Good Manufacturing Practice for Drugs (2010 Revision) (from government website)

Good Manufacturing Practice for Drugs (2010 Revision)

Order of the Ministry of Health No.79

January 17, 2011

The Good Manufacturing Practice for Drugs (2010 Revision), adopted at the executive meeting of the Ministry of Health on October 19, 2010, is hereby promulgated and shall go into effect as of March 1, 2011.

Minister Chen Zhu

Chapter I General Provisions

Article 1 These provisions of Good Manufacturing Practice (GMP) for Drugs, in accordance with the Drug Administration Law of the People's Republic of China and the Regulations for Implementation of the Drug Administration Law of the People's Republic of China, are enacted to regulate the manufacturing and quality management of Drugs.

Article 2 The manufacturer should establish a quality management system. The system should cover all factors that influence the quality of drugs, including all organized and planned activities with the objective of ensuring that the drugs are of the quality required for their intended use.

Article 3 GMP, as part of the quality management system, is the basic requirement of production and quality control of drugs, to ensure the products are consistently manufactured in accordance with the registration requirements, and are suitable for their intended use, by minimizing the risks of contamination, cross-contamination and mixups or errors in manufacturing process.

Article 4 The manufacturer should strictly implement GMP with integrity. Any falsification and fraud is forbidden.

Chapter II Quality Management

Section 1 Principle

Article 5 The manufacturer should establish a quality objective to meet quality management requirements so that all registration requirements related to drug safety, efficacy and quality are systematically implemented throughout the entire process of production, control, product release, storage and distribution, to ensure that the products are manufactured in accordance with the registration requirements, and are suitable for their intended use.

Article 6 The attainment of the quality objective is the responsibility of senior management and requires the participation and commitment by staff at all levels within the manufacturer, by the manufacturer's suppliers and by the distributors.

Article 7 The manufacturer should be adequately resourced with competent personnel, suitable and sufficient premises, equipment and facilities for achieving its quality objective.

Section 2 Quality Assurance

Article 8 Quality Assurance is a part of the quality management system. The manufacturer should establish the Quality Assurance system with the support of a complete documentation system to ensure its effective operation.

Article 9 The system of Quality Assurance should ensure that:
1. Drugs are designed and developed in a way that takes account of the requirements of GMP.
2. Production and quality control operations are in compliance with GMP.
3. Managerial responsibilities are clearly specified.
4. Arrangements are made for the purchase and use of the correct starting and packaging materials.
5. All necessary controls on intermediate products are effectively carried out.
6. Qualifications and validations are carried out.
7. Drugs are correctly processed, checked, tested, and verified, according to the defined procedures.
8. Each batch of products is not released before the approval of the Qualified Person.
9. Satisfactory arrangements exist to ensure that the drugs are stored, distributed and subsequently handled.
10. Self-inspection is regularly carried out to appraise the effectiveness and applicability of the Quality Assurance system, according to the procedures.

Article 10 The basic requirements of production and quality control are that:
1. All manufacturing processes are clearly defined, systematically reviewed and shown to be capable of consistently manufacturing drugs of the required quality and complying with their specifications.
2. Steps of manufacturing processes and significant changes to the process are validated.
3. All necessary resources are provided including:
(1) Appropriately qualified and trained personnel;
(2) Adequate premises and space;
(3) Suitable equipment and services;
(4) Correct starting materials, packaging materials and labels;
(5) Approved master manufacturing documents and operation procedures;
(6) Suitable storage and transport.
4. Instructions and procedures are written in clear and unambiguous language.
5. Operators are trained to carry out procedures correctly.
6. Records should be made during the entire manufacture and any deviations are investigated and recorded accordingly.
7. Records of manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form.
8. The distribution of the products minimizes any risk to their quality.
9. A system is available to recall any batch of product, from sale or supply.
10. Complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent reoccurrence.

Section 3 Quality Control

Article 11 Quality Control is concerned with organization and documentation, and with sampling, testing and etc., which ensure that the necessary tests are actually carried out and that materials or products are not released, until their quality has been judged to be satisfactory.

Article 12 The basic requirements of Quality Control are that:
1. Adequate facilities, equipment, instruments and trained personnel are resourced, to ensure the related quality control activities are done effectively and reliably.
2. Approved procedures are available for sampling, inspection and testing starting materials, packaging materials, intermediate, bulk, and finished products, and stability study, and where appropriate for monitoring environmental conditions, to ensure the compliance with GMP.
3. Samples of starting materials, packaging materials, intermediate, bulk and finished products are taken by authorized personnel with approved methods.
4. Testing methods are validated or verified.
5. Records are made for sampling, inspecting and testing. Any deviations are investigated and recorded.
6. Records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification.
7. Sufficient reference samples of starting materials and finished products are retained to permit future inspection and testing of the product when necessary, and that the finished product is retained in its final package unless exceptionally large packages are produced.

Section 4 Quality Risk Management

Article 13 Quality risk management is a systematic process for the assessment, control, communication and review of the risk to quality throughout the entire product life cycle. It can be applied both proactively and retrospectively.

Article 14 The evaluation of the risk to quality is based on scientific knowledge and experience, to ensure the quality of products.

Article 15 The level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk.

Chapter III Organization and Personnel

Section 1 Principle

Article 16 The manufacturer should establish a management structure and have an organization chart. The quality management department should be independent from other departments to carry out responsibilities of Quality Assurance and Quality Control. The quality management department can be structured into the quality assurance department and the quality control department separately.

Article 17 The quality management department should participate in all quality related activities, and review all GMP related documents. The responsibilities of quality management personnel are not permitted to be delegated to personnel of other departments.

Article 18 The manufacturer should have an adequate number of managerial and operating personnel with appropriate qualifications (with respect to, including education, training, and practical experience). The responsibilities of each department and each position should be clearly specified. There should be no gaps or unexplained overlaps in the responsibilities. The responsibilities placed on any one individual should not be extensive.
All personnel should be fully aware of and understand their responsibilities, be familiar with related requirements, and receive necessary training, including initial training and continuing training.

Article 19 Duties normally should not be delegated to other personnel. If deemed necessary, the duties can only be delegated to designated deputies of a satisfactory qualification level.

Section 2 Key Personnel

Article 20 Key posts should be occupied by full-time personnel, which should at least include the heads of the manufacturer, production management, quality management, and the Qualified Person.
The heads of production and quality management must be independent from each other. The head of the quality management and the Qualified Person can be the same person. Procedures should be established to ensure the independence of the Qualified Person for fulfilling responsibilities, without interference from the head of the manufacturer or other personnel.

Article 21 The head of the manufacturer
The head of the manufacturer is principally liable for product quality and routine operation. In order to achieve the manufacturer's quality objective and compliance with GMP, the head of the manufacturer should provide necessary resources, make appropriate plan, organization and coordination, and ensure that the quality management department can fulfill its responsibilities independently.

Article 22 The head of production management
1. Qualification: The head of production management should, at a minimum, possess a college degree in pharmaceutical or relevant specialties (or with an intermediate professional technique certificate or a pharmacist's license), with at least three years of practical experience in pharmaceutical production and quality management, among which at least one year in production management, with necessary training relating to the products being manufactured.
2. Main responsibilities:
(1) To ensure that products are produced and stored according to approved master manufacturing documents in order to obtain the required quality;
(2) To ensure strict implementation of the procedures relating to production operations;
(3) To ensure that the batch records of processing and packaging are evaluated and signed by a designated person before they are sent to the quality management department;
(4) To ensure that the premises and equipment are maintained and serviced to function in a sound operating state;
(5) To ensure that the necessary validations are done;
(6) To ensure that required initial and continuing training of personnel in production is carried out and adapted according to need.

Article 23 The head of quality management
1. Qualification: The head of the quality management should, at a minimum, possess a college degree in pharmaceutical or relevant specialties (or with an intermediate professional technique certificate or a pharmacist's license), with at least five years of practical experience in pharmaceutical production and quality management, among which at least one year in quality management, with necessary training relating to the products being manufactured.
2. Main responsibilities:
(1) To ensure that all starting materials, packaging materials, intermediate, bulk and finished products meet the registration requirements and specifications;
(2) To ensure that the batch records are reviewed before product release;
(3) To ensure that all necessary testing is carried out;
(4) To approve specifications, sampling instructions, testing methods and other quality management procedures;
(5) To review and approve all quality related changes;
(6) To ensure all significant deviations and out-of-specification results are timely investigated and handled;
(7) To approve and monitor any contract analysis;
(8) To check the maintenance of premises and equipment for the purpose of maintaining a sound operating state;
(9) To ensure the necessary qualifications or validations are done appropriately, and to review and approve validation protocols and reports;
(10) To ensure self-inspection is done;
(11) To assess and approve material suppliers;
(12) To ensure all quality related complaints are timely and properly investigated and handled;
(13) To ensure the implementation of on-going stability study and make the stability data available;
(14) To ensure that the product quality reviews are done;
(15) To ensure that the necessary initial and continuing training of personnel in Quality Control and Quality Assurance is carried out and adapted according to need.

Article 24 The heads of production and quality management generally have some shared, or jointly exercised, responsibilities relating to quality, including:
1. The review and approval of master manufacturing documents, procedures, etc;
2. The monitoring of manufacturing environment and plant hygiene;
3. Ensuring the critical equipment has been qualified;
4. Ensuring the completion of manufacturing process validation;
5. Ensuring the required initial and continuing training of all related personnel of the manufacturer is carried out and adapted according to need;
6. The approval and monitoring of contract manufacturers;
7. The designation and monitoring of storage conditions for materials and products;
8. The retention of records;
9. The monitoring of compliance with GMP;
10. The monitoring of the factors that may affect product quality.

Article 25 Qualified Person
1. Qualification: The Qualified Person should, at a minimum, possess a college degree in pharmaceutical or relevant specialties (or with an intermediate professional technique certificate or a pharmacist's license), with at least five years of practical experience in pharmaceutical production and quality management, with work experience in in-process control and quality testing.
The Qualified Person should possess necessary theoretical knowledge in relevant specialties,be trained in product release so as to fulfill its responsibilities independently.
2. Main responsibilities:
(1) To participate in quality management activities such as establishment of the quality system, self-inspection, external quality audit, validation, adverse drug reaction reporting and product recalls;
(2) To be responsible for product release and to ensure that the production and testing of each batch of released products are in accordance with the related regulations, the registration requirements and specifications;
(3) Prior to the release of each batch, the Qualified Person must issue a review record for product release according to the requirements in the above paragraph 2, and archive it to the batch record.

Section 3 Training

Article 26 The manufacturer should designate a specific department or person(s) to take charge of training activities. A training program and plan reviewed or approved by the head of production management or quality management should be available. Training records should be retained.

Article 27 Training should be provided for all personnel in production and quality activities. The content of the training should be appropriate to the responsibilities assigned to them. Besides the training on the theory and practice of the Provisions, there should be training on relevant laws and regulations, and job related responsibilities and skills. The practical effectiveness of the training should be periodically assessed.

Article 28 Personnel working in high-risk areas (e.g. production areas for highly active, toxic, infectious or sensitizing materials) should be given specific training.

Section 4 Personnel Hygiene

Article 29 All personnel should receive training of hygiene requirements. The manufacturer should establish personnel hygiene operation procedures to minimize the risks of contamination in drug production caused by personnel.

Article 30 The personnel hygiene operation procedures should include contents relating to the health, hygiene practices and clothing of personnel. Every person whose duties take him into the production and quality control areas should correctly understand and follow these procedures. The manufacturer should take measures to ensure the implementation of these procedures.

Article 31 The manufacturer should have management on the employee's health and establish health archives. Personnel engaged in manufacturing who is in direct contact with drugs should receive medical examination before being assigned to work, and the examination should be carried out at least annually afterward.

Article 32 The manufacturer should take measures to ensure that no person having open lesions on the exposed surface of the body, affected by an infectious disease or other diseases that may contaminate the products, is engaged in the manufacture of drugs.

Article 33 Visitors or untrained personnel should, preferably, not be taken into the production and quality control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing.

Article 34 Every person entering manufacturing areas should wear protective garments as required. The material and style of garments, and way of gowning should be appropriate to the specific work conducted, and the required air cleanliness level.

Article 35: Persons entering clean areas should not wear make-up, jewelry or similar accessories.

Article 36 In production and storage areas, smoking or eating and drinking, or the storage of food, drink, cigarettes or personal medication, as well as other goods not for manufacturing should be prohibited.

Article 37 Direct contact should be avoided between the operator's hands and the exposed product, immediate packaging materials, as well as with any part of the equipment that comes into contact with the products.

Chapter IV Premises and Facilities

Section 1 Principle

Article 38 The location, design, lay-out, construction, adaption and maintenance of premises should suit the drug production requirements, and should minimize the risk of contamination, cross-contamination, mixups and errors, as well as permit effective cleaning, operation and maintenance.

Article 39 Premises should be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimal risk of causing contamination of materials or products.

Article 40 The manufacturer should have a neat manufacturing environment. The ground, roads, and transportation in plant area should not introduce contamination to the manufacturing. The general layout of production, administration, living and ancillary areas should be well designed to avoid interference from each other. Premises and buildings should be well designed to ensure the logical flow of materials and personnel.

Article 41 Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures.

Article 42 Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the product quality during their manufacture and storage, or the accurate functioning of equipment.

Article 43 Premises and facilities should be designed and equipped so as to afford maximum protection against the entry of insects or other animals. Necessary measures should be taken to avoid the contamination to equipment, materials and products caused by raticide, insecticide, fumigation reagent, etc.

Article 44 Measures should be taken in order to prevent the entry of unauthorized people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them.

Article 45 Drawings of premises, facilities and the fixed pipes should be archived as built or after modification.

Section 2 Production Area

Article 46 In order to minimize the risks of contamination and cross-contamination, premises, facilities and equipment should be designed, laid out and used appropriately in accordance with the properties of the manufactured product and its process, as well as the corresponding cleanliness level, and the following requirements should be met:
1. A comprehensive consideration of the aspects such as properties of products, processes and intended uses etc. should be given, so as to determine the feasibility of sharing premises, facilities and equipment for different products, along with an assessment reports.
2. Dedicated and self-contained premises, facilities and equipment must be used for the production of products with particular properties such as highly sensitizing products (e.g. penicillins) or biological preparations (e.g. Bacillus Calmette Guerin vaccine or any other products derived from live microorganisms). Dust generating operation areas in penicillin production should maintain relatively negative pressure, the exhaust air should be decontaminated as required, and the air outlet should be far away from the air inlet of other air-handling systems.
3. Dedicated facilities (e.g. a dedicated air handling system) and equipment must be used in production of β-lactam products and sex hormonal contraceptives, and their production areas must be strictly segregated from those of other products.
4. Dedicated facilities (e.g. a dedicated air handling system) and equipment should be used for some hormonal, cytotoxic and highly potent chemical products. In exceptional cases, the principle of campaign working in the same facilities and equipment can be accepted provided that specific precautions are taken and the necessary validations are made.
5. The exhaust air from the air handling system in above paragraphs 2, 3 and 4 should be decontaminated;
6. The production of non-drugs with adverse effects on drug should not be allowed in premises used for drugs.

Article 47 The adequacy of the production area and storage area should ensure the orderly positioning of equipment, materials, intermediate, bulk and finished products, so as to avoid mixups, cross-contamination between different products and materials, and to avoid the omissions or errors of any of the manufacturing or quality control steps.

Article 48 Production areas should be effectively ventilated, with air control facilities (including temperature, humidity and filtration) appropriate to the products handled, the operations undertaken within them and the external environment, to ensure that the production environment is in accordance with the requirements.
The air pressure differential between clean and non-clean areas, or between differently classified clean areas should not be less than 10Pa. When necessary, an appropriately-graded pressure differential should be maintained between rooms of different functions (operation rooms) with the same cleanliness level.
The exposed processing areas for oral liquid and solid preparations, drugs applied through tract (including recta), epidermal products, and other non-sterile products, as well as the exposed processing areas for handling immediate packaging materials should be designed as Grade D according to requirements in Annex 1 of GMP for sterile products. The manufacturer may take appropriate measures to monitor the microorganism, in accordance with product specifications and property.

Article 49 Interior surfaces (walls, floors and ceilings) of a clean area should be smooth, free from cracks, open joints and dust retention, and should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.

Article 50 Pipes, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, they should be accessible from outside the manufacturing areas for maintenance.

Article 51 Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but when unavoidable, shallow channel are recommended to facilitate cleaning and disinfection.

Article 52 Weighing of starting materials for preparations usually should be carried out in a separate weighing room designed for that use.

Article 53 Operation areas where dust is generated (e.g. during sampling, weighing, mixing and packaging of dry materials and products) should be kept under relatively negative pressure, and specific measures should be taken to avoid dust diffusion and cross-contamination, and to facilitate cleaning.

Article 54 Premises or areas for the packaging of drugs should be reasonably designed and laid out, so as to avoid mixups or cross-contamination. Where several packaging lines are in the same area, there should be segregation in place.

Article 55 Production areas should be well lit, particularly where visual on-line controls are carried out.

Article 56 In-process controls areas may be set up within the production area without bringing any risk to product quality.

Section 3 Storage Areas

Article 57 Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled.

Article 58 Storage areas should be designed or constructed to ensure good storage conditions, with ventilation and lighting facilities.
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