Behind the scenes of the pharmaceutical industry

There are more than a hundred drug manufacturers in Ukraine, but only a few conduct clinical trials and create their own drugs in accordance with GMP standards that regulate the quality of manufacture.

One of them is "Darnitsa", the largest pharmaceutical manufacturer in Ukraine, which occupies 14% of the market in terms of packaging. In 2018, every seventh package sold in Ukrainian pharmacies bore its logo.

In recent years, the company has invested EUR 200 million in infrastructure, technology and processes. We visited the Darnitsa plant in Kyiv and saw how famous Ukrainian medicines are born: a coverage.
Quality as part of DNA
The first thing that catches your eye when entering the closed territory is sterile cleanliness, short-cut lawns and the absence of trees.

– Is it for security reasons? I ask the head of the board of directors Darnitsa Group Dmytro Shymkiv who accompanied us.

– Vegetation creates an additional burden on purification filters, therefore, its amount should be minimal according to standards.

In "Darnitsa", they like to remind you how much attention is paid here to in-process safety and product quality.

"Product quality, state-of-the-art equipment and strict control are the part of DNA. You can see it for yourself by visiting our manufacturing facilities. Would you?" Shymkiv asks.

An interview is scheduled for this day (you can read it here >>>), so we agree on a tour in a week.

In the planned route we have: a fully automated logistics complex, a tablet manufacturing workshop and the site that the company is especially proud of – the manufacture of infusion solutions.
Being your own warehouse
An automated logistics complex (or as the company calls it – a distribution center) is the first place where raw materials for the manufacture of drugs go and the final stage before sending ready-made drugs to customers around the world.

Three-storey building with 12 floors, an area of 15,000 square meters, is divided into three zones – one on each floor: picking, unloading and shipment.

The heart of the complex is a fully automated high-rise warehouse.

To understand what it looks like, imagine a huge black box, seven-storey building high (length is 80 m, width is 28 m, height is 26 m) and stuffed with various latest technology mechanisms.
The high-bay warehouse is operated almost without human involvement, controlled by a computer system, and is connected to the other areas by conveyor and elevator network. This organism has a "memory" and knows everything about each unit of raw materials, materials, or finished products: from the composition and quantity to the manufacturing site and expire date.

Artificial intelligence allows the robot to make logistics decisions on its own, in accordance with the logic prescribed by programmers. For example, a heavier pallet is sent higher, drugs with a minimum shelf life are placed closer, for a more rapid delivery.
"The system is operated by an engineer and two technicians, the rest of the employees are involved only in warehouse accounting (the entire complex is serviced by 13 people – Ed.). Four Noresta robots move inside, they can work around the clock, distributing pallets and executing commands of the automated system. Automation is fully responsible for inventory optimization, climate control and product storage. At the time it was opened in 2008, it was the first project of such a scale in Eastern Europe".

Dmytro Shymkiv
Chairman of the Board of Directors of Darnitsa Group
All year round, the temperature in the room is + 15-25°C and humidity is up to 60%. These conditions are suitable for storing 90% of Darnitsa's products and are ideal for the operation of equipment.

Some part of the warehouse is reserved for cells with special conditions, where more sensitive products are stored. There are two modes: + 2-8°C and + 8-15°C. In the whole complex there is not a single battery: the warehouse cools and heats itself due to air circulation.

All units of the company (manufacture of tablets, infusions, ampoules, creams and ointments, etc.) are connected with the warehouse complex with galleries. This allows to move all products and raw materials, eliminating the influence of the external environment.

The same gateways are used to put boxes with medicines directly to refrigerated vehicles that deliver goods to customers both in Ukraine and for export: to Iran, Iraq, Georgia, Belarus, etc.
Important: the raw materials (chemical reagents, semi-finished products) supplied to the manufacture do not intersect with the finished product – these zones are divided.
"The warehouse is a strategic facility, the performance of which makes the entire company function", says technician Yurii Polubynskyi. If the system fails, the reception/shipment of products and raw materials is blocked, so stopping the conveyor for more than 30 minutes is considered critical. If it is not possible to fix the problem on our own, German experts intervene who have remote access to the warehouse servers".

According to him, for 12 years of use due to emergency situations, the warehouse was stopped only twice for several hours.

Why do we need such an advanced warehouse?

The main advantage is the access time and speed of processing products and raw materials.

"Previously, the freight handler needed up to 20 minutes on average to cope with one pallet, now it is coped with 10 times faster – within 2 minutes", explains Polubynskyi.

Moreover, the system allows simultaneous loading and unloading, which also saves time.
Darnitsa uses special wooden euro-pallets which are custom-made at one of the Ukrainian furniture factories. The pallets are made from specially aged wood that does not dry out. Here, even nails are hammered in a certain order and to a specified depth.

This is necessary so that pallets, regardless of external conditions, are placed in a warehouse materials-handling machine. Even a gap of 1-2 cm can block the movement of shelving.

One such Euro-pallet costs €30 and is in use for 2-3 years. An alternative is more durable plastic German pallets. Among the cons are: the price is €300 per unit.
The second advantage is the minimization of the human factor. "What you put on the pallet, you get at the output. Owing to the barcode on each package, the system is never mistaken – for 12 years it has never confused pallets with products", they say in Darnitsa.

Third is saving space. A section of 80 m by 26 m can contain 10,000 pallets of 1,000 kg each. If all of them are laid out on the floor, you will need a warehouse with an area which is 15 times bigger.
The next destination is a tablet formulation manufacturing complex. The employees call it simply – "Tablet".

Darnitsa produces drugs in 15 different dosage forms, of which solid is the most common. The assortment of tablets Darnitsa has more than 100 items.

The manufacturing facilities cover 15,000 square meters and allows the manufacture of 4.5 billion tablets per year. According to the State Service on Medicines, the share of Darnitsa in the Ukrainian tablet market is 30%.

The complex occupies two separate buildings. One of them is allocated for the manufacture of antibiotics and is physically isolated from the rest. In fact, it is a factory in a factory.

Here is the highest cleanroom class – D: employees are allowed exclusively in special airtight suits, reminding space suits of astronauts.
All rooms in the manufacturing facilities for pharmaceuticals are divided in accordance with a certain cleanroom class: the higher the class, the more sterile the manufacture. The GMP provides four levels of cleanliness: A, B, C, D is the cleanest. Compliance with a specific microclimate with specified parameters of temperature, air humidity, pressure cascade is controlled by an independent monitoring system.
We plan to visit the second building, where, among other things, one of the most popular drugs in the company's line is manufactured – Citramonum-Darnitsa.
How Citramonum is made
At the entrance to the workshop we find ourselves in a special zone – a sanitary inspection room. This is the room that separates the corridor and manufacturing rooms with a higher class of cleanliness. All sanitary inspection rooms in Darnitsa are divided into female and male.

We put on a special protective gown on outdoor clothing, a cap on the head, shoe covers on the feet, and wash hands with an antibacterial agent. This is to minimize the entry of microorganisms into indoor air.

All employees of the site go through the same procedure daily. It is impossible to get into the clean zone without passing the sanitary inspection room.

What is the peculiarity of the preparation of Citramonum?
"The components of the tablet (starch, caffeine, paracetamol, cocoa), as well as air heated to a certain temperature, are fed into the container. The process of thorough mixing and preparation of the tablet mass is launched", says Pavlo Adamov, lead engineer. – We add moisturising liquid and get a dough-like mixture. We pass it through the calibrator grid. The resulting granules are dried and then "dusted". Then the powder goes through the press".

After pressing, the tablets are dust-free and checked for metal inclusions. Before obtaining permission for packing from the quality control department, finished tablets are stored in special bin tanks. One bin holds from 200 to 300 kg of tablets (0.55 grams each). A batch usually consists of two bins and amounts to 148,000 blister cards.

From the bin, the machine sends the finished tablets to the final stage: packing and packaging.
Packaging line

The main workshop has six packaging lines. Two of them are for bulk products, four – for packaged products. For example, Citramonum.

The lines form blister cards, pack up tablets, glue the foil and film, form bundles, put patient information leaflets into them and tighten them into a plastic film. At the same time, blister machines monitor the presence of tablets in the cells and identify visual defects. Everything is automatic.

"In the process of packing and packaging, with the established frequency for each drug, samples are taken for the quality control department. For example, after every thousand units, one blister card is selected for verification", says Adamov.

Before this, the sample was taken twice: at the stage of receipt of raw materials and the creation of an intermediate product (bulk tablet). Another, final control is carried out with the finished product.
The line that packs Citramonum can produce up to 20 names of various drugs.

In total, within 8 hours the packaging machine produces 148,000 packages of Citramonum. In 2017, Darnitsa set a record for Ukraine, releasing 121,578,463 packs of tablets.

After placing the finished tablets in blister cards, the machine distributes them into packages, then boxes and on pallets. One box contains 1,350 packages of Citramonum. There are 42 boxes on a pallet. After filling the pallets, the finished product is sent to the warehouse.
Infusion is Elixir of Life
The manufacture of infusion solutions, or as they are popularly called "droppers," was launched in 2015. The company invested EUR 20 million. According to Dmytro Shymkiv, the project should pay off in 7 years – by 2023.

Infusion manufacture is one of the most innovative areas for Darnitsa.

In fact, infusions are the usual injection solutions in ampoules, but are available in large volume packaging – from 100 ml and more. The main drugs in Darnitsa's portfolio are sodium chloride and glucose.

What is innovative?

Darnitsa was the first in the Ukrainian market to start manufacturing infusions in polypropylene bottles.

"As a rule, several types of primary packaging are used in the manufacture of infusion: polyethylene, polypropylene or glass. Glass is the most common", says manufacture director Liudmyla Denesiuk. – We decided to use polypropylene. It does not get deformed, does not break and survives regulated sterilization methods – 121°C for 15 minutes. The polythene cannot survive them, and the glass can break".
Examples of Darnitsa polypropylene packaging for infusion
Bottles are formed directly in the complex from polypropylene granules using the blow-fill-seal technology (BFS)".

The granules are fed by vacuum into a small loading hopper, which is transferred to a special machine which processes them with the help of temperature into a liquid mass from which a bottle is directly formed. It is filled with liquid and sealed. Then the bottle enters the cap welding station", says Denesiuk.

The eurocap protected by a film prevents the contamination of the interior of the packaging and the leakage of the product.
Ready-to-pack bottles of Darnitsa infusion solutions
How are solutions prepared?

An important component in the manufacture of infusions is water. In Darnitsa, it is their own – it is extracted from a 300-meter artesian well in the territory of the plant.
Water treatment process
Softened and initially prepared water is purified using a double osmosis system. After evaporation, water for injection is made. It constantly circulates in the system at a certain temperature. This is necessary so that the water does not stagnate and is protected from the influence of microorganisms.

"The solutions are prepared directly in two special reactors with a volume of 15 cubic meters each", says Denesiuk. – They maintain a constant temperature of 23°C".
Finished solutions, sealed in bottles, are sent for sterilization. Then quality control, packaging and storage of finished products.

Darnitsa stores all data on the manufacturing process for 5 years, if necessary, the information can be taken from the archive.
The distribution of infusions is made approximately in equal proportions between medical institutions (hospitals), which get for about 40% of the drugs, and pharmacy chains, which get 60% of the solutions.
Innovation and future
"Over the past 10 years, the Zagorys (owners of the Darnitsa company – Ed.) has invested more than €200 million in the manufacturability of the entire manufacture and GMP compliance", says Shymkiv.

Digitalization investments are constantly growing. Every year, Darnitsa invests more than 10% of gross income in development and research. In 2018, the amount was €3.5 million.

Recently, the company rebranded and is negotiating a strategic partnership with European and American pharmaceutical companies. In addition, the possibility of acquiring pharmaceutical facilities abroad or co-manufacture of drugs is being considered.
Text and layout: Denys Katsylo
Photos: Andrii Gudzenko, Depositphotos, Darnitsa
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