The Center for Food and Drug Inspection (CFDI) organized to conduct a total of 431 inspections throughout the year, including pre-approval inspection, GMP certification inspection, GMP follow-up inspection, unannounced inspection, overseas inspection , GSP unannounced inspection and inspection observation.
Part I Pre-approval Inspection
I. Overview of Inspections
A total of 29 inspection tasks were received in 2016, of which 21 tasks were from the Center for Drug Evaluation of CFDA (hereinafter referred to as CDE), 8 tasks were from the Department of Drug and Cosmetics Registration of CFDA and discipline inspection and supervision departments (for-cause inspection tasks). A total of 178 person-times, 43 inspection teams have been sent out to conduct pre-approval inspection on 34 varieties; 42 on-site inspection reports have been completed, of which 34 passed the inspection, accounting for 81%; and 8 failed or proactively withdrew registration applications, accounting for 19%.
Table 1-1 Information of On-site Inspections
Figure 1-1 Diagram of the Number of Pre-approval Inspection Tasks in Recent Five Years
Figure 1-2 Diagram of Dosage Form Distribution in Pre-approval Inspections
II. Main findings
In the pre-approval inspections in 2016, such problems in data integrity as untraceable data and untruthful application dossier were still prominent while insufficient process validation and instable production process and inconsistency between production process or parameters with approved ones were also identified, which were specifically as follows: (All issues found in inspection have been dealt in accordance with the law.)
(I) Problems in data integrity
1. Testing data were untraceable. A few enterprises failed to retain samples as required and conduct stability investigation. No retained preproduction samples and retained samples for stability test of the inspected varieties were found in pre-approval inspection, and enterprises also failed to provide both the requisition and destruction records of corresponding retained samples and the samples for stability test and use records of the equipment for stability test.
2. Batch production records were untruthful and incomplete and inconsistent with application dossier.
(II) The process validation was insufficient and production process was instable
The process validation for the variety was insufficient. During the dynamic production of the enterprises, some procedure had serious deviation or batch product yield had a greater deviation from the validated batch.
(III) The production process or key process parameters and inner packaging materials were inconsistent with the approved ones and no study and assessment was conducted
1. The production process was inconsistent with that approved / under application.
2. Key process parameters were inconsistent with the production process approved / under application.
3. The manufacturer of inner packing materials was inconsistent with that under registration application, and the enterprise did not conduct comparison study.
(IV) Necessary deviation investigation was not conducted
There was significant abnormality in dynamic production, but the investigation was insufficient and the primary cause was not identified. The results of the process validation of three batches and dynamic production batch of the chemical APIs under application by an enterprise showed that there was significant difference in the rate of finished products among four batches, but the enterprise did not analyze and identify the reasons.
Part II Pharmaceutical GMP Certification Inspection
I. Overview of Inspections
Based on the spirit in the Announcement of China Food and Drug Administration on Relevant Issues of Halting the Production by the Enterprises Failing to Pass the Pharmaceutical GMP (revised in 2010) Certification and Decentralizing the Certification of Sterile Pharmaceuticals (2015 No.285), China Food and Drug Administration no longer accepted the application for pharmaceutical GMP certification as of January 1st, 2016. For the certification applications that have been accepted, on-site inspection as well as review and certificate-issuing continued to be completed.
In view of above situation, the inspections on 16 pharmaceutical manufacturers have been arranged, 16 copies of on-site inspection reports have been received and 14 copies have been reviewed throughout the year of 2016. Among them, 12 pharmaceutical manufacturers passed pharmaceutical GMP certification inspection, 2 pharmaceutical manufacturers failed to pass pharmaceutical GMP certification inspection and 5 pharmaceutical manufacturers were issued with Warning Letter; and another two pharmaceutical manufacturers have not yet received approval document for registration so the GMP certification process is suspended.
The dosage forms under application for certification included large volume injection of three enterprises, small volume injection of three enterprises, c of three enterprises, powder injection of one enterprise, radiopharmaceutical of one enterprise, vaccine of two enterprises and other biologics of three enterprises.
Table 2-1 Information of On-site Inspections
Table 2-2 The Distribution of Dosage Forms Subject to Certification Inspection in 2016 (unit: enterprises)
II. Main findings
A total of 220 deficiencies were identified, including 23 major deficiencies and 197 general deficiencies. There were 41 deficiencies in Quality Control and Quality Assurance, 32 deficiencies in Documentation Management, 24 deficiencies in Institutions and Personnel, 23 deficiencies in Equipment and 21 deficiencies in Verification and Qualification. The distribution was basically consistent with that in 2015.
The two manufacturers of in vitro diagnostic reagents receiving certification inspection all failed this year. The main problems were as follows:
(I) Quality Management System. Quality management system could not be effective operated and failed to meet the production and quality requirements of the products; The personnel mobility was frequent, there lacked professionals and the training was not conducted, which could not meet the quality management requirements in routine production; The operability of the documents were poor and data were incompletely recorded; relevant changes were not subject to change control in accordance with change procedure.
(II) Verification and Qualification. The enterprises failed to conduct process validation for all the products under application for GMP certification, and the cleaning validation for public equipment and facilities was not in place; part of validation records was incomplete; and some re-validation work was not conducted as required.
Part III Pharmaceutical GMP Follow-up Inspection
I. Overview of Inspections
In 2016, it was planned in the Announcement to conduct follow-up inspection on 215 enterprises, a total of 228 inspections. Among them, 58 inspections were conducted on the enterprises out of production or having no production for a long time, and other 170 inspections have all been conducted.
In addition, follow-up inspection was conducted on 21 sterile drug manufacturers passing provincial certification, and double random inspection was conducted on 13 enterprises. A total of 204 follow-up inspections were completed.
Table 3-1 Information of GMP Follow-up Inspections
Table 3-2 Information of Inspection Distribution
12 enterprises failed in follow-up inspection, accounting for 5.9%, and 58 enterprises were issued with Warning Letter, accounting for 28.9%.
Among 12 enterprises failing in the inspection, there were 5 enterprises unqualified in casual inspection in 2015, 4 enterprises subject to double random inspection, 2 manufacturers of citicoline sodium injection and 1 manufacturer of ossotide injection. (All issues found in inspection have been dealt in accordance with the law.)
(I) The situation of casual inspection of the varieties in quality report in 2015
10 enterprises accepted the follow-up inspection on such dosage forms and varieties as eye drops, bendazol tablets and APIs of sodium benzoate, of which 5 enterprises failed, accounting for 50%, and 4 enterprises were issued with Warning Letter.
(II) Double random inspection
In order to implement the requirements of innovating the supervision inwards and afterwards by the State Council, in accordance with the unified arrangement by CFDA, double random inspection system for pharmaceuticals was initially operated in December 2016, follow-up inspection was conducted on the 13 selected enterprises. The inspections distributed in 9 provinces and involved 3 chemicals, 2 APIs and 8 TCMs. 4 enterprises failed in the inspection, and the pass rate was only 69%. In addition, 3 enterprises were issued with Warning Letter.
(III) Vaccine manufacturers
38 vaccine manufacturers that have obtained GMP certificate were marketed in the follow-up inspection plan in 2016. Except for 1 enterprise having production license and GMP certificate revoked in 2014 and 1 enterprise failing to get GMP certification in 2015 due to the application for the change of production address, the follow-up inspection was conducted on other 36 vaccine manufacturers. All 36 enterprises passed the inspection, and 7 enterprises which found general risks and can be improved by rectification were issued with Warning Letter. According to experts assessment that one critical deficiency that was evaluated by inspectors on site should be decreased to major deficiency, being low risk. On the whole, the quality risks in vaccine production are controllable and the manufacturers have a standardized production and quality management.
(IV) Blood product manufacturers
26 blood product manufacturers were marketed in the follow-up inspection plan in 2016. Except for 1 enterprise in production suspension and rectification, the follow-up inspection was conducted on other 25 blood product manufacturers. All 25 enterprises passed the inspection, and 4 enterprises which found general risks and can be improved by rectification were issued with Warning Letter. On the whole, the quality risks in blood product production are controllable, the manufacturers have a standardized production and quality management, but the supervision shall be intensified for individual enterprises.
(V) The manufacturers issued with warning letter in 2015
Follow-up inspection has been conducted on 32 manufacturers issued with warning letter in 2015. The manufacturers were basically met the requirements, but 14 manufacturers were issued with warning letter again.
(VI) The situation of casual inspections on the sterile drug manufacturers passing provincial certification after the decentralization of certification
21 sterile drug manufacturers passing provincial certification received casual inspection. All of them passed the inspection and 6 enterprises were issued with Warning Letter. According to the inspection result, the Provincial Bureau can undertake the GMP certification inspection functions smoothly down.
(VII) Special inspection on high-risk varieties
This year, follow-up inspection was mainly conducted on the injection of three products including ossotide, fructose diphosphate and citicoline sodium. It was planned to conduct 114 special inspections on high-risk varieties. 47 enterprises were not inspected because of failing in GMP (2010 version) certification, out of production for a long time and transfer of approval number, and 67 inspections were actually conducted. In the inspections, 1 ossotide injection manufacturer and 2 citicoline sodium injection manufacturers failed, and 21 manufacturers were issued with Warning Letter.
II. Main findings
(I) Overall situation
A total of 2271 deficiencies were identified in 204 inspections, of which there were 22 critical deficiencies, 210 major deficiencies and 2039 general deficiencies. Compared with GMP certification and follow-up inspections in 2015, the number of critical deficiencies was increased.
Among the manufacturers of high-risk varieties subject to special inspection, out of production for a long time or failing in pharmaceutical GMP (2010 version) certification were prominent. The common problems identified in the inspections were as follows:
1. Individual enterprise had inconsistency between its production process and registered process.
2. The problems in data integrity and authenticity still existed, including falsification of production records, indiscriminate use of maps and arbitrary modification of data in inspection records and inconsistency in relevant content in production, equipment and material records.
3. The process validation was insufficient, and the enterprises failing to conduct process validation after changing production lot size had more problems.
4. The problems in the standardization of data management were prominent, mainly manifesting as failing to control the permission setting of the system, audit tracking function and the permission for the modification and deletion of documents and data, and having no reasonable control and explanation for deleting, selecting and using data.
5. There was certain gap between the implementation of the Appendix of Computer System and Appendix of Qualification and Validation and regulatory requirements, and many problems were identified.
6. There was a weak management of deviations and changes, mainly manifesting as failing to effectively identify and record the deviations that occurred, and lacking necessary assessment and validation for the changes.
Figure 3-1 Distribution of the Deficiencies Identified in Follow-up Inspections
(II) The enterprises unqualified in casual inspections in 2015
A total of 11 critical deficiencies, 27 major deficiencies and 84 general deficiencies were identified in the inspections on 11 enterprises.
Figure 3-2 Distribution of the Deficiencies of the Enterprises Unqualified in Casual Inspection
Main findings were as follows:
1. Production process was inconsistent with registered process
2. Problems in data integrity
3. Problems in process validation
(III) Double random inspection
A total of 5 critical deficiencies, 24 major deficiencies and 123 general deficiencies were identified.
Figure 3-3 Distribution of the Deficiencies Identified in Double Random Inspections
Main findings were as follows:
1. Record falsification
2. Potential hazards in product quality and safety
3. Problems in data integrity
4. Problems in process validation
5. Non-standardized material management with the risks in pollution, confusion and error.
6. Incomplete cleaning, which cannot effectively prevent contamination and cross-contamination.
(IV) Vaccine manufacturers
38 major deficiencies and 383 general deficiencies were identified.
Figure 3-4 Distribution of the Deficiencies of Vaccine Manufacturers identified in the inspections
1. Equipment. There was a too long stagnant water section between the stainless steel pipe valve through which water for injection preparation system enters into injection water storage tank and water generator; Individual device had rust.
2. Materials and Products. The quantity of the destructed items was not recorded in the destruction records of the non-conforming finished products; the enterprise failed to establish the background information of whole-genome sequence of main bacterial and viral seeds for production.
3. Documentation Management. Individual document was not specifically specified and was poor in its operability. The content specified in the document was inconsistent with the actual situation; individual record had incomplete content; the batch production records were unreasonably designed and were not timely filled in actual operation.
4. Quality Control and Quality Assurance
(1) Quality management of laboratories: the enterprise failed to request necessary test data and maps from the institutions conducting entrusted test; some material was subject to infrared test after sample mixing.
(2) the Deviation handling: The training and implementation of the documents related to deviation handling was not conducted; the enterprise failed to timely initiate the investigation for individual deviation; the reason analysis and corrective and preventive measures for a few deviations were not in place, and there was in adequate assessment on the potential impact of the deviations on the quality of products.
(3) Change control: The enterprise failed to handle the changes in accordance with change process and submit supplementary application for registration. There was no or inadequate assessment on some changes;
(4) Supplier management: There was incomplete auditing content for the suppliers of some materials, and the enterprise failed to determine the auditing content for suppliers based on the impact of the material on product quality.
(5) Product quality review: The enterprise failed to conduct annual quality review by varieties.
5. Computer System. The enterprise has developed document system for computer system management, but did not conduct classification management in accordance with the system, and did not take effective measures to reduce risks for the situation that existing conditions failed to comply with the document; there was no permission setting for the login screen of HPLC testing equipment in quality verification laboratory, and no measures to prevent the login by the unauthorized person.
(V) Blood product manufacturers
In the inspections on 25 enterprises, 13 major deficiencies and 241 general deficiencies were identified, and no critical deficiency was identified.
Figure 3-5 Distribution of the Deficiencies of Blood Product Manufacturers Identified in the Inspections
1. Institutions and Personnel. There lacked training for the personnel at some posts.
2. Premises and Facilities. The contamination and cross contamination cannot be effectively controlled.
3. Equipment. Some sensors failed to cover the actual use range; some instruments and equipment for testing were not regularly calibrated or insufficiently calibrated, and the records were incomplete; the equipment had no status identification and calibration identification.
4. Materials and Products. There lacked the source, validity period and other information on the label of the cryo in allocated supply, and the label was a card, which was easy to be lost and confused.
5. Verification and Qualification. In simulated filling test of culture media, sampling monitoring was conducted for both hands, forearms and chest of operators only after the production was over, and the sampling of clothes as well as the confirmation was not specified.
6. Documentation Management. The technological procedure and operating procedure was not specific in content, poor in operability and not standardized in the provisions..
7. Production Management. There lacked microbial control measures for the octylic acid sodium solution added before inactivation; The time to place the settlement plate under Level A laminar flow was not confirmed.
8. Quality Control and Quality Assurance
(1) Management of quality control laboratories: the machine account for the receiving and dispatching of tested products had incomplete content, and there was no receiving information of the test samples of intermediates and semi-finished products; the plate culture medium outsourced for environmental monitoring was not tested; negative control was not set for sterility test in accordance with the pharmacopoeia;
(2) Product stability study: Invalidity period was formulated for intermediate products, but there lacked the support of continuous stability investigation or validation data;
(3) Change control: Change control and management was not in place. Some changes were not or insufficiently assessed;
(4) Deviation handling: the enterprise failed to timely initiate the investigation for individual deviation; some deviation investigation and corrective and preventive measures were insufficient;
(5) Supplier management: The allocated suppliers of cryo was not included in the directory of qualified suppliers of the enterprise;
(6) Product quality review: Some information was not included in annual product quality review;
(7) Product delivery and recall: The enterprise failed to specify the shipment means for the sample in batch release;
(8) Computer System: there were incomplete documents for computer system, and there lacked comprehensive and effective control and assessment for internal computer system and relevant data. There was no auditing and tracking function for some instruments and equipment in QC laboratory; the system did not set access permission at different levels, and there was a risk of data and system modification; the safety and reliability of HPLC data transfer was not confirmed.
(VI) The manufacturers issued with Warning Letter in 2015
For the inspections on 32 manufacturers, a total of 2 critical deficiencies, 32 major deficiencies and 328 general deficiencies were identified.
Figure 3-6 Distribution of the Deficiencies of the Enterprises Issued with Warning Letter Identified in the Inspections in 2015
Main findings were as follows:
1. Problems in data integrity
2. No records and investigations for the deviations
3. There were certain problems in sterility guarantee and relevant verification and qualification work was inadequate.
(VII) The Sterile Drug Manufacturers Passing Provincial Certification
In the inspections on 21 enterprises, a total of 15 major deficiencies and 209 general deficiencies were identified, but no critical deficiency was identified.
Figure 3-7 Distribution of the Deficiencies of the Sterile Drug Manufacturers Passing Provincial Certification in Follow-up Inspections
The main problems identified manifested as: there is insufficient risk assessment for sharing production line in the production of small volume injection; there was cleaning validation for single variety, but no cleaning risk assessment for all the varieties; some inspection records had incomplete content; the validation and audit of computer system has not yet been carried out; materials were improperly managed, and there were risks of confusion and error.
(VIII) Special inspections on high-risk varieties
In the inspections on 61 enterprises, a total of 3 critical deficiencies, 64 major deficiencies and 658 general deficiencies were identified.
Figure 3-8 Distribution of the Deficiencies of High-risk Varieties Identified in Special Inspection
Main findings were as follows:
1. Ossotide injection
(1) The company bought 7 batches of foreleg bone from XX Co. Ltd., but failed to conduct procurement and acceptance inspection according to stipulations. The company failed to formulate procurement order according to procurement SOP. After the arrival of materials, the company failed to request and check the inspection report issued by the supplier in accordance with the SOP for the acceptance inspection, warehousing and storage of materials; for the acceptance inspection, the company failed to request temperature monitoring record of cold chain transportation of pig legs.
(2) The virus inactivation for the stock solution of compound ossotide was not validated; there was validation data to support that the four pig legs shall be stored for 25 days after requisition and the time from filling to sterilization initiation of compound ossotide injection is five hours; the time from the end of preparation to the end of the filling of compound ossotide injection was 10 hours, which lacked the microbial limit detection data.
(3) The continuous stability test scheme failed to set and inspect such activity indicators and related safety indicators as allergic experiment, pyrogen, and abnormal toxicity.
2. Fructose diphosphate injection
(1) The criteria for microbial limit in internal control standard of fructose diphosphate manufacturers failed to be revised in accordance with corresponding provisions in Chinese pharmacopoeia (2015 edition).
(2) For the compound enzyme reagent used for the content determination of the APIs of fructose diphosphate, the expiration date was December 2015. It was found in on-site inspection that the enterprise still used such enzyme reagent to conduct content determination of 14 batches of APIs of fructose diphosphate after the expiration date.
3. Citicoline sodium injection
(1) The inner quality standard for the APIs of citicoline sodium was unreasonably developed, and the item of toluene residue was not added with reference to the quality standard of APIs manufacturers.
(2) For the comparison of the content determination methods of intermediates and finished products of citicoline sodium injection, it was conducted only for the detection result of one batch and was not representative.
(3) The enterprise of citicoline sodium injection failed to conduct process validation for the APIs of different manufacturers respectively; the enterprise failed to provide compatibility test data of sterilizing filter for citicoline sodium injection.
Part IV Unannounced Inspection for Pharmaceuticals
I. Overview of Inspection
In accordance with the requirements for relevant departments of CFDA, based on the Working Procedure for Unannounced Inspection on Pharmaceutical GMP, a total of 45 unannounced inspection tasks from CFDA have been received in 2016, of which 39 unannounced inspections on Pharmaceutical GMP have been completed with the results reported, and others are on-going. The 39 inspections with the results reported involved 20 provinces (municipalities) including Beijing, Jiangsu and Guangdong etc., and covered 9 manufacturers of biochemical drugs, 20 manufacturers of TCMs, 9 manufacturers of chemicals and 1 manufacturer of blood product. The distribution was as follows:
Of the unannounced inspection tasks in 2016, 33 tasks were from the Department of Drug and Cosmetics Supervision of CFDA, and 6 tasks were from the Department of Drug and Cosmetics Registration and other departments of CFDA. The tasks from the Department of Drug and Cosmetics Supervision of CFDA accounted for 85%, which was the main source of unannounced inspection tasks. Among 39 unannounced inspections, the inspections on TCMs accounted for 51% of all the unannounced inspection work while that on chemicals and biochemical drugs accounted for 23%, respectively. In the unannounced inspection in 2016, 21 drug manufacturers failed, accounting for 54%. It was suggested to revoke the pharmaceutical GMP certificate of 14 enterprises and to open an investigation for 10 enterprises. The problematic products of 7 enterprises were ordered to be recalled. In pharmaceutical GMP unannounced inspection, TCMs and chemical drugs were identified to have more problems. All issues found in unannounced inspection have been dealt in accordance with the law.
Table 4-1 Handling of unannounced inspections
II. Main findings
(I) Main problems identified in TCMs manufacturers
In 2016, a total of 66 person-times in 18 teams of inspectorates were sent for unannounced inspections on 20 TCMs manufacturers, of which there were 6 manufacturers involving letter reporting, there were 3 manufacturers of calculus bovis factitious, 7 manufacturers of the products containing bezoar, 3 enterprises identified to have problems in exploration study and inspection and 1 manufacturer of prepared slices of Chinese crude medicines.
In the unannounced inspection on 20 TCMs manufacturers, 12 manufacturers failed to meet pharmaceutical GMP requirements, of which three manufacturers were transferred to provincial administration for handling relevant problems, one manufacturer was issued with Warning Letter, one manufacturer had no relevant production and three manufacturers met the requirements.
1. Chinese patent medicine manufacturers
(1) The problem of unauthorized changes to the process was prominent.
In order to reduce the production cost of oral preparation of Chinese patent medicine, the phenomenon of unauthorized changes to the pretreatment and extraction process is still a prominent problem. The unannounced inspections conducted this year were due to the problems identified in exploratory inspection, such as the enterprise failed to extract some Chinese herbal medicine in the prescription that should be extracted in accordance with technological procedure, but conducted a direct feeding after smashing.
(2) The Chinese herbal medicine and prepared slices of Chinese crude medicines was in disordered management.
In order to cope with the supervisory inspection by the drug regulatory authorities at all levels, individual manufacturer of Chinese patent medicine falsified machine account of warehouse materials and stock in and stock out record. The relevant machine account and records of the materials for internal operation in such enterprises can correspond to each other, but failed to respond to the invoice or voucher for the purchase. Or, such enterprises took advantage of such policy that the Chinese herbal medicine can be purchased directly from farmers, reversely inferred the usage of Chinese herbal medicine from the production of Chinese patent medicine, and then fabricated the machine account of materials according to the demand.
(3) The purchased Chinese herbal medicine and prepared slices of Chinese crude medicines were not subject to strict full inspection and the data integrity was doubtable.
Traditional manufacturers of Chinese patent medicine have many varieties of products and involve may varieties of Chinese herbal medicine and prepared slices of Chinese crude medicines. Because the precision analysis instruments and QC personnel equipped were not adapted to the scale of production, it cannot be ensured that each batch of the purchased Chinese herbal medicine and prepared slices of Chinese crude medicines can be inspected, resulting in no full inspection for the Chinese herbal medicine and prepared slices of Chinese crude medicines of some batch, or using a graph for multi-purpose to deal with the inspection.
2. Calculus bovis factitius
Because calculus bovis factitious is marketed under the classification of “Medicinal Materials and Prepared Slices” in the Chinese pharmacopoeia, it belongs to raw materials for Chinese patent medicine, resulting in that relevant enterprises cannot organize the production in accordance with pharmaceutical GMP requirements. In particular, there were seriously insufficient requirements for the auditing and management of the suppliers of upstream industry chain of calculus bovis factitious, causing that hygienic conditions of processing site were bad, the raw materials could not be traced and the processing process was uncontrollable. Main fingings:
(1) The management of suppliers was weak.
(2) The authenticity of microbial limit test was doubtful.
(3) It failed to be included in quality assurance system.
3. Prepared slices of Chinese crude medicines
A variety of information showed that the dispensing for sales was very common for the prepared slices of Chinese crude medicines outsourced. The problems in content determination of purchased Chinese herbal medicines or process products were prominent, dyeing and weight increment problems occurred occasionally, and authenticity of batch production records was doubtful.
(1) Untruthful batch production records.
(2) Being suspected of dispensing and sale of outsourcing prepared slices.
(3) Authenticity problems in data integrity.
(II) Biochemical drugs
1. Inspection on " monosialotetrahexosylganglioside sodium”
In 2016, a total of 4 manufacturers of " monosialotetrahexosylganglioside sodium” were inspected, and it was found that there was certain risk in the management of the quality of raw materials and the pig brain suppliers.
(1) Supplier management shall be improved, for the management of suppliers by the enterprise cannot ensure effective traceability.
(2) There was insufficient management of electronic data of the monitoring of cold chain transport of pig brain.
2. Inspection on " hepatocyte growth-promoting factors for injection”
In 2016, a total of 4 manufacturers of " hepatocyte growth-promoting factors for injection” were inspected, of which 2 manufacturers had their Pharmaceutical GMP Certificate revoked while 2 manufacturers were issued with Warning Letter.
(1) Fabricate the record file.
(2) Problems in data integrity
(3) Inconsistency with registered production process
(4) Unable to effectively ensure the quality of the liver as raw material.
Part V Overseas Inspections for Imported Pharmaceuticals
I. Overview of Inspections
(I) Overview of annual inspection tasks
The total number of CFDA Overseas Inspection was 49 inspections.
Figure 5-1 Amount of Overseas Inspection Tasks in 2011-2016
(1) The inspection tasks in 2016 involved 19 countries. There were relatively more varieties in Europe and North America, the varieties of such countries with high regional quality risks as India and Vietnam account for certain proportion, and at the same time, the inspection on the varieties in South America and Australia was also intensified.
Figure 5-2 Country Distribution of Planned Inspection Tasks in 2016
(2) The inspection followed the principle that inspection shall serve the evaluation and approval and took into consideration the safety requirements for the marketed products. The proportion of the varieties under review was increased, and the product under application for clinical trials, application for production and re-registration and in the stage of supplementary application shall all be included in the scope of inspection. The reason for the inspection on the marketed products was mainly port quality inspection problems. The iodoprestamine injection, a variety with high risks in adverse reaction monitoring manufactured by a foreign company, was added for inspection.
Figure 5-3 Registration Status of Inspection Tasks in Recent Years
(3) The inspection tasks were characterized as comprehensive varieties and broad dosage forms, and the extended inspection on chemical preparations was intensified. 40 chemicals were involved, including injections, solid preparations, implant and nasal sprays, of which there were 3 biochemical products, 6 APIs for extended inspection; 11 vaccines, blood products and therapeutic biological products; and 4 botanical drugs.
Figure 5-4 Classification of Inspection Tasks
(II) The implementation of the inspections in 2016
Due to the inspection tour of CFDA and CFDI in the first half year, the change in relevant foreign affairs and production arrangement of enterprises, CFDI submit the inspection tasks of 37 varieties throughout the year: the inspection tasks of 15 varieties have been completed, of which on-site inspection was conducted on 7 varieties, and three of them failed, accounting for 42%; the enterprises of 8 varieties proactively withdrew the import registration certificate or had their application returned during the organization of the inspections, account for 17% of total annual plan. For another 21 varieties, due to production scheduling of enterprises, the inspection is scheduled to be completed in the first quarter of 2017, and relevant formalities of foreign affairs are being dealt with. For the other 12 varieties, because the enterprises cannot accept inspection in the first quarter of 2017, CFDI has reported to the Department of Drug and Cosmetics Supervision to include them in the overseas inspections in 2017.
Figure 5-5 The Situation of the Inspections in 2016
II. Main findings in overseas inspections
Among 7 varieties that have been inspected, three varieties failed, and the failure rate was slightly increased compared with previous years. 117 deficiencies have been identified in the inspections, of which there were 3 critical deficiencies and 18major deficiencies. The problems mainly focused on Quality Control and Quality Assurance, Material System and Change Management; and critical deficiencies were mainly the problems in the consistency of production process and data integrity. All issues found in overseas inspection have been dealt in accordance with the law.
Figure 5-6 Summarization and Analysis of the Deficiencies Identified in the Overseas Inspections in 2016
Main and serious problems were as follows:
1. Actual production process and production site was inconsistent with those in registration application and major changes were implemented without submitting application in China.
2. There were significant problems in data integrity, which serious affected the product quality.
3. There were an increasing number of varieties handled by off-site inspection.
Part VI GSP unannounced inspection
I. Overview of Inspections
In 2016, China Food and Drug Administration conducted centralized remediation on illegal distribution behaviors in drug circulation field, further reorganized and regulated drug circulation order through self-inspection and rectification by enterprises, supervision and inspection by provincial administration and unannounced inspection by CFDA and cracked down illegal distribution behaviors. Throughout the year, 3 batches of inspections have been conducted on 53 pharmaceutical wholesalers. The results of unannounced inspections were announced by CFDA.
Table 6-1 Information of annual tasks of pharmaceutical circulation inspection in 2016
The teams of inspectorates conducted unannounced inspection on relevant enterprises based on the Announcement of CFDA on Remediating Illegal Distribution Behaviors in Drug Circulation Field (2016 No.94) and Good Supply Practice for Pharmaceuticals. It was identified in the results that the violations were very common in drug circulation enterprises, and the situation was as follows.
Figure 6-1 Results of unannounced inspection on 53 pharmaceutical wholesalers
II. Main findings
(I) The situation of violations of CFDA Announcement No.94
Table 6-2 The situation of violations of CFDA Announcement No.94 by enterprises identified in unannounced inspection in drug circulation enterprises
Figure 6-2 Distribution of the Clauses in Announcement No.94 Violated by Enterprises
1. Fail to store and transport the drugs and monitor the temperature and humidity in accordance with the regulations.
2. For purchase and sales of drugs, the certificate (license certificate), bills (invoice, the sheet along with the goods), account (materials account, financial account), goods (drugs) and money (payment for drugs) cannot be corresponding to or consistent with each other; fail to warehouse the drugs with concealed accounts established, fail to manage the drugs after including them into quality management system, use personal account to conduct business dealings, and other situations.
3. The enterprises falsified the source for drug procurement, fabricated sales flow of drugs, tampered the data of computer system and temperature and humidity monitoring system, and concealed the real drug purchase-sales-storage records, bills, voucher and data, the drug purchase-sales-storage records were incomplete and untruthful and distribution behaviors were untraceable.
(II) The situation of violation of Good Supply Practice for Pharmaceuticals (GSP) of CFDA by enterprises
Figure 6-3 The Distribution of GSP Deficiencies in Unannounced Inspections in Drug Circulation Field
Figure 6-3 Distribution of the Deficiencies of GSP Violations by Enterprises
The GSP deficiencies of drug circulation enterprises mainly focused on the General Provisions, Storage and Maintenance, Sales. The main problems were:
1. Fail to conduct business in accordance with the law and have false and cheating behaviors.
The enterprise changed the registered business address without authorization; established warehouses to store drugs beyond the scope of business license; provided conditions for illegal distribution of drugs; falsified the procurement source and sales flow of drugs; concealed bills and provided false materials; provided untruthful self-inspection report; falsified tax return; and tampered temperature and humidity monitoring data.
2. Fail to store the drugs in accordance with regulations and fail to conduct effective monitoring and control of the temperature and humidity of warehouse.
3. The bills, account, goods and payment was inconsistency for the purchase and sales of drugs, and the enterprise failed to implement national regulations for the sales of special medicines.
Part VII GMP Observation Inspection by Foreign Organizations
I. Overview of Inspections
Based on the requirements in the letter from the Department of International Cooperation of China Food and Drug Administration, CFDI organized to complete 81 observation inspections on pharmaceutical manufacturers in 2016, involving 76 manufacturers, covering 20 provinces (municipalities) including Zhejiang and Shandong etc., of which Zhejiang, Shandong, Jiangsu, Guangdong, Hubei, Hainan and Hebei accounted for 80%, which was basically consistent with last year, but the proportion of each province showed a slight change.
Figure 7-1 Distribution of Foreign Pharmaceutical Observation Inspections in Provinces (Municipalities) in 2016
In 2016, the inspection organizations involved in the observation inspection included 12 international organizations or foreign drug regulatory authorities, such as World Health Organization (WHO), European Directorate for Quality Medicines (EDQM), United States Food and Drug Administration (US FDA), Germany BGV, Agência Nacional de Vigil?ncia Sanitária (ANVISA) and French National Agency for Medicines and Health Products Safety (ANSM). Nine pharmaceutical manufacturers were identified with critical deficiencies and failed the on-site inspections by foreign regulatory authorities / inspection organizations (accounting for 11%).
Figure 7-2 Fails in Foreign Pharmaceutical Observation Inspections in 2016
Compare with that in 2015, the fail rate was slightly increased. Among 9 enterprises failing in the inspection, most critical deficiencies involved the problems in data integrity (including conducting repeated tests until qualified, conducting tests after changing system time, deleting data, deleting the audit and tracking records, selectively using data, modifying the name of the electronic data, test sample injection, failing to record timely, untruthful records, loss of data and records, insufficient file record control, etc.), and some enterprises involved such aspects as unreasonably developed material standards and inadequate measures to avoid cross contamination. Overall, the problems in the data integrity is relatively prominent and were also the main reasons for the increase of fails of domestic enterprises in foreign inspections in 2016, which also reflects the change tendency of the current drug inspection.
The observation inspections this year involved a total of 172 drugs, including 119 APIs, 23 oral solid preparations, 19 injections，5 biological products and 6 other products. Of the 81 inspections, there were 62 inspections involving APIs, accounting for 69%, and there were 12 inspections involving oral solid preparations, accounting for 13%. Of the drugs involved, APIs had the largest proportion, followed by oral solid preparations, and there was relatively less export of other dosage forms. Compared with that in 2015, the proportion of other dosage forms (including sterile products and biological products) receiving inspection increased, from 10% in 2015 to 18% in 2016.
Table 7-1 Distribution of Drug Types in the Inspections by Different Inspection Organizations
Figure 7-3 Distribution of Inspections in Different Dosage Form
II. Main findings
The 1108 deficiencies were identified and recorded in the observation inspection in 2016. It was identified in the classification analysis on the deficiencies based on Chinese GMP (2010 version) that: the deficiencies in six categories including Quality Control and Quality Assurance, Documentation Management, Equipment, Materials and Products, Verification and Qualification and Premises and Facilities accounted for 88% of all the deficiencies. Compared with those in 2015, the deficiencies in Documentation Management increased from the 4th place to the second place in terms of its ranking and still showed an increase of 7% (from 10.5% to 17.3%) under an atmosphere that enterprises are gradually strengthening the management of data integrity, fully reflecting the concern extent and strict requirements for data integrity in currently foreign inspections.
Figure 7-4 Distribution of the Deficiencies Identified in Pharmaceutical GMP Observation Inspection by Foreign Organizations
In pharmaceutical GMP inspections by foreign organizations, the deficiencies in “Quality Control and Quality Assurance” topped the list, accounting for 27.3%. Main problems focused on the management of computerized analysis instruments in the laboratory, deviation handling and CAPA, product quality review, change control, OOS/OOT result processing, the laboratory’s failing to meet the provisions for control procedure, microbial inspection management, quality risk management and stability test. The deficiencies in “Documentation Management” ranked the second, mainly focusing on four aspects including the completeness and traceability of records, life cycle management of documents, document completeness and record operation. The deficiencies in “Equipment” ranked the third, of which the deficiencies in the using and cleaning, calibration, maintenance and repair of equipment and water preparation system accounted for 83.6%. The deficiencies in “Materials and Products” focused on supplier management, identification of materials and products, process management of materials, compliance with material and product standards and release management. The deficiencies in “Verification and Qualification” mainly included the scientificity of validation, validation management and validation documents and records. The deficiencies in “Premises and Facilities” mainly included environmental control, management of storage area, the measures to prevent pollution and cross-pollution and life cycle management of premise and facilities.
III. Analysis on pharmaceutical GMP inspection of different organizations
In terms of inspection content, there was certain difference in the inspection focus among different pharmaceutical GMP inspection agencies, but it was found in the analysis on the deficiencies identified in the observation inspections in 2016 that there were relatively more deficiencies in six aspects including Quality Control and Quality Assurance, Documentation Management, Equipment, Materials and Products, Verification and Qualification and Premises and Facilities. As for the number of deficiencies in the final inspection report,
EDQM and WHO proposed more deficiency data, averaging 20 deficiencies in each inspection. For each deficiency, the problems identified during the inspection have been described. After the finish of inspection, such problems have been organized for preparing final inspection report (usually a month). US FDA proposed relatively less deficiencies in the inspections, averaging 7 deficiencies in each inspection, and did not take all the problems identified during the inspection as final deficiencies. The inspectors proposed the final deficiencies after the judgment based on the problems identified in combination with the product risks, and notify the enterprises in written form (Table 483) when holding the last inspection meeting.
（Note:The English version of this report is for reference only）