What should be included in the content of the gmp equipment cleaning and maintenance protocols for APIs

Article I according to the "Chinese people's *** and the State Drug Administration Law" stipulates that the formulation of this specification. Article II of this specification is the basic guidelines for drug production and quality management. Applicable to the whole process of drug preparation production, API production affects the quality of the finished product of the key processes. Article III drug manufacturers should establish production and quality management organizations. The responsibilities of institutions and personnel at all levels shall be clearly defined, and equipped with a certain number of managers and technicians with professional knowledge, production experience and organizational ability appropriate to the production of drugs. Article IV of the enterprise in charge of drug production management and quality management of the person in charge should have pharmaceutical or related professional college degree or above, with drug production and quality management experience, the implementation of this specification and product quality is responsible for. Article 5 the person in charge of drug production management department and quality management department shall have college degree or above in medicine or related majors, have practical experience in drug production and quality management, and have the ability to make correct judgments and deal with the actual problems in drug production and quality management. The persons in charge of the drug production management department and the quality management department shall not be appointed concurrently with each other. Article 6 The personnel engaged in the operation of drug production and quality inspection shall be professionally and technically trained, with basic theoretical knowledge and practical skills. Engaged in high biological activity, high toxicity, strong contamination, high allergenicity and special requirements of the drug production operation and quality inspection personnel should be by the appropriate professional technical training. Article VII of the personnel engaged in the production of drugs at all levels should be in accordance with the requirements of this specification for training and assessment. Article VIII of the pharmaceutical production enterprises must have a clean production environment; plant ground, pavement and transportation should not cause pollution of the production of drugs; production, administration, living and auxiliary areas of the overall layout should be reasonable, and shall not interfere with each other. Article IX plant should be according to the production process and the required air cleanliness level for reasonable layout. Production operations in the same plant and between neighboring plants shall not interfere with each other. Article 10 of the plant should prevent insects and other animals to enter the facilities. Article XI in the design and construction of the plant, should consider the use of easy access to clean work. Clean room (area) of the inner surface should be flat and smooth, no cracks, tight interfaces, no particles off, and can withstand cleaning and disinfection, the junction of the wall and the ground should be curved or take other measures to reduce dust accumulation and easy to clean. Article XII of the production area and storage area should be compatible with the production scale of the area and space for the placement of equipment, materials, to facilitate production operations, storage of materials, intermediate products, to be examined and finished products, should minimize errors and cross-contamination. Article XIII of the clean room (area) in a variety of pipes, lamps, air intake and other utilities, in the design and installation should be considered to avoid the use of parts that are not easy to clean. Article XIV clean room (area) should be based on production requirements to provide adequate lighting. The main studio illumination should be 300 lux; special requirements for the illumination of the production parts can be set up local lighting. Plant should be emergency lighting facilities. Article XV into the clean room (area) of the air must be purified, and according to the requirements of the production process to divide the air clean level. Clean room (area) the number of microorganisms in the air and the number of dust particles should be regularly monitored, the monitoring results should be recorded and archived. Article XVI of the clean room (area) of the windows, the canopy and into the indoor piping, air intake, lamps and lanterns and walls or canopy connection parts should be sealed. Air clean level of different static pressure difference between neighboring rooms should be greater than 5 Pa, clean room (area) and the outdoor atmosphere should be greater than 10 Pa static pressure difference, and there should be an indication of the pressure difference device. Article XVII of the clean room (area) temperature and relative humidity should be compatible with the requirements of the pharmaceutical production process. No special requirements, the temperature should be controlled at 18 ~ 26 ℃, relative humidity control at 45% ~ 65%. Article XVIII of the clean room (area) installed in the pool, floor drains shall not be contaminated with drugs. Article 19 different air cleanliness levels of clean room (area) between the personnel and materials in and out, there should be measures to prevent cross-contamination. Article 20 the production of penicillin and other highly allergenic drugs must use independent plants and facilities, packaging room should maintain a relative negative pressure, exhaust to the outdoors should be purified and meet the requirements, the exhaust port should be away from the other air purification system intake; the production of β-lactam structure of drugs must be the use of special equipment and independent air purification system, and other drug production areas are strictly separated. Article 21 of the contraceptive drugs production plant should be separated from other drug production plant, and equipped with independent special air purification system. Production of hormones, anti-tumor chemicals should be avoided with other drugs using the same equipment and air purification system; unavoidable, effective protective measures should be used and the necessary verification. The production, packaging and storage of radiopharmaceuticals should use specialized, safe equipment, the air discharged from the production area should not be recycled, the exhaust should be avoided to contain radioactive particles, in line with national requirements and regulations on radiation protection. Article 22 of the production of bacterial strains and non-production of bacterial strains, production of cells and non-production of cells, strong and weak poisons, dead and live poisons, detoxification and detoxification of products and live vaccines and inactivated vaccines, human blood products, preventive products, etc., shall not be processed or filled at the same time in the same production plant, and their storage should be strictly separated. The processing and filling of different kinds of live vaccines shall be separated from each other. Strongly toxic microorganisms and bacteriophage products of the region and adjacent areas should maintain a relatively negative pressure, and have an independent air purification system. Article 23 The pre-treatment, extraction, concentration of Chinese herbal medicines, as well as the washing or treatment of animal organs and tissues and other production operations must be strictly separated from the production of their preparations. Steaming, frying, sizzling, calcining and other concoctions of Chinese herbal medicines should be well ventilated, smoke removal, dust removal, cooling facilities. Screening, slicing, crushing and other operations should be effective dust removal, exhaust facilities. Article 24 of the plant should be necessary to prevent dust and dust capture facilities. Article 25 of the direct contact with the drugs dry air, compressed air and inert gas should be purified, in line with production requirements. Article 26 The storage area should be kept clean and dry. Lighting, ventilation and other facilities and temperature, humidity control should meet the storage requirements and regular monitoring. Storage area can be set up in the raw material sampling room, sampling environment of air cleanliness level should be consistent with the production requirements. If not in the sampling room sampling, sampling should be to prevent contamination and cross-contamination measures. Article 27 According to the requirements of the pharmaceutical production process, clean room (area) set up in the weighing room and preparation room, the air cleanliness level should be consistent with the production requirements, and dust capture and prevention of cross-pollution facilities. Article 28 of the quality management department according to the need to set up the test, Chinese medicine specimens, samples to observe and other types of laboratories should be separated from the drug production area. Biological testing, microbial limit testing and radioisotope testing should be carried out in separate rooms. Article 29 of the special requirements of the instrument, instrumentation, should be placed in a special instrumentation room, and facilities to prevent static electricity, vibration, moisture or other external factors. Article 30 of the experimental animal room should be strictly separated from other areas, and its design and construction should be in line with the relevant state regulations. Article 31 of the equipment design, selection, installation should be consistent with the production requirements, easy to clean, disinfect or sterilize, easy to operate and repair and maintenance of production, and can prevent errors and reduce pollution. Article 32 of the equipment in direct contact with the drug surface should be clean, smooth, easy to clean or disinfect, corrosion-resistant, no chemical changes with the drug or adsorption of drugs. The lubricants and coolants used in the equipment shall not cause pollution to the drugs or containers. Article 33 and equipment connected to the main fixed pipeline should be marked with the name of the material in the pipe, flow direction. Article 34 The preparation, storage and distribution of purified water and water for injection shall be able to prevent the growth and contamination of microorganisms. The materials used in the storage tanks and transportation pipelines should be non-toxic and corrosion-resistant. The design and installation of pipelines should avoid dead ends and blind pipes. Tanks and pipelines should be provided with cleaning and sterilization cycles. The air vent of the storage tank for water for injection should be installed with hydrophobic sterilizing filters that do not shed fibers. The storage of water for injection can be used above 80 ℃ heat preservation, above 65 ℃ heat preservation cycle or below 4 ℃ storage. Article 35 for the production and inspection of instruments, meters, gauges, scales, etc., its scope of application and precision should be in line with the production and inspection requirements, there is a clear sign of conformity, and regular calibration. Article 36 of the production equipment should have obvious status signs, and regular repair, maintenance and verification. Equipment installation, repair and maintenance operations shall not affect the quality of the product. Unqualified equipment, if possible, should be moved out of the production area, should be clearly marked before moving out. Article 37 of the production and inspection equipment should be used, repair and maintenance records, and managed by specialized personnel. Article 38 The purchase, storage, distribution and use of materials used in the production of drugs should be formulated management system. Article 39 of the materials used in the production of drugs should be in line with drug standards, packaging material standards, biological product regulations or other relevant standards, shall not adversely affect the quality of drugs. Imported raw materials should be port drug testing center of the drug test report. Article 40 The Chinese herbal medicines used in the production of drugs shall be purchased according to the quality standards, and their places of origin shall be kept relatively stable. Article 41 of the materials used in the production of drugs should be purchased from the units in line with the provisions of the regulations, and in accordance with the provisions of the storage. Article 42 The materials to be tested, qualified and unqualified shall be strictly managed. Unqualified materials should be stored in a special area, with easy to identify the obvious signs, and in accordance with the relevant provisions of the timely disposal. Article 43 of the temperature, humidity or other conditions have special requirements of materials, intermediate products and finished products, should be stored in accordance with the specified conditions. Solid and liquid raw materials should be stored separately; volatile materials should be careful to avoid contamination of other materials; concocted, sorted and processed net herbs should be used clean containers or packaging, and with unprocessed, concocted herbs strictly separate. Article 44 narcotic drugs, psychotropic drugs, toxic drugs (including herbs), radioactive drugs and flammable, explosive and other dangerous goods acceptance, storage, custody should be strictly enforced the relevant state regulations. The acceptance, storage, custody, use and destruction of strains of bacteriophages shall be implemented in accordance with the relevant national regulations on the custody of strains of medical microorganisms. Article 45 materials should be stored according to the specified period of use, no specified period of use, its storage generally does not exceed three years, the expiration of the period should be re-examined. If there are any special circumstances during the storage period, it should be re-examined in time. Article 46 of the drug labeling, instructions for use must be approved by the drug supervision and management department with the content, style, text consistent. Labeling, instructions for use shall be proofread by the quality management department of the enterprise after printing, distribution, use. Article 47 of the drug labels, instructions for use should be kept by a person, the receipt of its requirements are as follows: 1. labels and instructions for use should be according to the variety, specifications have a special cabinet or special storage, with the batch of packaging instructions issued by the actual need to receive the amount of 2. labels should be counted and issued by the receiver to check, sign, the use of the number of residual number of the number of residual number should be in line with the number of the number of the receipt of the residual number of residual or leftover labels with the lot number should be counted by a person responsible for the destruction. Should be counted by a person responsible for the destruction. 3. Label issuance, use, destruction should be recorded. Article 48 drug manufacturers should prevent pollution of health measures, the development of health management system, and by a person in charge. Article 49 of the pharmaceutical production workshops, processes, positions should be in accordance with the requirements of the production and air cleanliness level of the development of plant, equipment, containers and other cleaning procedures, which should include: cleaning methods, procedures, intervals, the use of detergents or disinfectants, cleaning tools cleaning methods and storage locations. Article 50 The production area shall not store non-production items and personal sundries. Waste from production shall be disposed of in a timely manner. Article 51 locker rooms, bathrooms and toilets shall not be set up to adversely affect the clean room (area). Article 52 of the selection of work clothes, style and wear should be compatible with the production operation and air cleanliness level requirements, and shall not be mixed. The texture of clean work clothes should be smooth, do not produce static electricity, do not shed fibers and particulate matter. Sterile overalls must cover all hair, beard and feet, and can retain human shedding. Different air cleanliness levels of use of work clothes should be washed, organized, disinfected or sterilized if necessary. No additional particulate matter should be brought in when the work clothes are washed and sterilized. Work clothes should be developed cleaning cycle. Article 53 clean room (area) is limited to the region's production operators and approved personnel to enter. Article 54 into the clean room (area) of the personnel shall not make-up and wear jewelry, not bare hands in direct contact with drugs. Article 55 clean room (area) should be regularly disinfected. The disinfectant used shall not pollute the equipment, materials and finished products. Disinfectant varieties should be regularly replaced to prevent the production of drug-resistant strains. Article 56 of the drug production personnel should have health records. Production personnel in direct contact with drugs at least once a year for a physical examination. Infectious diseases, skin disease patients and people with wounds on the body surface shall not be engaged in direct contact with the production of drugs. Article 57 of the drug production verification should include plant, facilities and equipment installation confirmation, operation confirmation, performance confirmation and product verification. Article 58 of the product production process and key facilities and equipment should be verified according to the verification program. When the main factors affecting product quality, such as process, quality control methods, the main raw materials and auxiliary materials, the main production equipment, etc. change, as well as the production of a certain period of time, should be re-validated. Article 59 should be validated according to the object of the proposed validation project, develop a validation program, and organization and implementation. Validation work should be written after the completion of the validation report, by the person in charge of the validation work review and approval. Article 60 of the validation process data and analysis of the content should be filed in the form of documents to save. Validation documents should include the validation program, validation report, evaluation and recommendations, approver and so on. Article 61 drug manufacturers should have production management, quality management systems and records: 1. Plant, facilities and equipment use, maintenance, maintenance, overhaul and other systems and records; 2. Material acceptance, production operations, inspection, issuance, sales of finished products and user complaints and other systems and records; 3. Non-conforming product management, material withdrawal and scrapping, emergency handling and other systems and records; 4. Environment, Environment, plant, equipment, personnel and other health management system and records; 5. This specification and professional and technical training and other systems and records. Article 62 of the product production management documents include: 1. production process regulations, job operation law or standard operating procedures production process regulations include: product name, dosage form, prescription, production process requirements, materials, intermediate products, finished products, quality standards and technical parameters and storage precautions, the calculation of material balance, finished product containers, packaging materials requirements. The contents of job operation law include: production operation methods and points, review and recheck of key operations, intermediate product quality standards and control, safety and labor protection, equipment maintenance, cleaning, handling and reporting of abnormalities, process hygiene and environmental hygiene. The contents of SOPs include: title, number, formulator and date of formulation, reviewer and date of review, approver and date of approval, issuing department, effective date, distributing department, title and text.2. Batch Production RecordsThe contents of batch production records include: name of the product, production batch number, date of production, signatures of the operator and the reviewer, the relevant operation and equipment, and the number of products in the relevant production stage, Calculation of material balance, control records of the production process and records of special problems. Article 63 The main product quality management documents are: 1. application and approval documents of drugs; 2. quality standards of materials, intermediate products and finished products and their inspection procedures; 3. product quality stability inspection; 4. batch inspection records. Article 64 Drug manufacturers shall establish a management system for drafting, revising, reviewing, approving, withdrawing, printing and keeping documents. Distribute, use the documents shall be approved current text. Revoked and outdated documents shall not be present at the work site except for keeping them in the file for inspection. Article 65 of the development of production management documents and quality management documents requirements: 1. The title of the document should be able to clearly explain the nature of the document; 2. Various types of documents should be easy to identify the text, type of systematic coding and date; 3. Documents using the language should be precise, easy to understand; 4. Fill in the data should be enough space; 5. Documentation should be clearly formulated, reviewed and approved by the responsibility for the signatures of the responsible person. Article 66 of the production process regulations, job operating law and standard operating procedures shall not be changed arbitrarily. If there is a need to change, the procedures should be revised and approved procedures in accordance with the development of the program. Article 67 Each batch of products should be checked according to the material balance of production and quantity. If there is a significant difference, the cause must be identified, and only after arriving at a reasonable explanation and confirming that there is no potential quality incident, can it be processed according to normal products. Article 68 The batch production records shall be in clear handwriting, true content, complete data, and signed by the operator and reviewer. Records should be kept neat and clean, shall not be torn and arbitrarily altered; change, sign at the change, and make the original data is still recognizable. Batch production records should be filed according to the batch number and kept until one year after the expiration date of the drugs. The batch production records of medicines without specified expiration date shall be kept for at least three years. Article 69 A certain number of medicines having the same nature and quality within the prescribed limits and produced in the same consecutive production cycle shall be a batch. Each batch of medicines shall be prepared with a production lot number. Article 70 in order to prevent contamination and confusion of drugs, production operations should take the following measures: 1. Before production should confirm that there is no remnants of the last production; 2. Dust should be prevented from generating and spreading; 3. Different product varieties, specifications of production operations shall not be carried out at the same time in the same production operations; there are a number of packaging lines at the same time for packaging, should be taken to isolate the or other effective prevention of contamination or confusion of the facilities; 4. Production Production process should prevent materials and products produced by the gas, steam, spray or organisms caused by cross-pollution; 5. Each production room or production equipment, containers should have the production of product or material name, batch number, quantity and other status symbols; 6. After picking herbs should be washed with flowing water, the water used shall not be used to wash other herbs. Herbs with different medicinal properties shall not be washed together. The washed herbs and the cut and shelled products should not be dried in the open air. The sterilization method of herbs and their intermediate products should be based on the principle of not changing the efficacy and quality of herbs. Powdered herbs directly into medicine should be microbiologically examined before dosing. Seventy-one according to the product process procedures for the selection of process water. Process water should meet the quality standards, and regular inspection, inspection is recorded. Should be based on the results of the verification, the inspection cycle. Article 72 of the product should be batch packaging records. The contents of the batch packaging records should include: 1. to be packaged product name, batch number, specifications; 2. printed with the batch number of labels and instructions and certificates of conformity of the product; 3. to be packaged products and packaging materials to receive the number of issuers and distributors, recipients, checkers signatures; 4. has been packaged the number of products; 5. the previous packaging operation of the clearing record (copy) and the packaging of clearing the record (original); 6. this After the completion of the packaging operation test check results, checker signature; 7. Signature of the person in charge of production operations. Article 73 After the completion of each production stage of each batch of drugs must be cleared by the production operator, fill in the clearance record. The contents of the clearance record include: process, product name, production batch number, date of clearance, check items and results, signature of the person in charge of the clearance and review. Clearance records should be included in the batch production records. Article 74 The quality management department of the pharmaceutical manufacturer shall be responsible for the quality management and inspection of the whole process of pharmaceutical production, under the direct leadership of the enterprise. Quality management department shall be equipped with a certain number of quality management and inspection personnel, and with the scale of drug production, varieties, inspection requirements of the premises, instruments and equipment. Article 75 The main responsibilities of the quality management department: 1. develop and revise materials, intermediate products and finished products of internal control standards and test procedures, develop sampling and sampling system; 2. develop the test equipment, instruments, reagents, reagents, test solutions, standards (or controls), titrant, media, laboratory animals and other management law; 3. decide the use of materials and intermediate products; 4. review the finished product before the release of batch production Records, the decision to issue finished products; 5. Review the handling procedures for nonconforming products; 6. Sampling of materials, intermediate products and finished products, inspection, retention of samples, and the issuance of inspection reports; 7. Monitoring of the clean room (area) of the number of dust particles and the number of microorganisms; 8. Evaluation of raw materials, intermediate products and finished products of the quality of the stability of the material, for the purpose of determining the storage period of the material, the expiration date of the drug to provide data; 9. Development of quality management and inspection personnel's Responsibilities. Article 76 The quality management department shall work with relevant departments to assess the quality system of major material suppliers. Article 77 Each batch of finished products should have sales records. According to the sales records can trace the sale of each batch of drugs, if necessary, should be able to recover all in a timely manner. Sales records should include: product name, dosage form, batch number, specifications, quantity, receiving unit and address, date of delivery. Article 78 sales records shall be kept until one year after the expiration date of the drugs. No expiration date of the drugs, its sales records should be kept for three years. Article 79 Drug manufacturers shall establish written procedures for the return and retrieval of drugs, and have records. The contents of the records on the return and retrieval of medicines shall include: name, lot number, specification, quantity, unit and address of the returned and retrieved medicines, reasons for the return and retrieval of the medicines and the date thereof, and opinions on the handling of the medicines. Pharmaceutical preparations returned and withdrawn for quality reasons shall be destroyed under the supervision of the quality management department, and shall be handled at the same time when other lot numbers are involved. Article 80 enterprises shall establish an adverse drug reaction monitoring and reporting system, and designate specialized agencies or personnel responsible for management. Article 81 of the user's drug quality complaints and adverse drug reactions should be recorded in detail and investigated. Adverse drug reactions should be promptly reported to the local drug supervision and management departments. Article 82 of the drug production of major quality problems, should be promptly reported to the local drug supervision and management departments. Article 83 drug manufacturers should regularly organize self-inspection. Self-inspection shall be carried out in accordance with predetermined procedures, personnel, plant, equipment, documents, production, quality control, sales of drugs, user complaints and the handling of product recalls and other items on a regular basis to confirm consistency with this specification. Article 84 Self-inspection should be recorded. Self-inspection should be formed after the completion of the self-inspection report, including the results of self-inspection, evaluation of the conclusions and improvement measures and recommendations. Article 85 of the specification of the following terms mean: material: raw materials, auxiliary materials, packaging materials, etc.. Batch number: used to identify the "batch" of a set of numbers or letters and numbers. Used to trace and review the production history of the batch of drugs. To be tested: the material in the allowed feeding or factory before the state of shelving, waiting for test results. Batch Production Record: All production records for a batch of product to be packaged or finished. Batch production records provide a history of the production of the batch, as well as quality-related conditions. Material Balance: A comparison between the theoretical production or usage of a product or material and the actual production or usage, with due regard to allowable normal deviations. Standard Operating Procedure (SOP): A generalized document or governing law approved to direct operations. Manufacturing Process Protocol: A document or set of documents that specifies the quantities of starting materials and packaging materials required to produce a certain number of finished products, as well as the process, processing instructions, precautions, including control during the production process. Process water: water used in the pharmaceutical production process, including: drinking water, purified water, water for injection. Purified water: distillation, ion exchange, reverse osmosis or other suitable methods for pharmaceutical water, does not contain any additives. Clean room (area): the need for dust particles and microbial content control room (area). Its building structure, equipment and its use have the function of reducing the intervention, generation and retention of sources of contamination in the area. Validation: A documented series of activities that demonstrates that any procedure, production process, equipment, material, activity or system actually achieves the desired result. Article 86 of different categories of drugs in the production of quality management of special requirements are included in the appendix to this specification. Article 87 of this specification by the State Drug Administration is responsible for interpretation. Article 88 of this specification since August 1, 1999 shall come into force.