culture and enzyme reaction, the temperature generally needs to be controlled between 20°C and 25°C, and the humidity should be maintained between 45%RH and 65%RH. Different biological processes may vary, and the temperature and humidity range needs to be determined according to specific process standards.
Selection and configuration of environmental control equipment
Air conditioning system: For temperature control, high-efficiency and energy-saving air conditioning equipment that can accurately adjust the temperature should be selected. These air conditioners should have stable cooling and heating capabilities to ensure that the ambient temperature can be stabilized within the set range. For example, in a biomedical purification workshop, air conditioning equipment is required to accurately maintain the temperature at the level required by the process.
Humidification/dehumidification equipment: Configure the corresponding humidification or dehumidification equipment according to the humidity requirements. If the humidity requirement is low, such as for the production environment of medicines or materials that are easy to absorb moisture, it is necessary to configure equipment with strong dehumidification capacity; if the humidity requirement is high, it is necessary to equip appropriate humidification equipment. And these devices should be able to automatically adjust the working state according to the ambient humidity to maintain a stable humidity level.
Reasonable airflow organization and design
Use appropriate airflow organization forms, such as airflow supply from upper and return to lower or supply from side and return to side in the cleanroom. This can avoid airflow short circuit and eddy current phenomena. By adjusting the volume of air supply and return as well as the layout and angle of the air inlets and outlets, the temperature and humidity can be evenly distributed in the space, ensuring that the temperature and humidity requirements can be met in the entire process area.
Management on personnel and materials
Set up dedicated access for people and goods, and equip them with corresponding purification facilities such as changing rooms, air showers, etc. The activities of personnel and the entry and exit of materials may cause fluctuations in temperature and humidity. Such management can reduce the impact of such fluctuations on the temperature and humidity of the bioprocess environment.
3、 Methods for real-time monitoring of data changes
Installation of temperature and humidity sensor
Install high-precision temperature and humidity sensors at key locations in bioprocess-related environments. These sensors should have the characteristics of fast response, high precision, and long-term stability, and be able to accurately collect temperature and humidity data in real time. For example, install temperature and humidity sensors at key locations in the cleanroom to monitor the temperature and humidity in the workshop in real time and record data.
Construction of monitoring system
Data collection and transmission: Establish a temperature and humidity monitoring system, and the data collected by the sensor should be able to be transmitted to the control center in a timely manner. Data can be uploaded through RS485, Ethernet, RF433 wireless communication (select the appropriate communication method according to the actual situation) to achieve centralized display and control of data.
Automatic processing and alarm function: The system should have an automatic adjustment function to automatically adjust the working state of the air conditioner, humidifier or dehumidifier according to the preset temperature and humidity range. At the same time, the system also needs to have an alarm function to issue an alarm in time when the temperature and humidity exceed the preset range to remind the operator to handle it.
Regular testing and calibration
Regularly test and calibrate the temperature and humidity sensors and control systems to ensure their accuracy and reliability. Only in this way can the monitored temperature and humidity data be accurate, so that abnormal changes in temperature and humidity can be discovered in time and measures can be taken to adjust them.
4、 Is it possible to provide one-stop service from design, construction to verification?
AIRKEY can provide you with the whole process service of cleanroom construction:
Initial design and construction
In the initial design and construction stage of the cleanroom, factors such as the cleanroom layout, material selection, and air purification system design need to be considered. These factors directly affect the performance of the cleanroom and subsequent maintenance work.
Daily maintenance and management
Daily maintenance and management of cleanrooms are the key to ensuring their long-term stable operation, including personnel management, equipment maintenance, and environmental monitoring.
Technical guidance and system upgrade
With the development of technology and changes in production needs, cleanrooms may need to undergo technical upgrades and system transformation. This includes the evaluation of existing systems, research on transformation plans, system debugging and optimization, etc. For example, the full life cycle services provided by Airkey include services such as yield improvement and transformation and upgrading, capacity expansion, and on-site operation and maintenance after the project is officially put into operation.
Emergency system recovery and problem solving
During the operation of the cleanroom, various unexpected problems may occur, and measures need to be taken quickly to perform emergency system recovery. This includes diagnosing system failures, developing recovery plans, and debugging the system. For example, the requirements for cleanroom system maintenance mention that when users encounter problems or cleanroom systems fail, they need to quickly locate the problem and the cause of the failure through test diagnosis, and find solutions to the problem and the best implementation steps.
