FDA Regulation of Bulk Pharmaceutical Chemical

The US FDA’s inspection of companies focuses on timeliness and dynamics, and timeliness is based on current GMP (ie CGMP). Because GMP is a management model that is constantly improving and spiraling upwards, there is no best, only better, so the current GMP represents a more advanced management level during a certain period of time. Dynamicity emphasizes the dynamic inspection of the varieties that are applied for registration at the time of inspection; the applicants are reviewed every two years to ensure that the company is in a good and continuous state in accordance with the current GMP management.

FDA inspectors conduct inspections in the order in which the APIs are produced, from raw materials to finished packaging and ex-factory. The FDA places great emphasis on the validation of operating conditions, methods, and equipment for some of the key steps in the process.

The FDA attaches great importance to key process control, cross-contamination prevention measures, process validation, cleaning methods, equipment verification, change control, water, environment, inspection, and verification of inspection methods that affect product quality.

The FDA focuses on the following aspects of the company’s on-site inspection:
1. Pay great attention to the quality control and management of raw materials for raw materials

These include the storage, stacking, marking and labeling of raw materials, the inspection and distribution system, and the storage conditions of the warehouse.

2. Raw material medicine production process
The first step of the first reaction to produce key intermediates is usually examined, and for non-synthetic drugs, the first step is the separation and extraction of the drug.

3. Verify
The FDA has decided to verify the production process since 1991. For those manufacturers that have not undergone process validation, the FDA should emphasize the inspection of process validation. For a new product, a complete verification system should be established from the pilot stage until amplification. Industrial scale, a retrospective verification of the production process that has been used for many years, the production process verification is generally not permanent, and any changes (process, equipment, raw materials, quality standard inspection methods) should be re-verified.

4. Cleaning procedures for production equipment such as fermenters, seed tanks, crystallization tanks, reaction tanks, centrifuges, dryers, mixers should be validated, especially when cross-use equipment produces different products.

5. The volume of finished products for export to the United States is larger for general US end users, which can reduce the cost of batch inspection. However, the division of batches must be able to achieve homogeneity, and the homogeneity should be verified, including every barrel, every machine, and so on.

5. The FDA requires information on quality standards and test results for the production process water of the plant. The requirements for formulation water are more stringent than for APIs, and trend analysis is performed every quarter of the month.

6. The label on the packaging container of the API should be strictly controlled as the requirements for the preparation.

7. Standard operating procedures for the operation of each process and position in production, the management of finished products and raw materials of warehouses, the operation and management of quality control and quality assurance.

8. The FDA attaches great importance to the inspection of production records. It requires complete original records and complete batches for the storage, inspection and distribution of raw materials, control of production processes, quality inspection of finished products and verification of various key projects. Record, FDA officials in the factory to check the sampling records, the authenticity and complete performance of the batch records reflect the level of GMP management of the factory.

9. The production equipment includes the building structure of the production workshop and the quality inspection department, the series of equipment of the production line, the auxiliary facilities of water, electricity, steam and compressed air, and the layout of the equipment. The FDA requires the applicant to make a detailed description in the DMF document. FDA officials only focus on inspections.

10. All instruments, instruments, etc., which are used in production and need to be regularly calibrated, shall have calibration procedures and cycles and shall have complete calibration records. Records must be kept by both the self-study and the external school, and a qualification certificate is required.

11. The FDA believes that the management of laboratory laboratories is of the utmost importance in the raw material plant. If the impurity status of the product is not known, the production process cannot be fully verified and the process change cannot be evaluated. The factory should describe this in the DMF.

12. The FDA’s requirements for process control are process control analysis, which should be performed by competent personnel using a complete analytical instrument.

13. The FDA requires that APIs, especially antibiotic APIs, have a defined expiration date and that there is a complete set of procedures for product stability testing and proper implementation. This is described in DMF and provides examples and data.

14. The FDA requires all ≥ 0.1% impurities to have a definitive name and structure.


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