Prequalification Team Inspection services WHO PUBLIC INSPECTION REPORT. Haffkine Bio-Pharmaceutical Corporation Limited (HBPCL).

Transcription

1 Prequalification Team Inspection services WHO PUBLIC INSPECTION REPORT Part 1 General information Manufacturers details Company information Name of manufacturer Corporate address of manufacturer Contact person Inspected site Address of inspected manufacturing site if different from that given above Unit / block / workshop number Manufacturing license number Inspection details Acharya Donde Marg, Parel, Mumbai , Maharashtra, India. Phone: (24 hours), , Fax: qa@vaccinehaffkine.com Mr. Subhash V. Shankarwar, General Manager gmhaffkine@gmail.com Tel Extn- 206 Tel- (Direct) Dr S. S. Karnik Quality Assurance Manager Phone: (24 hours), , Fax: qa@vaccinehaffkine.com Acharya Donde Marg, Parel, Mumbai , MAHARASHTRA, INDIA. Global Positioning System (GPS) coordinates: , Oral Polio Vaccine Facility Manufacturing license number: N 5 in Form 28D as per Drugs and Cosmetic Act, issued by State Licensing Authority FDA and Drugs Controller General of India. Dates of inspection 12 to 14 and 16 September 2016 Type of Routine inspection inspection Introduction Brief summary of the manufacturing activities General Haffkine Bio-Pharmaceutical Corporation Limited (HBPCL) manufactures Oral Polio Vaccines starting from the blending of the sterile polio drug substances received from the subcontractor, filling, packaging, labeling, laboratory testing, storage, batch release and distribution of the bivalent Oral Polio Vaccines (OPV type 1 & type 3) and the monovalent Oral Polio Vaccine (OPV type 1). The Haffkine Institute was bifurcated by the Government in 1975, with a view to Page 1 of 13

2 information about the company and site expand the production activities to meet the growing demands for medicines and lifesaving drugs. The production activities were entrusted to the Haffkine Bio- Pharmaceutical Corporation Limited (HBPCL), a fully owned State Government of Maharashtra Undertaking, registered under the Companies Act, The Chairman & Board of Directors of the Company are appointed by the Government of Maharashtra state. HBPCL has expertise in the manufacture and supply of a wide range of Biological and Non-biological products comprising of Bacterial and Viral vaccines, Antisera, Toxoids, Injectable and Pharmaceuticals in the pursuit of its mission of "Service to Mankind in the Health Care Sector''. History The Company plays a pioneering role in the development and production of a wide range of Bacterial and Viral Vaccines i.e. diphtheria, tetanus, whooping cough, plague and poliomyelitis. The company has manufacturing experience of tablets, capsules, liquid orals & external use preparations like antiseptic creams and antiseptic liquids. In November 2004, NRA inspected the OPV facility, after renovation and granted approval for the manufacturing of OPV. In the Year , there was facility audit by WHO and recommended for acceptability of topv, filled by HBPCL, for purchase by UN agencies, in February 2006 and has been prequalified by WHO. In the year the facility was audited by WHO for mopv1 and was recommended to UNICEF, and it was accepted for mopv1, filled by HBPCL, for purchase by UN agencies, in December 2008 and supplied OPV vaccine to UNICFF. In the year 2010 the facility was audited by WHO for bopv (1 and3) and recommended for acceptability of bopv (1 and3), filled by HBPCL, for purchase by UN agencies, in March 2010 and supplied OPV vaccines to UNICEF. In the year 2010, a follow up site visit was conducted by WHO team related to assessment of acceptability of Live Oral Poliomyelitis vaccine (OPV, mopv1 & bopv 1 &3) filed by HBPCL for Procurement by UN agencies. In the year 2012, a follow up site visit was conducted by WHO team related to assessment of acceptability of Live Oral Poliomyelitis vaccine (OPV, mopv1 & bopv 1 and 3) filed by HBPCL for Procurement by UN agencies. In year 2013, an inspection was conducted by NRA team for verification CAPA submitted to WHO which relate to audit conducted by them in February 2012 and also for compliance verification as per annual central inspection plan of NRA. In the year 2014, an inspection was conducted by NRA team for verification of CAPA submitted to NRA for grant of WHO-GMP and also for compliance verification as per annual central inspection plan of NRA. Page 2 of 13

3 In the year 2016, an inspection was conducted by NRA team with respect to risk based approach for vaccine manufacturing facilities. Brief report of inspection activities undertaken Scope and limitations Areas inspected WHO product numbers covered by the inspection The inspection is related to the assessment of acceptability of live oral poliomyelitis vaccines filled by Haffkine Bio Pharmaceutical Corporation LTD (HBPCL) for purchase by UN Agencies. The inspection focused on the production including the blending of the sterile polio drug substances, filling, packaging, labeling, laboratory testing, storage, batch release and the distribution of the bivalent type 1 and type 3 as well as the monovalent type 1 Oral Poliomyelitis vaccines (OPV). Bivalent type 1&3 Oral Poliomyelitis vaccine Monovalent type 1 Oral Poliomyelitis vaccine Page 3 of 13

4 Abbreviations AHU Air Handling Unit ALCOA Attributable, Legible, Contemporaneous, Original and Accurate APQR Annual Product Quality Review APS Aseptic Process Simulation BMR Batch Manufacturing Record BPR Batch Packaging Record CA Compressed Air CAPA Corrective Actions and Preventive Actions CC Change Control CCID Cell Culture Infective Dose CFU Colony-Forming Unit CIP Cleaning In Place CoA Certificate of Analysis CPE Cytopathic Effect DQ Design Qualification EDI ElectroDeIonization EM Environmental Monitoring FMEA Failure Modes and Effects Analysis FTA Fault Tree Analysis GMP Good Manufacturing Practices GPT Growth Promotion Test HBSS Hank s Balanced Salt Solution HDPP High Density Polypropylene HEPA High Efficiency Particulate Air HVAC Heating, Ventilation and Air Conditioning IQ Installation Qualification LAF Laminar Air Flow LIMS Laboratory Information Management System MB Microbiology MBL Microbiology Laboratory MEM Minimum Essential Medium MF Master Formulae MFT Media Fill Test MR Management Review NCA National Control Authority NCL National Control Laboratory NRA National Regulatory Agency OPV Oral Poliomyelitis Vaccine OQ Operational Qualification PHA Process Hazard Analysis PM Preventive Maintenance PQ Performance Qualification PQR Product Quality Review Page 4 of 13

5 PQS Pharmaceutical Quality System PW Purified Water QA Quality Assurance QC Quality Control QCL Quality Control Laboratory QMS Quality Management System QRM Quality Risk Management RA Risk Assessment RCA Root Cause Analysis RO Reverse Osmosis SIP Sterilization In Place SOP Standard Operating Procedure TAMC Total Aerobic Microbial Count UN United Nations UNICEF United Nations Children's Fund URS User Requirements Specifications UV Ultraviolet-Visible Spectrophotometer VVM Vaccine Vial Monitor WFI Water for Injection WHO World Health Organization Page 5 of 13

6 Part 2 1. Pharmaceutical quality system Brief summary of the findings and recommendations (where applicable) In general, the pharmaceutical quality system (QMS) and all of the elements were in place. The quality management organizations of the company include quality assurance department (QA) and quality control department (QC). The production is independent from the quality control department. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the QMS. Quality risk management (QRM) Procedures for performing quality risk management were in place. QRM examples were spot checked. However, this aspect of the QMS was fairly basic and requires further utilization for fuller maturity and to make best use of resources. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the QRM. Change Control (CC) Procedures for change control management were implemented. Changes were categorized as major, moderate and minor. Timelines for change control implementation were in place. The list of change control was reviewed and change control reports were spot checked. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the change control management. Deviations management Procedures for deviation management were in place. There were no defined timelines for handling of deviations and no trending of the deviations was in place. There was a definition and a categorization of the deviations (critical, major and minors) however there was no definition of incidents. According to the company, the incidents occurring during the manufacturing operations were not recorded and not reviewed; e.g. according to the company staff, a jar of drug substance that falls on ground would not be recorded as incident. The list of the deviations has been presented; only few deviations were reported. The deviation reports were spot checked. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the deviation handling. Product quality review (PQR) Provisions for Product Quality Reviews were in place. Since 2010, no batch of mopv was manufactured and therefore no PQR of mopv were available. The PQR of bopv covering the manufacturing period from 1 st April 2015 to 31 March 2016 (112 batches of topv and 201 bopv) was spot checked. The timeline for approval of the PQR was not mentioned in the SOP. A Page 6 of 13

7 capability of the process was performed annually for the titer. Trend analysis for potency was performed on a monthly basis using Excel build charts for graphic representation and Systat software for statistical analysis. There was a monthly review of the test results however for each month separately. There was no trending of the IPC and the other quality control test results. Rejections related to visual inspection defects were not trended. The results are presented in Excel sheets with 3 standard deviation (SDV) for titer. No other trending tools were in place. Some of the results were borderline with the established specifications and this was not documented and discussed. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the PQR. Process for Lot Release Provisions for lot release were in place according to the implemented procedure. All lots are subject to the official release by the National Control Laboratory (NCL), the Central Drug Laboratory, Central Research Institutes, Kasauli. The batch release at the company is performed provided that the official batch release certificate from the NCL is received. Batch Manufacturing Record Review The batch manufacturing record (BMR) is issued and the date of issuance is recorded. The Batch Processing Records were spot checked. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the good documentation practices of the batch records. 2. Good manufacturing practices for pharmaceutical products 3. Sanitation and hygiene In general terms, resources were available, including trained personnel, premises, equipment and services, approved procedures and instructions, laboratories and equipment for in-process and other controls. Manufacturing processes, instructions and procedures were generally defined and available including materials, containers and labels. Qualification and validation of equipment, manufacturing processes and quality control testing methods were considered. Operators were trained to carry out procedures, and records were made for production. The operations were essentially compliant but a number of areas need further improvement to be in compliance with WHO GMP guidelines. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues. The company had provisions for personal hygiene and sanitation in its production facility. Smoking, eating, drinking, chewing, and keeping plants, food, drinks, smoking material and personal medicines was not permitted in production, laboratory and storage areas. Wrist-watches, cosmetics and jewelry were not observed as being worn in clean areas. Manufacturing areas are provided with airlocks for personnel and materials entries and exits. Gowning procedures for access to the classified manufacturing areas were in Page 7 of 13

8 place. Changing rooms were provided instructions describing the gowning procedures. In general terms, the level of hygiene observed and the measures taken to maintain this were considered satisfactory. 4. Qualification and validation In general terms provisions for qualification and validation were in place and covered premises, equipment, utilities and processes and procedures at periodic intervals and when major changes have been made. Protocols and reports of the validation and qualification were in place. The validation and qualification protocols and reports were spot checked for the following systems including sterile filtration of bopv, cleaning validation of the product contact surfaces vessels, cleaning and sanitization, depyrogenation tunnel, pure steam, autoclaves, aseptic processes validation, manufacturing process validation and the validation of the Hanks solution preparation, sterilization, cooling and blending. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the qualification and validation. Preventive maintenance (PM) Preventive maintenance was performed as per implemented procedures. The maintenance was performed monthly by the maintenance department for the equipment identified as critical. The definition of critical equipment was not defined in the SOP. The labels indicating dates of last and due maintenances of the equipment were not available. The log books of the equipment were not all containing the information regarding the preventive maintenance for record and verification purposes. The company has diesel generators as backup power supply and critical equipment have also Uninterrupted Power Supply systems and these are controlled each month. The volume of the pipettes for sampling were either controlled by a subcontractor or in house as per the implemented procedure however there were no instructions on the measures to be taken in the case of a confirmed failure for a pipette delivering a wrong volume. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the preventive maintenance. HVAC System Every 6 months the grade A LAFs were re-qualified and the classification was performed at rest and in operation with simulated activities. Water System The P&ID was reviewed indicating a loop of purified water at room temperature produced by RO and EDI which is also the source of WFI produced by distillation and circulating at around 90 C. Page 8 of 13

9 The sampling plan for potable, PW and WFI requires a daily control for the critical user points at the Hanks preparation area. The water microbial results trend showed no excursion. 5. Complaints Provisions for handling of the market complaints were implemented. Received product complaints were investigated by the QA. The complaints were bifurcated into product packing complaints and product quality complaints. The complaints were classified as critical, major and minor. In case of critical complaints / AEFI complaints, medical opinion is considered and the investigation could lead to the product recall if necessary. The complaint is informed to the local FDA authority and & concerned regulatory authority along with the action taken and records are maintained. 6. Product recalls Provisions for recall were in place as per the implemented procedure. HBPCL has 2 major clients Government of India (GOI) and UNICEF. Provisions for AEFI were in place as per the implemented procedure. The last AEFI recorded was in March Contract production, analysis and other activities 8. Self-inspection, quality audits and suppliers audits and approval OPV monovalent bulk was imported from M/s. P.T. BioFarma, Bandung, Indonesia. The Oral Polio monovalent bulk was received in cold chain along with the detailed manufacturing and test protocols including neurovirulence test results, Certificate of Analysis and release certificates from the National Agency for Drug an Food Control (NADFC/BPOM) of Indonesia. Provisions for self-inspection were in place according to the implemented procedures. The SOP Self audit and corrective action was spot checked. The auditors were qualified based on the experience and practical observation of the audit process. A full audit of OPV manufacturing activities was performed every six months and the planning during the last 3 years was available.. Supplier qualification Provision for vendor registration, audit and approval were described as per the implemented procedures including the raw material, packaging material and other materials and services suppliers. A questionnaire comprising GMP aspects is sent to the suppliers before proceeding to the vendor on-site audit. Received questionnaires are assessed by the vendor audit team. The vendor audit team comprising of QA, QC, Production and Material Management team, perform the site audit of the vendor for evaluation. Accordingly, the approved vendors are included in the approved vendor list from which the material can be order purchased. The list of critical materials with approved supplier and their audit dates was spot checked. The suppliers of critical materials were audited on three-year basis. 9. Personnel Organizational chart showing the relationships between different areas including quality assurance, production and quality control, with identification Page 9 of 13

10 by name and title of key personnel has been provided in the site master file and during the briefing meeting. Personnel training: Provisions for basic and ongoing training were in place. The revised Training Plan for 2016 was spot checked. General training and department training were planned. Training of the staff for critical operations were conducted and evaluated, such as aseptic media fill and aseptic behavior trainings for polio department. Training on data integrity and Good Documentation Practice were performed in Aug General principle of WHO TRS 986 Annex 5 was referenced in the training, the company stated that the SOP of data integrity and the Good documentation practice was drafted however not yet implemented. Personal health and hygiene: All personnel undergo health checks annually, and the new staff undergoes physical examination prior to the employment. The vaccination registration for the staff was established, and the persons were vaccinated with appropriate specific vaccines and have regular health checks. 10. Premises and Equipment Overall, the premises and equipment used in the production of OPV vaccines at Haffkine (HBPCL) site were considered suitable for the operations to be carried out. The company has provided the Site Master File with relevant documentation regarding the OPV manufacturing process, buildings, equipment, materials and personnel flows, utilities and maintenance plans. In general terms, the premises were designed to ensure flow of materials and personnel in order to reduce contamination, cross contamination and mix ups during the production of the monovalent (type 1) and the bivalent (type 1 and 3) OPV vaccine. OPV Production Department encompasses an area of sq. meters which includes manufacturing vaccine blending and filling, supporting activities for manufacturing process, visual inspection, labeling and packaging areas and cold storage areas for quarantine 2-8 C and finished product -22 ± 2 C. The Quality Control (Biologicals) testing facility dedicated to IPC and finished product testing comprises of an area of sq. meters. Adequate storage space is provided for storage of control samples and reference standards. Separate AHUs are provided for microbiological, biological potency testing and cell line maintenance. A separate room is provided for instruments to protect them against electrical interference, vibration, contact with excessive moisture and other external factors. Testing of raw materials and packing materials of OPV is carried out in the QC (Chemical section) located on the 2nd floor of the General Administrative Building of HBPCL. This area comprises of 413 sq. meters. A Dispatch Section dedicated to the distribution of released batches of OPV to Page 10 of 13

11 Consignees in cold chain is located on the site and comprises of an area of sq. meters. Premises are fully dedicated to OPV manufacturing and quality control. Warehouse, services area, production and quality control are located on ground floor. The OPV facility comprising of the following sections is housed in dedicated facility: Stores for Raw materials and Packaging materials (both primary & secondary). OPV Production Department. Quality Control (Bio) testing unit Finished product storage Packing and Dispatch Unit. Maintenance and Engineering support manufacturing activities QA department; QC (Chemical) department; Utilities, Engineering and Maintenance department are located in the same premises in separate buildings. Quality Control Laboratories: QC was divided accordingly to the category of tests performed on starting materials, packing materials or finished products: chemistry or biological. QC chemistry performs physico-chemistry assays i.e. TOC analysis or appearance assay. Raw materials room All chemical products including acids, bases or inflammable products and their dilutions were stored on the shelves of the laboratory benches. Instruments room This room contains all analysis appliances. Packing materials room Aluminium seals, type I glass vials, stoppers, droppers were tested according to Indian Pharmacopeia. Control samples room Retained samples were stored in this dedicated room and discarded 3 months after expiry date of the corresponding raw material. Furnace room This room contains LAF for manipulation of chemical products, autoclave and some highly concentrated chemical products. QC biologicals perform assays like titration of finished products or sterility tests for monitoring environment. This area is GMP classified area of the production premises. It was physically separated from production zone through MAL and sealed security door. Page 11 of 13

12 Although the premises and equipment involved and dedicated to the production of OPV at Haffkine site was considered suitable to the operations to be carried out, deficiencies were raised. The company has provided the remedial corrective and preventive actions adequately addressing the raised issues regarding the premises and equipment. 11. Materials Provisions for incoming materials, monovalent bulks and finished products were in place for reception, quarantine and release processes. Equipment and storage conditions were in place. 12. Documentation A documentation system was in place to guide production and control of products. These included Validation Master Plans (VMP); standard operating procedures; Batch Manufacturing and Packaging Instructions and records; specifications of starting materials, packaging materials, monovalent bulks and finished products; standard testing procedures, analytical records and certificates of analysis; qualification and validation protocols and reports. 13. Good practices in production 14. Good practices in quality control The manufacturing building for OPV was dedicated. Zone segregation principles based on cleanliness grades were considered for premises. Production unit has individual HVAC systems, assuring the balance of pressure difference and air exchange frequency rates. Pressure differentials between the premises with different cleanliness grade are provided. Cleaning and disinfection of premises and equipment were considered. Attention was paid to the personnel training, monitoring of the staff hygiene requirements, correct behavior, clothes changing etc. Regarding the waste management, procedures for discarding wastes in production area have been spot checked. Solid and liquid wastes were decontaminated via autoclave. Procedures were in place for sampling and testing of starting materials, packaging materials, intermediate products, bulk products and finished products as well as environmental monitoring, water systems and gases. Testing methods were validated and described in procedures. Equipment were qualified and calibrated. Out of Specification management was in place. Stability studies of bopv: Three commercial batches per year are considered for long term stability studies. Potency was checked after 3, 6, 12, 18, 24 and 30 months. The stability reports were spot checked showed satisfactory results. Assessment of the site master file Page 12 of 13

13 PART 4: CONCLUSION Based on the areas inspected, the personnel met and the documents reviewed, and considering the findings of the inspection, including the deficiencies listed in the Inspection Report, as well as the Corrective Actions taken and planned, the Haffkine Bio-Pharmaceutical Corporation Limited (HBPCL), located at Acharya Donde Marg, Parel, Mumbai , Maharashtra, India, was considered to be operating at an acceptable level for compliance with WHO GMP guidelines. All the non-conformances 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. Page 13 of 13