inter - evrogeneks sitemasterfile goce … skopje,2016 smf page3of50 “ goce delcev” 12; r....

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Skopje, 2016 SMF Page 2 of 50

“

Goce Delcev” 12; R. Makedonija 2434 Novo Selo;

PHARMACEUTICAL INDUSTRY

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Good Manufacturing Practice (GMP) for finished Pharmaceuticals (WHO, EEC, PIC)

Prepared by: Verified by: Approved by:

Prim. M-r RomilSandzakoski

Sepc PharmaceuticalTechnology

_____________________

B.S.Pharm.Spec.Blagica Jakimovska

_____________________

Dipl Ing.Ivan Gjorgjiev

_____________________

Quality Management and Environmental Management

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TABLE OF CONTENTS:

Title Page No.1. GENERAL INFORMATION ON THE MANUFACTURER 5

1.1 Contact information of the manufacturer 51.2 Authorized pharmaceutical activities carried out on the

site6

1.3 Any other manufacturing activities carried out on the site 82. QUALITY MANAGEMENT SYSTEM OF THE

MANUFACTURER9

2.1 The quality management system of the manufacturer 92.2 Release procedure of finished products 102.3 Use of outside scientific, analytical or other technical

assistance in relation to manufacture and analysis11

3. PERSONNEL 133.1 Organizational chart 133.2 Number of employees engaged in quality assurance,

production, quality control, storage and distribution13

3.3 Qualifications, experience and responsibilities of keypersonnel

13

3.4 Arrangements for basic and in-service training and howrecords are maintained

15

3.5 Health requirements for personnel engaged in production 153.6 Personnel hygiene requirements including clothing 15

4. PREMISES AND EQUIPMENT 164.1 Premises 164.1.1 Brief description of the heating, ventilation and air

conditioning (HVAC) systems16

4.1.2 Brief description of water systems 174.1.3 Brief description of other relevant utilities, such as steam,

compressed air, nitrogen, etc.18

4.2 Equipment 184.2.1 Listing of major production and control and GMP critical

systems18

4.2.2 Cleaning and sanitation 195. DOCUMENTATION 206. PRODUCTION 22

6.1 Type of products 226.2 Process validation 286.3 Material management and warehousing 286.3.1 Receipt, storage and approval of raw materials 286.3.2 Receipt, storage and approval of packaging material 296.3.3 Sampling of semi-finished and finished products 30

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6.3.4 Release of finished products 306.3.5 Handling with rejected materials and products 31

7. QUALITY CONTROL (QC) 328. DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND

RECALLS33

8.1 Distribution 338.2 Complaints, product defects and recalls 33

9. SELF INSPECTIONS 34APPENDICIES 35

I Copy of valid manufacturing authorizationII Copy of valid GMP CertificateIII Copies of valid Environmental Management CertificatesIV Copies of valid Quality Management CertificatesV Copy of valid Free Sale CertificateVI Copy of valid FDA Facility Registration FormVII List of products currently manufactured on-site

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1. GENERAL INFORMATION ON THE MANUFACTURER

1.1 Contact information of the manufacturer

NAME:“INTER-EVROGENEKS” - DOOEL

ADDRESS:“Goce Delchev” Str. No.122434 Novo Selo - StrumicaRepublic of Macedonia

Phone: +389 2 3215 800Fax: +389 2 3215 801Mob: +389 70 316 011

Contact person: Cventancho Gjorgjiev (M.Sc.Eng.)

E-mail: [email protected]

Web: www.interevrogeneks.comwww.varumin.com.mk

Representative office:

“Inter-Evrogeneks”, Nikola Vapcarov Str. No. 20/7, 1000 Skopje

Phone: +389 2 3215 800Mob: +389 2 70 259 222

GPS coordinates - 41.410931, 22.87899

mailto:[email protected]

http://www.interevrogeneks.com

http://www.varumin.com.mk

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1.2 Authorized pharmaceutical manufacturing activities carried out on the site

The pharmaceutical industry “Inter-Evrogeneks” was established on 12.12.1998, 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 - NikolaVapcarov Str. No. 20/7.

In 1999, the factory started with primary production of its own patented herbal medicalproducts. The company has technology for primary processing (chopping, sieving,packaging), for extraction of herbal drugs, as well as for production of different finisheddosage 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 andpharmaceutical control are carried out in compliance with the GMP requirements andother international standards, assuring the quality of our products and the strictcompliance with environmental management standards.

In October 2006, “Inter-Evrogeneks” received a GMP certificate (Appendix II), issued bythe Ministry of Health of the Republic of Macedonia. In that same year, reconstructionand modernization of the factory was made. The capacities were enlarged and also newequipment 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 wasmade 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 madeby 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 madeby the certification company SGS from Zurich, Switzerland. (Appendix IV)

“Inter-Evrogeneks” has a manufacturing program, composed of medicines for humanuse (in form of solutions and solids for oral use) and supplement products. The firstproduct registration categorized them as adjuvant medical products; from the year of2009, certain products were registered as herbal medicines. The quality of the medicinesproduced by “Inter-Evrogeneks” is regularly controlled by the Institute for Public Health

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of the Republic of Macedonia and the Faculty of Pharmacy, Skopje – Republic ofMacedonia.In March 2015, “Inter-Evrogeneks” certified its Quality Management System (QMS)according to the requirements of ISO 9001:2008 (Appendix IV) and its EnvironmentalManagement System, according to the requirements of ISO 14001:2004 standards.(Appendix III). The certification was made by the certification company TUV AUSTRIACERT from Austria.

In the period 2012-2015, “Inter-Evrogeneks” became an export-oriented company,finishing the registration process for most of its products in many EU and someworldwide countries (including the USA). “Inter-Evrogeneks” already exports its ownproducts in the following countries: USA, Canada, Australia, New Zealand, Lebanon,Qatar, Slovakia, Croatia, Bulgaria, Albania, Serbia, Kosovo, Montenegro, Bosnia andHerzegovina, Slovenia, Sweden, Holland, Czech Republic, Poland, Ukraine, Poland,Azerbaijan etc.

In June 2015, “Inter-Evrogeneks” received FDA Registration Number, enabling thecompany to export all of its products on the US market. (Appendix VI)

From 2014-2015, “Inter-Evrogeneks” has improved its manufacturing capacity andencampment, by implementing new production line for different dosage forms. Ourequipment is of the highest technological level, meeting the highest standards requiredby the EU member states.

In accordance with the manufacturing activities approved by the Ministry of Health ofthe 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 continuousgrowth of our EU export, thus awarding “Inter-Evrogeneks” with an ExcellenceCertificate for being the highest quality company, recommended to the foreigncompanies. Currently, “Inter-Evrogeneks” is a highly competitive factory, with its high-quality products, intensively conquering world markets.

Types of actual products manufactured

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1.3 Any other manufacturing activities carried out on the site

Non- pharmaceutical activities carried out on the site include: storage andtransportation; manufacturing and sales; development.

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2. QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER

Our quality policy meets all the requirements, needs and expectations of our customersand employees. Our goal is to establish and maintain an image of a successful and areliable company, while at the same time mastering new markets and improving the lifequality of our products.

2.1 The quality management system of the manufacturer

“Inter-Evrogeneks” continuously monitors the EU legislation and obtains itsimplementation in the process of finishing the products, which makes it a respectablecompany with export orientation towards the world market.

This is accomplished by strict compliance with the GMP guidelines and application ofhighest international standards, warranting the quality of the products and theenvironmental safety. There is also a continuous improvement of quality in everybusiness process; permanent training of staff; application of up-to-date technologicalsolutions; 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 EnvironmentalGuidelines. Giving an appropriate place to quality and being continuously engaged inQuality Policy Implementation, it always meets the needs and expectations of thecustomers. The company’s management is responsible for the implementation of theQuality Policy.

The personnel responsible for Quality Management and Environmental Managementhas the following responsibilities and authorities:

- Development, maintenance and supervision of Quality System and EnvironmentalManagement System

- Quality documentation management (SOPs, batch production records, batchpackaging 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 ispermanently improved in accordance with GMP requirements, ISO 9001:2008 and ISO 14001:2004 standards.

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Efficacy of the system is ensured by establishment of work organization and clearlydefined authorities and responsibilities, as set up in the Quality and EnvironmentalManagement Manuel, the Performance Rules and the individual job descriptions.

The functioning system is supervised through internal inspections / audits (GMP, ISO9001:2008 and ISO 14001:2004 standards), external inspections, as well as preventiveand corrective actions.

Internal audit (ISO 9001:2008 and ISO 14001:2004) is performed at least once a year andit covers all elements of quality management and environmental management systems.Quality management system audit or quality and environmental system audit can also bedone upon customers’ requests, when willing to meet their requirements; while thecontract accomplishment, aimed at system efficacy verification, undergoes revision, incase of organizational changes or in case of doubt in correctness in certain procedureactivities.

2.2 Release procedure of finished products

In the production course, all stages of technological process are constantly controlled. Inthe 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 writtenprocedure for selection of raw material, its preparation and incorporation in the mixturefor making the finished product, including its homogenization, are fully respected for thesake of avoiding any possible error.

The finished products, duly marked, are put into quarantine and set aside until a finallaboratory 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 shownschematically in the process of production. (pp. 22-26)

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 theconclusions from the internal audit. After the audit, appropriate measures are taken toavoid any future mistakes.

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2.3 Use of outside scientific, analytical or other technical assistance in relation tomanufacture and analysis

Institute for Public Health, Republic of Macedonia

Address: 50 Divizija Str.No.6, 1000 Skopje, Republic of MacedoniaTel.: +389 2 3 223 354Fax: +389 2 3 223 033

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 MacedoniaTel.: +389 2 3 223 354Fax: +389 2 3 223 033

“Inter-Evrogeneks” has an expert cooperation with the Institute for Farmakognosy at theFaculty of Pharmacy, Skopje.

Faculty of Mathematics and Natural Sciences, Skopje

Address: Gazi Baba bb, 1000 Skopje, Republic of MacedoniaTel.: +389 2 3 249 999Fax: +389 2 3 228 141

Part of the comparative analysis and determination of the validated methods are madeat the Institute for Chemistry at the Faculty of Mathematics and Natural Sciences, Skopje.

Institute for Herbal Medicines (plants), Prague, Czech Republic

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Bulgarian Academy of Sciences

Address: 15 Noemvri Str. No.1, 1040 Sofia, Republic of BulgariaTel.: +359 2 979 53 33Fax: +359 2 979 52 23

“Inter-Evrogeneks” has an established cooperation with the Department forMicrobiology and Virology at the Bulgarian Academy of Sciences.

Faculty of Agricultural Sciences and Food

Address: Aleksandar Makedonski Blvd. bb, 1000 Skopje, Republic of MacedoniaTel.: +389 2 3 115 277Fax: +389 2 3 134 310

“Inter-Evrogeneks” has an established cooperation with the Department forMicrobiology and Parasitology at the Faculty of Agricultural Sciences and Food - Skopje.

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3. PERSONNEL

3.1 Organizational chart

3.2 Number of employees engaged in quality assurance, production, quality control,storage and distribution

3.3 Qualifications, experience and responsibilities of key personnel

POSITION QUALIFICATIONSWORKINGEXPERIENCE

(in years)RESPONSIBILITIES

TOTAL EMPLOYEES UNIVERSITY DEGREE

INTER-EVROGENEKS 28 15

Quality Assurance 2 2

Production 14+5 11

Quality Control 1 1

Storage and Distribution 4 /

Technical & EngineeringSupport Services 2 1

Marketing and Sales

Legal Sector

General Services

Liquid Forms

Teas

Solid Forms

Marketing

Purchase

Sales

Administration Manufacture

General Manager

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Ivan Gjorgjiev

GeneralManager

M.Sc.Eng. 30 General Manager

RumjanaGjorgjieva

GeneralSecretary

B.S.Tch 25 General Secretary

BlagicaJakimovska

Director ofproduction

B.S.Pharm.Spec. 25Responsible forPharmaceuticalProduction

RomilSandzakoski

Advisor

B.S.Pharm.Spec.

Prim.38 Responsible for

Pharmacovigilance

CvetanchoGjorgjiev

Quality controlB.S.Pharm. 2

Responsible for

Quality Control

TomislavAngelov

MarketingManager

B.S.E. 22Responsible for

Marketing and Sales

Dimitar Mitev

HVACMaintainer

B.Sc.Eng. 2 Responsible forHVAC maintenance

Ilija Hristov

LegalDepartment

LL.B. 10 Responsible for thelegal department

KristijanJovanovski

IT Department

Bachelor ofcomputer science 7

Responsible for ITsolutions andproblems

Dragi Panziev

Warehouse-manChemicaltechnician 12

Responsible for rawmaterialswarehouse

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3.4 Arrangements for basic and in-service training and how records are maintained

“Inter-Evrogeneks” regularly organizes educational trainings for the employees, likeseminars and courses. This enables them to constantly exchange different experienceswith other companies, which have achieved progress in a certain area, and laterimplement them in the process of production. These trainings are conducted by aselected person responsible for staff educational development, who has respectablequalifications and knowledge in the education area. Such trainings are obligatory foreach employee and depend on the degree of development of the company in the area ofGMP 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 pharmaceuticalindustry. Later, all employees are obliged to undergo medical check-ups on every threeyears. Each employee coming into direct contact with a product, during the jobperformance, is obliged to undergo a sanitary inspection, prior to getting employed.Consequent regular sanitary inspections are carried out, according to the plan andprogram related to the current year, and in compliance with the Plan and Program forWork 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. Theworking clothes and their quality are appropriate for the work process and the workingenvironment, ensuring the product from contamination. Use and change of frequencyare proscribed in the procedure. The personnel are well acquainted with the hygienicstandards in the individual hygienic zones, required in the pharmaceutical production.Every person is expected to come to work clean, tidy and healthy. In manufacturing andlaboratory spaces, consumption and keeping of food, drinks or cigarettes is stronglyprohibited. 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 washhis hands in the hygienic areas. These areas are provided with appropriate washingagents (liquid soap and hand disinfectants, paper towels/ hand driers).

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4. PREMISES AND EQUIPMENT

4.1 Premises

“Inter-Evrogeneks” covers a total area of 22.000 m2. The site is located in themunicipality of Novo Selo (20 km from the town of Strumica), bordering with privateagricultural land. It is 4 km distanced from the border of the Republic of Bulgaria and 4km from the border of the Republic of Greece.

Surfaces of manufacturing plants are as follows:

- Production area 1250 m2

- Storage area 1: 360 m2




- Area for preparation of plant material 120 m2

- Development 40 m2

- Control laboratory 30 m2

“Inter-Evrogeneks” produces liquid and solid pharmaceutical dosage forms. System ofhorizontal production line is implemented on the ground floor of the factory, occupyingarea of 1250 m2. All standards are obtained. The used materials meet the requirementsof GMP standards, by which the required quality of the product is achieved.

4.1.1 Brief description of the heating, ventilation and air conditioning (HVAC) systems

The walls are made from special materials (multi-layer laminates) and the finishes aretreated with temperature-resistant and chemical-resistant material, which allowsmaintenance of the purity in the area. The finishes of the angles and the edges are madeof rubber silicone materials, by which the unity of the area is formed. The floors aremolded with PVC material, having thickness of 10 mm.

The air is treated through HVAC unit, where it is being heated or cooled, humidified ordehumidified, filtered (F4, F6 and F9) and then let into the manufacturing areas throughabsolute filters (EU 13). When passing through the exhaust units, the air is filtered (F9and EU13) and exhausted in the environment. The number of changes in the air isappropriate for the area of the production. Each HVAC unit is conducted with control ofthe system and with regular change of the filter. The air of the manufacturing area isremoved with extracting AHU systems and is released in the atmosphere, without mixingwith the fresh air. Four to eight changes of air are made during one hour, with possibility

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to increase the number of changes according to the needs. The temperature ismaintained on 22°C and the humidity on 55% RH ± 20% RH.

4.1.2 Brief description of water systems

The capacity of the system for purified water is 3200 lit/h. The system is designed andexecuted according to GMP requirements, enabling the quality of the produced purifiedwater, to meet the requirements of Ph.Eur. The system for purified water is madeaccording to the requirements of Ph.Eur., and it consists of:

1. Pre-filtration2. Water softening3. Filtration with active coal4. pH Adjsutment5. Secure filtration6. UV sterilization7. Electro-deionization (EDI)8. Water storage and distribution9. 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 areimplemented. All instruments are calibrated and checked, according to the program forassuring the quality of the system.

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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 1.000 kg/h- Deionizator for pure water with capacity of 3.200 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 10.000 bottles/h- Machine for closing bottles with capacity of 10.000 bottles/h- Labeling machine with capacity of 10.000 bottles/h- Granulator with capacity of 100 l/h- Rotating tableting machine with capacity of 160.000 tablets/h- Vacuum filing machine- TQ Multi-functional machine extracting tank- Automatic blister packing machine DPB - 250 h

4.2 Equipment

4.2.1 Listing of major production control and GMP critical systems

All machines are constructed according to GMP regulations, and each surface cominginto contact with the product is made out of stainless steel.

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The whole manufacturing process is checked by in-process control, carrying out theanalyses and measuring the semi-finished products and finished products. The majorequipment 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 ofproduction, quality control, technical personnel and development personnel. For thispurpose, protocols are made for validation and calibration of the instruments. Also plan-programs for calibration and maintenance of the equipment are made and kept inseparate files. “Inter-Evrogeneks” has contracts with competent companies formaintenance of the technical systems, the equipment and the measuring instruments.

4.2.2 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 theSOP. Types of cleaning agents and their preparation (specific concentration), as well asthe cleaning frequency, are also defined in SOPs.

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5. DOCUMENTATION

The documentation system in “Inter-Evrogeneks” is in compliance with GMPrequirements and requirements of ISO 9001:2008 and ISO 14001:2004 standards,representing a significant element of quality management and environmentalmanagement.

DOCUMENTS USED BY

1 Quality policy / Company’sEnvironmental Guidelines All

2 Quality and EnvironmentalManagement Manual All

3 Quality and Environmental plans,laws, guidelines, guides All

4 SOP-quality and environmentalsystem All

5Technological, registration, manufacturing,control documentation, operational andexaminational instructions, etc.

All

6 Records All

“Inter-Evrogeneks” has an established and documented system of documentationcontrol, covering systemic, process and external documentation.

Internal and external documentation is recorded in the Master Documentation List onbehalf of the employee who is in charge of the documentation. All activities related toissuing, approving, revising and filling of documentation and data are defined in thedocumented 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 personnelresponsible for the original document. Non-valid documentation is immediatelywithdrawn from use.

“Inter-Evrogeneks” applies the documentation system, where every phase in the statusof controlling/testing the materials and the equipment is defined - from receipt, controland testing during the process, through final control, up to the final verification anddelivery.

Entry control and validated test methods are applied for checking the raw materialsquality and for compliance of the packing materials with the specification.

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During the manufacturing process and packaging, the compliance with the masterformula and the instructions for manufacturing and packaging are checked.

Before the verification and delivery, finished product control and finished productquality 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. Laterthey 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 qualityrecords management.

Receipt control, in-process control and final control are made by employees responsiblefor quality control. Records on these activities are filed by employees responsible forquality control.

This established documentation system, enables only the material or product which haspassed all the required controls and is in compliance with all specified qualityrequirements, to be approved for any further processing or use.

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6. PRODUCTION

Production is performed in compliance with approved technological procedure. Detaileddescription of the manufacturing procedure, together with the critical process points aregiven in the master formula. Production is carried out and headed by competentpersonnel. During the production, batch production and batch packaging records arefilled in. Individual phases, including key parameters, are controlled and documented byin-process control. Separate appropriate procedures are being respected for thehandling 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

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ACTIVITIES CHART

YES

NO

NO

YES

NO

Annual Sales Plan

Annual Production Plan

Annual Production Plan Three-month production plan

Raw material and packagingmaterials supplies

Production Planning

Receipt

Sampling

Quality Control

Refusal

Claim Approval

YES

Issuing of documentationfor a batch

Dispensing of materials fora batch (weighing)

Production process

In-process control

Measure

Semi-product

Sampling

Quality Control forsemi-product

Approval

Continued on next page

Approval

Measurements

Continued from previous page

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NO

YES

Packaging

In-process control

Quarantine for finalproduct

Quarantine control forfinal product

Approval

Batch Release

SALES

Refusal

Measurements

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COURSE OF PRODUCTION FOR SOLID ORAL DRUG FORMS

Sieving

Mixing MixingWet granulation

Dispensed raw material receipt

Drying

Sieving Excipients

Final mixing Excipients

Tabletting

PackagingPrimary packaging

material

Glass bottles

PackagingSecondary

packaging material

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COURSE OF PRODUCTION FOR NON-STERILE LIQUID FORMS

Dispensed raw material receipt

Liquid form processing(mixing, heating)

Dissolving

Filtering

Filling in glass bottles

Packaging

Primary packagingmaterial

Secondarypackaging material

Active components

Excipients

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COURSE OF PRODUCTION FOR TEAS

Raw material Milling and sieving

Homogenization

Weighing

Packaging

Dosing

In-process control

In-process control

Chemical andmicrobiologicalanalysis of final

product

In-process control

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6.2 Process validationProcess 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

6.3.1 Receipt, storage and approval of raw materials

Receipt, storage and approving of raw materials is carried out in accordance with GoodStoring Practice (GSP), Good Manufacturing Practice (GMP) and SOPs.

Receipt of raw materials is carried out by competent personnel, in compliance withwritten procedures in Raw Materials Warehouse. The procedure’s requirements are asfollows:

- checking of compliance for shipment, delivery note (for domestic supplies), invoice(for international supplies), certificate and purchase order; these checks are carriedout in area intended for receipt

- labeling of raw materials and moving into the quarantine area

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- 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 rawmaterials), after an analysis of samples has been made in accordance with thespecifications.

Approved materials are labeled and transferred to intermediate storage in raw materialswarehouse. Storing conditions for raw materials are as follows:

- temperature: 10 - 25 °C- humidity: 50 ± 20 %,

in case not otherwise declared by manufacturer / supplier. Temperature and humiditymonitoring is done on everyday basis.

Shelves and pallets in intermediate storage are uniformly designated and identified. Onlyone raw material is allowed to be placed on one shelf / pallet, and at different levels ofthe same shelf, different batches of the same raw material, may be placed. The shelvesare 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 ofraw materials only.

Handing out of materials is done on first in - first out principle. The activities of preparingand dispensing are carried out in a separate area of hygiene class 3, in raw materialswarehouse. Dispensing is done under supervision of a production technologist. Non-approved raw materials after the claim settlement, are either returned tomanufacturer / supplier or transferred to waste material storage, according to theprocedure.

6.3.2 Receipt, storage and approval of packaging material

Receipt, storage and approval of packaging material are carried out in accordance withGSP principles.

Receipt of packaging material is carried out by competent personnel in the packagingmaterial 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

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Sampling is performed by following the written instructions in the SOP.

Report on packaging materials quality is issued (approval or refusal for using thepackaging materials), after an analysis of samples is made in accordance with thespecifications.

Approved packaging materials are labeled and transferred to intermediate storagewithin packaging materials warehouse. Storing conditions for packaging materials are asfollows:

- temperature: 10 - 25 °C- humidity: 50 ± 20 %,

if not otherwise declared by manufacturer / supplier. Temperature and humiditymonitoring 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 materialare stored in separated areas.

Handing out of materials is done on first in - first out principle. The shelves are raisedabove the floor (height of pallet) and pulled away from the walls (15 cm - 25 cm), foreasier cleaning of the areas. Packaging material can be handed out on materialrequisition slip, referring to one batch of product only. Non-approved packagingmaterials are labeled and immediately transferred into not-in-use storage (separatedarea in packaging materials storage, for goods inappropriate for manufacturing process).

6.3.3 Sampling of semi-finished and finished products

Sampling of intermediaries, semi-finished products and finished products is carried outby the appropriate personnel. Sampling is carried out in accordance with writtenprocedures. Every product is sampled according to an appropriate sampling plan.

6.3.4 Release of finished products

Release or rejection of a batch of finished product is within the scope of responsibility ofQuality Control. The system for approving the entering materials and the finishedproducts is in accordance with the law, the current specifications, the GMP requirementsand the international standards.

For production and sales respectively, only the entering materials and finished productsreleased 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 isbased on evaluation of all available information about the batch, like: test results,

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certificates, batch production records, batch packaging records and reports ondeviations.

Assessment of information, when deciding on a release of finished product for usage, isbased on reviewing the following documents:

- Batch production records and batch packaging records (weather the information iscorrectly filled in and whether it is in compliance with the requirements; is thecomplete 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 areforwarded to those applying and to those who will use the entering materials andfinished products, all according to the written procedure. Documentation on batch ofincoming material is also recorded, for raw materials - in the period of 10 years, and forpackaging material - 2 years. Documentation on finished product’s batch is stored forone year, after the expiry of the shelf life of the product.

6.3.5 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 rawmaterials storage; raw materials with expired shelf life or raw materials intended forproducts which are no more manufactured

- Pharmaceutical waste from damaged / inappropriate product during production ordevelopment, 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 ismarked with a label SPECIAL WASTE. In the container, there is a PVC bag for collectingpharmaceutical waste. Bags containing pharmaceutical waste are to be properly closedand 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.

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7. QUALITY CONTROL

Quality Control is part of GMP and GLP regulations for handling samples, specificationsand testing, as well as organization, documentation and approval of procedures,providing that the necessary and appropriate tests are carried out and that the materialsare not released for usage or the products for sales/supplies, until their quality isascertained to be satisfactory.

The activities of Quality Control sector are as follows:

- Preparing of specifications and test methods for physical-chemical, microbiologicaland biological investigation of entering materials, intermediaries, semi-finishedproducts, 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 ofMacedonia, on the basis of a Cooperation Agreement.

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8. DISTRIBUTION, CLAIMS ANDWITHDRAWAL OF PRODUCTS

8.1 Storage and distribution

Finished goods are stored in Finished Goods Warehouse. They are placed on pallets at asufficient distance from each other, in order to avoid swarming and enable an easierrequisition 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 ofbuyer, 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. Onecopy is distributed to Finished Goods Warehouse, and kept there one year, after theexpiry 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 describedin accordance with the standard operating procedure. Every claim must be investigatedobjectively and in details, regardless of its nature.

The mode for handling the product, not meeting the specified quality, but which isnevertheless found in the market and must be withdrawn, is described in details in therespective procedure. The procedure involves the persons responsible for decisions onrecall, 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, accordingto the information obtained on the basis of: postproduction inspection of drugs, claim ofbuyer, or any other external client.

The extent of recall (the whole shipment, part of shipment) depends on the potentialimpact on health. The recall may be made on behalf of: warehouse, wholesaler, hospitalstorage, pharmacy or an individual user. Decision on recall is taken by the GeneralManager.Products withdrawn from the market are stored in a separate dedicated area markedRECALLED PRODUCTS and RECALL. Recalled products in all recalling phases must behandled in such a way, which does not allow repeated distribution. Recalled productsmust be destroyed (transferred into Pharmaceutical waste storage). The documentationregarding decisions and execution of recall is kept. The period for keeping of thedocumentation in recall is one year, after the expiry date of the product being subject ofthe recall.

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9. SELF INSPECTION

Internal inspection covers all activities inside and outside “Inter-Evrogeneks”, which canhave an impact on product quality, level of fulfillment of GMP requirements, legalregulations or any other regulations related to drug manufacturers. Inspection areas arethe areas foreseen in GMP, i.e.: personnel, areas, equipment, documentation,production, quality control, distribution of products, claims and recalls settlement, aswell as inspection of raw materials suppliers and in-bulk product suppliers.

Internal inspection is carried out according to the annual plan of internal inspection andexceptionally, it can be made upon the request of the General Manager.

Results from the internal inspection are given in internal inspection reports. Reports oninspection, 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 GeneralManager. The report is sent no later than 20 days and it is a strictly confidentialdocument 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 aproposal for corrective measures and improvement activities.

The internal inspector is following up the progress of actions, for the purpose ofimplementing future corrective measures.

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APPENDICIES

Appendix I: Copy of valid manufacturing authorization

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Appendix II: Copy of valid GMP Certificate 2006,

Certificate obtained from the Ministry of Health of the Republic of Macedonia, for meetingthe requirements of GMP

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Certificate of GMP 2013 - Compliance of a Manufacturer (2 pages)

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Certificate of GMP 2016 Compliance of a Manufacturer (2 pages)

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Appendix III: Copies of valid Environmental Management Certificates

Certificate obtained from MKS MAKKONTROL for Environmental Management,according to standards of ISO 14001:2004

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Certificate obtained from TUV AUSTRIA CERT for Environmental Management, accordingto standards of ISO 14001:2004

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Certificate obtained from TUV NORD for Environmental Management, accordingto standards of ISO 14001:2004

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Appendix IV: Copies of valid Quality Management Certificates

Certificate obtained fromMKS MAKKONTROL for Quality Managament, according tostandards of ISO 9001:2000

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Certificate obtained from SGS for Quality Management, according to standards of ISO9001:2008

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Certificate obtained from TUV AUSTRIA CERT for Quality Management, accordingto standards of ISO 9001:2008

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Certificate obtained from TUV NORD for Quality Management, accordingto standards of ISO 9001:2008

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Appendix V: Copy of valid Free Sale Certificate

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Appendix VI: Copy of valid FDA Facility Registration Form

“Inter-Evrogeneks” has its own FDA Facility Registration Number - 18060520592, andVarumin has its own FDA Food Facility Number - 18888596962, which guarantees freeimport and sales of Varumin and al l the other products, on the USA market.

1st page of the FDA Facility Registration Form:

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Appendix VII: List of products currently manufactured on-site

BRAND NAME FORM

VARUMIN solution

Glukonormin forte tablets

Varuklim tablets

Varuprostin tablets

Varutensin tablets

Varupotent tablets

Paradental solution

Varuhemoroidal solution

Varuflu solution

Varumin herbal Medical tea

Glukonormin Medical tea

Varuklim Medical tea

Varuprostin Medical tea

Varutensin Medical tea

Varuascitofin Medical tea

Gorka Dinja suspension