PHARMACEUTICAL INDUSTRY INTER - EVROGENEKS SITE MASTER FILE. Skopje, 2016 SMF Page 2 of 50

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1 Skopje, 2016 SMF Page 2 of 50

2 Good Manufacturing Practice (GMP) for finished Pharmaceuticals (WHO, EEC, PIC) Prepared by: Verified by: Approved by: Prim. M-r Romil Sandzakoski Sepc Pharmaceutical Technology B.S.Pharm.Spec. Blagica Jakimovska Dipl Ing. Ivan Gjorgjiev Quality Management and Environmental Management Skopje, 2016 SMF Page 2 of 50

3 TABLE OF CONTENTS: Title Page No. 1. GENERAL INFORMATION ON THE MANUFACTURER Contact information of the manufacturer Authorized pharmaceutical activities carried out on the 6 site 1.3 Any other manufacturing activities carried out on the site 8 2. QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER The quality management system of the manufacturer Release procedure of finished products Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis PERSONNEL Organizational chart Number of employees engaged in quality assurance, 13 production, quality control, storage and distribution 3.3 Qualifications, experience and responsibilities of key 13 personnel 3.4 Arrangements for basic and in-service training and how 15 records are maintained 3.5 Health requirements for personnel engaged in production Personnel hygiene requirements including clothing PREMISES AND EQUIPMENT Premises Brief description of the heating, ventilation and air 16 conditioning (HVAC) systems Brief description of water systems Brief description of other relevant utilities, such as steam, 18 compressed air, nitrogen, etc. 4.2 Equipment Listing of major production and control and GMP critical 18 systems Cleaning and sanitation DOCUMENTATION PRODUCTION Type of products Process validation Material management and warehousing Receipt, storage and approval of raw materials Receipt, storage and approval of packaging material Sampling of semi-finished and finished products 30 Skopje, 2016 SMF Page 3 of 50

4 6.3.4 Release of finished products Handling with rejected materials and products QUALITY CONTROL (QC) DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS Distribution Complaints, product defects and recalls SELF INSPECTIONS 34 APPENDICIES 35 I Copy of valid manufacturing authorization II Copy of valid GMP Certificate III Copies of valid Environmental Management Certificates IV Copies of valid Quality Management Certificates V Copy of valid Free Sale Certificate VI Copy of valid FDA Facility Registration Form VII List of products currently manufactured on-site Skopje, 2016 SMF Page 4 of 50

5 1. GENERAL INFORMATION ON THE MANUFACTURER 1.1 Contact information of the manufacturer NAME: INTER-EVROGENEKS - DOOEL ADDRESS: Goce Delchev Str. No Novo Selo - Strumica Republic of Macedonia Phone: Fax: Mob: Contact person: Cventancho Gjorgjiev (M.Sc.Eng.) Web: varumin@t.mk Representative office: Inter-Evrogeneks, Nikola Vapcarov Str. No. 20/7, 1000 Skopje Phone: Mob: GPS coordinates , Skopje, 2016 SMF Page 5 of 50

6 1.2 Authorized pharmaceutical manufacturing activities carried out on the site The pharmaceutical industry Inter-Evrogeneks was established on , by Mr. Ivan Gjorgjiev, holding the title of M.Sc. in Agricultural Engineering. The premises of the company are located in the municipality of Novo Selo - Strumica, while the representative office is based in Skopje, on the following address - Nikola Vapcarov Str. No. 20/7. In 1999, the factory started with primary production of its own patented herbal medical products. The company has technology for primary processing (chopping, sieving, packaging), for extraction of herbal drugs, as well as for production of different finished dosage forms (tablets suspensions, solution medicine teas). Inter-Evrogeneks is aware that quality is the background of every business success, and a key-factor for productivity and market competitiveness. Production and pharmaceutical control are carried out in compliance with the GMP requirements and other international standards, assuring the quality of our products and the strict compliance with environmental management standards. In October 2006, Inter-Evrogeneks received a GMP certificate (Appendix II), issued by the Ministry of Health of the Republic of Macedonia. In that same year, reconstruction and modernization of the factory was made. The capacities were enlarged and also new equipment for production of solid pharmaceutical forms (tablets) was introduced. In September 2007, Inter-Evrogeneks certified its Environmental Management System (EMS) according to the requirements of ISO 14001:2004 standards. The certification was made by the certification company MKS MAKKONTROL from the Republic of Macedonia. (Appendix III) In January 2008, Inter-Evrogeneks certified its Quality Management System (QMS) according to the requirements of ISO 9001:2000 standards. The certification was made by the certification company MKS MAKKONTROL from the Republic of Macedonia. (Appendix IV) In November 2009, Inter-Evrogeneks certified its Quality Management System (QMS) according to the requirements of ISO 9001:2008 standards. The certification was made by the certification company SGS from Zurich, Switzerland. (Appendix IV) Inter-Evrogeneks has a manufacturing program, composed of medicines for human use (in form of solutions and solids for oral use) and supplement products. The first product registration categorized them as adjuvant medical products; from the year of 2009, certain products were registered as herbal medicines. The quality of the medicines produced by Inter-Evrogeneks is regularly controlled by the Institute for Public Health Skopje, 2016 SMF Page 6 of 50

7 of the Republic of Macedonia and the Faculty of Pharmacy, Skopje Republic of Macedonia. In March 2015, Inter-Evrogeneks certified its Quality Management System (QMS) according to the requirements of ISO 9001:2008 (Appendix IV) and its Environmental Management System, according to the requirements of ISO 14001:2004 standards. (Appendix III). The certification was made by the certification company TUV AUSTRIA CERT from Austria. In the period , Inter-Evrogeneks became an export-oriented company, finishing the registration process for most of its products in many EU and some worldwide countries (including the USA). Inter-Evrogeneks already exports its own products in the following countries: USA, Canada, Australia, New Zealand, Lebanon, Qatar, Slovakia, Croatia, Bulgaria, Albania, Serbia, Kosovo, Montenegro, Bosnia and Herzegovina, Slovenia, Sweden, Holland, Czech Republic, Poland, Ukraine, Poland, Azerbaijan etc. In June 2015, Inter-Evrogeneks received FDA Registration Number, enabling the company to export all of its products on the US market. (Appendix VI) From , Inter-Evrogeneks has improved its manufacturing capacity and encampment, by implementing new production line for different dosage forms. Our equipment is of the highest technological level, meeting the highest standards required by the EU member states. In accordance with the manufacturing activities approved by the Ministry of Health of the Republic of Macedonia (Appendix I), Inter-Evrogeneks produces: - Finished pharmaceutical products - OTC products - Herbal products in different dosage forms - Veterinary and agricultural products In 2013, Macedonia has recognized the quality of our products and the continuous growth of our EU export, thus awarding Inter-Evrogeneks with an Excellence Certificate for being the highest quality company, recommended to the foreign companies. Currently, Inter-Evrogeneks is a highly competitive factory, with its highquality products, intensively conquering world markets. Types of actual products manufactured Skopje, 2016 SMF Page 7 of 50

8 1.3 Any other manufacturing activities carried out on the site Non- pharmaceutical activities carried out on the site include: storage and transportation; manufacturing and sales; development. Skopje, 2016 SMF Page 8 of 50

9 2. QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER Our quality policy meets all the requirements, needs and expectations of our customers and employees. Our goal is to establish and maintain an image of a successful and a reliable company, while at the same time mastering new markets and improving the life quality of our products. 2.1 The quality management system of the manufacturer Inter-Evrogeneks continuously monitors the EU legislation and obtains its implementation in the process of finishing the products, which makes it a respectable company with export orientation towards the world market. This is accomplished by strict compliance with the GMP guidelines and application of highest international standards, warranting the quality of the products and the environmental safety. There is also a continuous improvement of quality in every business process; permanent training of staff; application of up-to-date technological solutions; commitment of managers at all levels to continuous quality improvement; involvement of suppliers into our quality system and development of partnerships. Inter-Evrogeneks is aware of the environmental impact of its products and services, thus it coordinates its activities in compliance with the Company s Environmental Guidelines. Giving an appropriate place to quality and being continuously engaged in Quality Policy Implementation, it always meets the needs and expectations of the customers. The company s management is responsible for the implementation of the Quality Policy. The personnel responsible for Quality Management and Environmental Management has the following responsibilities and authorities: - Development, maintenance and supervision of Quality System and Environmental Management System - Quality documentation management (SOPs, batch production records, batch packaging records, QA Agreements, etc.) - Validations - Supervision of quality system, examinations of efficiency and compliance with quality standards requirements, GMP and ISO standards - Claims processing - Recalls processing - QA Agreements for contract manufacturing The Quality Management System and Environmental System are established, documented, applied and maintained by Inter-Evrogeneks ; their efficiency is permanently improved in accordance with GMP requirements, ISO 9001:2008 and ISO :2004 standards. Skopje, 2016 SMF Page 9 of 50

10 Efficacy of the system is ensured by establishment of work organization and clearly defined authorities and responsibilities, as set up in the Quality and Environmental Management Manuel, the Performance Rules and the individual job descriptions. The functioning system is supervised through internal inspections / audits (GMP, ISO 9001:2008 and ISO 14001:2004 standards), external inspections, as well as preventive and corrective actions. Internal audit (ISO 9001:2008 and ISO 14001:2004) is performed at least once a year and it covers all elements of quality management and environmental management systems. Quality management system audit or quality and environmental system audit can also be done upon customers requests, when willing to meet their requirements; while the contract accomplishment, aimed at system efficacy verification, undergoes revision, in case of organizational changes or in case of doubt in correctness in certain procedure activities. 2.2 Release procedure of finished products In the production course, all stages of technological process are constantly controlled. In the step preceding the finalization of the product, in-process control is also performed, so that the required product quality can be confirmed. The orders in the written procedure for selection of raw material, its preparation and incorporation in the mixture for making the finished product, including its homogenization, are fully respected for the sake of avoiding any possible error. The finished products, duly marked, are put into quarantine and set aside until a final laboratory analysis for drug control is made. Then, they are taken in the warehouse, from where they are distributed to the clients. All these processes are shown schematically in the process of production. (pp ) Qualified and responsible people in the production process are given in 3.2. (pg. 12) Following the audit, a report on the performed audit is made, summarizing the conclusions from the internal audit. After the audit, appropriate measures are taken to avoid any future mistakes. Skopje, 2016 SMF Page 10 of 50

11 2.3 Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis Institute for Public Health, Republic of Macedonia Address: 50 Divizija Str.No.6, 1000 Skopje, Republic of Macedonia Tel.: Fax: We have an agreement with the Institute for Public Health of the Republic of Macedonia, ensuring quality control of each batch and any other type of analysis. Faculty of Pharmacy, Skopje Address: 50 Divizija Str. No.6, 1000 Skopje, Republic of Macedonia Tel.: Fax: Inter-Evrogeneks has an expert cooperation with the Institute for Farmakognosy at the Faculty of Pharmacy, Skopje. Faculty of Mathematics and Natural Sciences, Skopje Address: Gazi Baba bb, 1000 Skopje, Republic of Macedonia Tel.: Fax: Part of the comparative analysis and determination of the validated methods are made at the Institute for Chemistry at the Faculty of Mathematics and Natural Sciences, Skopje. Institute for Herbal Medicines (plants), Prague, Czech Republic Skopje, 2016 SMF Page 11 of 50

12 Bulgarian Academy of Sciences Address: 15 Noemvri Str. No.1, 1040 Sofia, Republic of Bulgaria Tel.: Fax: Inter-Evrogeneks has an established cooperation with the Department for Microbiology and Virology at the Bulgarian Academy of Sciences. Faculty of Agricultural Sciences and Food Address: Aleksandar Makedonski Blvd. bb, 1000 Skopje, Republic of Macedonia Tel.: Fax: Inter-Evrogeneks has an established cooperation with the Department for Microbiology and Parasitology at the Faculty of Agricultural Sciences and Food - Skopje. Skopje, 2016 SMF Page 12 of 50

13 3. PERSONNEL 3.1 Organizational chart General Manager Administration Manufacture Marketing and Sales Legal Sector Liquid Forms Marketing General Services Teas Purchase Solid Forms Sales 3.2 Number of employees engaged in quality assurance, production, quality control, storage and distribution TOTAL EMPLOYEES INTER-EVROGENEKS Quality Assurance 2 2 Production Quality Control 1 1 Storage and Distribution 4 / Technical & Engineering Support Services 2 1 UNIVERSITY DEGREE 3.3 Qualifications, experience and responsibilities of key personnel POSITION QUALIFICATIONS WORKING EXPERIENCE (in years) RESPONSIBILITIES Skopje, 2016 SMF Page 13 of 50

14 Ivan Gjorgjiev General Manager Rumjana Gjorgjieva General Secretary M.Sc.Eng. 30 General Manager B.S.Tch 25 General Secretary Blagica Jakimovska Director of production B.S.Pharm.Spec. 25 Responsible for Pharmaceutical Production Romil Sandzakoski Advisor B.S.Pharm.Spec. Prim. 38 Responsible for Pharmacovigilance Cvetancho Gjorgjiev Quality control Tomislav Angelov Marketing Manager Dimitar Mitev HVAC Maintainer Ilija Hristov Legal Department B.S.Pharm. 2 B.S.E. 22 B.Sc.Eng. 2 LL.B. 10 Responsible for Quality Control Responsible for Marketing and Sales Responsible for HVAC maintenance Responsible for the legal department Kristijan Jovanovski IT Department Bachelor of computer science 7 Responsible for IT solutions and problems Dragi Panziev Warehouse-man Chemical technician 12 Responsible for raw materials warehouse Skopje, 2016 SMF Page 14 of 50

15 3.4 Arrangements for basic and in-service training and how records are maintained Inter-Evrogeneks regularly organizes educational trainings for the employees, like seminars and courses. This enables them to constantly exchange different experiences with other companies, which have achieved progress in a certain area, and later implement them in the process of production. These trainings are conducted by a selected person responsible for staff educational development, who has respectable qualifications and knowledge in the education area. Such trainings are obligatory for each employee and depend on the degree of development of the company in the area of GMP and GLP standards. 3.5 Health requirements for personnel engaged in production Prior to getting employed, each employee is obliged to undergo a medical check-up, determining his/her health capability to perform the assigned job in pharmaceutical industry. Later, all employees are obliged to undergo medical check-ups on every three years. Each employee coming into direct contact with a product, during the job performance, is obliged to undergo a sanitary inspection, prior to getting employed. Consequent regular sanitary inspections are carried out, according to the plan and program related to the current year, and in compliance with the Plan and Program for Work Safety in Quality Management and Environmental Management Sector. 3.6 Personnel hygiene requirements including clothing Personnel working in the manufacturing plant always wear clean working clothes, trousers, blouses, gloves, caps, masks, clogs, in accordance with the procedure. The working clothes and their quality are appropriate for the work process and the working environment, ensuring the product from contamination. Use and change of frequency are proscribed in the procedure. The personnel are well acquainted with the hygienic standards in the individual hygienic zones, required in the pharmaceutical production. Every person is expected to come to work clean, tidy and healthy. In manufacturing and laboratory spaces, consumption and keeping of food, drinks or cigarettes is strongly prohibited. Direct contact of the operator s hands with the starting materials, intermediaries or parts of the equipment coming into direct contact with the product, are not allowed. After the work is finished, each member of the personnel must wash his hands in the hygienic areas. These areas are provided with appropriate washing agents (liquid soap and hand disinfectants, paper towels/ hand driers). Skopje, 2016 SMF Page 15 of 50

16 4. PREMISES AND EQUIPMENT 4.1 Premises Inter-Evrogeneks covers a total area of m 2. The site is located in the municipality of Novo Selo (20 km from the town of Strumica), bordering with private agricultural land. It is 4 km distanced from the border of the Republic of Bulgaria and 4 km from the border of the Republic of Greece. Surfaces of manufacturing plants are as follows: - Production area 1250 m 2 - Storage area 1: 360 m 2 - Storage area 2: 120 m 2 - Storage area 3: 60 m 2 - Storage area 4: 150 m 2 - Area for preparation of plant material 120 m 2 - Development 40 m 2 - Control laboratory 30 m 2 Inter-Evrogeneks produces liquid and solid pharmaceutical dosage forms. System of horizontal production line is implemented on the ground floor of the factory, occupying area of 1250 m 2. All standards are obtained. The used materials meet the requirements of GMP standards, by which the required quality of the product is achieved Brief description of the heating, ventilation and air conditioning (HVAC) systems The walls are made from special materials (multi-layer laminates) and the finishes are treated with temperature-resistant and chemical-resistant material, which allows maintenance of the purity in the area. The finishes of the angles and the edges are made of rubber silicone materials, by which the unity of the area is formed. The floors are molded with PVC material, having thickness of 10 mm. The air is treated through HVAC unit, where it is being heated or cooled, humidified or dehumidified, filtered (F4, F6 and F9) and then let into the manufacturing areas through absolute filters (EU 13). When passing through the exhaust units, the air is filtered (F9 and EU13) and exhausted in the environment. The number of changes in the air is appropriate for the area of the production. Each HVAC unit is conducted with control of the system and with regular change of the filter. The air of the manufacturing area is removed with extracting AHU systems and is released in the atmosphere, without mixing with the fresh air. Four to eight changes of air are made during one hour, with possibility Skopje, 2016 SMF Page 16 of 50

17 to increase the number of changes according to the needs. The temperature is maintained on 22 C and the humidity on 55% RH ± 20% RH Brief description of water systems The capacity of the system for purified water is 3200 lit/h. The system is designed and executed according to GMP requirements, enabling the quality of the produced purified water, to meet the requirements of Ph.Eur. The system for purified water is made according to the requirements of Ph.Eur., and it consists of: 1. Pre-filtration 2. Water softening 3. Filtration with active coal 4. ph Adjsutment 5. Secure filtration 6. UV sterilization 7. Electro-deionization (EDI) 8. Water storage and distribution 9. Control system The water is filtered through a filter sized 0.2 µm, before it is being stored in the tank. The temperature is maintained from 17 C to 19 C. The standards IQ and OQ are implemented. All instruments are calibrated and checked, according to the program for assuring the quality of the system. Skopje, 2016 SMF Page 17 of 50

18 4.1.3 Brief description of other relevant utilities, such as steam, compressed air, nitrogen, etc. The technological process is carried out, by using the following equipment: - Grinding machine for plant material with capacity of kg/h - Deionizator for pure water with capacity of l/h - Duplex extractor with capacity of 3000 l/h - Homogeniser with capacity of 3000 l/h - Dosing machine for glass bottles with capacity of bottles/h - Machine for closing bottles with capacity of bottles/h - Labeling machine with capacity of bottles/h - Granulator with capacity of 100 l/h - Rotating tableting machine with capacity of tablets/h - Vacuum filing machine - TQ Multi-functional machine extracting tank - Automatic blister packing machine DPB h 4.2 Equipment Listing of major production control and GMP critical systems All machines are constructed according to GMP regulations, and each surface coming into contact with the product is made out of stainless steel. Skopje, 2016 SMF Page 18 of 50

19 The whole manufacturing process is checked by in-process control, carrying out the analyses and measuring the semi-finished products and finished products. The major equipment for in-process control, consists of: - ph Meter - Picnometer - Balance - Instrument for determination of hardness of tablets - Instrument for determination of decomposition of tablets - Instrument for determination of disintegration of tablets The responsible personnel for validation is composed of experts in the area of production, quality control, technical personnel and development personnel. For this purpose, protocols are made for validation and calibration of the instruments. Also planprograms for calibration and maintenance of the equipment are made and kept in separate files. Inter-Evrogeneks has contracts with competent companies for maintenance of the technical systems, the equipment and the measuring instruments Cleaning and sanitation Cleaning procedures for manufacturing areas and equipment are defined in SOPs. Preparing of cleaning material and cleaning techniques are described in-depth within the SOP. Types of cleaning agents and their preparation (specific concentration), as well as the cleaning frequency, are also defined in SOPs. Skopje, 2016 SMF Page 19 of 50

20 5. DOCUMENTATION The documentation system in Inter-Evrogeneks is in compliance with GMP requirements and requirements of ISO 9001:2008 and ISO 14001:2004 standards, representing a significant element of quality management and environmental management DOCUMENTS Quality policy / Company s Environmental Guidelines Quality and Environmental Management Manual Quality and Environmental plans, laws, guidelines, guides SOP-quality and environmental system Technological, registration, manufacturing, control documentation, operational and examinational instructions, etc. USED BY All All All All All 6 Records All Inter-Evrogeneks has an established and documented system of documentation control, covering systemic, process and external documentation. Internal and external documentation is recorded in the Master Documentation List on behalf of the employee who is in charge of the documentation. All activities related to issuing, approving, revising and filling of documentation and data are defined in the documented procedure and instructions. Documents are stored in various places, depending on the nature of the document. The revision of controlled documents is subject to the same requirements of preparing, checking, issuing and approving as the original document, and it involves the personnel responsible for the original document. Non-valid documentation is immediately withdrawn from use. Inter-Evrogeneks applies the documentation system, where every phase in the status of controlling/testing the materials and the equipment is defined - from receipt, control and testing during the process, through final control, up to the final verification and delivery. Entry control and validated test methods are applied for checking the raw materials quality and for compliance of the packing materials with the specification. Skopje, 2016 SMF Page 20 of 50

21 During the manufacturing process and packaging, the compliance with the master formula and the instructions for manufacturing and packaging are checked. Before the verification and delivery, finished product control and finished product quality check is made, in compliance with the specification. All checks on compliance with the specifications for raw materials, packing materials, intermediate products and finished products are recorded in appropriate forms. Later they are verified and approved by competent persons, as records on quality. Finally, these are filed in the places and for the period, defined in the procedures on quality records management. Receipt control, in-process control and final control are made by employees responsible for quality control. Records on these activities are filed by employees responsible for quality control. This established documentation system, enables only the material or product which has passed all the required controls and is in compliance with all specified quality requirements, to be approved for any further processing or use. Skopje, 2016 SMF Page 21 of 50

22 6. PRODUCTION Production is performed in compliance with approved technological procedure. Detailed description of the manufacturing procedure, together with the critical process points are given in the master formula. Production is carried out and headed by competent personnel. During the production, batch production and batch packaging records are filled in. Individual phases, including key parameters, are controlled and documented by in-process control. Separate appropriate procedures are being respected for the handling of raw materials, packaging materials, bulk materials and finished products - from the sample taking, through the release from quarantine, up to the final storage. 6.1 Types of products The process undergoes the following controls: - time of mixing (homogenizing) - drying temperature - angle of repose - reposed and tapped density - compressibility index - humidity - homogeneity of content - homogeneity of mass - average mass - hardness - fragility - disintegration Skopje, 2016 SMF Page 22 of 50

23 ACTIVITIES CHART Annual Sales Plan Annual Production Plan Annual Production Plan Three-month production plan Raw material and packaging materials supplies Production Planning Receipt Issuing of documentation for a batch Sampling Dispensing of materials for a batch (weighing) NO Quality Control Production process Refusal YES In-process control YES NO Measure Semi-product Claim Approval Sampling Approval Measurements NO Quality Control for semi-product YES Approval Continued on next page Continued from previous page Skopje, 2016 SMF Page 23 of 50

24 Packaging In-process control Quarantine for final product Quarantine control for final product NO YES Approval Batch Release Refusal Measurements SALES Skopje, 2016 SMF Page 24 of 50

25 COURSE OF PRODUCTION FOR SOLID ORAL DRUG FORMS Dispensed raw material receipt Sieving Mixing Wet granulation Mixing Drying Sieving Excipients Final mixing Excipients Tabletting Packaging Primary packaging material Glass bottles Packaging Secondary packaging material Skopje, 2016 SMF Page 25 of 50

26 COURSE OF PRODUCTION FOR NON-STERILE LIQUID FORMS Dispensed raw material receipt Liquid form processing (mixing, heating) Dissolving Excipients Active components Filtering Filling in glass bottles Primary packaging material Packaging Secondary packaging material Skopje, 2016 SMF Page 26 of 50

27 COURSE OF PRODUCTION FOR TEAS Raw material Milling and sieving Weighing Homogenization In-process control Dosing In-process control Packaging In-process control Chemical and microbiological analysis of final product Skopje, 2016 SMF Page 27 of 50

28 6.2 Process validation Process validation protocol contains at least the following information: - Purpose of validation - Description of production process (chart of process course) - Major formula - List of equipment in use - Details about active component(s) - Test program - analysis of critical phases of production process - critical process parameters - kind of test - sampling plan (where, when and how many samples) - acceptable limits - Request for revalidation - Persons responsible for performance of validation 6.3 Material management and warehousing Receipt, storage and approval of raw materials Receipt, storage and approving of raw materials is carried out in accordance with Good Storing Practice (GSP), Good Manufacturing Practice (GMP) and SOPs. Receipt of raw materials is carried out by competent personnel, in compliance with written procedures in Raw Materials Warehouse. The procedure s requirements are as follows: - checking of compliance for shipment, delivery note (for domestic supplies), invoice (for international supplies), certificate and purchase order; these checks are carried out in area intended for receipt - labeling of raw materials and moving into the quarantine area Skopje, 2016 SMF Page 28 of 50

29 - request for analysis to the appropriate personnel Sampling is performed by following the written instruction in the SOP. Report on the quality of raw materials is issued (approval or refusal for using the raw materials), after an analysis of samples has been made in accordance with the specifications. Approved materials are labeled and transferred to intermediate storage in raw materials warehouse. Storing conditions for raw materials are as follows: - temperature: C - humidity: 50 ± 20 %, in case not otherwise declared by manufacturer / supplier. Temperature and humidity monitoring is done on everyday basis. Shelves and pallets in intermediate storage are uniformly designated and identified. Only one raw material is allowed to be placed on one shelf / pallet, and at different levels of the same shelf, different batches of the same raw material, may be placed. The shelves are raised above the floor (height of pallet), and pulled away from walls (15 cm - 25 cm), for easier cleaning of the areas. Raw materials can be handed out on material requisition slip, referring to one batch of raw materials only. Handing out of materials is done on first in - first out principle. The activities of preparing and dispensing are carried out in a separate area of hygiene class 3, in raw materials warehouse. Dispensing is done under supervision of a production technologist. Nonapproved raw materials after the claim settlement, are either returned to manufacturer / supplier or transferred to waste material storage, according to the procedure Receipt, storage and approval of packaging material Receipt, storage and approval of packaging material are carried out in accordance with GSP principles. Receipt of packaging material is carried out by competent personnel in the packaging material warehouse, by following the written procedures. The procedure is as follows: - Checking of the shipment compliance with order (name and kind of material, number of purchase order, quantity, manufacturer s certificate, etc.) - Labeling of packaging material and moving into the quarantine area - Request for analysis to the appropriate personnel Skopje, 2016 SMF Page 29 of 50

30 Sampling is performed by following the written instructions in the SOP. Report on packaging materials quality is issued (approval or refusal for using the packaging materials), after an analysis of samples is made in accordance with the specifications. Approved packaging materials are labeled and transferred to intermediate storage within packaging materials warehouse. Storing conditions for packaging materials are as follows: - temperature: C - humidity: 50 ± 20 %, if not otherwise declared by manufacturer / supplier. Temperature and humidity monitoring is made on everyday basis. Shelves and pallets in intermediate storage are uniformly designated and identified. Different kinds as well as different batches of the same packaging material are stored in separated areas. Handing out of materials is done on first in - first out principle. The shelves are raised above the floor (height of pallet) and pulled away from the walls (15 cm - 25 cm), for easier cleaning of the areas. Packaging material can be handed out on material requisition slip, referring to one batch of product only. Non-approved packaging materials are labeled and immediately transferred into not-in-use storage (separated area in packaging materials storage, for goods inappropriate for manufacturing process) Sampling of semi-finished and finished products Sampling of intermediaries, semi-finished products and finished products is carried out by the appropriate personnel. Sampling is carried out in accordance with written procedures. Every product is sampled according to an appropriate sampling plan Release of finished products Release or rejection of a batch of finished product is within the scope of responsibility of Quality Control. The system for approving the entering materials and the finished products is in accordance with the law, the current specifications, the GMP requirements and the international standards. For production and sales respectively, only the entering materials and finished products released by a person responsible for release of materials and products, can be used. Decision on release or rejection of a batch of entering material or finished product is based on evaluation of all available information about the batch, like: test results, Skopje, 2016 SMF Page 30 of 50

31 certificates, batch production records, batch packaging records and reports on deviations. Assessment of information, when deciding on a release of finished product for usage, is based on reviewing the following documents: - Batch production records and batch packaging records (weather the information is correctly filled in and whether it is in compliance with the requirements; is the complete description of manufacturing process given) - In-process control results - Results in Report on semi-finished products quality - Results on the monitoring of environmental conditions - Results in Report on finished products quality - Attestation of in-process control of packed finished product Report on quality and license for entering material and finished product usage are forwarded to those applying and to those who will use the entering materials and finished products, all according to the written procedure. Documentation on batch of incoming material is also recorded, for raw materials - in the period of 10 years, and for packaging material - 2 years. Documentation on finished product s batch is stored for one year, after the expiry of the shelf life of the product Handling with rejected materials and products Pharmaceutical waste in Inter-Evrogeneks is classified into the following categories: - Raw materials for production of drugs being damaged when entering the raw materials storage; raw materials with expired shelf life or raw materials intended for products which are no more manufactured - Pharmaceutical waste from damaged / inappropriate product during production or development, exhaust from machines or wasted from air-conditioning units - Finished product of expired shelf life - Filters for dust, contaminated by raw materials or products - Remainders of tested samples - Control samples with no obligation for detainment (pharmaceutical products) - solid forms - Product recalls Every production unit has a container for special waste collection. Every container is marked with a label SPECIAL WASTE. In the container, there is a PVC bag for collecting pharmaceutical waste. Bags containing pharmaceutical waste are to be properly closed and labeled. The label contains data about the type of material, its weight, date, together with the signature of the responsible person. Access to storage is allowed to authorized persons only. Skopje, 2016 SMF Page 31 of 50

32 7. QUALITY CONTROL Quality Control is part of GMP and GLP regulations for handling samples, specifications and testing, as well as organization, documentation and approval of procedures, providing that the necessary and appropriate tests are carried out and that the materials are not released for usage or the products for sales/supplies, until their quality is ascertained to be satisfactory. The activities of Quality Control sector are as follows: - Preparing of specifications and test methods for physical-chemical, microbiological and biological investigation of entering materials, intermediaries, semi-finished products, finished products and in-process control - Validation of analytical methods - Analysis of entering materials, intermediaries, semi-finished, finished products and in-process controls - Approving or disapproving of entering materials, intermediaries, semi-finished and finished products - Filing and recording of documentation for production and control - Product stability follow-up The Quality Control is performed by the Institute for Public Health of the Republic of Macedonia, on the basis of a Cooperation Agreement. Skopje, 2016 SMF Page 32 of 50

33 8. DISTRIBUTION, CLAIMS AND WITHDRAWAL OF PRODUCTS 8.1 Storage and distribution Finished goods are stored in Finished Goods Warehouse. They are placed on pallets at a sufficient distance from each other, in order to avoid swarming and enable an easier requisition and cleaning. This also prevents any possible arising confusion. Temperature is monitored on everyday basis. Limit values are 15 C - 25 C. Issuing of goods from the Warehouse is performed on the basis of a delivery order - dispatch note. The dispatch note contains: order number, date, name and address of buyer, name of product, quantity, batch and way of dispatch. Issuing of goods is performed according to first in - first out principle. The delivery order at the same time represents the records on product distribution. One copy is distributed to Finished Goods Warehouse, and kept there one year, after the expiry date of the product. Second copy of order is retained by the buyer. 8.2 Claims, product defects and recalls Procedures and responsibilities for handling product claims on the market are described in accordance with the standard operating procedure. Every claim must be investigated objectively and in details, regardless of its nature. The mode for handling the product, not meeting the specified quality, but which is nevertheless found in the market and must be withdrawn, is described in details in the respective procedure. The procedure involves the persons responsible for decisions on recall, reports, as well as coordination of the recall. Recall is done when quality of the products (for instance: composition, appearance, packaging, expiry date, etc.) does not comply with the defined requirements, according to the information obtained on the basis of: postproduction inspection of drugs, claim of buyer, or any other external client. The extent of recall (the whole shipment, part of shipment) depends on the potential impact on health. The recall may be made on behalf of: warehouse, wholesaler, hospital storage, pharmacy or an individual user. Decision on recall is taken by the General Manager. Products withdrawn from the market are stored in a separate dedicated area marked RECALLED PRODUCTS and RECALL. Recalled products in all recalling phases must be handled in such a way, which does not allow repeated distribution. Recalled products must be destroyed (transferred into Pharmaceutical waste storage). The documentation regarding decisions and execution of recall is kept. The period for keeping of the documentation in recall is one year, after the expiry date of the product being subject of the recall. Skopje, 2016 SMF Page 33 of 50

34 9. SELF INSPECTION Internal inspection covers all activities inside and outside Inter-Evrogeneks, which can have an impact on product quality, level of fulfillment of GMP requirements, legal regulations or any other regulations related to drug manufacturers. Inspection areas are the areas foreseen in GMP, i.e.: personnel, areas, equipment, documentation, production, quality control, distribution of products, claims and recalls settlement, as well as inspection of raw materials suppliers and in-bulk product suppliers. Internal inspection is carried out according to the annual plan of internal inspection and exceptionally, it can be made upon the request of the General Manager. Results from the internal inspection are given in internal inspection reports. Reports on inspection, including proposed corrective actions on the terms and the persons in charge, are verified by an internal inspector, and are then delivered to the company s General Manager. The report is sent no later than 20 days and it is a strictly confidential document of strictly limited circulation. The internal inspector is obliged to annually report on the work of the internal inspection. The report contains inspection frequency data and global conclusions, as well as a proposal for corrective measures and improvement activities. The internal inspector is following up the progress of actions, for the purpose of implementing future corrective measures. Skopje, 2016 SMF Page 34 of 50

35 APPENDICIES Appendix I: Copy of valid manufacturing authorization Skopje, 2016 SMF Page 35 of 50

36 Appendix II: Copy of valid GMP Certificate 2006, Certificate obtained from the Ministry of Health of the Republic of Macedonia, for meeting the requirements of GMP Skopje, 2016 SMF Page 36 of 50

37 Certificate of GMP Compliance of a Manufacturer (2 pages) Skopje, 2016 SMF Page 37 of 50

38 Skopje, 2016 SMF Page 38 of 50

39 Certificate of GMP 2016 Compliance of a Manufacturer (2 pages) Skopje, 2016 SMF Page 39 of 50

40 Skopje, 2016 SMF Page 40 of 50

41 Appendix III: Copies of valid Environmental Management Certificates Certificate obtained from MKS MAKKONTROL for Environmental Management, according to standards of ISO 14001:2004 Skopje, 2016 SMF Page 41 of 50

42 Certificate obtained from TUV AUSTRIA CERT for Environmental Management, according to standards of ISO 14001:2004 Skopje, 2016 SMF Page 42 of 50

43 Certificate obtained from TUV NORD for Environmental Management, according to standards of ISO 14001:2004 Skopje, 2016 SMF Page 43 of 50

44 Appendix IV: Copies of valid Quality Management Certificates Certificate obtained from MKS MAKKONTROL for Quality Managament, according to standards of ISO 9001:2000 Skopje, 2016 SMF Page 44 of 50

45 Certificate obtained from SGS for Quality Management, according to standards of ISO 9001:2008 Skopje, 2016 SMF Page 45 of 50

46 Certificate obtained from TUV AUSTRIA CERT for Quality Management, according to standards of ISO 9001:2008 Skopje, 2016 SMF Page 46 of 50

47 Certificate obtained from TUV NORD for Quality Management, according to standards of ISO 9001:2008 Skopje, 2016 SMF Page 47 of 50

48 PHARMACEUTICAL INDUSTRY Goce Delcev 12; 2434 Novo Selo; R. Makedonija Appendix V: Copy of valid Free Sale Certificate Skopje, 2016 SMF Page 48 of 50

49 Appendix VI: Copy of valid FDA Facility Registration Form Inter-Evrogeneks has its own FDA Facility Registration Number , and Varumin has its own FDA Food Facility Number , which guarantees free import and sales of Varumin and all the other products, on the USA market. 1 st page of the FDA Facility Registration Form: Skopje, 2016 SMF Page 49 of 50

50 Appendix VII: List of products currently manufactured on-site BRAND NAME FORM VARUMIN Glukonormin forte Varuklim Varuprostin Varutensin Varupotent Paradental Varuhemoroidal Varuflu Varumin herbal Glukonormin Varuklim Varuprostin Varutensin Varuascitofin Gorka Dinja solution tablets tablets tablets tablets tablets solution solution solution Medical tea Medical tea Medical tea Medical tea Medical tea Medical tea suspension Skopje, 2016 SMF Page 50 of 50