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Interview with the production manager at Tchaikapharma’s plant in Plovdiv – Vasil Pavlov.

The requirements for the production of medicinal products resulting from the GMP (good manufacturing practices) enforced around the world approximate (and in many cases exceed) the requirements for operating rooms in hospitals. Medicines are produced in a rigorously monitored environment to ensure that there is absolutely no pollution, especially of the air, so that microorganisms and contamination by other drugs could not be introduced into the finished products.

GMP fully regulates each step: from production of the substance, through mixing with excipients and tabletting, to packaging, storage, transportation. Distribution and sales in pharmacies is regulated by GDP.

Generally the active substances are manufactured in China or India. The synthesis of these essential substances is quite energy intensive and highly polluting, so even large Western pharmaceutical companies buy them from these countries. The quality requirements for the said substances are listed in the current editions of the European Pharmacopeia, which are mandatory for the respective country.

Any substance or excipient comes with a certificate. Nevertheless these products are re-checked in the onsite laboratory. And not only that – subject to verification is even whether the laboratory parameters of the manufacturer of the substance are identical to those that are approved for sale in the country.

“Once the ingredients arrive from the manufacturers, they are placed in an area under quarantine until they pass all laboratory testing”, explained the production manager at Tchaikapharma’s plant in Plovdiv – Vasil Pavlov.

The release from this area takes place only after a complete match between the results from different laboratories and the approved specifications was established.

The laboratory equipment is state of the art, because the quality requirements for the medicinal products are steadily increasing as a result of regulatory pressure in line with the advancement of science. As the plant produces exclusively generics, to market such medicinal product, its manufacturer must have registered in the Bulgarian Drug Agency the dossier which corresponds to the entire dossier of the original drug. And it is full of laboratory and clinical test results that should be met in the generic product. Without achieving these targets, the medicinal product simply could not reach the market because the Bulgarian Drug Agency would not allow it.

We begin the tour from the room where the barrels with substances are received. It is built as a pass box – if the door on one side of this compartment is open and a truck is being unloaded, the other door cannot be opened in order to avoid mixing of flows as from one side external persons have access to this room. Beside the other door is the so called grey area where higher purity requirements are applied. The highest requirements are in the blue zone where the medicinal products are manufactured.

Moreover, the people can move in one direction only – they cannot exit the sterile zone and then re-enter without preparing again for this – they should dress in clothes that tightly cover the entire body, wear mouth mask and head cover cap, shoe covers or special work shoes. On the hands they should wear gloves. And nonetheless they are washed separately with a solution for disinfection.

One cannot move randomly from one room to another, because frequently a certain product is produced in one room and another in the other.

The most important for the production premises where medicines are manufactured is the control of the number of solid particles in the air, since the microorganisms are carried precisely by the solid particles. It is scientifically proven that most microbes are carried by particles with a size between 0.5 and 5 microns. Therefore, ventilation and air conditioning system should not allow infiltration of precisely such particles. This is achieved by circulating and filtering the air. Automatically a temperature of 22 degrees, 45% humidity and a higher air pressure than in the outside area are maintained, which helps blow out the solids through special vents.

Before entering the production premises the personnel passes through another pass box. There the people change clothes. “This is being done because human beings are the biggest polluters that enter the premises”, says Vasil Pavlov.

Before entering the working environment, everyone can see the parameters of the room which is to be entered. They are shown on special screens on every door. They provide information on temperature, pressure and humidity. If the parameters are out of norm, the screen indicates that the person should not enter.

After the pass box there are premises where all the technological processes take place. There are a lot of glass partitions and windows that allows to see what is going on in every room, without having to enter it.

Currently tablet forms are manufactured there. Night shift is avoided even when very busy, because at night more mistakes are made. When there is a lot of work, they work overtime, but during the day.

In the first room is the formulation department. In large machines formulations for various drugs are entered and a software ensures that operators do not make mistakes in the amount or type of material. The addition of materials is performed in strict sequence. A tightly closed container that contains all the ingredients of the medicinal product exits this premise. The mixture is moistened by applying a particular technology with the addition of solutions. Thus granules with different sizes for different medicines are obtained and the most common dimensions are in microns.

In a separate room the so called dry mixing is carried out in order to obtain a homogeneous mixture. The “Mixer” is quite special – it rotates at different speeds for different times and, most notably, spins the mixture in several directions. Thus, it is certain that each tablet will have all the ingredients.

Throughout the technological process for the manufacture of medicines who did what is recorded, who prepared the container, who washed it afterwards, who prepared the tableting press, who then washed the machine parts, etc. There is also a laboratory for intermediate control where the solution and mixtures are tested to check whether all the ingredients are there, to control the moisture, the weighs of each volume of the mixture.

The friability of the tablets is tested – the medicine is rotated and the pressed to see how much of it will be lost.

The works are performed with high precision using analytical scales that measure weight in grams with several digits after the decimal point. Any equipment that enters the separate zones is previously washed and sampled to check whether it is cleaned well.

For washing purified water, alcohol, detergents and disinfectants are used. After this procedure samples are taken from the containers to ensure that every time they were washed in the same way.

We come to the most important machines – those that produce the tablets. The operator has no access to the mixture during the production process – the mixture moves with the help of vacuum and enters the presses that make tablets. Each tableting press can produce up to 150,000 – 200,000 tablets per hour.

Packaging in blisters and cartons is done in a room on another floor and half of the packing line, where the tablets are brought before being closed in blisters, is in a controlled environment.

Some of the tablets are film-coated – this is an additional guarantee that the active substances will not disintegrate. Only medicines with unstable substances are film-coated. Some tablets are pelleted because the taste of the drugs is usually not very pleasant. Very soon the plant will have an installation for the manufacture of capsules.

The walls in manufacturing facilities are cladded with special pharmaceutical panels. They are perfectly smooth, do not retain any particle, and ensure that any dirt will be washed of with detergent only. The silicone which seals joints between the panels is special also and ensures that the preparations will not damage it over time. It is produced for pharmaceutical companies and operating rooms.

Currently at Tchaikapharma 80 % of the distributed medicinal products are in-house manufacture, and 20 % are imported as finished medicinal products or are only packaged at Tchaikapharma.

[The original article was published in the specialized business edition “.bg”, March – May 2017; author Georgi Vasilev. The text should be perceived as an attempt by the author to present in popular intelligible language the high-tech processes which were presented to him by Tchaikapharma’s team during the plant tour in Plovdiv.]

Bortezomib-Tchaikapharma 3.5 mg powder for solution for injection is Tchaikapharma High Quality Medicines’ newest medicinal product which obtained a Marketing Authorisation by the Bulgarian Drug Agency in the beginning of February 2017. The active substance contained is Bortezomib (as a mannitol boronic ester).

The medicinal product is subject to medical prescription.

ATC code: L01XX 32

Tchaikapharma High Quality Medicines Inc. received another Marketing Authorization by the Bulgarian Drug Agency with which the company updated its list of injectable products. The new oncological drug product is called Pemetrexed-Tchaikapharma 500 mg powder for concentrate for solution for infusion and is used in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.

Еаch phial contains the active substance Pemetrexed (Pemetrexed disodium hemipentahydrate) and is subject to medical prescription.

ATC code: L01BA04

Bortezomib-Tchaikapharma 3.5 mg powder for solution for injection is Tchaikapharma High Quality Medicines’ newest medicinal product which obtained a Marketing Authorisation by the Bulgarian Drug Agency in the beginning of February 2017. The active substance contained is Bortezomib (as a mannitol boronic ester).

The medicinal product is subject to medical prescription.

ATC code: L01XX 32