(Amended in 1998)SDA Order #9
Chapter 1: General Provisions
Article 1: This Regulation is enacted in accordance with the "Drug Administration Law of The People's Republic of China".
Article 2: This Regulation is promulgated as the basic guideline for manufacturing and quality control of pharmaceutical products. This Regulation shall be applicable to all the manufacturing processes of drug preparations and to the key manufacturing processes of raw materials which may cause variation in the quality of finished products.
Chapter 2: Organization and Personnel
Article 3: A pharmaceutical enterprise shall establish production and quality control departments. The responsibilities of departments at all levels and personnel shall be clarified, and each department shall be staffed by an appropriate number of management and technical personnel with expert knowledge, manufacturing experience and organization ability.
Article 4: The enterprise personnel responsible for supervision of manufacture and quality control shall, at a minimum, have a bachelor's degree in medicine, pharmaceuticals, or related sciences, and have appropriate experience in drug manufacturing and quality control. They shall be responsible for the implementation of the GMP regulations and the quality of products.
Article 5: The responsible person of the manufacture and quality control departments shall, at a minimum, have a college degree of medicine, pharmaceuticals or related sciences, have actual management experience in production and quality control, and have the ability to correctly decide and handle practical problems in production and quality control.
The managers of production and quality control departments shall be independent of each other.
Article 6: All personnel engaged in drug manufacture and quality control shall have been professionally and technically trained so as to acquire the basic theory and practical technical skills.
Personnel engaged in the production and quality control of products with high organic activity, high toxicity, strong contamination, high sensitivity and other substances with special requirements shall have received corresponding professional technical training.
Article 7: Personnel at all levels who are engaged in drug manufacturing shall be trained and pass examinations in accordance with the requirements of this Regulation.
Chapter 3: Building and Facilities
Article 8: A pharmaceutical enterprise shall be located in a clean environment. The surface of the ground and roads and transportation of the plant area shall not be a source of contamination of drug products. The general lay-out of the production, administration, living and ancillary areas shall be appropriately arranged and not interfere with each other.
Article 9: Buildings shall be appropriately located in accordance with the technological process and requisite cleanness levels. The manufacturing operations undertaken in the same and nearby areas shall not interfere with each other.
Article 10: Buildings shall have the facilities to protect against the entrance of vermin and other animals.
Article 11: The ease and convenience to conduct cleaning shall be considered in the design and construction of buildings. The interior surfaces of the clean room (area) shall be smooth, without cracks, with airtight junction points. The interior surfaces shall not shed any particulate granules and shall withstand washing and disinfecting. The joints between walls and floors are preferably constructed with round corners or by other means so as to reduce the collection of dust and for ease of cleaning.
Article 12: In production and storage areas, there shall be adequate floor and air space for the orderly placement of equipment and materials so as to facilitate production, operations, storage of materials, in-process products, finished products and those under quarantine, and to the greatest degree possible minimize errors and cross-contamination.
Article 13: The various pipes, light fixtures, ventilation points and other public facilities in the clean room (area) shall be designed and installed so as to avoid areas being difficult to clean.
Article 14: The clean room (area) shall be provided with sufficient lighting according to the production requirements. Illumination for main production rooms shall be 300 Lux. For production areas with special requirements, appropriate lighting shall be installed. Emergency lighting shall be provided in the facilities.
Article 15: Air supplied into the clean room (area) must be purified and the clean level of the area shall be classified in accordance with the requirements of the production process. The number of microorganisms and particulates in the air of the clean room (area) shall be tested periodically and the results shall be filed.
Article 16: The windows, ceilings, entering pipes, ventilation, light fixtures and joints between walls and ceilings in clean room (area) shall be airtight. The static pressure difference between areas of different cleanliness class shall be maintained more than 5 Pa, the static pressure difference between clean rooms (area) and the atmosphere outside shall be maintained at more than 10 Pa and devices for indicating pressure difference shall be installed.
Article 17: The temperature and relative humidity in the clean rooms (areas) shall comply with the requirements of the production process. When there are no special requirements, the temperature and relative humidity may be controlled at 18-26íŠ and 45-65%, respectively.
Article 18: Sinks and drains in clean rooms (areas) shall be installed so that drugs will not be contaminated.
Article 19: Measures shall be taken to protect against cross contamination of personnel and materials entering or leaving clean rooms (areas) of different cleanliness class.
Article 20: Separates buildings and facilities must be used in the production of highly sensitive drugs, such as penicillin. In filling rooms of these drugs a negative pressure shall be maintained relative to other rooms. Before being discharged outside the room, the used steam (or air) shall be cleaned so as to comply with the requirements. The opening for the discharge of used steam shall be far away from the air intake or other air cleaning systems. Drugs with the structure of B-lactam must have specialized equipment and a separate air cleaning system and the production area must be strictly separated from other production areas.
Article 21: Buildings for production of contraceptives shall be separated from those of other drugs. An independent dedicated air cleaning system shall be installed. Chemical drugs such as hormones and anti-tumor pharmaceuticals shall not use the same equipment or air-cleaning system with other drugs; however, if such use cannot be avoided, effective precautions must be taken and necessary validations obtained.
Dedicated and safe equipment shall be used in the processing, packaging and storage of radioactive drugs. Air discharged from the production area shall not be circulated for use. Discharged air shall not contain radio active particles and the requirements and regulations regarding radiation protection shall be complied with.
Article 22: The processing or filling of: bacterial and viral strains used for production or non-production, cells used for production or non-production, wild and attenuated strains, dead and live strains, pre-detoxified and post-detoxified products, live or inactivated vaccines, human blood products and preventive products; shall not be conducted in the same building, and their storage shall be strictly separated from each other. Treatment and filling of different types of live vaccines shall be separated from each other. The production area for wild microorganisms and spore-forming microorganisms preparations shall be under negative pressure relative to neighboring areas and shall have an independent air cleaning system.
Article 23: The pretreatment, extraction, concentration (evaporation) of TCM and the washing and treatment areas of animal organs and tissues shall be strictly separated from the production areas of other preparations.
The steaming, stir-frying, roasting and baking processes for preparing Chinese crude drugs shall be carried out in areas equipped with ventilation, de-fuming, dust extraction, and cooling facilities. The process of selection, slicing, and mashing shall be carried out in areas equipped with effective dust-catching and ventilation facilities.
Article 24: The buildings shall be provided with dust protection devices and dust-catching devices if necessary.
Article 25: Air directly in contact with products which has been dried, compressed or made inert shall be cleaned and shall comply with the requirements of production.
Article 26: Storage areas shall be kept clean and dry. The facilities of lighting, ventilation, etc. as well as temperature control and humidity shall comply with the storage requirements and shall be periodically tested.
Storage areas may be equipped with sampling room(s) for raw materials provided the air cleanliness class is the same as that of production requirements. If sampling is not conducted in a sampling room, measures to prevent contamination and cross-contamination shall be adopted.
Article 27: In accordance with requirements of the production process, the air cleanliness class of the weighing room and material preparation (to get material ready for production) room in the clean room (area) shall be the same as the production requirements and shall be provided with facilities to catch dust and to protect against cross contamination.
Article 28: Rooms for testing, Chinese crude drug specimens, sample retention and other similar laboratories as determined by the quality control department shall be separated from the production area. Areas for biological, micro-biological, or radioactive isotope tests shall be separated from each other.
Article 29: Instruments and meters with special requirements shall be placed in a dedicated instrument room and facilities to protect against static electricity, vibration, humidity or other external factors shall be provided.
Article 30: Any animal experiment house shall be strictly separated from other areas and its design and construction shall comply with relevant national regulations.
Chapter 4: Equipment
Article 31: The design, selection and installation of equipment shall comply with the production requirements and the equipment shall be easy to clean, disinfect or sterilize, convenient to operate and maintain and be able to prevent errors and minimize contamination.
Article 32: The surface of equipment which comes into direct contact with drugs shall be smooth and even, easy to clean and disinfect and be corrosion resistant. The lubricants or coolant of the equipment shall not contaminate the products or their containers.
Article 33: The main fixed pipelines connected to equipment shall be marked with the name of material inside the pipe and flow direction.
Article 34: The preparation, storage and distribution of purified water and water for injection shall be protected from microorganism breeding and contamination. Storage tanks and delivery pipelines shall be made from non-toxic and corrosion-resistant materials. Inaccessible places and dead spots shall be avoided in design and installation of pipelines. Storage tanks and pipelines shall be cleaned periodically. Vents of tanks of water for injection shall be protected by a non-fiber-releasing hydrophobic microbial air filter. Water for injection shall be stored at 80íŠ minimum, or at 4íŠ maximum or maintained in constant circulation at 65íŠ minimum.
Article 35: Each instrument, meter, weighing and measuring device used for production and testing shall have a range of operation and precision meeting production and testing requirements and shall be clearly labeled as certified and be calibrated periodically.
Article 36: Equipment for production shall have its condition clearly marked and shall be periodically maintained and validated. It's installation, maintenance and repair shall not affect product quality. Non-conforming equipment shall be moved from the production area, if possible, and shall be clearly marked before moving.
Article 37: The equipment for production and testing shall have records of use, maintenance and repair and these records shall be kept by a designated person.
Chapter 5: Materials
Article 38: Written procedures for purchase, storage, dispatching, use, etc. of materials for production shall be established.
Article 39: Materials for drug production shall comply with drug specifications, package material specifications, biological product processes or other relevant standards, and shall not have any adverse influence on drug quality. An imported bulk chemical shall have a certificate issued by the coastal institute for drug control.
Article 40: All Chinese crude drugs for drug production shall be purchased in accordance with quality standards and the production site shall be kept stable.
Article 41: All materials used for drug production shall be purchased from units complying with the national regulations and, in entering the factory, shall be placed in storage according to the regulations.
Article 42: Materials whether quarantined, qualified or unqualified shall be strictly controlled. The unqualified materials shall be stored in special areas clearly marked which are easy to recognize and be duly handled according to regulations.
Article 43: Materials, semi-finished or finished products which have special in temperature, humidity or other requirements, shall be stored in accordance with regulations. Solid and liquid materials shall be separately stored. Volatile materials shall be stored so as to avoid contaminating other materials. Prepared, selected, and pretreated Chinese crude drugs shall be packed in clean containers or packages and strictly separated from unprocessed and processed Chinese crude drugs.
Article 44: The acceptance, storage and keeping of narcotics, psychotropics, toxic drugs (including crude drugs), radioactive drugs, flammable and explosive materials and other dangerous substances shall strictly comply with relevant national regulations. The acceptance, storage, keeping, usage and destroying of bacterial and viral strains shall comply with the national regulations on storage and keeping of medical microorganism strains.
Article 45: Materials shall be stored within the period of validity. For those without a regulated expiration date, the storage period generally shall not be more than 3 years and upon expiration shall be retested. In special cases, the retest shall be conducted immediately during storage.
Article 46: Drug labels and insert sheets (direction for use) shall be consistent with those approved by drug regulatory authorities in content, style and written language. Labels and insert sheets cannot be printed, dispatched and used until they are checked by the quality control department of the enterprise.
Article 47: Drug labels and insert sheets shall be kept and drawn by designated persons, and shall meet the following requirements:
1. Labels and insert sheets shall be placed in a dedicated cabinet or dedicated storehouse according to varieties and specifications. They are to be distributed in accordance with batch package instruction and drawn in according to the practical need;
2. The labels shall be counted as distributed, and the designated person shall check and sign. The sum of the distributed, damaged and remaining labels shall be reconciled. The damaged and remaining labels with batch number shall be counted and destroyed by the designated person(s);
3. The dispatching, usage and destruction of labels shall be recorded.
Chapter 6: Hygiene and Sanitation
Article 48: Drug manufacturing enterprises shall adopt hygiene and sanitation measures to prevent contamination and establish hygiene and sanitation system for which a designated person shall be responsible.
Article 49: Cleaning procedures of building, equipment, containers, etc. shall be established for the production plant, work rules and job classifications in accordance with production requirements and cleanliness classes. The content includes cleaning methods, cleaning process, cleaning interval, detergents or disinfectants used, cleaning method for cleaning tools and place for their storage.
Article 50: Non-production articles and materials and personal items shall not be placed in production area. Production discharges shall be duly handled.
Article 51: The dressing rooms, bath rooms and toilets shall not have any adverse influence on the clean rooms (areas).
Article 52: The material, style and way of wearing of protective garments shall be appropriate to the requirements of operation and cleanliness class and shall not be otherwise used.
The garments used in clean areas shall be smooth, free from static electricity, and not shed fibers and particulates. The aseptic garments shall be able to cover completely hair, beard and feet and prevent body materials from being left.
The garments used for production of different cleanliness classes shall be cleaned and arranged separately and disinfected or sterilized if necessary. Granules shall not be added into garments when being washed and sterilized. The cleaning frequency of garments shall be fixed.
Article 53: The entrance to clean rooms (areas) shall be limited only to the operators working in the area and other authorized personnel.
Article 54: Personnel entering into clean rooms (areas) are not allowed to put on any cosmetics, wear any ornaments and touch drug products with bare hands.
Article 55: Clean rooms (areas) shall be periodically disinfected. The disinfectants used shall not cause any contamination on equipment, material and finished products. The different varieties of disinfectants shall be used alternatively so as to prevent the development of resistant strains of microorganisms.
Article 56: Health files shall be established and kept for personnel engaged in production. As to those who have direct contact with drug products, a physical examination shall be conducted at least once a year. No person with an infectious disease, skin disease or wound on an exposed surface of the body shall be engaged in the production which comes into direct contact with the drug.
Chapter 7: Validation
Article 57: The validation of drug production refers to: installation qualification of building and facilities (IQ), operational qualification (OQ), performance qualification (PQ) and product validation (PV).
Article 58: The validation of production process and key facilities and equipment shall be conducted according to a protocol. Re-validation shall be conducted at defined intervals or after any significant modifications that may affect the product quality, e.g. manufacturing process, quality control method, important raw material and excipient, or equipment, etc.
Article 59: The items to be validated, validation protocol and its implementation shall be made on the basis of the validation objectives. A validation report shall be written after validation is finished, which shall be reviewed and approved by the responsible person.
Article 60: The data and content of analysis obtained in the validation process shall be recorded and filed. The files should include validation protocol, validation report, evaluation and suggestions, approval person, etc.
Chapter 8 Documentation
Article 61: Drug manufacturing enterprises shall have the following management documents and records for production and quality control:
1. written procedures and records for use, maintenance and repair of buildings, facilities and equipment;
2. written procedures and records for material checking and acceptance, production operation, testing, material dispatching, releasing, finished product distribution and consumer complaints, etc;
3. written procedures and records for control of unqualified materials and products, return of goods to the warehouse, disposal reports, and handling of emergencies, etc.
4. written procedures and records for hygiene and sanitation of the environment, building, equipment and personnel, etc, and
5. written procedures and records for GMP and professional technical training.
Article 62: Production control documents mainly include:
1. Master formula, job position instructions or standard operating procedures. Master formula includes: drug name, dosage form, formula, the operational requirements of process, quality standards of materials, in-process product and finished product, technical parameter as well as storage precautions, reconciliation of materials, requirements of packaging materials and container for finished products.
Job position instructions include: production operation methods and key points, checking and review of critical operations, specification and its control of in-process products, safety and labor protection, maintenance and cleaning of equipment, treatment and report of abnormal situation, process and environmental sanitation, etc.
Standard operating procedure includes: title, numbering code, writer, date of establishing, reviewer and reviewing date, approval person and approving date, issuing department, date of effect, receiving and distributing departments, heading and text.
2. Batch production records
Batch production records include: product name, batch number, production date, signature of operator and checker, a description of related operations and equipment, quantity in relevant production stages, reconciliation of material, process control records as well as records of special problems.
Article 63: The product quality control documents mainly include:
1. all application and approval documents of the drug;
2. specification of materials, in-process products and the finished product and their test procedures;
3. stability testing records of the product; and,
4. batch test records.
Article 64: Written procedures for drafting, revising, reviewing, approving, withdrawing, distributing and retaining of documents shall be established in drug manufacturing enterprises. Only the approved current documents may be distributed and used. Withdrawn and out-of-dates documents shall not be present at work site, except those maintained in archives for reference purposes.
Article 65: The requirements for establishing production and quality control documents are as follows:
1. the title shall clearly describe the nature of the document;
2. the documents shall have a numbering code system as well as date to identify their version and category ;
3. the language used in documents shall be exact and understandable;
4. the documents shall have a sufficient space to fill in the data;
5. the responsibility for drafting, reviewing and approving documents shall be clearly defined, and there shall be the signature of the responsible person on documents.
Chapter 9: Production Management
Article 66: Master formula, post instruction or standard operating procedures shall not be changed arbitrarily. If there is a necessity to revise, the amendment to such documents shall be reviewed and approved in accordance with the same procedures as in the preparation of the original documents.
Article 67: Checks on yields and reconciliation of quantities should be carried out for each batch. If there is a significant difference, the cause shall be identified and products shall not be treated as normal products unless the cause is rationally explained and no potential quality risk is confirmed.
Article 68: The batch production record shall be completed in a timely manner, written clearly, truthful in content and complete in data and shall be signed by both the operator and checker. The records shall be kept clean and tidy, and shall not be destroyed and changed arbitrarily. When there is a revision, the reading of the original information shall be permitted and the person making the revision shall sign his name at the place of the revision.
Batch production records shall be filed with batch number and kept one year after the expiration date of the product. The production records of the drugs without expiration date shall be kept at least for three years.
Article 69: A defined quantity of drug product with identical properties and quality within a specified limit, produced continuously in a same production cycle is called a batch. A batch number shall be assigned to each batch of product.
Article 70: The production operations shall adopt the following measures to prevent drugs from contamination and mix-ups:
1. confirm before production that there are no residues from the previous batch;
2. prevent the generation and spreading of particulates;
3. products of different varieties and specifications shall not be produced in the same room at the same time. When several package lines are in operation at the same time, segregation or other measures shall be adopted to prevent contamination or mix-up;
4. during production, the cross-contamination caused by gas, vapor, spraying substances or biological bodies generated from materials and products shall be prevented;
5. each production room, equipment and container shall be labeled with the name of product or material, batch number and quantity, etc.
6. circulating water is required for the washing of selected crude drugs, recovered water is not allowed to be used for washing of other crude drugs. Crude drugs of different properties may not be washed together. Outdoor drying is not appropriate for washed, sliced, and processed crude drugs.
The sterilization of crude drugs and in-process products shall not change their effect and quality. A micro-biological test shall be conducted before directly injecting drugs with crude drug powder and preparation materials.
Article 71: Processing water shall be selected in accordance with the master formula which shall comply with quality specifications, be tested and recorded periodically. The test interval shall be defined in accordance with validation results.
Article 72: A batch package record shall be provided for each batch of products. The record shall include:
1. the name, batch number and specification of the bulk product;
2. label with batch number, insert sheet as well as product quality certificate;
3. the received quantities of bulk product and package materials, signatures of the dispatcher, the receiver and the checker;
4. the quantities of packaged product;
5. line-clean record of previous packaging batch (duplicate original) and the record of this batch (original);
6. the post completion inspection and checking results of this packaged batch and signature of the checker;
7. the signature of the person responsible for the production operation.
Article 73: Line-clean must be conducted and recorded by operators after completion of each production stage. The record shall include section (stage), name of the product, production batch, line-clean date, items of examination and their results, signatures of the person performing the line-clean and the checker. The line-clean records shall be included in the batch record.
Chapter 10: Quality Management
Article 74: The quality control department of drug manufacturing enterprises shall be responsible for the quality management and testing of the whole process of drug production and shall be directly led by the enterprise leaders. Quality control department shall be staffed by an adequate number of quality management and testing personnel and shall be provided with the space, facilities, instruments and equipment adapted to the requirements of production scale of the drug, product variety and tests.
Article 75: The main responsibilities of quality control department are as follows:
1. to establish and revise in house specification and analytical operational procedure of materials, in-process and finished products, and to establish sampling and sample retention procedures;
2. to establish the procedures for controlling testing equipment, instrument, reagent, testing solution, standard substance (or reference substance), titration solution, culture medium, experiment animals, etc;
3. to decide the use of material and in-process products;
4. to review the batch production record before releasing a finished product and to decide the release of a finished product;
5. to review the treatment procedure of rejected products;
6. to sample, test, retain samples and issue analytical reports for materials, in-process and finished products;
7. to monitor the number of particulates and microorganisms in the clean room (area);
8. to evaluate the stability of raw material, in-process and finished product and to provide data for determining the storage period of materials and expiration date of a drug; and,
9. to establish the responsibilities of the people engaged in quality management and quality test.
Article 76: The quality control department together with other related departments shall audit the quality system of suppliers of main materials.
Chapter 11: Product Distribution and Recall
Article 77: Distribution records shall be available for every batch of finished product. The marketing of each batch of drugs shall be traced according to the distribution record and, if necessary, the batch shall be duly recalled. The distribution record shall include: drug name; dosage form, batch number, specifications; quantity, unit receiving goods and its address and dates of distribution.
Article 78: Distribution records shall be kept for one year after expiration date of the product. The records of the drugs with no expiration date shall be kept for five years.
Article 79: A drug manufacturing enterprise shall establish the written procedures and records of drug return and recall. Drug return and recall record shall include: drug name, batch number, specifications, quantity, units from whom the product is returned or recalled and their address, the reason and date of return and recall and suggestions of treatment.
If drug preparations are returned or recalled for quality problems, then, under the supervision of quality control department, the drugs shall be destroyed. If other batches are affected, they should also be handled at the same time.
Chapter 12: Complaints and Adverse Reactions Report
Article 80: A drug manufacturing enterprise shall establish a reporting system for supervising drug adverse reactions. The designated technical organization or personnel shall be responsible for the management of the system.
Article 81: Any complaints on drug quality from the consumer and drug adverse reactions shall be recorded in detail and treated based on thorough investigation. Drug adverse reactions shall be duly reported to the local drug administration authorities.
Article 82: A report shall be provided to local drug regulatory authorities whenever any serious problems in drug production occur.
Chapter 13: Self-Inspection
Article 83: Self inspection shall be periodically conducted by drug manufacturing enterprises. Self inspection shall be the periodical inspection of personnel, buildings, equipment, documents, production, quality control, drug distribution, consumer's complaint and the treatment of product recall in accordance with the predetermined procedure so as to confirm consistency with GMP.
Article 84: Self inspection reports shall be kept. The report shall be written after the completion of self-inspection, and it shall include the results of self-inspection, conclusions of evaluation as well as improvement measures and suggestions.
Chapter 14: Miscellaneous
Article 85: The terms used in this Regulation are defined as follows:
1. Materials: raw materials, excipient, packaging materials, etc;
2. Batch number: A distinctive combination of numbers and/or letters by which one is able to trace and review the manufacturing history of the batch of the drugs;
3. Quarantine: The status of material, in-process and finished products being held and waiting for evaluation result.
4. Batch production record: All documents associated with the manufacture of a batch of bulk product or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product.
5. Reconciliation : A comparison, making due allowance for normal variation, between the amount of product or materials theoretically produced or used and the amount actually produced or used.
6. Standard Operation Procedure (SOP): An authorized documented procedure giving instructions for performing operations of a general nature or describing management methods.
7. Master Formula: A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls.
8. Water for processing: Water used in the production process of drugs, including drinking water, purified water, water for injection;
9. Purified water: Water for pharmaceutical use obtained by methods of distillation, ion exchange, reverse osmosis, or other proper methods, without any additional agents;
10. Clean Room (Area): An room (area) with defined environmental control of particulates and microbilogical contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.
11. Validation: The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.
Article 86: The special requirements on production quality management for various categories of drugs are included in the Appendix of this Regulation.
Article 87: The State Drug Administration of P.R.China is responsible for interpretation of this Regulation.
Article 88: This Regulation shall be effective from August 1, 1999.