Main findings:

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.

　　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.

　　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.

　　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.