China GMP (version GMP(20 10):

Article 9 The quality assurance system shall ensure that the design and research and development of drugs reflect the requirements of this specification. Article 13: Quality risk management is a systematic process of evaluating, controlling, communicating and auditing quality risks in a forward-looking or retrospective way throughout the product life cycle.

Who and eu GMP require:

GMP should include the whole life cycle from the production of clinical trial drugs, technology transfer, commercial production to product delisting. However, as stated in ICH Q 10, the drug quality management system can be extended to the research and development stage of drug life cycle. Although this is not mandatory, it should also promote innovation and continuous improvement, and strengthen the link between drug development and production management activities.

2. Requirements of laws and regulations on R&D quality system -ICH Q 10

Pharmaceutical companies should plan and implement a monitoring system for process performance and product quality to ensure that they are under control. An effective monitoring system can ensure the continuity of the process and provide corresponding control, so as to ensure the production of products that meet the quality requirements and determine the areas that need improvement.

Application of process performance and product quality monitoring system in product life cycle

Application of corrective and preventive measures system in the whole product life cycle

Application of change management system in the whole product life cycle

Application of process performance and product quality management in the whole product life cycle

Drug development: The knowledge of process and product formed and the monitoring of process and product in the whole development process can be used to establish production control strategy.

Explore the variability of products and processes. CAPA method can make a difference when corrective measures and preventive measures are integrated into the process of repeated design and development.

Changes are an inherent part of the development process and should be recorded. The form of change management process should be consistent with the product development stage.

Technology transfer: monitoring in the process of process amplification can provide a preliminary indication of the performance of concept stocks, so that they can be successfully integrated into production. The knowledge gained in transmission and process amplification is helpful for further control strategy.

CAPA can be used as an effective system for feedback, feedforward and continuous improvement.

The change management system shall provide process adjustment management and technology transfer documents.

Commercial production: Good process performance and good product quality monitoring system should be used to ensure that the process performance is controlled and the improvement area is determined.

CAPA should be used and its effect should be evaluated.

Commercial production should have a formal change management system. The supervision of the quality department should ensure the scientific performance and risk assessment.

Stop production: once stop production, we should continue to implement monitoring measures such as stability study until the inspection work is completed. We should continue to take appropriate measures for the products sold according to the requirements of local laws and regulations.

CAPA shall continue to be used after the product is terminated. Factors that still exist in the market and other products that may be affected should be considered.

Any change after product termination needs to go through an appropriate change management system.

3, Guangdong Province, drug registration research and development quality management guide

Article 2 Drug R&D institutions shall establish a quality management system for drug R&D registration, which shall cover all factors affecting the quality of drug R&D registration, including all activities of drug R&D quality registration, to ensure that the drugs developed meet the intended use and registration requirements, and to ensure the quality and efficiency of drug R&D process.

Article 7 A drug research and development institution shall establish quality objectives that meet the quality management requirements of drug research and development, and systematically implement the requirements of truthfulness, completeness and standardization of drug research and development process into drug research and development and registration declaration, so as to ensure truthfulness and completeness of drug research and development data and controllable risks in the research and development process.

Article 14 A drug research and development institution shall set up a special R&D quality management department, which is mainly responsible for the quality management in the process of drug R&D registration, participating in all quality-related activities, and reviewing documents related to R&D quality. The personnel of R&D Quality Department shall not concurrently work in other departments. If the scale of drug research and development institutions is limited, at least qualified personnel should be appointed to engage in quality management.

4. Drug Administration Law

Article 7 In the research and development, production, marketing and use of drugs, laws, regulations, rules, standards and norms shall be observed to ensure the truthfulness, accuracy, completeness and traceability of the information in the whole process.

Seventeenth engaged in drug development activities, should abide by the quality management norms of drug non-clinical research and drug clinical trials, to ensure that the whole process of drug development continues to meet the statutory requirements.

Eighteenth to carry out non-clinical research on drugs, it should comply with the relevant provisions of the state, with personnel, venues, equipment, instruments and management systems suitable for the research project, and ensure the authenticity of relevant data, materials and samples.

Interpretation: The new version of the Drug Administration Law clearly points out that it is necessary to strictly manage the drug research and development process.

5, China drug registration management procedures.

chapter two

Article 13 The applicant shall provide sufficient and reliable research data to prove the safety, effectiveness and quality controllability of the drug, and be responsible for the authenticity of all information.

Article 16 In the process of drug registration, the pharmaceutical supervisory and administrative department shall conduct on-site verification and causality verification of non-clinical research and clinical trials, and approve the on-site inspection of production before listing, so as to confirm the authenticity, accuracy and completeness of the application materials.

Twenty-second pre-clinical research of drugs should implement the relevant management regulations, in which the safety evaluation research must implement the "Quality Management Standards for Non-clinical Research of Drugs".

chapter three

Article 35 Clinical trial drugs shall be prepared in workshops conforming to good manufacturing practice, and the preparation process shall strictly comply with the requirements of good manufacturing practice. The applicant is responsible for the quality of drugs used in clinical trials.

6, to carry out on-site verification

China has successively issued the requirements documents for conformity evaluation and development site verification;

On-site verification of development is mainly the process of on-site confirmation of pharmaceutical research (including prescription and process research, sample trial production, in vitro evaluation, etc.). ), review of original records, confirmation of authenticity, consistency and data reliability of application materials, and compliance of development process.

Note: The focus of foreign inspection and transnational audit will gradually expand from QC laboratory, production and change to R&D site.

7, formulate the principle of on-site inspection decision.

(1) Confirm the investigation situation and conditions on the spot, and recheck the original records and data in the investigation process. If no authenticity problems are found, the verification conclusion is judged as "passed".

(two) found one of the following circumstances, the verification conclusion is judged as "failed". 1. Found the authenticity problem; 2. There are inconsistencies with the application materials; 3. Lack of original records of key research activities and data leads to non-traceability; 4. There are serious data reliability problems (see next page for data reliability principles); 5 do not cooperate with the inspection, resulting in the on-site inspection can not continue.

Data reliability principle

Traceability attribution: who obtained the data when or by whom.

Legible: Can you identify the data and all the laboratory records?

Synchronization: generated/entered synchronously with the operation.

Original: First-hand records, which can be printed materials, observation records or certified copies.

Available: Records can be used for review, audit or inspection during the service life.

Long-term: Records are well preserved within the specified filing period and are not easy to be deleted or discarded.

Consistent: consistent with the actual generated logical order, and the displayed recorder is consistent with the actual operator.

Complete: no omission, including all data related to sample reanalysis.

Accurate: consistent with the actual operation, without subjective fraud or objective input error. About the availability of complete complete.