Specification for the Quality Management of Pharmaceutical Manufacturing (2010 Revision)
Medical Oxygen Appendix
(Draft)
Chapter 1 Scope
Article 1 The medical oxygen referred to in this appendix refers to liquid oxygen and gaseous oxygen prepared from air by low temperature separation.
Article 2 This appendix applies to the industrialized production process of medical oxygen, excluding the production and disposal of medical oxygen within medical institutions.
Article 3 The requirements for the industrialized production of other medical gases are referred to this appendix.
Chapter II Principles
Article 4 The production and quality control of medical oxygen should be in accordance with the requirements of this appendix and relevant state regulations. The production process should avoid cross-contamination with other gases.
Chapter III Personnel
Article 5 The person in charge of the production management of the enterprise should have a college degree or above in chemical engineering, pharmacy, chemical analysis, machinery and other related disciplines or intermediate professional and technical titles, with more than 3 years of experience in the production and quality management of medical oxygen, of which at least one year of experience in the management of medical oxygen production.
Article VI The person in charge of quality management and quality authorized person of the enterprise shall have college degree or above or intermediate professional and technical title in pharmacy, chemical analysis, chemical industry and other related majors, and have more than 5 years of experience in the production and quality management of medical oxygen.
Article VII The personnel engaged in the production of medical oxygen shall be trained in the knowledge related to the specific operation of medical oxygen and obtain the qualification certificates of the relevant management departments in accordance with the relevant provisions of the state. Such as: quality and technical supervision departments issued by the cylinder filling qualification certificate, transportation and transport management departments issued by the dangerous goods escort certificate, safety supervision departments issued by the safety officer certificate and so on.
Article VIII color-blind patients shall not engage in the production of medical oxygen and quality inspection work.
Article IX Employees of medical oxygen enterprises shall be equipped with appropriate work clothes and safety protection articles according to production needs.
Chapter IV Plant and Equipment
Article X. The production environment of medical oxygen production enterprises shall be clean and tidy. The overall layout of production, administration, living and auxiliary areas shall be reasonable.
Article XI of the plant should be rationally arranged according to the requirements of medical oxygen production process. Cylinder filling area should be clearly marked, empty cylinders and different stages of product cylinders (such as to be filled, filled, to be inspected, qualified, unqualified) should be clearly labeled and placed separately, and can be differentiated by appropriate methods such as landmarks, partitions, fences and signage. Production area and storage area should be appropriate to the production scale of the area and space, and ventilation, lighting, fire prevention, explosion-proof, anti-static and other facilities.
Article XII medical oxygen filling production workshop should be kept clean, the ground is smooth, wear-resistant and non-slip, and set up a special locker room; filling production workshop should be separated from the maintenance workshop.
Article 13 The equipment used for production and analysis shall be confirmed and calibrated regularly.
Article XIV The production and testing equipment shall be regularly maintained and serviced; any repair and maintenance work of the production equipment shall not affect the quality of medical oxygen.
Article 15 The gas compression equipment in the process of medical oxygen production shall prohibit the use of fluorine plastic material piston seal compressor and water lubrication compressor.
Article XVI of the liquid oxygen gasification filling gaseous oxygen, must use low-temperature liquid oxygen pump, pressurized gasification filling.
Article XVII of the medical oxygen containers (tankers, storage tanks and cylinders) should be dedicated, and with other gas containers to distinguish the obvious signs.
Article XVIII of the medical oxygen filling should use special equipment, filling fixture should be anti-error device.
Chapter V Document Management
Article 19 Each batch of cylinder filling records shall include
(1) product name, specifications, batch number;
(2) the date and time of the filling operation;
(3) the use of the equipment and the number;
(4) the number of cylinders, cylinder inspection before filling;
(5) before and after filling cylinder checking;
(6) the number of cylinders and the time of the filling operation. (v) the number and specifications of cylinders before and after filling;
(vi) the signature of the operator of each step and, if necessary, the signature of the reviewer;
(vii) the relevant production operations or activities, process parameters and the scope of control;
(viii) the results of the quality inspection of the medical oxygen prior to filling;
(ix) the results of the examination and confirmation of the filled cylinders;
(x) Sample of package label;
(xi) Description and treatment of deviation in the production process with signature approval;
(xii) Confirmation signature and date of the person in charge of the filling.
Article 20 The air separation producer of medical oxygen shall have a document describing the purity of the gas, other components and possible impurity components of the gas source and purification process.
There shall be flow charts describing the individual process steps.
Key process parameters should be documented, such as temperature control for the separation and purification process.
Article 21 shall formulate the management system of gas cylinder scrapping, and establish the record of gas cylinder scrapping.
Chapter VI Production Management
Article 22 All key steps of the production process should be verified.
Article 23 The production of liquid oxygen shall follow the following principles:
(1) The separation and purification process shall be verified and daily monitored according to the process requirements. For the maintenance and replacement of consumable parts (such as purification filters), they shall be carried out according to the results of validation and monitoring.
(ii) The production process shall have continuous quality and impurity monitoring measures with monitoring records.
(c) computer systems used to control or monitor the process should be validated.
(d) continuous production process batch division should be documented, and sampling and testing by batch.
(E) liquid oxygen filling and transfer operations and other steps should be prevented from contamination measures, transfer lines should be equipped with check valves or other equivalent measures. Special attention should be paid to the connection of adapters and hoses.
(F) to add liquid oxygen to the liquid oxygen storage tank containing liquid oxygen, must prove that the quality of liquid oxygen added to meet the requirements. Sampling may be done before addition or after mixing.
Article 24 The filling and production process of medical oxygen shall conform to the following provisions:
(1) The production lot number shall be divided into batches of medical oxygen filled in the same continuous production cycle.
(ii) The cylinders shall comply with the relevant regulations and shall not be filled with cylinders other than their own.
(iii) Filling equipment and piping shall be cleaned and replaced in accordance with written protocols and checked and confirmed prior to use, especially after system maintenance or when system integrity has been compromised.
(d) The main factors affecting the quality of the product, such as handling and cleaning of cylinders prior to use, shall be verified, and appropriate operating procedures shall be established.
(e) the recovery of cylinders should be confirmed that the cylinder is the Company's medical oxygen cylinders.
(F) The inspection of cylinders before filling shall at least include the following steps:
1. The color markings on the outer surface of the cylinders are in line with the specified markings of medical oxygen;
2. Check the residual pressure (0.3-0.5Mpa) to confirm that the cylinders are not completely empty, and for the cylinders equipped with residual pressure retention valves, it is sufficient if the residual pressure is positive;
3. If the cylinder If the cylinder shows no residual pressure, it should be sorted out and tested to confirm that it is not contaminated with water or other contaminants; contaminated cylinders should be cleaned using a validated method;
4. Confirm that all batch labels and other labels on the cylinders have been removed;
5. Conduct a visual inspection of the exterior of each valve and cylinder, visually inspecting for dents, curved burns, debris, oils, and other damage.
6. Check each cylinder or cryogenic container valve fitting to ensure that it is suitable for medical oxygen filling;
7. Check the cylinder "inspection date" to confirm that the cylinder has been inspected in accordance with the relevant regulations and is within the validity period.
8. Confirm that the safety accessories of the gas cylinder are complete and meet the safety requirements.
(7) reuse of gas cylinders should be cleaned and disinfected before filling the bottle, and release all the bottom gas in the bottle, and then use the replacement method or vacuum method to qualified.
For cylinders equipped with residual pressure retention valve, as long as the residual pressure is positive, 15KPa evacuation is effective enough; as an alternative, you can also carry out a full inspection of the residual gas for each cylinder.
(viii) should be used to check the appropriate method to confirm that the cylinder has been filled. Because of the gas cylinder in the filling process temperature has a small increase, can be used to touch the outside of the cylinder to sense the temperature change confirmation.
(ix) after the filling of medical oxygen, each cylinder needs to be checked for leakage, and the bottle nozzle, bottle valve protection, the valve outlet should be affixed with a sealing label, and wear a bottle cap and anti-vibration ring.
(J) each cylinder should be affixed with a product label, the label should indicate: name, company name, production lot number, date of production, expiration date, the number of oxygen, pressure, and implementation standards.
Chapter VII Quality Control
Article 25 The producer of dispensed medical oxygen shall purchase liquid oxygen from the enterprise which has the medical oxygen production certificate, and do the full inspection before dispensing.
Article 26 The validity period of medical oxygen shall not exceed the validity period of the packaging container.
Article 27 The gas cylinder must be approved by the qualification of the unit for periodic inspection, qualified before use. Cylinders in the process of use, such as serious corrosion or serious damage, should be tested in advance.
Article 28 before the release of medical oxygen, must be in accordance with quality standards for full inspection, and in line with the "Chinese Pharmacopoeia" standards.
Article 29 The water used for hydrostatic pressure testing at least potable water and regularly monitor the level of microbial contamination.
Article 30 For cryogenic containers kept by customers, the filling company uses a special mobile tanker to fill medical oxygen on the spot, and if the filling company submits the test report of the samples taken from the mobile tanker, it is not necessary to take samples for testing after filling. Cryogenic containers kept by the customer shall be inspected periodically to confirm that the contents meet the requirements of the Chinese Pharmacopoeia.
Article 31 Unless otherwise specified, the product is not required to retain samples and conduct stability tests.
Chapter VIII Storage, Release and Sale
Article 32 The filled cylinders shall be fully inspected and qualified, and can be sold only after being reviewed and released by the quality authorized personnel.
Article 33 The gas cylinders shall be stored in the area which is covered and can avoid extreme temperature. The storage area shall be clean, dry, well ventilated and free of flammable substances to keep the cylinders clean until the use session.
Article 34 The medical oxygen shall be stored in a relatively independent area, and the area of empty cylinders and real cylinders shall be segregated, and can ensure the turnover in accordance with the principle of first-in-first-out.
Article 35 The cylinders shall be able to prevent the damage of adverse weather during transportation.
Article 36 The production, storage, transportation and sale of medical oxygen shall comply with the regulations of relevant state departments and obtain relevant documents. Such as: such as dangerous chemicals safety production license or dangerous chemicals safety operation license, dangerous chemicals transportation license, permanent cylinder filling license.
Article 37 The following terms mean:
Cryogenic container
A static or movable insulated container used to contain liquefied or cryogenic gases. The gas may be removed in a gaseous or liquid state.
Hydrostatic Pressure Test
A test performed in accordance with national or international guidelines to confirm that a gas cylinder or tank can withstand high pressure for safety reasons.
Valve
A device that opens or closes a container.
Residual Pressure Retention Valve (Minimum Pressure Retention Valve)
A valve that is equipped with a check system to prevent contamination during use, and that maintains a defined pressure (approximately 0.3 to 0.5 MPa above atmospheric pressure).
Check valves
Valves that allow only one-way flow.
Tanker
A container fixed to a vehicle to transport liquefied or cryogenic gases.
Annex 2
Code of Practice for the Quality Management of Pharmaceutical Manufacturing (Revised 2010)
Appendix on Chinese Medicinal Tablets
(Draft for Comment)
Chapter 1 Scope
Article 1 This appendix applies to the production, quality control, storage, issuance and transportation of Chinese medicinal tablets.
Article 2 Ethnic medicines refer to this appendix.
Chapter II Principles
Article 3 The quality of Chinese medicine tablets is closely related to the quality of Chinese herbal medicines and the concocting process, the quality of Chinese herbal medicines and the concocting process should be strictly controlled; in the process of concocting, storing and transporting, measures should be taken to control contamination, to prevent deterioration, and to avoid cross-pollution, confusion and errors; the production of Chinese medicine tablets for direct oral administration should be controlled by microorganisms.
Article 4 The base material of Chinese herbal medicines shall conform to the standard, and the origin shall be relatively stable.
Article 5 Chinese medicinal herbs must be prepared in accordance with the national pharmaceutical standards; if the national pharmaceutical standards are not stipulated, they must be prepared in accordance with the preparation specifications or standards formulated by the drug supervision and administration departments of the people's governments of the provinces, autonomous regions and municipalities directly under the central government; if the enterprises formulate their own production processes and quality standards, they shall be subject to the approval of the drug supervision and administration departments of the people's governments of the provinces, autonomous regions and municipalities directly under the central government.
Chapter III Personnel
Article 6 The person in charge of production and management of enterprises should have a college degree in medicine or intermediate professional and technical titles or licensed pharmacist qualifications, more than five years of production and management of traditional Chinese medicine tablets of practical experience, or more than secondary education in medicine, more than eight years of production and management of traditional Chinese medicine tablets of practical experience.
Article 7 The person in charge of quality management and the quality authorized person of an enterprise shall have college education or above in pharmaceutical majors or intermediate professional and technical title or licensed pharmacist qualification and more than five years of practical experience in the production or quality management of traditional Chinese medicine tablets, including at least one year of quality management experience.
Article 8 The key personnel of the enterprise as well as the personnel of quality assurance and quality control shall be the full-time working personnel of the enterprise.
Article 9 The quality assurance and quality control personnel shall have the practical ability to control the quality of Chinese herbal medicines and Chinese herbal medicinal tablets, and have the ability to identify the authenticity and superiority of Chinese herbal medicines and Chinese herbal medicinal tablets.
Article 10 The operators engaged in the preparation of Chinese herbal medicines shall have professional knowledge and practical skills in the preparation of Chinese herbal medicines; the operators engaged in the production of toxic Chinese herbal medicines and other special requirements shall have the relevant professional knowledge and skills, and be familiar with the relevant labor protection requirements.
Article 11 The personnel responsible for the procurement and acceptance of Chinese herbal medicines shall have the ability to identify the authenticity of Chinese herbal medicines.
Article XII of the conservation, warehousing and storage personnel should master the Chinese herbal medicines, Chinese medicine storage and maintenance of knowledge and skills.
Article XIII of the enterprise shall be responsible for training management, training content should include professional knowledge of Chinese medicine, job skills and knowledge of drug GMP-related regulations.
Article XIV of the personnel into the production area should be changed, wash their hands; into the clean area of the selection of materials, styles of work clothes and wear should be in line with the requirements of the General Rules; engaged in toxic and harmful to the human body, the operation of the personnel should be dressed according to the provisions of the protection of the special work clothes and other operators should be washed, organized, and to avoid cross-contamination.
Chapter IV Plant and Facilities
Article 15 The production area shall be strictly separated from the living area, shall not be located in the same building.
Article XVI of the plant and facilities should be rationally laid out according to the production process, and set up its production scale appropriate to the net system, cutting, shelling and other operations. Between the production operations in the same plant and the production operations between neighboring plants shall not interfere with each other.
Article XVII of the direct oral drinking tablets crushing, sieving, packaging and other production areas should be set up with reference to the requirements of Class D clean area, the enterprise shall be based on the product standards and characteristics of the region to take appropriate microbial monitoring measures.
Article 18 The processing and concocting of toxic Chinese herbal medicines shall use specialized facilities and equipment, and be strictly separated from other beverage production areas, and the waste produced shall be treated and meet the requirements.
Article 19 The internal surfaces of the plant floor, walls and ceiling shall be smooth, easy to clean, not easy to produce shedding material and not easy to breed mold; there shall be facilities to prevent the entry of insects, birds or rodents.
Article 20 of the Chinese herbal medicine net selection should be set up picking table, the surface of the table should be smooth, not easy to produce off material.
Article 21 In the process of Chinese herbal medicine tablets concocting process of producing heat and vapor, shall set up necessary ventilation, smoke removal, moisture removal, cooling and other facilities; picking, screening, cutting, crushing and other easy to produce dust process, shall take effective measures to control the spread of dust, avoid pollution and cross-contamination, such as the installation of dust-catching equipment, air exhaust facilities and so on.
Article 22 The warehouse should have enough space, the area and production scale. Chinese herbal medicines and Chinese medicine tablets should be stored in separate warehouses; toxic Chinese herbal medicines and tablets and other special requirements of Chinese herbal medicines and Chinese medicine tablets should be set up in special warehouses, and have the appropriate anti-theft and monitoring facilities.
Article 23 The warehouse shall be equipped with appropriate facilities, and take effective measures to monitor the temperature and humidity to ensure that the Chinese herbal medicines and Chinese medicinal herbs and tablets in accordance with the prescribed conditions of storage, cool storage temperature should be no higher than 25 degrees Celsius; the storage of easy to crosstalk, fresh and live Chinese herbal medicines should be appropriate special storage or refrigeration and other facilities.
Chapter V Equipment
Article 24 shall be based on the different characteristics of Chinese herbs, Chinese medicinal herbs and concoctions of the needs of the process, the choice of equipment to meet the requirements of the production process.
Article 25 The equipment, tools and containers that are in direct contact with the Chinese herbal medicines and Chinese medicine tablets shall be easy to clean and disinfect, and not easy to produce offsets, and shall not adversely affect the quality of the Chinese herbal medicines and Chinese medicine tablets.
Article 26 The water used for the production of Chinese medicine tablets shall be at least potable water, and the enterprises shall regularly monitor the quality of the water used for production, and the potable water shall be sent to the relevant testing departments for testing at least once a year.
Chapter VI Materials and Products
Article 27 The purchased materials shall be in accordance with the standards for medicines, packaging materials and other relevant standards, and the batch numbers shall be compiled and managed separately; the materials used shall not adversely affect the quality of Chinese medicine tablets.
Article 28 The quality management department shall assess the quality of the suppliers of production materials, and establish quality files; directly from the farmers to purchase Chinese herbal medicines should be collected from the farmers' identification materials, assess the quality of the purchased Chinese herbal medicines, and establish quality files; purchased from the place of origin while the fresh processing of Chinese herbal medicines, should be assessed for the quality of its processing.
Article 29 of each reception of Chinese herbal medicines should be classified according to the origin, supplier, harvesting time, herb specifications, etc., respectively, the preparation of batch number and management.
Article 30 The purchase of Chinese herbal medicines, each package should be clearly labeled, indicating the name, specifications, quantity, origin, harvesting, processing time and other information, toxicity of Chinese herbal medicines and other special requirements of Chinese herbal medicines should be clearly marked on the outer packaging.
Article 31 Chinese medicine tablets should be selected to ensure the quality of its storage and transportation during the packaging materials or containers. Packaging must be printed or labeled, indicating the name, specifications, origin, manufacturer, batch number, date of production, implementation standards, the implementation of the approval number management of Chinese medicine tablets must also indicate the approval number of the drug.
Article 32 The packaging materials in direct contact with the Chinese medicine tablets should be at least in line with the food packaging material standards.
Article 33 The Chinese herbal medicines, Chinese medicine tablets should be stored according to the quality requirements, maintenance, storage during the various maintenance operations should be established with a record; maintenance methods should be safe and effective, so as not to cause contamination and cross-contamination.
Article 34 The transportation of Chinese herbal medicines and Chinese medicinal herbs shall not affect their quality, and effective and reliable measures shall be taken to prevent the deterioration of Chinese herbal medicines and Chinese medicinal herbs.
Article 35 The imported medicinal materials shall have supporting documents approved by the State Drug Administration, as well as documents proving the import procedures in accordance with the relevant provisions.
Chapter VII Confirmation and Verification
Article 36 Enterprises shall carry out process verification according to varieties, and key process parameters shall be reflected in the process verification.
Article 37 The key production equipment and instruments shall be confirmed, and key equipment shall be cleaned and verified.
Article 38 After a certain cycle of production should be re-verification.
Article 39 The validation documents shall include the validation master plan, validation program, validation report and records to ensure the authenticity of validation.
Chapter VIII Document Management
Article 40 The quality management documents of Chinese herbal medicines and Chinese medicinal tablets shall at least contain the following contents:
(1) Formulation of the purchase, acceptance, storage and maintenance system of the materials, and formulation of the operation procedures for the maintenance of the Chinese herbal medicines and Chinese medicinal tablets in a categorized manner;
(2) Formulation of the production process protocols for each type of Chinese medicinal tablets, and the key process parameters must be clear. The key process parameters must be clear, such as: the amount of Chinese herbal medicines, the amount of auxiliary materials, infiltration time, slice type, frying temperature and time (fire), cooking pressure and time and other requirements;
(3) according to the quality of Chinese herbal medicines, the amount of ingredients, production process and other factors, to develop a range of limits of the rate of each type of Chinese herbal medicinal tablets, the key process should be formulated material balance parameters.
(D) the development of each type of Chinese herbal medicines, Chinese medicine and tablets of quality standards and the corresponding test procedures, the development of intermediate products, quality control indicators.
Article 41 The production, hygiene and quality control of the whole process from the production and packaging of Chinese medicinal tablets shall be recorded, and the batch records shall include at least the following:
(1) the names, batch numbers, feeding quantities, and feeding records of the Chinese herbal medicines, as well as of the auxiliary materials;
(2) the number of the equipment of the cutting and concocting process;
(3) the records of the pre-production Records of inspection and verification;
(iv) Production operation records of each process, including the actual technical parameters of each key process;
(v) Clearance records;
(vi) Records of inspection and audit records of key control points and process implementation;
(vii) Actual samples of product labels;
(viii) Yields of different processes, the necessary aspects of the Calculation of material balance;
(ix) records of special problems and unusual events, including deviation from the production process protocols and other deviations from the description and investigation, and signed and approved;
(x) Chinese herbal medicines, intermediate products, Chinese herbal medicines and tablets of the inspection records and audit release records.
Chapter IX Production Management
Article 42 The production of Chinese medicine tablets shall be organized in accordance with the varieties of process regulations.
Article 43 shall not be purchased intermediate products of Chinese medicine tablets or finished products for sub-packaging or change the packaging label.
Article 44 The purified Chinese herbal medicines and Chinese medicine tablets shall not directly touch the ground. The drying of Chinese herbal medicines and traditional Chinese medicine tablets shall have effective anti-pollution measures against insects and rain.
Article 45 The flow of drinking water shall be used to wash Chinese herbal medicines, and the used water shall not be used to wash other Chinese herbal medicines. Different Chinese herbal medicines shall not be washed and moistened in the same container at the same time.
Article 46 The production operation of toxic Chinese herbal medicines and toxic Chinese medicinal tablets shall have measures to prevent contamination and cross-contamination, and the whole process of preparation of Chinese herbal medicines shall be effectively monitored.
Article 47 Chinese medicine tablets shall take the date of feeding of Chinese herbal medicines as the date of production.
Article 48 The batch number of Chinese medicine tablets shall be a batch of a certain number of relatively homogeneous Chinese medicine tablets produced from the same batch of Chinese herbal medicines in the same consecutive production cycle.
Article 49 There shall be effective isolation measures for the simultaneous production of different varieties and specifications of Chinese medicine tablets in the same operation room.
Chapter X Quality Management
Article 50 Chinese herbal medicines and Chinese medicinal tablets shall be tested in accordance with the statutory standards; if the test results of Chinese herbal medicines and intermediate products are used for the quality evaluation of Chinese medicinal tablets, product quality standards for Chinese herbal medicines and intermediate products shall be formulated in line with the quality standards of Chinese medicinal tablets, and the quoted test results shall be indicated in the test report of Chinese medicinal tablets.
Article 51 Enterprises should be equipped with the necessary testing equipment, and the corresponding standard operating procedures and records of use; testing equipment should be able to meet the requirements of the actual production varieties, in addition to heavy metals and hazardous elements, pesticide residues, aflatoxin and other special test items and the use of less frequent use of large-scale instrumentation, in principle, is not allowed to commissioned tests.
Article 52 Each batch of Chinese herbal medicines and Chinese medicinal tablets should be retained. Chinese herbal medicines to stay at least meet the needs of identification, Chinese medicine tablets should be twice the amount of samples tested. Sample time should be specified, Chinese medicine tablets sample time for at least one year after the release.
Article 53 Enterprises should be set up in Chinese medicine specimen room (cabinet), specimen varieties include at least the production of Chinese herbal medicines or Chinese medicine tablets.
Article 54 The enterprise shall select the larger production and quality of unstable varieties of annual quality review analysis, other varieties should also be regularly review the analysis of product quality, review the analysis of the varieties should cover all the range of the enterprise's concoctions.
Chapter XI Terminology
Article 55 The meaning of the following terms:
(1) direct oral Chinese medicine tablets
refers to the standard explicitly used in the process of decoction is not required, can be taken directly by mouth or punch Chinese medicine tablets.
(B) the origin of freshly processed Chinese herbal medicines
The standard requires the origin of freshly cut Chinese herbal medicines for processing of Chinese herbal medicines.