Prequalification of Medicines Programme. WHO PUBLIC INSPECTION REPORT (WHOPIR) API Manufacturer

Transcription

1 Prequalification of Medicines Programme. WHO PUBLIC INSPECTION REPORT API Manufacturer WHO PUBLIC INSPECTION REPORT (WHOPIR) API Manufacturer Part 1: General information Name of Manufacture Unit number Zhejiang Huahai Pharmaceutical Co Ltd East Zone, Chuannan Site Production block Workshop N 5 Physical address Coastal Industrial Zone, Duqiao, LINHAI, Zhejiang, , China Contact person and address Mr.Jenson (Cunxiao) Ye Zhejiang Huahai Pharmaceutical Co., Ltd. jenson@huahaipharm.com Date of inspection 7 to 10 April 2014 Type of inspection Routine inspection Active Pharmaceutical Ingredient(s) included in the inspection Summary of the activities performed by the manufacturer Nevirapine (APIMF76) Manufacturing and quality control of Non sterile APIs 1

2 Part 2: Summary General information about the company and site Zhejiang Huahai Pharmaceutical Co. Ltd. was established in January 1989 with corporate address Xunqiao, Linhai, Zhejiang Province, , China and, since listing on the Shanghai Stock Exchange from March 2003, is a public limited company. The site inspected is located in the Coastal Industrial Zone in Duqiao after ground breaking in October 2003, was put into use in The Chuannan site is divided into East Zone and West Zone through a central plaza. Of the 34 planned workshops, 25 were in use at the time of inspection. 18 workshops in East Zone have now been devoted to chemical production of APIs. The production block, where Nevirapine API was manufactured, is located in the East Zone at the time of inspection staff was employed at the site at the time of inspection. Zhejiang Huahai Pharmaceutical Co. Ltd. manufactures a range of APIs at the Chuannan site, but they have stated that no beta-lactams, steroids or hormones are handled on the site. History of WHO and/or regulatory agency inspections The site was licensed by the Chinese Food and Drugs Administration. This was the second inspection conducted by WHO PQP; the first being in September The site had also been inspected and approved by the BGV (2011), ANVISA (2012), CFDA (2012) and Mexico authority (2013) since last inspection. Focus of the inspection The inspection focused on the production and control of Nevirapine API. The inspection covered all the sections of WHO Good Manufacturing Practices for Active Pharmaceutical Ingredients. Topics include premises, equipment, documentation, control of materials, validation, sanitation and hygiene, production, quality control and utilities. 2

3 Inspected Areas Day 1 Opening meeting Confirmation of Inspection Plan Presentation by the Company about the site, Company profile, manufacturing capabilities, and location of the production of the various APIs. Inspection history Site layout Process Description Raw materials and FG warehousing Utilities location Documents Personnel Job Descriptions Quality Unit Product Quality Review (PQR) and related SOP Quality Risk Management, Change Control and deviation CAPA Management System Day 2 Feedback from Day 1 Inspection of Warehousing Receiving sampling Solids Drum liquids Bulk solvents Corrosive materials Water sensitive materials Charcoal Finished Products (quarantined and approved) 3

4 Workshop 5 Technical Area Controlled area Day 3 Feedback from Day 2 Documents: Training Job Description-Production Supplier Approval Assessment of Contractors Handling rejected API starting materials Product release BMR review Complaints and Recalls Reprocessing and Reworking Reactor Qualification Self-inspection Purified Water System qualification and test results Quality Control Laboratories Chemical and Physical Lab: Sampling and sample handling, work allocation, Specifications and test methods, SOPs, logbooks, records, worksheets and test reports, Stability program, OOS results, evaluation of results, Release and rejection procedures, Chemicals and reagents, Reference standards, Retention samples, Equipment, instruments and devices 4

5 Microbiology Lab: Facility, media preparation, test procedures and results, OOS Day 4 Documents Process Validation Cleaning Validation Batch testing record review Engineering - Preventive maintenance Calibration and maintenance procedure Summary of the observation for the day Closing meeting with company representatives 2.1 QUALITY MANAGEMENT The quality management system was generally well established, documented and implemented. The site organizational structure was reviewed and was acceptable. Quality-related activities were defined and documented. The Quality Assurance department was independent from production. The persons authorized to release intermediates and APIs were specified. Responsibility of Quality Unit Responsibilities of the Quality Unit were defined in written documents. Responsibilities included all those required in the WHO GMP Guidelines. Job Descriptions of QA Manager and QA Assistant Director were reviewed and were acceptable. Responsibility for product release was with the QA Manager. In the absence of the QA Manager, products were released by the QA Assistant Director. 5

6 Responsibility of Production Unit Responsibilities of the Production Unit were described in SOP. Included were the requirements of the WHO GMP Guidelines. The Job Descriptions for Deputy Plant Director and Production Manager in charge of the East Blocks and the manager for Workshop 5 were reviewed and acceptable. Self-Inspection The Self Inspection Management Procedure was described in SOP. Corporate QA conducted annual inspections and the local QA department conducted monthly inspections. Follow-up of corporate inspections was conducted locally. The latest local inspection was on 11/03/14. The summary table of findings showed a CAPA completion of 15/04/14. The procedure and implementation were adequate. Product quality review (PQR) PQRs were conducted on an annual basis according to SMP of Annual Product Review Management System. The required elements had been considered and documented, and were generally found acceptable. However, the procedure was not clear whether the product PQR should cover the different grades of the same API or whether they should be reviewed separately. There were three different grades of Nevirapine manufactured: C5021 Chinese Pharmacopeia grade C5028 USDMF/WHO C5023 USP 2012 and 2013 APQR for Nevirapine were reviewed. OOS, OOT, deviations, changes, validation studies stability, complaints, recalls and returns were reviewed. Details were given of intermediates and also starting materials. Utilities, including the Purified Water System, were reviewed with details in specific documents. The PQR contained references to these documents. 6

7 Quality Risk Management Elements of risk management were referred to in the SMP of Quality Risk Management. 2.2 PERSONNEL Personnel qualifications According to the SMF, key personnel were suitable qualified with appropriate tertiary qualifications and experience in the manufacture of API products. Training The Corporate Training System was described in an SOP. Human Resource Department was in charge of compiling and implementing the training programme and QA were responsible for the content of the GMP training. The 2013 plan showed GMP training was held in May New employees were required to attend training session in GMP and each employee is provided with their own copy of ICH Q7 Guidelines. The training of the Manager of Workshop 5 was reviewed. Details were recorded. For major topics in a training session, assessment was conducted by a written test with a pass mark. Minor issues were assessed by oral tests. Personnel Hygiene Direct contact with intermediates or APIs was avoided. Overshoes and gowning were required in areas where product was exposed. Hand washing was required before entering these areas. 2.3 BUILDINGS AND FACILITIES Design and construction Buildings and facilities used in the manufacture of intermediates and APIs were located, designed, and constructed to facilitate cleaning, maintenance and operations as appropriate to the type and stage of manufacture. The final purification, drying and packaging for the inspected APIs was performed in grade D areas. 7

8 Warehousing Materials were handled in the Raw material Warehouses according to SMP Management Systems of API Material Supplies.. Different buildings were used for raw materials, packing materials and finished goods. Tanks for bulk solvents were installed in a bunded area. Finished Goods were stored in a room controlled at C and not more than 75% RH. Readings were recorded. A hotspot had been identified. Standards were generally adequate. Workshop 5 Workshop 5, which was inspected, was dedicated to the manufacturer of two different products Nevirapine and Hydrochlorothiazide. In general, the building was adequate for the activities carried out. Utilities Cooling and nitrogen systems and auxiliary power generation equipment were installed in the specified buildings. Steam was supplied from a central generation plant feeding the industrial area. Each workshop was equipped with its own compressed air supply. Compressed air was not used in direct product contact. These utilities were not covered by this inspected. Rodent and pest control was the responsibility of each department as described in SOP. No poisons were used. Traps and insectocutors were observed to be installed as appropriate. 8

9 Water Purified water was used in the final purification of Nevirapine and as part of the equipment cleaning procedure. For intermediate steps process water (incoming potable water) was used. The operation of the Purified Water System was as described in SOP of Equipment Maintenance Procedure of Purified Water System. Sanitisation was conducted by the use of ozone. The procedure, and removal of residual ozone before purified water was used, has been validated. The loop was equipped with two pumps, one to be used and the other on standby. During sanitisation, both pumps were in operation. Records of sanitisation and cleaning were kept in a QA-controlled logbook. Air Handling Unit (AHU) Five AHU systems had been installed in Workshop 5. System AHU K1 was chosen as an example of one such system supplying the Class D (controlled) section of Workshop 5 where the final crystallisation, isolation and milling of Nevirapine were carried out. Three extraction systems were associated with AHU K1. Maintenance Workshop The maintenance workshop appeared to be adequately equipped but there were some housekeeping issues. These are discussed below. 2.4 PROCESS EQUIPMENT Design and construction Equipment used for the APIs within the scope of the inspection was generally of a good standard and suitable for intended use. Where necessary to prevent crosscontamination, the equipment used to produce Nevirapine in chemical area and the blender in clean area were dedicated. The other equipment including for final purification were shared with Hydrochlorothiazide. 9

10 Equipment maintenance and cleaning Equipment was maintained by the engineering department according to SOP Periodic Maintenance Requirements of Production Equipment and other specific SOPs for each type of equipment. For example, there was an SOP for Maintenance Procedure of Reactor. Specific items to be checked were detailed, such as checking for corrosion, agitator drive assembly oil and mechanical seals. A schedule of equipment requiring maintenance and requirements for each equipment was documented. As an example, the schedule, procedure and records for one reactor were reviewed. These were acceptable. Separate procedures were in place for the maintenance of associated equipment, such as heat exchangers and receivers. Relevant procedures were described in the SOP of Equipment Maintenance in Cleanrooms and Equipment Repair Provisions. This last SOP was concerned with maintenance requests. Details would be entered onto a specified form. Calibration Where necessary, measuring equipment was labelled with a calibration tag. All of those reviewed indicated that the calibration was within date. The system appeared to be working effectively. Process equipment was adequately installed and with product contact surfaces that were suitable for the tasks involved. Each piece of equipment was allocated a QAcontrolled logbook. The controlling procedure was as per SOP. Computerized Systems No computer systems were used in the warehouse and in production. All steps were manually operated and recorded. There was no central computer system in QC although individual pieces of equipment, such as the HPLC, had their own dedicated recording and calculating systems, all of which are off-the-shelf and have standard programmes. There was a simple data record system in QC in which results from the 10

11 lab work sheets are entered and this is then used to print out the Certificates of Analysis. 2.5 DOCUMENTATION AND RECORDS Documentation system and specifications SMP of Corporate Document System described the procedure for creating Quality Management System documentation, including SOPs. Requirements for authorizing documents were properly described. The procedure for regulation of files of production and quality management was described in an SOP. The SOP for computer system management of QC labs was reviewed and found acceptable in general. The observation regarding the control on the computer-generated data was discussed. The corrective action was made after the inspection and considered acceptable. Equipment cleaning and use record Procedures for cleaning equipment were available. Log books were maintained for major equipment. Records of raw materials, intermediates, API labelling and packaging materials All records reviewed relating to materials, including intermediates and APIs were acceptable in general. Master production instruction (master production and control records) Master production batch records for Nevirapine API were available. Similarly there were master QC worksheets. Controlled copies were used in production and in the QC laboratory for batch production and testing. Batch production records (batch production and control records) The in-process BMRs and the completed BMRs reviewed had been properly completed and were generally acceptable. 11

12 Laboratory control records The in-process QC records and the completed QC records reviewed had been properly completed and were generally acceptable. 2.6 MATERIALS MANAGEMENT General controls Suppliers of materials were required to be approved according to SMP Management System of API Material Suppliers. The purchasing department was responsible for identifying sources and procuring samples of three production batches of materials for critical raw materials, or a single sample for non-critical materials. QC would test and small scale trials conducted with QA reviewing all data and making the final decision. For Primary packaging, designated starting materials and final purification solvent(s) if required (as decided by QA) the suppliers sites would be audited. The manufacturing sites of other materials would be audited in the case of quality problems. For a supplier providing material with no quality or delivery problems, reauditing is conducted within five years. Receipt and quarantine Starting materials were received according to the SOP Material Warehouse Procedure. The procedure included cleaning of containers, a check for damage and a check for approved supplier. Sampling and testing of incoming production materials Sampling of starting materials was performed by QC personnel according to a documented sampling plan. Appropriate environmentally controlled sampling areas were available in the warehouses. 2.7 PRODUCTION AND IN-PROCESS CONTROLS There were no toxic or hazardous substances (including β lactams) handled on the site. The process equipment were designed and installed to facilitate logical flow of production. The last stages of the process were carried out in clean isolated areas. 12

13 Production operations Production operations in workshop 5 were inspected and generally found acceptable. There was a system to indicate the status of the equipment. Reactors were appropriately labelled with the batch in progress and the associated batch documentation was up to date. They were regularly cleaned and maintained according to approved procedures and records were maintained. Time limits Time limits were specified in the BMR where necessary. The SOP on holding time study for API and intermediates at in-process stage and holding time study of Nevirapine at in-process stages were reviewed and considered to be generally acceptable. In-process sampling and controls There were in-process controls conducted at appropriate stages of synthesis to monitor the quality of the intermediates and APIs. IPC testing to monitor the quality progress was carried out by QC, and there were written test procedures that describe how such testing should be carried out. 2.8 PACKAGING AND IDENTIFICATION LABELLING OF APIs AND INTERMEDIATES General Packaging and labelling operations were conducted as per standard operating procedures. Packaging materials were checked against the specifications; labels were generated from a computer data bank via a label printer. The containers and inside PE bags used to pack Nevirapine were fresh and not reactive, additive, or absorptive so as to alter the quality of the product and stability studies confirm that adequate protection was provided by the containers used. Containers for final product were not reused. 13

14 Label Issuance and Control Blank labels for each product were printed outside of the company; labels with product specific information such as batch number were produced as required in house and were issued for each batch separately. Labels used on containers indicate the name or identifying code, the batch number of the product, the retest date, the storage conditions and the name and address of the manufacturer. Packaging and labelling operations Packaging and labelling was performed in areas dedicated for this purpose. These areas were appropriately designed and classified, and routinely monitored. 2.9 STORAGE AND DISTRIBUTION The company had appropriate and separate storage warehouses and areas for starting materials, packaging materials, solvents, intermediates, and finished APIs. Appropriate records for stock and distribution for those monitored were maintained. The records of monitoring reviewed were acceptable. Packaging materials were stored in segregated areas with appropriate labelling and controls LABORATORY CONTROLS General controls The QC laboratories were responsible for physical, chemical and microbiological testing of starting materials, packaging materials, products (API s), environmental monitoring samples, purified water samples. Adequate laboratory facilities were available these being housed on three floors in the main administrative building of East Zone. There were dedicated rooms for activities like sample receipt and storage, wet chemistry, instrumentation, hot areas and balance room. The labs were clean and well maintained. There were adequate pieces of equipment with up to date calibration status. 14

15 Testing of intermediates and APIs Sample receiving and distribution were inspected and found to be well managed. QC testing was conducted as specified in the relevant specification and according to documented test methods. Samples for testing were kept in a designated area. The hardcopy and electronic test records for a selected batch of Nevirapine API were reviewed. The data security and access control of HPLC as well as procedure of manual data integration was reviewed. Corrective actions were made after inspection and considered acceptable. Primary pharmacopoeial reference standards were available and working standards prepared according to a corporate SOP. Stability monitoring of APIs The stability samples were taken according to the defined program/protocol and stored in a long-term 25 C/60% RH. The records for Nevirapine batches in the stability chamber were reviewed and found acceptable. Reserve/retention samples There was a designated temperature controlled area for storage of retention samples. Access to this area was restricted. A sample of each batch of API manufactured was kept here. Retention samples were stored in container systems that were comprised of the same materials as those used for the final API. Handling of out of specification (OOS) results The OOS/OOT handling procedure was available and considered to be acceptable VALIDATION The company had policy, procedures, protocols and reports for validation and qualification of processes, procedures, equipment, utilities etc, 15

16 Qualification Major pieces of equipment were qualified as per the written installation and operational qualification protocols before they were used in manufacturing processes. In general, qualification reports were available Process Validation Process validation for the production of Nevirapine was reviewed and had been conducted according to Protocol. All process stages had been included with a separate report for each. The conclusion was based on a summary report of the 3 batches and had been approved by all relevant personnel. Cleaning Validation The company had procedures, protocols and reports for the cleaning validation. The equipment used for manufacturing Nevirapine was dedicated to a large extent, except that the equipment used for purification at the final stage which was used for two different products. The validation data and report of the equipment used for final purification, has been reviewed. Cleaning Validation was conducted according to the SOP Cleaning validation (API). This SOP applied to all equipment. The equipment was first cleaned, ideally with water, but if this was not appropriate, a class 3 solvent. Class 1 solvents would never be used. Details were provided as to where swab samples should be taken. This included suitably annotated photographs. Qualification of Purified Water System At the time of the Inspection, the Water system qualification was described in SOP. Standards of installation and maintenance were satisfactory. The system was installed in 2005 and revalidated, following changes initiated in different years. Revalidation was being conducted at the time of the Inspection. Then a change regarding user points, raised in November 2013 will be implemented and a revalidation study started. An annual review was conducted using data up to the end of 2013 and 2014 data, up to the end of March, was also available. Results 16

17 were acceptable. For microbiological limits the alert and action limit were specified. Removal of ozone had been validated with the limit test conducted according to the Chinese Pharmacopeia 2010 edition. Reactor Qualification Reactors were qualified according to procedure SOP. There were requirements for DQ, IQ, OQ, PQ and a copy of the relevant Change Control form. There was also a reference to relevant training records CHANGE CONTROL The Change Control System was managed according to SMP. Incorporated was a Change Request Form. All departments were included. However, document changes not related to the content of specifications analytical methods or processes were handled according to the Corporate Documentation System SMP. All other documents were handled under Change Control REJECTION AND RE-USE OF MATERIALS Rejection Handling Procedures of Rejected (abnormal) Materials was described in the SOP, applied to purchased raw materials. QA had overall responsibility. An example was failed batches of toluene, which was rejected on the basis of benzene content being out of specification limit. The batch had been returned to the supplier but at the time of the inspection, no feedback had been received. The Purchasing department was attempting to find an alternative supplier. Reworking and Reprocessing Reworking and Reprocessing procedure were described in SMP Reprocessing and Reworking Management Procedure. This procedure applied to APIs and intermediates. It is understood that batches are never reworked. If reprocessing was required, the reprocessed batch number would have an R suffix. Based on QA evaluation, a reprocessed batch may be added to the stability programme. 17

18 Recovery of materials and solvents Recovery of solvents and materials at different stages of synthesis was done according to documented instructions and were tested to meet predefined specifications. Solvent recovery was done on site. The in house recovery processes were validated as part of the process validation. Recovered Toluene, ethanol and diglyme were used in the manufacturing process COMPLAINTS AND RECALLS Complaints Customer complaints were handled according to SMP Complaint Management Procedure. The complaint log book in 2013 were reviewed and found acceptable. Recalls Recalls were conducted according to SMP Product Recall Management System. QA are responsible for managing the product recall. Assessments were carried out according to the Risk management SMP. A Grade 1 risk would be one that might induce serious harm and a recall must be instigated within one day. A mock recall conducted in 2013 were reviewed and considered acceptable in general CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) No contract manufacturers or laboratories were used for Nevirapine by the company. Part 3: Conclusion Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, as well as the corrective actions taken and planned, API of Nevirapine (APIMF76) manufactured at Workshop N 5, Zhejiang Huahai Pharmaceutical Co Ltd, located in Coastal Industrial Zone, Duqiao, Linhai, Zhejiang, 18

19 317016, China was considered to be manufactured in compliance with WHO GMP for Active Pharmaceutical Ingredients. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the manufacturer, to a satisfactory level, prior to the publication of the WHOPIR This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive. 19