Site Master File

PHARMACEUTICAL INDUSTRY
INTER - EVROGENEKS
“Goce Delcev” 12; 2434 Novo Selo; R. Makedonija SITE MASTER FILE
Skopje, 2016 SMF Page 2 of 50

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Good Manufacturing Practice (GMP) for finished Pharmaceuticals (WHO, EEC, PIC)
Prepared by: Verified by: Approved by:
Prim. M-r Romil B.S.Pharm.Spec. Dipl Ing.

Sandzakoski
Blagica Jakimovska Ivan Gjorgjiev
Sepc Pharmaceutical
Technology
_____________________ _____________________ _____________________
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 5
1.2 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 9
MANUFACTURER
2.1 The quality management system of the manufacturer 9
2.2 Release procedure of finished products 10
2.3 Use of outside scientific, analytical or other technical 11
assistance in relation to manufacture and analysis
3. PERSONNEL 13
3.1 Organizational chart 13
3.2 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 15
3.6 Personnel hygiene requirements including clothing 15
4. PREMISES AND EQUIPMENT 16
4.1 Premises 16
4.1.1 Brief description of the heating, ventilation and air 16
conditioning (HVAC) systems
4.1.2 Brief description of water systems 17
4.1.3 Brief description of other relevant utilities, such as steam, 18
compressed air, nitrogen, etc.
4.2 Equipment 18
4.2.1 Listing of major production and control and GMP critical 18
systems
4.2.2 Cleaning and sanitation 19
5. DOCUMENTATION 20
6. PRODUCTION 22
6.1 Type of products 22
6.2 Process validation 28
6.3 Material management and warehousing 28
6.3.1 Receipt, storage and approval of raw materials 28
6.3.2 Receipt, storage and approval of packaging material 29
6.3.3 Sampling of semi-finished and finished products 30

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6.3.4 Release of finished products 30

6.3.5 Handling with rejected materials and products 31
7. QUALITY CONTROL (QC) 32
8. DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND 33
RECALLS
8.1 Distribution 33
8.2 Complaints, product defects and recalls 33
9. 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

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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.12
2434 Novo Selo - Strumica
Republic of Macedonia
Phone: +389 2 3215 800

Fax: +389 2 3215 801
Mob: +389 70 316 011
Contact person: Cventancho Gjorgjiev (M.Sc.Eng.)
E-mail: [email protected]
Web: www.interevrogeneks.com
www.varumin.com.mk
Representative office:
“Inter-Evrogeneks”, Nikola Vapcarov Str. No. 20/7, 1000 Skopje
Phone: +389 2 3215 800

Mob: +389 2 70 259 222
GPS coordinates - 41.410931, 22.87899

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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 - 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

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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 2012-2015, “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 2014-2015, “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 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 and
transportation; 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 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 14
001:2004 standards.

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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. 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 the
conclusions from the internal audit. After the audit, appropriate measures are taken to
avoid any future mistakes.

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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.: +389 2 3 223 354
Fax: +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 Macedonia

Tel.: +389 2 3 223 354
Fax: +389 2 3 223 033
“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.: +389 2 3 249 999
Fax: +389 2 3 228 141
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

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Bulgarian Academy of Sciences
Address: 15 Noemvri Str. No.1, 1040 Sofia, Republic of Bulgaria

Tel.: +359 2 979 53 33
Fax: +359 2 979 52 23
“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.: +389 2 3 115 277
Fax: +389 2 3 134 310
“Inter-Evrogeneks” has an established cooperation with the Department for

Microbiology and Parasitology at the Faculty of Agricultural Sciences and Food - Skopje.

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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 UNIVERSITY DEGREE

INTER-EVROGENEKS 28 15
Quality Assurance 2 2
Production 14+5 11
Quality Control 1 1
Storage and Distribution 4 /
Technical & Engineering
2 1
Support Services
3.3 Qualifications, experience and responsibilities of key personnel
WORKING
POSITION QUALIFICATIONS EXPERIENCE RESPONSIBILITIES
(in years)

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Ivan Gjorgjiev
General M.Sc.Eng. 30 General Manager
Manager
Rumjana
Gjorgjieva
B.S.Tch 25 General Secretary
General
Secretary
Blagica
Jakimovska Responsible for
B.S.Pharm.Spec. 25 Pharmaceutical
Director of Production
production
Romil
B.S.Pharm.Spec. Responsible for
Sandzakoski 38
Prim. Pharmacovigilance
Advisor
Cvetancho
Responsible for
Gjorgjiev B.S.Pharm. 2
Quality Control
Quality control
Tomislav
Angelov Responsible for
B.S.E. 22
Marketing Marketing and Sales
Manager
Dimitar Mitev
Responsible for
HVAC B.Sc.Eng. 2
HVAC maintenance
Maintainer
Ilija Hristov
Responsible for the
Legal LL.B. 10
legal department
Department
Kristijan Responsible for IT

Jovanovski Bachelor of
7 solutions and
computer science
IT Department problems
Dragi Panziev Responsible for raw

Chemical
12 materials
Warehouse-man technician
warehouse

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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, 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).

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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 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 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 of

horizontal production line is implemented on the ground floor of the factory, occupying
area of 1250 m2. All standards are obtained. The used materials meet the requirements
of 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 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

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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.
4.1.2 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.

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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 coming
into 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 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 plan-
programs 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.
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 the
SOP. Types of cleaning agents and their preparation (specific concentration), as well as
the cleaning frequency, are also defined in SOPs.

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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 USED BY
Quality policy / Company’s
1 All
Environmental Guidelines
Quality and Environmental
2 All
Management Manual
Quality and Environmental plans,
3 All
laws, guidelines, guides
SOP-quality and environmental
4 All
system
Technological, registration, manufacturing,
5 control documentation, operational and All
examinational instructions, etc.
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.

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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.

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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

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ACTIVITIES CHART
Annual Sales Plan
Annual Production Plan
Annual Production Plan Three-month production plan
Raw material and packaging Production Planning

materials supplies
Issuing of documentation
Receipt for a batch
Dispensing of materials for

Sampling a batch (weighing)
NO Production process
Quality Control
NO
In-process control
YES
YES Measure
Refusal
Semi-product
Claim Approval
Sampling
Approval NO Quality Control for

semi-product
YES
Measurements Approval
Continued on next page
Continued from previous page

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Packaging
In-process control
Quarantine for final

product
Quarantine control for NO

final product
YES
Refusal
Approval
Measurements
Batch Release
SALES

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COURSE OF PRODUCTION FOR SOLID ORAL DRUG FORMS
Dispensed raw material receipt
Sieving
Mixing Wet granulation Mixing
Drying
Sieving Excipients
Final mixing Excipients
Tabletting
Primary packaging
Packaging material
Glass bottles
Secondary
Packaging packaging material

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COURSE OF PRODUCTION FOR NON-STERILE LIQUID FORMS
Dispensed raw material receipt
Liquid form processing

(mixing, heating)
Excipients
Dissolving
Active components
Filtering
Primary packaging
Filling in glass bottles material
Secondary
Packaging packaging material

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COURSE OF PRODUCTION FOR TEAS
Raw material Milling and sieving
Weighing
Homogenization In-process control
Dosing In-process control
In-process control
Packaging
Chemical and
microbiological
analysis of final
product

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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
6.3.1 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

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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 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: 10 - 25 °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. Non-
approved raw materials after the claim settlement, are either returned to
manufacturer / supplier or transferred to waste material storage, according to the
procedure.
6.3.2 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

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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 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: 10 - 25 °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).
6.3.3 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.
6.3.4 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,

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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.
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 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.

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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.

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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.

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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.

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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 meeting
the 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, according
to standards of ISO 14001:2004

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Certificate obtained from TUV NORD for Environmental Management, according


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Appendix IV: Copies of valid Quality Management Certificates
Certificate obtained from MKS MAKKONTROL for Quality Managament, according to

standards of ISO 9001:2000

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Certificate obtained from SGS for Quality Management, according to standards of ISO
9001:2008

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Certificate obtained from TUV AUSTRIA CERT for Quality Management, according

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Certificate obtained from TUV NORD for Quality Management, according


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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, and
Varumin has its own FDA Food Facility Number - 18888596962, which guarantees free
import 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

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PHARMACEUTICAL INDUSTRY

Skopje, 2016 SMF Page 2 of 50

Prepared by: Verified by: Approved by:

Prim. M-r Romil B.S.Pharm.Spec. Dipl Ing.

Quality Management and Environmental Management

Skopje, 2016 SMF Page 2 of 50

Title Page No.

Skopje, 2016 SMF Page 3 of 50

6.3.4 Release of finished products 30

Skopje, 2016 SMF Page 4 of 50

1. GENERAL INFORMATION ON THE MANUFACTURER

1.1 Contact information of the manufacturer

Phone: +389 2 3215 800

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

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

Phone: +389 2 3215 800

GPS coordinates - 41.410931, 22.87899

Skopje, 2016 SMF Page 5 of 50

1.2 Authorized pharmaceutical manufacturing activities carried out on the site

The pharmaceutical industry “Inter-Evrogeneks” was established on 12.12.1998, by Mr.

“Inter-Evrogeneks” is aware that quality is the background of every business success,

In October 2006, “Inter-Evrogeneks” received a GMP certificate (Appendix II), issued by

In September 2007, “Inter-Evrogeneks” certified its Environmental Management System

In January 2008, “Inter-Evrogeneks” certified its Quality Management System (QMS)

In November 2009, “Inter-Evrogeneks” certified its Quality Management System (QMS)

“Inter-Evrogeneks” has a manufacturing program, composed of medicines for human

Skopje, 2016 SMF Page 6 of 50

of the Republic of Macedonia and the Faculty of Pharmacy, Skopje – Republic of

In the period 2012-2015, “Inter-Evrogeneks” became an export-oriented company,

In June 2015, “Inter-Evrogeneks” received FDA Registration Number, enabling the

From 2014-2015, “Inter-Evrogeneks” has improved its manufacturing capacity and

In accordance with the manufacturing activities approved by the Ministry of Health of

Types of actual products manufactured

Skopje, 2016 SMF Page 7 of 50

1.3 Any other manufacturing activities carried out on the site

Skopje, 2016 SMF Page 8 of 50

2. QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER

2.1 The quality management system of the manufacturer

“Inter-Evrogeneks” continuously monitors the EU legislation and obtains its

“Inter-Evrogeneks” is aware of the environmental impact of its products and services,

The personnel responsible for Quality Management and Environmental Management

- Development, maintenance and supervision of Quality System and Environmental

The Quality Management System and Environmental System are established,

Skopje, 2016 SMF Page 9 of 50

Efficacy of the system is ensured by establishment of work organization and clearly

2.2 Release procedure of finished products

Skopje, 2016 SMF Page 10 of 50

2.3 Use of outside scientific, analytical or other technical assistance in relation to

Institute for Public Health, Republic of Macedonia

Address: 50 Divizija Str.No.6, 1000 Skopje, Republic of Macedonia

Faculty of Pharmacy, Skopje

Address: 50 Divizija Str. No.6, 1000 Skopje, Republic of Macedonia

Faculty of Mathematics and Natural Sciences, Skopje

Address: Gazi Baba bb, 1000 Skopje, Republic of Macedonia

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

Skopje, 2016 SMF Page 11 of 50

Bulgarian Academy of Sciences

Address: 15 Noemvri Str. No.1, 1040 Sofia, Republic of Bulgaria

“Inter-Evrogeneks” has an established cooperation with the Department for