Make pills at home. What are medicines made from? Raw materials for the pharmaceutical industry

Biocad was founded by former banker Dmitry Morozov in 2001. A year ago, Roman Abramovich's Millhouse fund acquired a controlling stake in it, and Pharmstandard bought another 20% for $100 million. By that time, the company was one of the three largest drug manufacturers in Russia. Its revenue tripled last year, to 8.6 billion rubles. Now she is developing drugs for the treatment of cancer and autoimmune diseases based on monoclonal antibodies. The drug development process lasts about five years, most of which is spent on clinical trials. It takes 15 years from the idea to the implementation of the drug.

In total, the company has two production sites, in the Moscow region and in the St. Petersburg special economic zone. The Village visited the St. Petersburg plant and found out how the medicines of the future are made there.

Biocad

drug production

Location:
SEZ "St. Petersburg"

Number of employees in St. Petersburg: over 400

Production site area: 2000 m2

Several hundred people are working on the creation of a medicine: biologists, doctors, geneticists. The development of biosimilars takes five years. A biosimilar is a biological product that is similar in terms of safety, quality and efficacy to the original biological drug in an equivalent dosage form.

Idea

Drug development begins with an idea, which is discussed at the scientific and technical council. All scientific personnel of Biocad are involved in the formation and discussion of the idea - this is more than 300 scientists. By joint efforts, they choose a target and a method of influencing it to treat or prevent a disease, form an image of a target therapeutic molecule.

When the prototype (target profile) of the drug is formed, the process of developing a real molecule begins in accordance with the goals.

In the laboratory of molecular genetics, genetic constructs are being created to obtain human target proteins, which will be used in further work. In specially designed programs, they collect nucleotide sequences. Then they are passed on to cell technologists, who expose the resulting genetic vectors to mammalian cells to produce the necessary proteins. The resulting proteins are used to create antibody libraries.

An antibody library is a small tube that contains billions of genes for various antibodies, each of which is individual and capable of binding to a specific target.

In order for the library to be targeted and the proportion of antibodies to the selected target in it to be increased, the animals, in the main laboratory rats, are injected with the preparation of the target protein (immunized) before creating the library and waiting for a protective response - this is how immune libraries.

High-performance robots are involved in the selection of antibody libraries. They help developers to select from billions of molecules thousands, hundreds, tens and, finally, to find some of the best ones that completely repeat the target profile of a therapeutic molecule.

After selecting the fraction of bacteriophages capable of contacting the selected target, bacteria converted into mini-biofactories for the production of antibodies are used for further selection. The antibody genes from the library are introduced into the cells of the bacterial culture, and each bacterial clone begins to produce an individual antibody.

Researchers study the antibodies developed in individual clones, and after selecting several leader antibodies, the improvement of the resulting molecules begins. Mathematical modeling takes part in this process: bioinformaticians create 3D models and make “predictions” for their further improvement. Bioinformatics predictions are tested using a gene synthesis platform, where new ones are created. synthetic antibody libraries, from which the best candidates are again selected. In this way, scientists obtain molecules that have all the properties specified in the target profile.

Further cell technologies learn how to produce selected antibodies in mammalian cells, create optimal schemes for culturing and nourishing producer cells, gradually scaling up production from small wells in plates to 1000-liter reactors. Leading antibodies produced in large quantities are being tested on animals - small rodents, rabbits, guinea pigs, non-human apes.

Production

Before entering the production, where the components of the future medicine are grown in large devices - bioreactors, each employee must go through an air shower, in which dust particles remain.

A suite of sensors and systems monitor and control temperature, agitation, pH and dissolved oxygen levels to ensure the necessary conditions for cell growth. The number and viability of cells are monitored using a microscope or an automatic counter.

After the end of cultivation, the liquid is purified to obtain the target product - this process takes 28–29 days. After purification, the substance of monoclonal antibodies is sent for control and bottling into vials that will go to hospitals and pharmacies.

Photo: Dima Tsyrenshchikov

About what is put in tablets and why excipients are needed

All modern medicines are multicomponent and contain active and excipients. The active substance reduces the symptoms of the disease or completely cures it, being the basis of the drug. Excipients do not have a therapeutic effect on the body, but play an important role in determining taste, color, size (tablets), solubility and many other properties.

Security

Excipients have proven safety, do not cause harm to health and usually do not cause side effects. The exception is people who are hypersensitive to a particular excipient (lactose, nut butter, some sugars). As a rule, manufacturers of original drugs and generics (analogues) use the same additional components.

Filling agent

by the most simple example excipient may serve as a filler substance. It is used in the manufacture of tablets with a very small content of the active substance. The filler gives the drug hardness, maintains mechanical stability so that the tablet does not crumble while still in the package.

disintegrants

In order for the drug to start acting faster, disintegrants are added to it. These substances provide rapid decomposition of solid dosage forms upon contact with water. Tubules are formed that destroy strong bonds between the particles: the tablet swells and crumbles, dissolving in the liquid. One of the latest developments is disintegrants and binders based on microcrystalline cellulose. The new component alone performs two functions at once: it binds particles, helping to form a tablet, and promotes disintegration - disintegration after entering the body.

Binders (binders)

The purpose of binders is to firmly bind small and unstable particles of powders, granules or tablets to each other in order to ensure sufficient mechanical strength of the drug.

lubricants

Lubricants (usually magnesium stearate) are water-repellent. They are used at the stage of pressing and molding tablets so that the powder or granules do not remain in the factory forms, there is no loss of the active substance at the production stage.

Glidants

The shape of the finished tablet is supported by glidants, substances necessary for the tight contact of the particles. medicinal substance. Previously, talc was used for these purposes, today it is a colloidal form of silicon oxide. The concentration of excipients of this type usually does not exceed 0.2%.

Solvents or solvents

Water is the best solvent for medicines. It has excellent physiological compatibility with the human body, high dissolving power. But sometimes these properties can lead to instability medicinal product Moreover, water is a favorable substrate for the growth of bacteria. Sorbitol and dextrose, which are also used as solvents and sweeteners, have the same properties. These unpleasant properties are deprived of co-solvents - propylene glycol, glycerol, ethyl alcohol. Co-solvents provide antimicrobial properties, improve taste, so they are added to preparations intended for resorption. Also, these substances allow you to reduce the dose of the drug, better dissolving the drug.

Medicines for children

Medicines intended for children are subject to special requirements for safety and external characteristics. Of course, they must have good taste and a pleasant color. It is recognized that not all children are able to swallow solid drugs, so for many drugs it is necessary to develop liquid or other forms (for example, in the form of chewing gums). The single dose should be small, and the dosage accuracy should be high. Special requirements are also imposed on the size of the injection needle and the volume of the injected drug. Children are often afraid of one type of syringe.

Already born into this world, a person immediately gets acquainted with a variety of microbes and viruses. This acquaintance is not pleasant. Each of us has ever encountered illnesses and knows how difficult it is sometimes to cope even with a slight runny nose. At initial symptoms of any illness, the first thing that comes to mind for each of us is to go to the pharmacy and buy a life-saving pill. A modern person will certainly find the right medicine in the pharmacy.

If it doesn't heal, it will definitely help. The sale of drugs brings in more than a trillion dollars to the pharmaceutical industry. Isn't it a very profitable business? To start such a business, you need to clearly understand how drug production, significantly affecting human body, must be of high quality and meet all the standards specified in the legislation of the country.

If you are thinking about starting your own pharmaceutical business (for example, manufacturing activated carbon), then first include in your purchase of high-tech equipment. At production of quality medicines and tablets such costs are essential. Significant investments in equipment will quickly pay off. This is explained simply: high-tech production quickly begins to bring super-profits. Expensive equipment pays off in a matter of months, and with proper business management, it happens that even weeks. Sales market quality medicines very wide, bright enough to advertise medicines.

How do quality medicines:

Raw materials in the form of a powder enter the intermediate warehouse, where they are sorted, crushed, sifted, weighed, and packed in special containers. Then the prepared material is sent to the production department. The entire technological process is documented, the amount of suspended medicinal substance, performers, production conditions are recorded in the protocols for the production of each drug. The transparency of the documentation allows you to trace the entire manufacturing process of each drug.

The next process is dry or wet granulation of the substance. The pellet must acquire a certain weight. The finished granulate is placed in a container, which is marked with a label with the name of the drug, the name of the granulator, the date of manufacture, weight, and then fed to tableting.

Further tablet production associated with direct compression. This process consists of the steps of dosing, compressing, ejecting the tablet from the die and dropping it into the tablet receiving container. During the pressing process, the technologist should check from time to time the average weight of the tablet and its disintegration, its color and appearance.
After the tableting process, drugs are obtained that are almost ready for use. It remains to carry out the last examination in the chemical laboratory for product quality, for its compliance with accepted pharmaceutical standards. When laboratory research give a positive analysis, drugs are packaged.

Once in pharmacy chains, a pharmaceutical product brings significant income to businessmen. Still, the main thing in this business is concern for people's health and a responsible attitude to the quality of medicines.

Video how do tablets:

Medications, as you know, do not immediately get to the consumer, but only after going through a certain, sometimes long and difficult path. The interests of the consumer need to be protected, so the regulatory authorities in many countries take steps to ensure the quality of medicines in advance. These are, first of all, clinical trials, which are designed to provide appropriate indicators. And as a rule, this is the longest, most costly, responsible stage of drug development.

Development quality medicines- a type of business that requires quite tangible costs in terms of time and finances. Everything spent, of course, pays off and this is expressed not only in the form of profit, but also in the preservation of the health of people using the products of this business.

Many European countries, as well as the United States, developed a set of high requirements that began to be imposed on clinical trials of drugs prior to registration. This complex has been used since the late 70s of the twentieth century. These tests are called Good Clinical Practice.

A unified approach to clinical trials is an important step for the global community in the field of registration of medicines and requirements for them. There is the International Conference on Harmonization of Registration Requirements (ICN), formed in the 90s.

The basis for the adoption of a regulatory framework for drug licensing is the process of harmonization of registration requirements, expressed in the ICN program.

It was possible to develop common approaches, as technical obstacles in the international sphere of circulation of medicines were eliminated, in the form of mutual recognition of standards and the application of legislative acts for production and sale of medicines. This applied to all issues related to research, registration, form and structure of documents issued after registration.

In order for a medicinal product to enter the market, many countries require a registration dossier for the medicinal product. The difficulty in evaluating and recognizing the results of clinical trials was due to the variety of principles for conducting pre-registration trials in different countries.

In order to register a drug in another country (in the case of obtaining a trade license), it was necessary to conduct repeated clinical trials. This increased the cost of the medicine. In addition, the organization of a clinical trial requires specialists of various profiles - carriers of special knowledge.

Based on the stage of drug development, as well as on the task of testing, clinical pharmacologists and biostatisticians are involved in them. Drugs entered the market after a long period of time, depriving it of timeliness and effectiveness of use.

Howdoqualitydietary supplements:

The use of low-quality or insufficiently studied medicines leads to violations of human rights, tragedies associated with the health and life of people. A qualitative study of a new drug should be included in the business plan when calculating the timing of the drug's entry into the market and production costs.

Comprehensive drug trials- it is, first of all, a guarantee of the absence of damage to the health of patients. The use of low-quality or insufficiently studied medicines does not correspond to the most in this area. It is the planning of clinical trials in the future that will provide an assessment of the safety of a particular drug, as well as its effectiveness.

Investigators and their sponsors are faced with such tasks as audit, monitoring, inclusion of patients in clinical trials with the provision of information on the identification of possible risks, assessment of the benefit/risk ratio, selection of a clinical base, reporting of actually manifested serious side effects.

The application of the generally developed norms and rules in practice during the conduct of such studies will make it possible to improve the quality of tests, as well as ensure an active position of researchers in the study medicines on a global scale. Combining international efforts in this matter will increase confidence in the results obtained as significant and reliable.

Our today's photo essay is devoted to subjects that are very prosaic, but sometimes very necessary for us - we will go through the shopsOJSC Tatkhimfarmpreparaty , where more than 111 types of medicines of 30 pharmacological groups are produced.

The specifics of pharmaceutical production is such that on the same installations for the production of various dosage forms (solid - tablets, liquid - tinctures, soft - ointments) it is possible to manufacture different types of medicines of the same form according to the technological chain, which is established by the Industrial Regulations for production. After the release of a batch of medicinal product, installations and production facilities are cleaned, washed, checked for residues of the previous product and transferred to another drug of a similar dosage form. During my visit to the workshops of Tatkhimfarmpreparaty, tablets were being produced acetylsalicylic acid and ibuprofen. In the area of ​​soft forms - tetracycline ointment, and in the area of ​​liquid dosage forms - licorice root extract.

Personnel move along the corridors of the TCFP in transitional clothing - white coats or disposable clothing. In those shops where there is a direct production of drugs or contact with them, a special level of cleanliness has been established. Personnel get there through special vestibules, which are conditionally divided into "clean" and "dirty" zones. In the dressing preparation area, staff removes transitional clothing and places it in a closet. They move from the dressing preparation area (“dirty area”) to the changing area (“clean area”) by crossing the bench. When crossing the bench, change shoes. In the dressing area, put on clean technological clothes from the closet sequentially, starting from the head, tightly fastening and tying the sleeves and legs. After cleaning their hands with a disinfectant solution, the worker can enter production room. Technological clothing varies in color depending on the production: tablet production is blue, ointment production is green.

Tablet production

Raw materials for the production of solid dosage forms (tablets) in the form of powders from the general factory warehouse are supplied to the intermediate warehouse of raw materials in the workshop, or raw material vestibule. From the intermediate warehouse, the raw materials are transported to the site, where they are unpacked, if necessary, crushed, sieved, weighed, transferred to special containers for transfer to the production site. The raw material for the production of acetylsalicylic acid tablets is the acid itself and excipients (potato starch, medical talc, stearic and citric acids).

According to Olga Osyanina, head of the department of solid dosage forms of OAO"THFP", all stages production process are documented. Technological parameters, the amount of weighed raw materials and materials, production conditions, performers are recorded in the protocols for the production of each drug, which ensures the traceability of the manufacture of each series from the moment raw materials are received to the finished product.

The hung raw material enters the hall where the dryer-granulator is located. In this apparatus, the process of converting powdered materials into grains of a certain size - granules. This requires moistening the powders with starch paste, mixing and drying. The granulation process is necessary to obtain a tablet mass (granulate), from which tablets are then pressed. In order to obtain high-quality tablets, the granules must acquire a certain size. The size of the granules for each drug is developed technometrically.

The main and auxiliary raw materials are loaded into the product capacity of the dryer using vacuum. Warm purified air is supplied through the holes in the bottom of the product container, drying of wet materials takes place in a vortex layer of air. At the same time, the raw material is moistened with starch paste, which is fed inside by a pump through a nozzle. This is how granules are formed. The product dries within 1.5 hours.

The dryer-granulator operates in automatic mode, all process parameters are set on the control panel. Loading powdered materials and unloading the finished granulate is carried out through a pneumatic system. The finished granulate is placed in a container, which is supplied with a label with the name of the drug, the name of the granulator, the date of manufacture, and is weighted for tableting.

Tableting takes place in the second room. This is how the granulate is loaded.

The tablet mass is fed into the loading hopper, the matrices are filled through the feeder and agitator. The tableting process consists of the steps of dosing, compressing, ejecting the tablet from the die and dropping it into the tablet holder.

Pressing consists in compressing the granules in the matrix with the help of two punches - upper and lower. The finished tablet is pushed out of the die by the lower punch. The geometric size of the tablet is determined by the size of the press tool.

During the production process, the tablet operator periodically checks the average weight of the tablets, their disintegration and appearance. The tablet should have a flat, smooth surface, a smooth smooth bevel, white, without inclusions, the presence of risks is checked.

After the product series is ready, the semi-finished product is taken for analysis to a chemical laboratory, where it is checked for compliance with the requirements of regulatory documentation. After receiving a positive conclusion from the laboratory, the series is sent for packaging.

TCFP produces a number of sugar-coated products. Finished tablets are coated with a suspension in such a rotary kettle. The suspension enters the boiler in small portions, since the coating is applied for a very long time, in very thin layers. Simultaneously, the casing is dried with hot air.

In a separate cauldron coated with molten wax, the tablets are glossed. The wax is heated, the cauldron rotates, and the tablets are polished on the wax surface. When they are ready according to the technological cycle, they are placed in a container, provided with accompanying labels and again given to chemical analysis and then to packaging.

There are several types of packaging for tablets - cellular aluminum foil and PVC film, cellular PE-coated paper, glass jars and polymeric materials. The tablets are fed through the channels and placed in the cells of the molded material (PVC film) and sealed with a cover material (aluminum foil) passing through the thermogluing drum. The heating temperature of the thermogluing drum is set depending on the properties of the packed tablets. But thermal bonding can not always be used: not all preparations can withstand high temperature without losing their qualities. They use cold welded materials.

Information is applied by embossing: batch number, expiration date of the drug. The finished product, after being placed in a group package, is submitted for chemical and microbiological analysis to the quality control department. The OKC issues a finished product passport and a marketing authorization.

Ointment production

This is a site for melting the raw materials for the base for the ointment - lanolin and petroleum jelly. Vaseline is melted in a large bath, lanolin is melted in a small one.

The finished base after 40 minutes of sterilization is pumped into mixers, where it is cooled to 28 degrees. After cooling, the calculated amount of the main substance is loaded into the base, and everything is thoroughly mixed. The preparation time for eye ointment is 3 hours.

After it is prepared, samples are taken for analysis. In the laboratory, its homogeneity and the content of the main substance are checked. After receiving the analysis, the ointment is pumped into the keeper, from which it is fed for packing into tubing machines. There are two tube-filled machines on the site - for 10 gr. and 3 gr. - tubes are filled on them. Then the end cap of the tube is clamped with the number of the ointment series, month and year of manufacture. Filled tubes are packed in cardboard boxes.

Galenic production

Upon receipt, the raw materials pass the incoming control of the quality control department. Having received positive result analysis, the dried licorice root is crushed to the required size. After crushing, the root is fed for extraction. Extraction active substances carried out by the countercurrent method on a battery of 3 extractors. In each extractor, the raw material undergoes five extractions. The extraction is drained from "fresh" vegetable raw materials.

To clean the licorice root extract from ballast substances, boiling is carried out in the reactor. The boiled extract is filtered through a druk filter using compressed air.

Having determined the volume, the extract is fed for evaporation. It is necessary in order to remove excess liquid from the extract. The evaporation process is carried out under vacuum at a temperature not exceeding 80 degrees. The resulting one stripped off thick extract is unloaded into intermediate containers. The inspector of the quality control department takes a sample of the extract and submits it for analysis to the QCD laboratory. After receiving the analysis of the QCC, the semi-product of the licorice root extract goes to the production of "Licorice Syrup" and "Breast Elixir".

Today, every person uses pills, whether it is for the temperature of an adult, or in order to stop childhood illnesses.
There are three most common technological schemes for obtaining tablets: using wet or dry granulation and direct compression. Preparation of raw materials for tableting is reduced to their dissolution and hanging. Weighing of raw materials is carried out in fume hoods with aspiration. After weighing, the raw material is sent for sifting with the help of vibrating sieves.

Mixing

The medicinal and excipients that make up the tablet mixture must be thoroughly mixed to evenly distribute them in the total mass. Obtaining a tablet mixture homogeneous in composition is a very important and rather complex technological operation. Due to the fact that powders have different physical and chemical properties: dispersion, bulk density, humidity, fluidity, etc. At this stage, blade type batch mixers are used, the shape of the blades can be different, but most often worm or zetabular. Often also mixing is carried out in a granulator.

Granulation

This is the process of converting a powdered material into grains of a certain size, which is necessary to improve the flowability of the tableted mixture and prevent its delamination. Granulation can be "wet" and "dry". The first type of granulation is associated with the use of liquids - solutions excipients; in dry granulation, wetting liquids are either not used, or they are used only at one specific stage in preparing the material for tableting.

Wet granulation consists of the following operations:

1) grinding substances into a fine powder; 2) moistening the powder with a solution of binders; 3) rubbing the resulting mass through a sieve; 4) drying and processing of the granulate.

Usually, the operations of mixing and uniform moistening of a powder mixture with various granulating solutions are combined and carried out in one mixer. Sometimes mixing and granulation operations are combined in one apparatus (high-speed mixers - granulators). Mixing is provided by vigorous forced circular mixing of the particles and pushing them against each other. The process of mixing to obtain a homogeneous mixture lasts 3-5". Then, granulating liquid is supplied to the pre-mixed powder in the mixer, and the mixture is mixed for another 3-10". After the granulation process is completed, the unloading valve is opened, and with the scraper slowly rotating, the finished product is poured out. Another design of the apparatus for combining mixing and granulating operations is a centrifugal mixer - granulator.

Compared with drying in drying cabinets, which are inefficient and in which the duration of drying reaches 20 - 24 hours, drying of granules in a fluidized (fluidized) bed is considered more promising. Its main advantages are: high intensity of the process; reduction of specific energy costs; full automation of the process.

But the pinnacle of technical perfection and the most promising is the apparatus in which the operations of mixing, granulating, drying and dusting are combined. If the wet granulation operations are carried out in separate apparatuses, the drying of the granules is followed by the dry granulation operation. After drying, the granulate is not a uniform mass and often contains lumps of sticky granules. Therefore, the granulate is re-entered into the masher. After that, the resulting dust is sifted from the granulate.

Since the granules obtained after dry granulation have a rough surface, which makes it difficult to spill them out of the hopper during tableting, and besides, the granules can stick to the matrix and punches of the tablet press, which causes, in addition to weight loss, flaws in the tablets, resorted to to the operation of "dusting" the granulate. This operation is carried out by free application of finely divided substances on the surface of the granules. Gliding and disintegrating agents are introduced into the tablet mass by dusting.