Adopt the framework of basic requirements and appendices.
This revision carefully studied the overall structure design of GMP, and decided to adopt the model of "Basic Requirements and Appendices of Pharmaceutical GMP", which is the same as the overall structure of EU GMP and China's current GMP, and also conforms to the compliance habits of the Chinese public. The advantage of this model is that the basic requirements are relatively fixed and universal. Appendices have special requirements for specific drug types and technical management, which can be gradually increased according to the needs of supervision, and new appendices can be supplemented or updated at any time according to the needs of development and supervision. The revised GMP involves basic requirements and five appendices: sterile drugs, traditional Chinese medicine preparations, raw materials, biological products and blood products.
Second, the main content
The new GMP currently includes basic requirements and five appendices (sterile drugs, blood products, biology
Products, traditional Chinese medicine preparations, raw materials). The appendix requirements of non-sterile drugs in the original GMP version were merged into basic requirements.
Continue to use the appendix of Chinese herbal pieces, radioactive drugs and medical gas in GMP 98, and do not revise it for the time being. If it is not suitable for the new GMP, it shall be implemented according to the new GMP. In this way, enterprise drug GMP will have a basic requirement, five new appendices and three old appendices.
The basic requirements of GMP and the appendix of sterile drugs are the most important in this revision, and the appendix of blood products is a new appendix in this revision.
1. Basic requirements of drug GMP
The new version of GMP Basic Requirements * * * consists of 15 chapters, 335 articles and more than 35,000 words, which describes the basic requirements of drug production quality management in detail. The contents involved in the clause basically retain most chapters and main contents of the 98 version of GMP, covering the basic requirements of EU GMP and the main principles of WHO GMP, and are applicable to the production of all drugs.
The new GMP embodies the characteristics of attaching importance to the construction of personnel and quality system.
2. Appendix of sterile drugs
In order to ensure the safety of sterile drugs, this time it was revised according to the standards of the European Union and WHO.
The appendix of sterile drugs adopts the grading standards of A, B, C and D of the European Union and the latest WHO, which puts forward very specific requirements for the cleanliness level of sterile drug production.
In particular, the static and dynamic monitoring of suspended particles, the monitoring of planktonic bacteria, settling bacteria and surface microorganisms are set up in detail, and the monitoring conditions are clearly explained. The requirements of simulated filling, sterilization verification and culture medium management are refined, the specific requirements of aseptic operation are increased, and the measures to ensure sterility are strengthened, which provides legal and scientific basis for effectively ensuring the safety and quality of aseptic drugs.
3. Appendix of biological products
According to the characteristics of biological products production, the appendix of biological products emphasizes the strict control of production technology and intermediate process and a series of requirements to prevent pollution and cross-contamination, and strengthens production management, especially the management requirements of seed batch and cell bank system, production operation and specific requirements of raw materials.
4. Appendix of blood products
The Appendix of Blood Products is a brand-new appendix with reference to the relevant GMP appendices of the European Union, relevant laws and regulations of China, pharmacopoeia standards and the requirements of the 2007 Implementation Plan for the Production and Rectification of Blood Products.
The key content is to ensure the safety of raw plasma, intermediate products and finished blood products. Specific requirements are put forward for the safety of raw plasma, intermediate products and finished products in re-inspection, setting isolation period, traceability information of plasma suppliers and products, safety index inspection of intermediate products and finished products, management of in vitro diagnostic reagents for inspection, feeding production, virus inactivation and unqualified plasma treatment.
5. Appendix of traditional Chinese medicine preparation
The appendix of traditional Chinese medicine preparation strengthens the management requirements of quality control, extraction process control and extract storage of traditional Chinese medicine and traditional Chinese medicine decoction pieces.
Comprehensive requirements are put forward for the quality control items of Chinese medicinal materials and Chinese medicinal preparations, and also for the control of solvent recovery in extraction.
6.API appendix
The revision of the appendix of API is mainly based on Q7 of ICH, and at the same time, it deletes the content in Q7 that is duplicate with the basic requirements, and retains the special requirements for API. The appendix of API strengthens the software requirements, increases the control requirements of classical fermentation process, and defines the specific requirements of API recovery, rework and reprocessing.
Third, the main features
Focus on refining software requirements.
The focus of this revision is to refine the software requirements to make China's GMP more systematic, scientific and comprehensive, and to refine some principle requirements in the 98 version of GMP to make it more operable and avoid ambiguity as much as possible.
Strengthen file management.
The new version of GMP refers to the basic requirements of EU GMP and the relevant requirements of American GMP, and puts forward specific requirements for the compilation of main documents (such as quality standards, production process regulations, batch production and batch packaging records, etc.). ). Specific requirements are put forward for the copying and distribution of batch production and batch packaging records, which greatly increases the operation difficulty of illegal records and irregular records.
Absorbed the international advanced GMP standards.
The basic requirements and five appendices of the new GMP refer to international GMP standards in the revision process, and chapters such as quality risk management, supplier audit and approval, change control and deviation handling are added to strengthen the control and management of relevant links by domestic enterprises.
Some concepts are introduced or clarified.
Some of these concepts have been implemented in pharmaceutical production enterprises, and some are being tried out in some provinces in China.
(1) Qualified personnel for product release
The new GMP clearly stipulates the qualification, responsibility and independence of the person in charge of product release, greatly strengthens the requirements for product release, enhances the legal status of quality management personnel, and provides legal guarantee for quality management personnel to perform their duties independently.
(2) Quality risk management
The new GMP puts forward the basic requirements of quality risk management, and makes it clear that enterprises must implement the whole process management of drugs.
Each life cycle evaluates quality risks according to scientific knowledge and experience, which is ultimately related to the goal of protecting patients. In the process of quality risk management, the degree, form and documents of enterprise efforts should be adapted to the risk level.
(3) Design confirmation
It has been clarified and strengthened in the new edition. During the implementation of GMP in the early stage, pharmaceutical production enterprises lacked sufficient demonstration on the selection of newly built or renovated factories and equipment, resulting in large or small investment losses. On the basis of summing up the past experience and lessons, the "design confirmation" will be made more specific and clear, requiring enterprises to clarify their own needs and confirm whether the design of factories or equipment meets GMP requirements, so as to avoid blindness and increase science.
(4) Change control
Without changing the control requirements, it is common for enterprises to change prescriptions and production processes, quality standards and sources of raw materials and packaging materials that are in direct contact with drugs, production plants, facilities and equipment without retrospective explanation.
The new version of GMP has specially added a section on change control in the chapter of "quality management", and put forward the requirements of change classification management. The increase of these management requirements provides a management tool to stop the random behavior of enterprises, and with the change control requirements put forward in the recent drug registration management, it is helpful to form a joint force of drug production supervision and drug registration management.
(5) Deviation processing
The new GMP has added a section on deviation handling in the chapter on quality control and quality assurance. With reference to Q7 of ICH and GMP of FDA of the United States, the deviation is defined and the requirements of deviation classification management are stipulated, which provides an effective management method for enterprises to stop their arbitrary behavior of not carefully and strictly formulating documents.
(6) Corrective and Preventive Measures (CAPA)
In the new CMP, CAPA requirements have been added to the quality control and quality assurance chapter, requiring enterprises to establish a corrective and preventive measures system, investigate complaints, product defects, recalls, deviations, self-inspection or external inspection results, process performance and product quality monitoring trends, and take corrective and preventive measures. The depth and form of investigation should be commensurate with the degree of risk.
(7) Excellent Results Survey (OOS)
In the new GMP, the requirements of OOS investigation are added in the quality control and quality assurance chapter, which requires that the quality control laboratory of an enterprise should establish a written investigation procedure for exceeding the standard, and any results exceeding the standard must be investigated in full accordance with the written procedure and recorded accordingly, further standardizing the operation behavior of the laboratory.
(8) Review and approval of suppliers
The basic requirement of the new GMP is a separate chapter, which clarifies the specific requirements in supplier audit and approval, and further standardizes the supplier assessment system of enterprises.
(9) Retrospective analysis of product quality
The concept of "product quality review" is introduced into the basic requirements of the new GMP, which requires enterprises to regularly review and analyze the quality of each product or category produced in the previous year every year, and explain in detail the quality of all production batches and unqualified product batches, as well as their investigation, change and deviation, stability inspection and confirmation of production plants, facilities or equipment. The introduction of this new method can effectively promote enterprises to pay attention to product quality for a long time. We must pay attention to the quality of each product and its changes, especially the products that do not conform to the contents or requirements of registration and approval, and make regular summary and evaluation, which is consistent with the purpose of GMP implementation, that is, "to ensure the continuous and stable production of drugs suitable for the intended use and meet the requirements of registration and approval and quality standards."
(10) continuous stability inspection plan
The new edition of CMP Basic Requirements introduces the continuous stability inspection plan, which aims to promote pharmaceutical manufacturers to pay attention to the quality monitoring of drugs after listing and ensure the quality of drugs within the validity period. The new requirements clearly stipulate under what circumstances the stability of finished products or intermediate products needs to be tested, what contents should be included in the stability inspection plan, how to analyze and evaluate the changing trend of product quality according to the stability inspection results, and take corresponding measures for listed products. This is one of the ways to strengthen the post-marketing supervision of drugs.
Through these new or clearer requirements, the idea that the enterprise is the first responsible person has fallen to an operational and inspectable level, which urges the pharmaceutical production enterprises to take the initiative to prevent the drug injury incidents caused by the quality of pharmaceutical production.