Injection solutions: manufacturing technology, requirements and quality

Injection solutions are widely used in therapeutic practice. For their preparation, several dosage forms are used - solutions, suspensions, emulsions, powders, tablets, porous masses, which are dissolved immediately before parenteral administration. The production of such drugs is carried out taking into account the requirements of sterility, pyrogen-free, lack of mechanical impurities and physiology.

Technology system

The technology for the industrial production of injection solutions and medicines based on them includes several stages:

1. Preliminary processes: production of ampoules, preparation of containers, vials, closure material, solvents, preparation of premises, filters and personnel.
2. Direct manufacture of solutions: dilution of medicinal substances, stabilizers, preservatives and other auxiliary compounds; filtering the solution.
3. Ampoule - filling ampoules, vials, sealing them or capping.
4. Sterilization.
5. Leak test.
6. Quality control.
7. Drawing inscriptions, attaching labels.
8. Packaging and labeling.

Requirements

The main requirements for injection solutions are as follows:

• sterility (absence of microbiological impurities not specified by technical conditions);
• non-toxicity;
• purity relative to mechanical impurities;
• pyrogen-free (exclusion of waste products of microorganisms, or pyrogens);
• physiology.

Physiological solutions are understood as a combination of several parameters that make them possible for use by humans:

• isotonicity (osmotic pressure);
• isohydricity (the content of certain ions and trace elements);
• viscosity viscosity;
• isoionicity (constant concentration of hydrogen ions, pH ~ 7.36).

Such solutions can maintain normal functioning of cells, tissues and organs and do not cause pathological changes in the human body.

Aseptic conditions

Injectable solutions are prepared at a high degree of environmental cleanliness. The requirements for aseptic conditions are regulated by the international GMP standard. The classification of the cleanliness of industrial premises according to this regulatory document is carried out in two states: with and without working personnel. Class A rooms are the cleanest.

The content of microbiological components in such rooms should not exceed units in four parameters (units of measurement are indicated in brackets):

• in the air (colony forming units per 1 m ³ );
• deposition on a plate Ø90 mm (CFU for 4 hours of measurement);
• on contact plates Ø55 mm (CFU per 1 plate);
• on gloves with five fingerprints (CFU).

In the premises of group A, the following types of work for the manufacture of injection solutions are performed:

• unloading of sterile ampoules (bottles) and corking materials;
• spill of solutions;
• product clogging;
• assembly of filters for sterilization;
• sampling of control samples.

Stability

Under the stabilization of injection solutions is understood their property to maintain the invariability of the composition and concentration of active components over a period of time determined by the standard shelf life. This mainly depends on the quality of the solvents and starting compounds. The medicinal substances that make up the solutions must have the qualification of chemically pure - "chemically pure", PSA - "pure for analysis" or GDI - "suitable for injection." This indicator is indicated on the package with the drug and in the accompanying documentation.

The stabilization of injection solutions in pharmaceutical manufacturing technology can be enhanced in several ways:

1. Physical methods: saturation of injection water with carbon dioxide, pouring into ampoules in an inert gas atmosphere.
2. Improving the purity of the starting components: boiling injection water and its rapid cooling, recrystallization, treatment with adsorbents.
3. The introduction of acceptable antimicrobial preservatives and stabilizers.
4. Application of more modern technologies - sublimation, vacuum drying, frozen non-aqueous solutions and others.

In very alkaline and acidic environments, the sterilization process can exacerbate chemical changes. Therefore, the use of special stabilizers for such drugs is an inevitable measure.

In pharmacy, the following main types of stabilizers for injection solutions are used:

• hydrochloric acid solution;
• sodium hydroxide and bicarbonate;
• antioxidants (for drugs that are easily oxidized, for example, for ascorbic acid);
• special stabilizers (glucose solution and others).

Ensuring sterility and pyrogenicity

The main sources of contamination of drugs with microbial components are rooms, equipment, air suspensions, personnel, medical utensils and materials, basic and auxiliary substances, solvents. Requirements for injectable solutions regarding sterility (lack of viable microorganisms and their spores) are provided using the following technological measures:

• filtration;
• adsorption on sorbents;
• compliance with the temperature regime;
• holding the necessary time during sterilization;
• compliance with aseptic rules in production;
• the addition of antimicrobial substances.

When pyrogens enter the bloodstream, they can cause a person to have a febrile state. This is due to the presence of endotoxins, which are contained in the cell membrane of bacteria, fungi and viruses.

Sterilization methods

Sterilization of injection solutions is carried out in several ways and depends on the chemical composition and properties of the injection drug:

• Thermal (steam, air). Almost all pathogens die from exposure to wet steam. Processing is carried out at an excess pressure and a temperature of 120-132 ° C. The main method of processing injection solutions is autoclaving in pre-sterilized vials. Air sterilization is carried out with dry air, which is heated to 200 ° C.
• Chemical (solutions, gases). For these purposes, ethylene oxide and its mixture with carbon dioxide, freon, methyl bromide and other compounds are most often used; hydrogen peroxide, peracetic acid and formic acid.
• By filtering. This method is used for heat-sensitive solutions and for the purpose of purification from mechanical impurities. One of the most effective modern sterilization technologies is ultrafiltration through membrane filters.
• The radiation method is carried out by irradiating the solution. The source is a radioisotope element or a beam of electrons.

Antioxidants

The oxidation and change in the properties of injection solutions takes place under the influence of oxygen contained in the air of an ampoule or vial, light, temperature, acidity of the medium and other factors. In order to prevent this from happening, the following activities are carried out:

• the introduction of antioxidants;
• the use of complexones - organic substances that bind metal ions to persistent water-soluble complexes;
• creating the optimal level of acidity of the medium;
• decrease in oxygen concentration in the ampoule;
• the use of lightproof packaging.

The main requirements for injectable solutions with antioxidants are as follows:

• the harmlessness of the substances used to stabilize oxidation;
• possibility of application in the minimum concentration;
• safety of metabolic products;
• good solubility.

All types of antioxidants are divided into two large groups:

• direct - reducing agents in which the oxidizing ability is much higher than that of the medicinal substances for which they are used;
• indirect (anticatalysts), binding impurities in the form of metal cations, which stimulate oxidative processes.

The first group includes substances with the following mechanism of action:

• stopping the formation of radicals (aromatic amines, phenols, naphthols);
• destructive hydroperoxides (compounds with S, P, N atoms);
• breaking the oxidation chain at the stage of formation of alkyl radicals (molecular iodine, quinones, nitro compounds).

The most commonly used antioxidants are substances such as phenol derivatives, sodium sulfite and metabisulfite, aromatic amines, rongalite, trilon B, tocopherols, analgin, amino acids, unitiol, polybasic carboxylic and hydroxyacids (citric, salicylic, tartaric), thiourea, cysteine and other compounds.

Preservatives

Preservatives are auxiliary substances that serve to form the microbiological stability of injection solutions. Microorganisms and their waste products that enter the composition of the injection cause oxidation, hydrolysis and other reactions that affect the active substances. The choice of preservative mainly depends on the chemical properties of the components of the drug, the pH of the medium and the method of use of the drug. They are introduced into the composition of both multi-dose and single-dose medical devices. The use of preservatives is not a substitute for aseptic requirements.

The following classification of substances of this group exists (their permissible concentration is indicated in parentheses):

• By type of action: bacteriostatic - phenylethyl alcohol (0.5%), merthiolate, methyl parahydroxybenzoate, benzoic, sorbic acid and others; bactericidal - phenols, cresols.
• By chemical properties: inorganic - water with a content of silver ions (1-10 mg / l); organometallic - merthiolate (0.02%), phenylmercury acetate (0.02%), phenylmercury nitrate (0.004%); organic - essential oils (anise, laurel, lavender and others), alcohols (phenylethyl, benzyl - 2%), hydroxybenzene (0.5%), benzoic acid esters (0.5%), organic acids (benzoic, sorbic - 0 , 2%).

The following basic requirements apply to preservatives:

• the absence of toxic, sensitizing and irritating effects in the applied concentration;
• wide antimicrobial spectrum of action;
• good solubility;
• lack of chemical interaction with other components of the solution and packaging;
• stability at various values ​​of acidity and temperature;
• lack of influence on organoleptic properties (color, transparency).

Preservatives are not allowed in injectable preparations such as:

• intracavitary;
• intracardiac;
• intraocular
• having access to cerebrospinal fluid;
• formulations with a single dosage of more than 15 ml.

Water for injections

For the preparation of water-based injection solutions, water with a high degree of purification is used. Modern devices for its production include several stages of processing:

• preliminary cleaning;
• reverse osmosis;
• deionization;
• filtration (or ultrafiltration and ultraviolet sterilization).

Prepared water for injection dosage forms is stored after distillation for no more than a day in closed vials under aseptic conditions so that microorganisms do not enter. For those preparations for which sterilization is not provided, use sterile water for injection, poured into plastic or glass ampoules.

Non-aqueous solvents

The following compositions are used as non-aqueous solvents in the manufacture of injection solutions:

• Individual fatty oils (peach, apricot, almond and others). They are obtained using dehydration and subsequent cold pressing of seeds. The acid number of oils should be no more than 2.5, since with a higher value, irritation of nerve fibers occurs.
• Mixed solvents. They include mixtures of vegetable oils and cosolvents (ethyl oleate, propylene glycol, benzyl benzoate, glycerol esters, benzyl alcohol). Their advantage over the previous group is a large dissolving ability. Such formulations are used in the manufacture of injections with sparingly soluble substances (hormones, vitamins, antibiotics and others).

The disadvantages of oily solvents for injection include:

• increased viscosity;
• soreness at the injection site;
• prolonged resorption of the composition;
• side effects - the development of lipogranuloma (a focus of chronic inflammation).

Types of packaging

For solutions, several types of packaging are used:

• ampoules (their size can be from 0.3 to 500 ml);
• bottles (mainly for antibacterial and organotherapeutic drugs, high viscosity solutions);
• test tubes with two stoppers;
• syringe tubes with a needle;
• vessels and containers made of plastic.

Injection solutions in ampoules are the second most common after tablets. They produce 2 types of ampoules - open and sealed. The latter are of the greatest importance, since when they are sealed, the solution is completely isolated from the environment, which allows the manufacture of drugs with a long shelf life.

Ampoule production

Most often, ampoule glass is used to package injection and infusion solutions. There are two main requirements for its physicochemical properties:

• Transparency to provide easy visual control of the contents (absence of sediment, solids, spoilage).
• Chemical resistance.

The best indicators in relation to the latter indicator are quartz glass, however, it has a very high melting point - 1,800 ° C. To improve its technological qualities, the following compounds are added:

• oxides of sodium and potassium, which reduce refractoriness;
• CaO and MgO to increase chemical resistance;
• alumina and boron oxide for better sealing and preventing cracking.

Upon contact with water and injection solutions, sodium silicate is washed out from the surface of the glass ampoule, and a film consisting of silicic acid is formed. Alkaline compounds are particularly corrosive to glass. For medicinal compositions that are most sensitive to changes in pH (e.g. alkaloids), only glass of the first class is used.

In modern pharmaceutical factories, ampoules for injection solutions are produced according to the technology indicated below:

• calibration of glass tubes (sorting by diameter, length and curvature);
• washing in a boiling water chamber or in an ultrasonic bath;
• drying with hot filtered air;
• cutting tubes, their molding on a glass-forming machine or semi-automatic;
• heat treatment (annealing in furnaces) to eliminate residual stresses;
• a set of ampoules in cassettes, their external and internal multiple washing (syringe, shower, ultrasound).

Control

The quality of injection solutions is checked by several parameters:

• transparency;
• color;
• lack of mechanical impurities (they are controlled twice - before and after sterilization);
• authenticity (chemical analysis of the quantitative composition of the main and auxiliary substances);
• pH value
• the presence of endotoxins, sterility (control of water for injection, intermediate and final medicinal products);
• volume of vascular filling;
• tightness of the package.

Check for mechanical inclusions visually. Since this method is subjective, the verification error is high and amounts to about 3 0%. The absence of particles is controlled alternately on a black background (glass dust, insoluble particles, small fibers falling from the filters) and white (color, dark inclusions, overall integrity).

The main type of contamination of injection solutions is glass dust (up to 80% of the total). It is formed at the following stages of manufacture:

• ampoule production;
• a segment of capillaries;
• heat treatment.

Glass particles smaller than 1 μm penetrate through the walls of blood vessels, and then into almost all tissues and organs. In addition to glass, injection solutions may contain inclusions from metal, rubber, and plastic, which is caused by their ingress from the surfaces of equipment, containers, and from maintenance personnel.

At the preparatory stage, the ampoules and vials are rejected if they do not meet the manufacturing requirements. Control of injection solutions is carried out at each stage of the process. Tightness, sealing quality and sealing of containers are checked in several ways:

• evacuation;
• indicator solutions (for injection based on water);
• soap solution (for oil-based injections);
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