Proses Çözümleri Magazine, July (İlaç Üretim Prosesi) Issue
Santa Farma’s Answers to Questions
Santa Farma Gebkim Production and R&D Centre performs its operations under the coordination of the Plant Division, Quality Division and R&D Division.
1- Could you introduce yourself and the activities conducted in your division? (who is the director answering to the questions?)
My name is Uğur Çağlayan. I’m the Plant Director of Santa Farma. The Plant Operations are comprised of five main sections. Those are Production Planning, Manufacturing, Technical Services, Warehousing and Technical Operations. We perform our operations based on the simple thinking philosophy. Our motto is to perform our activities with zero error, zero accident, zero incompatibility, 100 per cent service level and minimum costs.
2- Could you tell us about production capacity of the plant, units, auxiliary plants, units and activities, product ranges etc.?
We have a manufacturing plant and R&D Centre comprised of an indoor area of 44 thousand sqm on a total land of 80 thousand sqm in Dilovası GEBKİM OSB. The plant was issued a production license and GMP (Good Manufacturing Practices) certificate from the Ministry of Health of Republic of Turkey in June 2015 and received the EU-GMP certificate (European Union Compliance with Good Manufacturing Practices) in 2016. The renewal inspection conducted by the Ministry of Health and EU-GMP authorities resulted satisfactorily in 2019. Also, we adopted the Data Integrity system in parallel with the leading global companies and performed satisfactorily in the audits conducted by several global corporations and authorities. Products in solid, semi-solid and liquid forms are manufactured in the plant. Boasting of a manufacturing capacity of 150 million boxes, the plant has the means to increase the capacity based on necessity. It is possible to expand the interior and exterior of the building in order to meet the requirements regarding capacity increases.
Out of its dedication to adopt innovative technologies, Santa Farma uses BMS (Building Management System) in order to control and monitor the infrastructure at its GEBKİM plant.
Santa Farma’s building management system is compatible with 21CFR Part 11 and makes it possible to guarantee cGMP (Current Good Manufacturing Practices) on a continual basis.
The building management system is comprised of 20,000 automation points such as HVAC automation, lighting automation, cooling automation, heating and water preparation systems automation which are intended to control and monitor manufacturing, warehousing, lab, stability and reference sample rooms, R&D and office spaces.
HVAC Automation
At Santa Farma GEBKİM production plant, we meet the requirements for ISO 9 E Class production zones and keep the temperature, relative humidity, and inter-zone pressure values under constant control.
The temperature of all rooms is kept at 22 ±1,5 °C in the production zones. The relative humidity is kept at maximum 60% RH. We use special dehumidifiers in order to adjust relative humidity up to maximum 15% at individual zones which require specific humidity control.
In order to eliminate cross-contamination risks, we use automatically adjustable dampers to keep pressure under control and achieve and monitor different pressure values. Room temperature-humidity-pressure values are monitored through digital indicators at all production zones.
All conditioned zones are monitored through the automation system equipped with monitors that proactively produce alarms before occurrence of any out-of-limit conditions at the production zones. Alarm reports are sent through text messages or e-mails.
The building management system records all temperature-humidity-pressure data and keeps event logs at all monitored zones and archives the relevant data for minimum 10 years.
Critical warehousing zones are equipped with 40 temperature-humidity sensors while the temperature-humidity conditions at cold rooms and stability rooms are controlled with the help of the building management systems.
HVAC requirements of Santa Farma GEBKİM plant are met through a total of 81 ventilation stations, comprised of 60 main air-conditioning plants, exhaust and fresh air systems, and 11 high performance dehumidifiers. The ventilation system and all cooling and heating sub-systems are operated under the control of the building management system.
Fire Detection Automation:
The fire detection system is integrated into the building management system. It consists of 8 main control panels, 17 distinctive fire loops and 2,300 fire sensors and detectors. Fire controls systems are equipped with optic smoke detectors, heat detectors, combined detectors, beam detectors for high volume zones, automated unmanned warehouse active air sampling detectors, addressed-type alarms, flashers and fire warning buttons.
System operations are monitored through a fire monitoring system computer. Control panels are allocated to specific fire zones while the safety centre is equipped with a repeater and monitoring panel. The fire system contacts and sends alarms to GEBKİM OSB fire department automation system.
Lighting Automation:
At Santa Farma GEBKİM plant, the peripheral lighting system is time adjusted and automatically controlled.
Passive infrared detectors are available at corridors and rarely used zones. Also, thanks to the building automation system, lights are turned on and off automatically at technical zones and other areas which are used for a certain period of time. 6 distinct automation panels are available for control of lighting systems centrally or locally.
There are 2,400 lighting fixtures at the indoor areas of the plant. Also, 800 battery operated lighting fixtures are available in emergency exits and other areas in order to keep the plant illuminated for 180 minutes at emergency conditions. In that respect, minimum 1 battery operated lighting fixture is available in each room as well as exit routes.
Electrical System:
Santa Farma Dilovası plant’s installed power is 7,500 kVA. GEBKİM OSB provides 34.5 kV energy which is transferred to main distribution panels through bus bars after performance of 34.5kV/400V conversion by means of 2,500 kVA ABB dry-type transformers available in the power plant. Also, the plant is equipped with 3 synchronous generators with a capacity of 2,500 kVA. Those generators are automatically activated in case of power outage. Mains-to-Generator changeover transfers are performed through automatic transfer units which allow for uninterrupted changeover. Generators are automatically activated and deactivated by means of the synchronization and transfer units according to the energy requirements at the plant.
The main panels are also equipped with a central compensation system which is designed according to the applicable power. Those systems are monitored through the central monitoring system established by OSB management as well as the individual energy monitoring system available at the plant. The monitoring activities are performed for keeping reactive consumption levels under control.
The plant is equipped with 2 uninterrupted power sources of 300kVA and 1 uninterrupted power source of 120kVA, all of which are used for guaranteeing uninterrupted operation of computers at offices and production zones, server and internet infrastructure, CCTV system, finger print / card scanners used for access control, emergency directional signs, plc and automation units of production equipment, ventilation automation panels and energy monitoring panels. Also, the entire IT infrastructure is independently powered through 2 independent uninterrupted power sources which are interconnected to each other.
CCTV:
We use a CCTV system comprised of 2 high-speed, auto-iris, optical zoom dome cameras and 338 steady cameras. All cameras have day/night function.
Pressurized Air System:
At Santa Farma Gebkim plant, we generate pressurized air by means of two screw-type compressors. Compressor air suction channels are positioned to the northern façade of the plant for energy saving purposes. Also, compressors contribute to energy saving through cycle control of varying air requirements. In line with GMP requirements, pressurized air is fed to production zones by means of two dryers capable of operating under conditions up to -70 ◦C. Pressurized air system is designed in the form of a ring with aluminium composite material in order to prevent leakage at air lines and increase energy saving. Thanks to all those technical designs, we use ISO 2 class pressurized air in our plant.
Steam System:
The plant is equipped with two steam boilers with a capacity of 7.5 tons/h. They are integrated to the automation system. The system is capable of measuring instant natural gas consumption and steam generation values. Also, since it is integrated into the energy monitoring system, it is possible to record and analyse the level of natural gas consumed for steam generation purposes. For energy saving, the ecominizer system is used for making use of stack gas heat. Boiler covers are insulated with aerogel material in order to minimize heat loss. Steam condense arising from the operations are constantly checked through boiler automation and redirected for steam generation by means of chemical dosing automation. The steam which is generated as a result of those operations is cycled to heat exchangers to be used in the form of hot water or steam.
Access Control System:
The plant is equipped with a card / finger print scanner system network at 209 different points. The system is comprised of personnel attendance control scanners (PDKS), door openers, magnetic door locks, door status control units and turnstiles. The turnstiles and magnetic doors available at the plant can be activated automatically in order to expedite eviction of the plant in emergencies such as fire alarms.
Authorization matrices are created for restricting access to production and product seasoning rooms at production zones for product safety purposes. Likewise, personnel and material air-lock systems are used between production zones and primary – secondary zones in order to ensure that the doors to such areas shall be kept closed by means of the locking mechanism.
Similarly, authorization for access to special rooms such as critical electric rooms and system rooms may be designated in line with the authorization matrices.
Card / finger print scanners are used for keeping access records and producing reports about the headcount and names of individuals inside the plant instantly.
3- What sort of investments does your company make for capacity and efficiency increase, modernization of control automation and similar matters? Could you share the details of those investments?
Santa Farma GEBKİM production plant is designed in line with the requirements of simple manufacturing processes. The plant is equipped with a number of systems and special equipment to promote efficiency and capacity increase. Let me give an example:
The Liquid Manufacturing section is equipped with a Sugar Feed System directed to manufacturing tanks with full automation and a closed system big-bag packing as well as a fully-dedicated and closed feed system with 3 control steps for transfer of 6 different raw materials. We have the fastest Syrup Line in Turkey. Combined with the parcelling machine, this line is used for performing filling activities by means of the robotic palletizer system. The semi-solid tube feeder equipped with the tube feed robot system meets all requirements to the utmost level. The solid manufacturing section is operated with fully closed vacuum production systems in order to perform efficient operations in terms of product and employee safety. CIP equipment washing systems equipped in granulation and film coating machines make it possible to perform all washing and cleaning operations without manual labour. High capacity tablet printing machines maximize production and product flexibility and capability thanks to the capacity to perform both mono layer tablet and bi-layer tablet printing operations.
In order to maximize our efficiency, we conduct kaizen and 5S activities with the involvement of all employees in line with our simple management system. Also, the outputs derived from the line/equipment data is used for performing pareto analyses in order to ascertain the improvement areas and take action accordingly.
Also, in all processes, we benefit from the data derived from process optimization activities in order to determine the lost time and minimize this loss by performing necessary activities. As a result of the efforts made for increasing the efficiency based on constant improvement philosophy, we were able to increase the operational equipment efficiency (OEE) by 54%.
4- What sort of activities do you perform for energy efficiency, reduction of raw material losses, and monitoring losses? And what are the capabilities of the control and monitoring system used for that purpose?
We use state-of-the-art equipment in all manufacturing zones. In that respect, the equipment used at the plant ensures positive results in terms of product efficiency in addition to minimizing raw material losses. Considering the product efficiency and loss data available for the industry, the efficiency of all our products is above the average level at the industry. Also, as we have noted above, kaizen, 5S projects and pareto analyses help us take informed actions for minimizing losses for all machines and products. We use loss tracking system in order to monitor the losses and take action to the extent necessary for continuous improvement purposes.
Energy Saving Efforts:
For our hot water needs at lavatories and showers, we recycle flush steam through the steam condensation system.
Also used for heating the plant, steam condensation systems recover stack gas energy by means of economizers.
Plant cooling systems, on the other hand, are comprised of 3 high efficiency inverter controlled centrifugal chiller systems with water cooling capacity. The total cooling capacity is 9,000 kW. This coolant group ensure 1.5 times more energy saving in comparison with the conventional systems. The coolant group is served by 3 closed type cooling towers with a total capacity of 9,600 kW.
The cooling towers meet cooling requirements by making use of the difference with ambient temperature without activating chiller coolant groups under suitable ambient conditions (December to April).
Known as free-cooling, this is controlled by the building management system in order to activate and deactivate the system automatically based on the ambient temperature-humidity conditions.
Also, the frequency inverter pump groups used for cooling purposes are also controlled through the building management system. They are meant to promote energy saving by operating the system in line with the capacity requirements.
HVAC units which are available throughout the building for increasing the comfort contribute to energy saving by making use of heat of the conditioned air released to outer environment by means of heat recovery cells and heat recovery batteries at hygienic type HVAC units.
Eco Mode-1 introduced to HVAC systems keep the temperature at production zones at 22 ± 1,5 °C as well as ensuring minimum 20 air changes / hour during manufacturing operations while the temperature is kept at 22 ± 3 °C with minimum 10 air changes / hour when manufacturing operations are not performed. This reduces the energy consumption of HVAC units in addition to minimizing heating and cooling loads for energy saving purposes.
Our plant has qualified for Eco Mode-1 ISO 9 E class by meeting all quality requirements thanks to the energy saving project approved by the Ministry of Health.
Eco Mode-1 enables the plant to switch to normal working order automatically. Also, the building management system calculates the necessary HVAC requirements automatically in order to ensure sustainability of the convenient conditions required for quality assurance.
Since Eco Mode-1 system was introduced by means of the time schedule of the building management system in 2019, our annual energy saving is 3,500,000 kW while the natural gas saving is as high as 300,000 sm³.
Energy Vision / Energy Management Tracking Programme:
The plant is equipped with 142 energy monitoring analysers along with 2 natural gas meters and 8 water meters which are all monitored by means of mod-bus communication protocol in order to keep track of energy consumption at individual zones, buildings and machines.
Also, this system enables us to fulfil energy management reporting tasks easily and swiftly in addition to making daily / monthly / annual comparisons with previous periods.
The system allows for recording and instant monitoring of data related to all energy sources and energy consumption points by means of a web-based application. Also, alarm reports are sent to relevant departments or individuals by text message or e-mail in case of detection of out-of-limit conditions.
5- How would you summarize the pharmaceutical production processes from raw material acceptance till shipment of final products?
All processes from receiving raw materials at the warehouse till shipment from the warehouse are conducted under controlled conditions and monitored through automation systems. All components used for manufacturing of products (raw materials / packaging materials) are kept in warehouse sections which are controlled in terms of temperature and humidity. We check and receive the components under controlled conditions. All components are involved in the quality control process. In that respect, components may be used for production only after their compatibility is guaranteed through the necessary analyses. Raw material and material warehousing / Monitoring of production processes are automatically controlled with SAP – WMS systems. Raw materials are weighed with Weighing Integration systems integrated into SAP system in order to eliminate risk of errors. Then, all components to be involved in manufacturing processes undergo a second control. At this phase, it is essential to make a comparison between the product formulae available in SAP system and the actual components to be used for manufacturing. Hence, all raw materials are weighed for the second time. Once they are weighed, raw materials are transferred to manufacturing equipment through closed systems and manufacturing processes are performed in line with the dosage form. Products in solid, semi-solid and liquid forms are manufactured in the plant. Granulation, tablet printing, hard gelatine capsule filling, sachet filling, powder filling, effervescent tablet, film tablet / pill coating processes are undertaken at solid manufacturing unit. Liquid forms are syrup, spray and drop while semi-solid forms are cream, pomade and gel. All semi-finished products are transferred to packaging units where primary and secondary packaging processes are conducted at integrated lines. All boxes manufactured at secondary packaging unit are registered through ITS (Pharmaceutical Track & Trace System). All manufacturing and packaging processes are entered into batch production records. Besides, all processes are confirmed by means of SAP system. After they are packaged and confirmed at SAP, the products are transferred to finished product warehouse. Finished products, like other materials, are stored and monitored through SAP –WMS systems.
6- What does the company do about analysis, measuring, in-process and control? Could you please tell us about your team and their activities?
My name is Zeynep Bodur Korkmaz. I’m the Quality Director of Santa Farma. The Quality Division is in charge of the quality systems at Santa Farma GEBKİM plant. Thanks to our state-of-the-art labs, well-designed electronic systems and modern infrastructure, we perform quality management activities in line with cGMP, Legal (TR and EU) and global requirements with our team of competent-qualified professionals. Every one out of ten employees is assigned at the quality team at Santa Farma. This signifies the importance of quality for our company.
The division consists of three departments which are Quality Assurance, Quality Control and Microbiological Control. Those departments analyse all kinds of starting materials, finished- or by-products on nine different fields five of which are related to in-process controls and three of which are quality controls and the remaining one field being related to microbiology. Plus, stability studies simulating different climactic zones are performed through process, cleaning, holding and analytical method validation activities.
Documentation, Change Control, Customer Complaints, Deviation, Audit, Training, Corrective-Preventive Action and similar matters which form the basis of Quality Management Systems are monitored and administered through our validated software (QMex).
Under the Data Integrity (DI) management system, all complex analysers (HPLC, GC etc.) available at the Quality Control Instrumental Lab conform to the requirements of CFR 21 Part 11 and DI thanks to use of Empower 3 Enterprise, Build 3471 Data Management software.
As we have mentioned in general, the plant was awarded TR and EU GMP certificates in 2015. Based on the satisfactory results achieved in the audits, those certificates were renewed in 2019 and they are still effective. In addition to certifying our compliance with the local and EU GMP requirements, we have been able to prove the effectiveness of our quality system, infrastructure, production and other qualifications related to cGMP at several audits conducted by the authorities of different countries (Jordan) and specific audits performed for contracted manufacturing operations undertaken on behalf of global corporations.
Hereafter, we aim to expand our global reach by increasing our production capacity, performing contracted manufacturing operations and producing safe and high quality products reflecting our global quality principles.
7- What is the process for creating investment ideas and what sort of investments do you plan to make? What are the important factors (eligibility criteria) for ascertaining the brands to be involved in the investment processes?
With more than 75 years history in pharmaceutical industry, Santa Farma is recognized for the prominent, innovative and high quality solutions developed for improving life quality of patients with its qualified team by using eco- and human-friendly technologies at its high capacity, state-of-the-art manufacturing plant and R&D centre in EU standards thanks to its vast experience in contracted manufacturing processes. Santa Farma aspires to become a contracted manufacturer of choice for local and global pharmaceutical companies in terms of both domestic manufacturing and export processes by offering competitive advantages to stakeholders in line with their specific needs and strategic procurement plans. We determine the potential investments based on our strategic planning and contracted manufacturing goals and finalize the investment decisions based on capacity, quality, deadline and pricing requirements with due regard for customers’ needs and specifications. Those investments are put into practice based on those criteria to the extent required for new product projects and continuous improvement efforts.
8- What if a company makes a mistake in its decisions regarding machinery, equipment and solutions? Could you give an example to the potential problems arising from wrong decisions? What sort of challenges do you come across when selecting the solutions?
Incorrect solutions will create challenges in terms of quality, capacity and time. Thankfully, we haven’t come across such a problem so far.
9- Is there anything you would like to add?
As a company dedicated to improving human health and product quality, Santa Farma continues to take action on Occupational Health and Safety, as well. OHSAS 18001 Management System is used for taking preventive measures and undertaking various projects to protect the employees from occupational diseases and accidents. In that respect, the company was awarded the grand prize for its “Closed Raw Materials and Transfer System” Investment at the Occupational Health and Safety Best Practices Awards organized by KİPLAS in 2019.
Santa Farma AR-GE Merkezi:
My name is Ersin Yıldırım. I’m the R&D Director of Santa Farma.
Santa Farma R&D Centre and Production plant is located in Dilovası GEBKİM OSB.
With its production plant and dedicated R&D centre with a closed space of 44,000 m2, it is one of the leading pharmaceutical manufacturers with domestic capital in Turkey.
Equipped with state-of-the-art production and lab instruments which conform to international standards, the centre was issued a production license and GMP (Good Manufacturing Practices) certificate by Turkish Ministry of Health. In addition, its production activities are approved by international authorities as it might be inferred from the EU-GMP (European Union-GMP) certificate which is valid in Europe as well as many other countries in the world.
Santa Farma R&D Centre is comprised of 4 levels on a land of around 3000 m2. At our modern and technology oriented R&D centre, we prioritize a solution oriented and scientific approach with the ultimate goal of creating high performance products and solutions under the guidance of globally accepted regulations. We perform R&D activities in order to create innovative and patented solutions not only for the local market but also for global markets.
Founded on pillars of innovation and differentiation, pharmaceutical R&D industry is strategically important for both domestic and global economy. Assuming a leading role in presenting the first generic product to the market at any therapeutic field is quite important in order to present alternative treatment methods, facilitate access to medication, reduce treatment costs and relieve the country from current account deficit as well as dependence on foreign markets. We believe that we need to focus on R&D activities in order to create difference and empower innovation in line with our vision to keep up with the changes in the global arena. Hence, we plan our strategies with a view to keeping our operations up-to-date in line with the changing conditions in the market.
As a result of this dedication, we managed to register more than 20 pharmaceutical and therapeutic products in the last three years. These new products are intended to be presented to Global Markets. Throughout 2020, several academics have continued to work on different patentable projects. As a matter of fact, there has been a considerable increase in the number of patent applications since the R&D centre was commissioned. We file patent applications for more than 10 innovative products every year. Apart from the ongoing research / development activities, we have been proudly awarded 7 different certificates as a result of our innovative approaches to research and development as of Q2/2020.
The R&D centre is also distinguished for its qualified workforce. Currently, we have 56 full-time researchers with Ph.D. and M.Sc. degrees. New hires undergo a special “mentoring program” which has proven to be very beneficial for adaptation and practical training.
The R&D centre is comprised of pharmaceutical technology laboratories, pharmaceutical analytical development laboratories, stability areas, project development, patent and bioequivalence-bioavailability offices. Innovative thinking, respect for the individual, systematic thinking, focus on science and culture, rational power, experience and competence remain at the core of our pharmaceutical product development activities.
Our “human” oriented philosophy is at the core of all our activities. We strive to promote the importance of research, quality and global vision in order to create innovative and value added products for the benefit of Turkish and international pharmaceutical industry.
At this point, it is critical to make innovation sustainable and therefore, we create strategies that promote respect for human beings, constant change and sustainable development.
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