Basic requirements for drug packaging material manufacturers
this year, the State Drug Administration changed the original license system for drug packaging materials into the registration management system for drug packaging materials, strengthened the supervision and management of drug packaging materials, container manufacturers and drug packaging users, and stipulated the corresponding punishment provisions. In the new system, drug packaging materials are divided into three categories: drug packaging materials and containers that are in direct contact with drugs and used directly are class I packaging materials; The drug packaging materials and containers that are in direct contact with drugs but easy to clean and can be disinfected and sterilized after cleaning in the actual use process are class II drug packaging materials; Class III drug packaging materials refer to other materials and containers for drug packaging that can directly affect the quality of drugs other than class I and II. According to the requirements of the production quality specification of class I drug packaging materials, the experimental machine is an indispensable and important testing instrument. According to the specific content of the "quality management specification of drug packaging materials containers" issued by the State Drug Administration, this paper expounds the specific work and requirements that should be done in the process of applying for the registration certificate of drug packaging materials. The quality management specification of drug packaging materials is the "GMP" of drug packaging enterprises ("GMP" is the English abbreviation of the good manu facturing practice, which is called the production quality management specification of drug packaging materials in China). This specification requires that the packaging materials and containers that directly contact drugs should be under strict control in the whole process of production, so as to prevent operational errors and mixed pollution and ensure product quality. The basic spirit of the specification mainly emphasizes two aspects: on the one hand, the requirements for the "hardware" facilities of drug packaging materials enterprises, and on the other hand, the basic requirements for the "software" of enterprise management. If the enterprise meets the requirements of the above two aspects in a down-to-earth manner, the quality of the drug packaging materials it produces can ensure the use quality of drugs, and finally achieve the purpose of ensuring the life safety of patients
I. Basic requirements for "hardware" facilities
1. production plant: there should be enough space and space in the plant to place equipment and materials, and the layout should be reasonable according to the production process and the required cleanliness level. All production operations in the same plant and adjacent plants shall not interfere with each other, and products with different cleanliness levels shall not be produced in the same production area. The plant and warehouse shall be provided with measures to prevent the entry of insects, birds, rats, etc. The workshop surface of the clean room and clean area should be flat and smooth without cracks and easy to clean. The junction of interior wall, ceiling and ground should be made into an arc, and the surface layer should not fall off, emit or absorb dust and particulate matter. The layout in the plant should be compatible with the product process, and the flow of people and logistics (the direction of operators and the direction of semi-finished products) should be reasonable. The pipes and lighting power lines in the plant should meet the relevant requirements, and the lighting degree of the production area should adapt to the process requirements. Sanitary passages, safe fire passages, fire-fighting facilities and personnel emergency evacuation passages shall be reasonably set in the plant, and shall comply with the relevant provisions of the national public security fire department. The cleanliness level of the workshop that produces packaging materials and containers that do not need to be cleaned by the pharmaceutical factory must be compatible with the production workshop of the packaged drugs, and the area and cleanliness level should be specifically delimited and determined according to the production process, process, quality and hygiene of the packaging materials and container products, which show excellent anti electromagnetic interference performance requirements. For example, class I drug packaging materials in direct contact with drugs and PTP aluminum foil for drug packaging require a cleanliness level of 100000, with dust ≥ 0.5 microns ≤ cubic meters, ≥ 5 microns ≤ 20000 cubic meters, and the number of floating microorganisms ≤ 500m3. The indoor ventilation rate is ≥ 15 times/h. to meet the requirements of this standard, the design of indoor air flow system mainly includes three parts. First, it is necessary to design a suitable air flow pattern; The second is to determine the form, size and layout of the return air outlet; The third is to calculate the parameters of air supply jet. The design principles are as follows: ① try to prevent the secondary flying of dust particles to reduce the pollution opportunities of dust particles to the production process. ② Try to reduce eddy current to avoid bringing dust particles outside the working area into the working area. ③ The working area is mainly due to the unstable price of raw materials and strict environmental regulations. The air velocity should meet the requirements of air cleanliness and human health, and the air flow direction should be single. The method of indoor clean air supply is generally high-efficiency filter with diffusion plate, which supplies air from the indoor ceiling. Return air is arranged at the lower part of one side wall. The windows and ceilings of the clean workshop, as well as the connecting parts of the indoor pipelines, air vents, lampshades and walls or ceilings should be air tight. The pressure difference between the clean area and the outdoor area should be greater than 9.8 Pa. the pressure difference between the clean areas with different cleaning levels should be greater than 4.9 Pa. there should be devices to indicate the pressure difference. The area with high cleanliness level should be relatively positive pressure to the adjacent area with low cleanliness level, and the infiltration of clean outdoor air is one of the reasons for polluting the clean room. In order to prevent the infiltration of surrounding air, the clean room must maintain a certain positive pressure. The realization of positive pressure in a clean room is achieved by making the indoor air supply volume greater than the sum of return air volume and exhaust air volume. Although the positive pressure value is too large, it is conducive to prevent the infiltration of clean outdoor air, but at the same time, it will shorten the service life of the high-efficiency filter due to the increase of the required outdoor fresh air volume, and it will make it difficult to open the room door. Therefore, the positive pressure value should not be too large. Generally, the positive pressure value of 10-20 PA should be maintained indoors. A buffer area shall be set in the clean area according to the process requirements, and personnel and materials shall enter through the buffer area corresponding to their production cleanliness level. Changing rooms and lavatories should be accessible. In the clean workshop, when there are flammable, explosive, toxic, harmful and highly chemically active materials in the production process, the exhaust gas emission should be strictly separated from the flow direction of clean air, and cross pollution should not be caused. For products with cleanliness requirements for the production environment, in addition to the production area being controlled according to the cleanliness level, the cleanliness level of its auxiliary material preparation room, inspection room, sampling room, intermediate products in the production area, storage room for products to be packaged, equipment and container cleaning room, clean work clothes washing and drying room should also be adapted to the production area
2. production equipment: the design, type selection and installation of the equipment should meet the production requirements, be easy to clean, facilitate production operation and maintenance, and ensure safety. The surface of the equipment used for products that directly contact drugs should be smooth and smooth, easy to clean or disinfect, corrosion-resistant, and do not cause chemical changes to the products. The lubricant, release agent and cleaning agent used in the equipment shall not pollute the products. After verification, the performance and accuracy of the automation or program-controlled equipment required for production should meet the production requirements. The application scope and accuracy of instruments, meters, measuring tools, weighing instruments, etc. used for production and inspection shall meet the requirements of production and quality inspection, with obvious status marks and specified correction period. The equipment shall be repaired, maintained and verified regularly, and its installation, maintenance and servicing operations shall not affect the quality of products. Equipment archives shall be established for production and inspection equipment, and their respective use registration shall be provided to record the actual situation of their use, maintenance and servicing, which shall be managed by a specially assigned person
3. Hygiene requirements in the production process: all staff of the enterprise should be trained in hygiene, and all personnel entering the production area should strictly abide by the relevant hygiene system. The production enterprise should have a hygienic and clean environment, no pollution sources in and around the plant, and the air, water quality and site in the production area should meet the production requirements. The contaminated materials, wastes and garbage conversion stations should be far away from the production area and should be closed for loading, unloading and storage as far as possible. The process posts in the production workshop should formulate the cleaning procedures of their plants, equipment and containers according to the requirements of production and cleanliness level. Non production materials shall not be stored in the production and operation area, and smoking, eating and drinking, and bringing into daily necessities are strictly prohibited. Changing rooms, washing facilities, disinfection facilities and toilets shall not adversely affect the cleanliness level of the plant, and waste shall not be stored in the production area. The material selection, style and wearing mode of work clothes should be consistent with the production operation and the cleanliness level of the plant. The work clothes of plants with different cleanliness levels should be strictly distinguished and should not be mixed. According to the requirements of cleanliness level, work clothes should use their own cleaning facilities and formulate cleaning cycle. The clean workshop should be disinfected regularly. The disinfectant or disinfectant used should not pollute the equipment, raw materials, auxiliary materials and finished packaging materials, but also prevent cross contamination of products. Cross pollution sources often come from raw material dust, gas, steam, microorganisms or workers' clothes in the production process. The severity of cross contamination varies depending on the type of pollution source, and some microorganisms are the most harmful. The methods to prevent cross contamination are as follows: ① products should be produced or packaged in isolated areas. ② Avoid producing different products at the same time in the effective isolation area. ③ Pay attention to cleaning the equipment in the clean room to remove the pollution source. 5 pay attention to the recirculation of untreated air or the discharged gas should not invade the clean room again
II. Basic requirements for enterprise management "software"
enterprises must meet the registration conditions and apply for the registration certificate of drug packaging materials according to the procedure. Only after obtaining the certificate can they produce or operate drug packaging materials. Corresponding production process procedures and post operation methods shall be formulated for each product, and the production shall be carried out according to the process procedures and post operation methods. Each batch of products shall have production records reflecting the actual situation of each production link. The production records shall be filed according to the batch number or production date and kept until one year after the expiry date of the products. Product records without a specified period of validity shall be kept for at least three years. The production and quality management documents shall determine the specifications and standards, production and inspection methods of all materials, stipulate the production and quality management standards, production and inspection methods, ensure that all production personnel and production and quality management personnel perform their duties as required, provide materials required for authorized personnel to decide whether each batch of products can be sold, and provide clues for investigating quality problems. The enterprise should have departments and personnel responsible for document and file management, and have complete production management and quality management documents, which include various management systems of production management department, quality management department and production auxiliary department, quality standards and management systems of raw materials, auxiliary materials and packaging materials, and production management documents of each product. For example: product formula, product production process procedures, post operation methods, production instructions, quality management documents of each product, such as raw material and auxiliary material packaging quality standards, inspection operation procedures, sampling and sample retention system, raw material and auxiliary material storage period and product validity confirmation system if the composite material project is successful, intermediate product management system, unqualified treatment and management system. The design, installation, use and maintenance system of plants, equipment, testing instruments, etc., and various health management systems of various departments. For example, the sanitation system of environment, plant, equipment and personnel, the management specifications of drug packaging materials and professional technical training system, and various records related to product production and quality management, such as material acceptance, inspection, distribution records, batch production records, batch packaging records, nonconforming product handling records, finished product sales and user feedback records. There are also finished products, raw and auxiliary materials, packaging materials in and out of the warehouse management system, material scrap system, emergency treatment system, etc. Enterprises should establish documents