2016 drug inspection report
The Verification Center organised a total of 434 drug registration production site inspections, drug GMP certification inspections, GMP follow-up inspections, flight inspections, inspections of overseas production of imported pharmaceuticals, circulation inspections, and inspections.
Section 1 Drug Registration Production Site Inspection
First, check the basic situation
In 2016, a total of 29 inspection tasks (including multi-stage inspections) were received, 21 were from the Drug Evaluation Center of the Directorate General (hereinafter referred to as “pharmaceutical examination centers”), and 8 were due to inspection tasks. A total of 43 inspection teams were sent to 178 person-times to conduct on-site inspections of 34 items; 42 field inspection reports were completed, of which 34 items passed, accounting for 81%; and 8 companies that had not passed the registration and actively withdrew their applications, accounting for 19%.
Second, found the main problem
In the on-site inspection in 2016, the data reliability problems of individual companies were still unrecoverable and the filing data was not true. Problems such as insufficient process validation, unstable production processes, inconsistent production processes or parameters, and verification were found.
Details are as follows:
(I) Data reliability issues
1. The test data cannot be traced. There was no sample retention and stability review. On-site inspections did not see sample retention and stability test samples for samples tested, nor could they provide corresponding records.
2. The batch production records are not true or complete and are inconsistent with the application materials.
(B) Inadequate process validation and unstable production process
The process verification of the variety is not sufficient. When the enterprise is in dynamic production, serious deviation occurs, the deviation of the batch production yield from the verification batch is large, the production equipment control system is unstable, and some equipment of the production line cannot fully meet the existing production requirements.
(III) Inconsistent production process or key process parameters, inner packaging materials and approved contents, and no research evaluation
1. The production process is inconsistent with the approved/declared production process.
2. The key process parameters are inconsistent with the approved/declared production process.
3. The manufacturer of the inner packaging material is inconsistent with the registration application, and the company has not conducted a comparative study.
(D) Did not conduct the necessary deviation survey
When major abnormalities occurred in dynamic production, individual companies did not investigate enough to find the root cause. The results of the three batches and dynamic production batch verification of a chemical raw material drug show that the yield of the four batches of finished products has a wide gap, and the company has not analyzed and found the reason.
Section II Inspection of Drugs GMP Certification
First, check the basic situation
According to the announcement of the State Food and Drug Administration’s announcement (No. 285 of 2015) on matters concerning the “Certification of Stopping Production and Declaring Sterile Drugs for Certification by Enterprises Who Failed to Pass the Quality Control Regulations for Drug Manufacturing (Revised in 2010)”, since 2016 On the 1st of the month, the State Food and Drug Administration will no longer accept GMP certification applications. For the accepted application for certification, continue to organize the completion of on-site inspection and certification.
In view of the above, in 2016, a total of 16 inspections were conducted, 16 on-site inspection reports were received, and 14 were completed. Among them, 12 drug manufacturers passed the GMP certification inspection, and two drug manufacturers did not pass the GMP certification inspection. Five enterprises issued admonition letters; and two other companies whose GMP certification inspections ended, but because they did not get the relevant registration approval certification documents, the certification process was suspended.
The types of applications for certification include large volume injections 3 times, small volume injections 3 times, freeze-dried powder injections 3 times, powder injections 1 dose, radioactive drugs 1 injection, vaccine products 2 times, and other biological products 3 times.
Second, found the main problem
220 defects were found, including 23 major defects and 197 general defects. Of these, 41 were quality control and quality assurance, 32 were document management defects, 24 were institutional and personnel defects, 23 were equipment defects, and 21 were defects in validation and verification. The distribution of flaws found in inspections in 2015 is basically the same.
This year's certification inspection of two in vitro diagnostic reagent manufacturers, the results are not passed, the main issues are as follows:
(a) quality management system. The quality management system can not operate effectively, can not guarantee the product's production and quality requirements; staff mobility, lack of professionals, training is not in place, can not meet the daily production quality management requirements; file operability is not strong, data records are incomplete; The change did not follow the change procedure for change control.
(b) Confirmation and verification work. All processes that apply for GMP certification have not been subjected to process verification. Cleaning verification work for public facilities and equipment is not in place; some verification records are incomplete; some re-verification work has not been carried out as required.
Section 3 Drug GMP Follow-up Inspection
First, check the basic situation
In 2016, the verification center announced 215 inspection and follow-up inspection plans, a total of 228 times. Among them, 58 enterprises were suspended production and had no production for a long time, and the remaining 170 were all inspected. In addition, 21 provincial-certified aseptic pharmaceutical manufacturers were followed for follow-up inspections and 13 were randomly selected. A total of 204 follow-up inspections were completed throughout the year.
There were 12 companies that did not pass the follow-up inspection, accounting for 6.1%. There were 59 companies that issued the letter, accounting for 29.6%.
Among the 12 companies that failed the inspection, there were five companies that failed the inspection in 2015, four companies that had undergone random inspections, two companies that had citicoline sodium injections, and one bone peptide injection manufacturer.
(I) Sample quality inspection of 2015 annual quality announcement
A total of 10 companies were tracked and checked, of which 5 failed to pass inspections, accounting for 50%, and another 4 enterprises were issued with admonition letters.
(b) Double Random Inspection
In order to implement the requirements of the State Department's innovation during and after the supervision, and in accordance with the unified deployment of the State Council, the Drug Double Random Inspection System was first launched in December 2016 and a follow-up inspection of the selected 13 companies was conducted in a layered, double-random manner. There are 3 chemical preparations, 2 raw material medicines and 8 traditional Chinese medicines distributed in 9 provinces. A total of 4 companies failed to pass the inspection, the passing rate was only 69%, and the other three companies issued a letter of trust.
(III) Vaccine manufacturers
The 38 vaccine manufacturers that obtained the GMP certificate of pharmaceuticals were included in the 2016 follow-up inspection plan, except that one drug product production license and drug GMP certificate were withdrawn in 2014, and one application for 2015 changed the production site's drug GMP certificate. A total of 36 vaccine manufacturers were followed up after the inspections were not conducted. All the inspection results passed, and a total of seven companies were issued a letter of trust. One of the companies was initially considered to be a serious defect due to the change of the analyzers. The latter experts held that the principle of the detector method before and after the change is consistent and the quality risk is low. The company is required to carry out further methodological verification and is reduced to the major defect. . In general, the risk of vaccine production quality is controllable, and the production and quality management of production enterprises are more standardized.
(D) Blood product manufacturers
Twenty-six blood product manufacturers were included in the 2016 follow-up inspection program. A total of 25 blood product companies were subject to follow-up inspections, and another company did not conduct inspections due to suspension of production reforms. All the inspection results passed, and a total of 4 companies were issued a letter of trust. In general, the risk of production quality of blood products in China is controllable. The production and quality management of production enterprises are more standardized, and individual enterprises still need to strengthen supervision.
(5) Enterprises that issued the letter in 2015
A total of 32 companies that issued a letter of credit in 2015 were followed and checked. Although the companies basically meet the requirements, they still issued a letter of reiteration to 14 companies.
(6) Checking the status of certified sterile pharmaceutical manufacturing enterprises at the provincial level after certification decentralization
A total of 21 provincial-certified aseptic pharmaceutical manufacturing enterprises were spot-checked, all of which passed and six of them were issued a letter of trust. Through spot checks, the scale of the provincial bureau's certification inspections is generally strict and all localities have smoothly undertaken the decentralized certification inspection functions.
(VII) Special inspection of high-risk varieties
In this year, the focus was on follow-up inspections of three injections of bone peptide, fructose sodium diphosphate, and citicoline sodium. A total of 114 high-risk product special inspections were planned, 47 of which were due to the company's failure to pass GMP ( (Amended in 2010) Inspections were not conducted for reasons such as certification, long-term production suspension of products, approval of document number transfer, etc. Actual inspections were conducted 67 times. One manufacturer of bone peptide injections and two manufacturers of citicoline sodium injection did not pass and issued letters to 21 companies.
Second, the main problems found
(a) The overall situation
A total of 2,260 defects were detected in 204 inspections, of which 22 were serious defects, 212 were major defects, and 2026 were general defects. Compared with the 2015 GMP certification and follow-up inspection, the number of serious defects increased.
The phenomenon of long-term production discontinuation or failure to pass the drug GMP (2010 revision) certification in high-risk species special inspection companies is quite prominent. Some of the common problems discovered during inspections are as follows:
1. There is an inconsistency between the production process and the registration process.
2. The problem of data reliability still exists, including falsification of production records, the use of maps in inspection records, unauthorized modification of data issues, and inconsistencies between relevant content in production, equipment, and material records.
3. Inadequate process validation, in particular, there are many problems without process validation after changing production lots.
4. The normative issues of data management are prominent, mainly reflected in the system permissions settings, audit tracking functions, file and data modification and deletion permissions are not controlled, and there is no reasonable control and interpretation of data deletion and selection of data.
5. There is a gap between the implementation of the computerized system, confirmation and verification of the two appendices and regulatory requirements, and more problems are found.
6. The management of deviations and changes is weak, mainly reflected in the fact that deviations cannot be identified and recorded, and there is no necessary assessment and verification of changes.
(II) Non-qualified companies with random inspection in 2015
Inspection of 10 companies found a total of 11 serious defects, 27 major defects, and 84 general defects.
The main problems discovered include: inconsistency between production process and registration process, data reliability issues, and process validation issues.
(c) Double Random Inspection
Five serious defects, 24 major defects, and 123 general defects were found.
The main problems identified include: falsified records, product quality and safety risks, data reliability problems, process validation problems, non-standard material management, risk of contamination, confusion, and errors, incomplete cleaning, and effective prevention of pollution and cross-contamination.
(IV) Vaccine manufacturers
Found 38 major defects and 383 general defects.
The main problems found include:
1 equipment. The water for injection preparation system enters the injection water tank and the stainless steel line valve is too long between the water generator.
2. Material and product aspects. The records of the destruction of finished non-conforming product have yet to be refined; individual place-cards are missing; background information on the whole gene sequence of the main seed of the bacterivory species used for production has not been established.
3. Document management. Individual documents are not specific enough, and they are not practical enough. The contents of the documents are slightly different from the actual ones; the contents of individual records are not comprehensive; the design content of the batch production records is irrational, and it is not easy to fill in the actual operations.
4. Quality Control and Quality Assurance
(1) Quality laboratory management: No inspection data and maps are requested from the agency that commissioned the inspection.
(2) Deviation treatment: training and implementation of relevant documents for enterprise deviation processing are not in place; individual deviations cannot start investigations in time; few analysis of deviation causes and corrective and preventive measures are not in place, and the potential impact on product quality caused by deviations is not sufficient. Evaluation.
(3) Change control: changes are not handled in accordance with the change process and apply for registered supplementary applications. There are no assessments or insufficient assessments of some of the changes.
(4) Supplier management: The audit content of key material suppliers needs to be refined, and the content of suppliers' audit content needs to be improved.
(5) Product quality review: Annual quality review should be carried out separately for each species, and the review of CAPA effectiveness is insufficient; the annual product quality review analysis report can be further refined.
5. Computerized system. The company has developed a file system for computerized system management. However, it has not managed completely in accordance with the system classification. If the existing conditions do not conform to the documents, no effective measures have been taken to reduce the risk; the quality inspection laboratory's HPLC testing equipment login interface permission requirements are required. Refinement.
(V) Blood product manufacturers
A total of 25 companies were inspected and found to have 0 serious defects, 13 major defects, and 241 general defects.
The main problems found:
1. In terms of organization and personnel, training for some positions is lacking.
2. In terms of factory buildings and facilities, there is a possibility that pollution and cross-contamination cannot be effectively controlled.
3. Equipment. Some equipment calibrations do not cover the actual scope of use; some inspection instruments and equipment are not regularly calibrated or the calibration is not sufficient, and the records are not perfect; some equipments are incompletely identified.
4. Materials and products. There is insufficient information in the price-distribution limulus label and the label is not fixed.
5. Confirmation and verification aspects. The media simulation filling experiment did not specify the specific requirements such as intervention requirements and rejection criteria.
6. Document management. The procedures, procedures, and other documents are not specific and the regulations are not standardized. Record the existence of non-standard behaviors such as failure to fill in and fill in incomplete.
7. Production management. The sodium octanoate solution added prior to inactivation lacks control measures for microorganisms; no confirmation of the settling time of the settling dish under Class A laminar flow.
8. Quality Control and Quality Assurance
(1) Quality control laboratory management: The content of the receipts and receipts of the inspection products is not complete, and the receiving information of the intermediate products and semi-finished product inspection samples is not recorded; the culture medium used for environmental monitoring that has not been purchased is detected; the sterility test is not performed. Set a negative control according to pharmacopoeia;
(2) Inspection of product stability: The intermediate product has a validity period, but lack of continuous stability inspection or verification data support;
(3) Change control: Change control management is not in place. No assessment or inadequate assessment of some of the changes;
(4) Deviation treatment: Individual deviations failed to start investigations in time; some deviation investigations and corrective and preventive measures were inadequate;
(5) Supplier management: The supplier of cold precipitation price was not included in the list of qualified suppliers;
(6) Product quality review: Certain information was not included in the annual product quality review;
(7) Shipment and recall of products: There is no provision for the method of shipment of batch-issued samples;
(8) Computerized systems: The management files of computerized systems are incomplete. Some QC laboratory equipment does not have an audit trail function; some electronic data are not saved and backed up after being imported into the computer; the system does not have different levels of access rights, and there are risks of data and system modifications.