Secrets of the production of medicines: we reveal the behind the scenes

Medical products (drugs, medicines, vitamins, medicines) are mentioned for informational purposes only. We do not recommend using them without a doctor’s prescription. Recommended reading: “Why can’t you take medications without a doctor’s prescription?”. The history of drug production goes back thousands of years. The first mention of them by historians and archaeologists dates back to 1550 BC. Modern drugs cannot be compared with them, because they are not only more effective and with a proven composition, but are also manufactured under sterile conditions. The pharmaceutical industry around the world is developing rapidly, factories and factories for the production of medicines are expanding their range so that every patient has the opportunity to recover from the disease, reduce its symptoms and improve the quality of life.

Pharmaceutical production is not a secret industry, but little is known to the average person about all the nuances of the processes for making tablets, syrups, solutions in ampoules.

Each company has its own characteristics of production

And indeed it is. Each manufacturer independently chooses the type of equipment, organizes the manufacturing process, but at the end, end-users: customers of pharmacies, pharmaceutical markets, patients – must receive a high-quality drug. For the manufacture of the same type of dosage form, but with a different active substance, the same equipment is often used.

The entire production process takes place in accordance with the technological stages established by the Industrial Regulations for production. After the release of, for example, cough tablets, all equipment is thoroughly cleaned, it is checked whether there is any residue of active and auxiliary substances. Only after that you can start producing tablets with another therapeutic effect. ^[1]

In recent years, the pharmaceutical industry has taken a significant step forward. Many companies have implemented full automation of all processes, so for manufacturing, the operator just needs to press a few buttons – and at the end he will receive a drug without errors and deviations from the declared composition. For example, the Ukrainian pharmaceutical company Farmak uses Siemens equipment ^[2]. Such a system allows you to automatically go through the entire production chain: from the creation of an electronic prescription to the packaging of the drug. Using a special application, the operator only checks:

• Are there enough raw materials?
• Are all components taken into account?
• whether the microclimate of the room meets the required criteria for the manufacture of preparations.

After that, the process starts, and the automatic system independently performs all its stages. The main advantage of such digitalization is the lack of contact of raw materials for the manufacture of dosage forms with a person. This is what ensures their maximum sterility.

What are medicines made from?

Finding out what is used to manufacture medicines is even more important and interesting than the process of making them. There are those who do not take pills, syrups, ointments and other forms of drug release because of the “chemistry” that is in the composition. But it should be understood that not all raw materials are “chemical”, and also that synthetic active ingredients in many cases are the only salvation from the disease.

The raw material base, on the basis of which medicines are produced, is more than diverse today and consists of several groups.

1. Raw materials of plant origin in their pure form, as well as products of its processing. Many preparations contain herbs, fruits, root systems of some plants, seeds, essential oils, juices, extracts. For example, comfrey ointment is just such a medicine, which contains herbal ingredients.
2. Animal products: muscle tissue, body fluids, glands, secretions, waste products. Example: the well-known drug Pancreatin, created on the basis of enzymes of the pancreas of cattle.
3. Inorganic minerals: minerals, products of the metallurgical sector after processing. Ammonia (ammonia solution) everyone knows for sure. And he is not the only representative of this group.
4. organic fossils. Activated charcoal is a well-known and commonly used drug belonging to this group.
5. Organic compounds that are produced by chemical enterprises in a large and varied range. ^[3]

Auxiliary substances – why are they needed, which ones are used

Particular attention in the manufacture of dosage forms is paid not only to active substances, but also to auxiliary ones. The properties and shelf life of the product depend on them, but most importantly, the additives themselves can affect the effect after taking tablets, syrup and any other dosage forms.

The list of excipients is quite wide. And the rapid development of medicine, the chemical industry predicts an expansion of the range of such drugs that can even change the possibilities of using pharmacological developments.

Today, the most relevant and commonly used excipients are:

• sodium citrate – in addition to the fact that it is introduced into the composition of instant drugs, it also lowers the level of acidity, therefore it is relevant in remedies for heartburn and hangovers;
• citric acid – used as a component stabilizer ^[4]. It also has antiseptic properties, reduces sweating;
• glycerin is the basis of liquid and soft dosage forms. It is used to prevent the fermentation of liquids. It is due to glycerin that the ointment or cream does not dry out;
• talc – such an auxiliary substance is thoroughly cleaned, dried and sterilized;
• gelatin – without it, most capsules or tablets with gelatin shells could not be produced. Due to the absence of smell and taste, it allows you to neutralize the unpleasant aftertaste of some drugs. Just imagine how many patients would refuse healthy fish oil without a capsule shell;
• boric acid is both a stabilizer and an antiseptic;
• methylparaben – added to medicines to increase their shelf life, and all because it inhibits the growth of gram-positive and gram-negative bacteria ^[5];
• potassium sorbate – is considered one of the safest preservatives. Today it is used all over the world, including in Ukraine, Russia;
• butanol – antiseptic and solvent;
• ethyl acetate – acts as a reagent in the manufacture of many drugs, for example, hydrocortisone or rifampicin ^[6].

Dosage form – the basis for the production of drugs

The discovery of the active substance, the proof of its effectiveness is only half the battle on the way to the production of an up-to-date and high-quality drug. That is why, before production, the dosage form must be selected. In this process, the accessibility to the absorption of the active substance, its stability, ease of administration of the drug, as well as compliance with GMP – Rules for Organization and Quality Control are assessed. It is the last criterion that is very important, so the manufacturing company must comply with hygiene, cleanliness, and production control. For example, there are no trees on the territory of the pharmaceutical factory “Darnitsa” so that they do not load the cleaning filters ^[7].

Only such combinations make it possible to create tablets or solutions, ointments, capsules and other dosage forms that restore our health.

Tablet manufacturing technology

The tablet form is the most popular variant of medicines. Tablets are convenient to carry, easy to dose, and can be taken by both children and adults. Such a dosage form is manufactured using one of three technologies ^[8]:

• direct pressing;
• dry granulation;
• wet granulation.

Regardless of the type of technology, the tablet manufacturing process begins with the weighing of raw materials in aspirated fume hoods. Then all components are thoroughly mixed with special batch mixers. It is this stage that is one of the main ones, because the components must be distributed uniformly over the mass, which is not so easy due to different dispersion, humidity, and density.

After mixing the components of future tablets, the mass proceeds to the last stage of production. Depending on the technology chosen, the process may differ. Direct pressing is characterized by the shortest cycle time, which is its advantage over granulation. But at the same time, the method is relevant only for those components whose physicochemical properties are almost identical. It is rather difficult to combine raw materials with different flowability by direct pressing into one tablet.

Wet granulation is considered the best option for making tablets. This technology consists of several stages:

1. Grinding – the process is carried out using ball mills.
2. Moisturizing, in which the binding components are water, sugar syrup, starch paste, gelatin.
3. Rubbing the resulting mass through a sieve. For this, special equipment granulators are used.
4. Drying and processing of the obtained granules – in drying cabinets or in the open air.
5. Pressing tablets.

Dry granulation differs from wet granulation in that there is no moistening stage, because there are components that decompose under the influence of water. Today, all three technologies are used in production, but new mechanisms for manufacturing tablets are already being developed. For example, the Linguagen company is working to ensure that the bitter taste of active ingredients is not just masked by auxiliary additives, but the receptors that perceive it are temporarily blocked. ^[9].

Features of the production of soft dosage forms

Ointments, creams, liniments, suppositories are an important dosage form that is relevant if you need to get local treatment. It has been used for thousands of years, but only in the last century has the production of drugs in soft form become high-tech, sterile.

The manufacture of ointments, creams, suppositories is associated with an increased risk of microbial contamination, so all stages are carefully controlled, and the premises are sterilized and thoroughly cleaned.

Another important feature of soft dosage forms is rheological properties, because they should be easily squeezed out of the tube, well distributed on the skin or mucous membrane, penetrate deeply, reaching the blood and lymph. Combining components that are different in structure and mechanical properties is a real pharmaceutical art.

The manufacturing process of soft molds consists of the following steps:

1. Preparation of raw materials and choice of base.
2. Introduction of the active substance into the base.
3. Homogenization.
4. Standardization.
5. Packing and storage ^[10].

Production of solutions for injections in the factory

There are special requirements for the production of injectables, primarily related to sterility and preservation of the properties of active substances. For this purpose, in the manufacture of packaging, glass ampoules or vials, polymer containers, vials, syringe-ampoules are used as packaging. The materials of such a container must be chemically inert – not react, which excludes a change in the therapeutic properties of the drug.

The manufacturing process of injectable medicines consists of two main stages: the preparation of solutions or powders and the manufacture of ampoules. The finished drug in liquid or powder form fills the vessels, which are then sealed on special equipment. All processes are carried out in rooms of the first and second class of cleanliness under aseptic conditions.

In fact, the volume of each ampoule slightly exceeds the nominal volume, which is necessary to be able to accurately dose the drug.

There are three main ways to fill ampoules, containers, syringes:

1. Syringe – performed by installations with special dispensers. Provides accurate dosing and fast filling without contaminating the vessel walls.
2. Vacuum – common in Russia, Ukraine and other neighboring countries. Characterized by high performance.
3. Vapor-condensation – initially involves the introduction of an inert gas into the ampoule, which displaces air, then a solution that does not actually come into contact with the environment ^[11].

The article describes the technology of the most common dosage forms, but they are far from the only ones, because every year about 5000 medicines are studied in the world. Many of them have an innovative form that can make the treatment effective and convenient.

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