Injection solutions are widely used in therapeutic practice. For their preparation, several dosage forms are used - solutions, suspensions, emulsions, powders, tablets, porous masses, dissolved immediately before parenteral administration. The production of such drugs is carried out taking into account the requirements of sterility, non-pyrogenicity, the absence of mechanical impurities and physiology.
Technological scheme
The technology of industrial production of injection solutions and medicines based on them includes several stages:
- Pre-processes: preparation of ampoules, preparation of containers, vials, closure material, solvents, preparation of premises, filters and personnel.
- Direct production of solutions: dilution of medicinal substances, stabilizers, preservatives and other auxiliary compounds; filtering the solution.
- Ampouling - filling ampoules, vials, sealing or corking them.
- Sterilization.
- Leak test.
- Quality control.
- Writing, labeling.
- Packaging and labeling of containers.
Requirements
The main requirements for injection solutions are as follows:
- sterility (no microbiological impurities not specified in the specifications);
- non-toxic;
- purity relative to mechanical impurities;
- non-pyrogenic (exclusion of waste products of microorganisms, or pyrogens);
- physiological.
Under the physiology of solutions understand the combination of several parameters that make them possible for use for humans:
- isotonicity (osmotic pressure);
- isohydricity (content of certain ions and trace elements);
- isoviscosity;
- isoionicity (constancy of hydrogen ion concentration, pH~7, 36).
Such solutions can support the normal functioning of cells, tissues and organs and do not cause pathological changes in the human body.
Aseptic conditions
Preparation of injection solutions is carried out at a high degree of purity of the environment. 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.
Contentmicrobiological components in such rooms should not exceed one in four parameters (units of measurement are indicated in brackets):
- in the air (colony forming units per m³3);
- deposition on a wafer Ø90 mm (CFU for 4 hours of measurements);
- on contact plates Ø55 mm (CFU per 1 plate);
- on five gloved fingers (CFU).
In the premises of group A, the following types of work on the manufacture of injection solutions are performed:
- unloading sterile ampoules (vials) and sealing materials;
- spill solutions;
- plugging the product;
- assembly of filters for sterilization;
- control sampling.
Stability
Under the stabilization of injection solutions is understood their property to maintain the composition and concentration of active components unchanged over the time specified by the standard shelf life. It mainly depends on the quality of solvents and starting compounds. Medicinal substances that are part of the solutions must have the qualification HCh - "chemically pure", ChDA - "pure for analysis" or GDI - "fit for injection". This indicator is indicated on the package with the drug and in the accompanying documentation.
Stabilization of injection solutions in pharmaceutical manufacturing technology can be improved in several ways:
- Physical methods: saturation of injection water with carbon dioxide, filling into ampoules ininert gas atmosphere.
- Improving the purity of starting components: boiling injection water and its rapid cooling, recrystallization, treatment with adsorbents.
- Introduction of acceptable antimicrobial preservatives and stabilizers.
- The use of more modern technologies - sublimation, vacuum drying, frozen non-aqueous solutions and others.
In highly alkaline and acidic environments, the sterilization process can intensify chemical changes. Therefore, for such drugs, the use of special stabilizers is an inevitable measure.
The following main types of stabilizers for injection solutions are used in pharmaceuticals:
- hydrochloric acid solution;
- sodium hydroxide and bicarbonate;
- antioxidants (for drugs that are easily oxidized, such as ascorbic acid);
- special stabilizers (glucose solution and others).
Ensuring sterility and pyrogenicity
The main sources of contamination of medicines with microbial components are premises, equipment, airborne particles, personnel, medical utensils and materials, basic and auxiliary substances, solvents. The requirements for injectable solutions regarding sterility (the absence of viable microorganisms and their spores in them) are provided using the following technological measures:
- filtering;
- adsorption on sorbents;
- compliance with the temperature regime;
- exposure of the required time during sterilization;
- observance of aseptic rules in production;
- adding antimicrobial agents.
Pyrogens, when they enter the vascular bed, can cause a feverish state in a person. This is due to the presence of endotoxins, which are found in the cell wall 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 pathogenic microorganisms die from exposure to wet steam. Processing is carried out at excess pressure and 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 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 and performic acids.
- Filtering. This method is used for temperature-sensitive solutions and for the purpose of cleaning 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 an electron beam.
Antioxidants
Oxidation and change in the properties of injection solutions takes place under the influence of oxygen contained in the air of the ampoule or vial, light, temperature, acidity of the medium and other factors. To prevent this from happening, the following activities are carried out:
- introduction to antioxidants;
- use of complexones - organic substances that bind metal ions into stable water-soluble complexes;
- creating an optimal level of acidity of the medium;
- reducing the oxygen concentration in the ampoule;
- use of lightproof packaging.
The main requirements for injectable solutions with antioxidants are as follows:
- 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, whose oxidizing power is much higher than that of the medicinal substances for which they are used;
- indirect (anti-catalysts), binding impurities in the form of metal cations that 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);
- interrupting 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 metabisulphite, aromatic amines, rongalit, trilon B, tocopherols, analgin, amino acids, unitiol, polybasic carboxylic and hydroxy acids (citric, salicylic, tartaric), thiourea, cysteine and other compounds.
Preservatives
Preservatives are excipients that serve to form the microbiological stability of injection solutions. Microorganisms and their metabolic products that enter 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 application 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.
There is the following classification of substances of this group (their permissible concentration is indicated in brackets):
- By type of action: bacteriostatic - phenylethyl alcohol (0.5%), merthiolate, methyl parahydroxybenzoate, benzoic, sorbic acids and others; bactericidal - phenols, cresols.
- By chemical properties: inorganic - water containing 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:
- absence of toxic, sensitizing and irritating effect in the applied concentration;
- broad antimicrobial spectrum;
- good solubility;
- no chemical interaction with other components of the solution and packaging;
- stability at different values of medium acidity and temperature;
- no effect on organoleptic properties (color, transparency).
Preservatives are not allowed in injectables such as:
- intracavitary;
- intracardiac;
- intraocular;
- having access to cerebrospinal fluid;
- formulations with a single dosage of more than 15 ml.
Water for injections
Water with a high degree of purification is used for the preparation of water-based injection solutions. Modern devices for its production include several stages of processing:
- pre-cleaning;
- reverse osmosis;
- deionization;
- filtration (or ultrafiltration and ultraviolet sterilization).
Ready water for injectable dosage forms is stored after distillation for no more than a day inclosed vials under aseptic conditions to prevent the entry of microorganisms. For those drugs that do not provide for sterilization, 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 by dehydration and subsequent cold pressing of the seeds. The acid number of oils should be no more than 2.5, since a higher value causes irritation of nerve fibers.
- Mixed solvents. They include mixtures of vegetable oils and co-solvents (ethyl oleate, propylene glycol, benzyl benzoate, glycerol esters, benzyl alcohol). Their advantage over the previous group is a large dissolving power. Such formulations are used in the production of injections with sparingly soluble substances (hormones, vitamins, antibiotics, and others).
Disadvantages of oily solvents for injections include:
- increased viscosity;
- pain at injection site;
- prolonged absorption of the composition;
- side effects - the development of lipogranuloma (a focus of chronic inflammation).
Types of packages
Several types of packaging are used for solutions:
- ampoules (their size can be from 0.3 to 500 ml);
- vials (mainly for antibacterial and organotherapeutic drugs, solutions with high viscosity);
- tubes with two stoppers;
- syringe tubes with a needle;
- vessels and containers made of plastic.
Injectable solutions in ampoules in terms of prevalence are in second place after tablets. 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 makes it possible to manufacture medicines with a long shelf life.
Production of ampoules
Most often, ampoule glass is used for packaging injection and infusion solutions. There are two main requirements for its physical and chemical properties:
- Transparency for easy visual control of contents (no sediment, mechanical impurities, spoilage).
- Chemical resistance.
Quartz glass has the best performance in relation to the latter indicator, but it has a very high melting point - 1,800 °C. To improve its technological qualities, the following compounds are added:
- sodium and potassium oxides that reduce refractoriness;
- CaO and MgO for improved chemical resistance;
- aluminum oxide and boron oxide for better soldering and cracking prevention.
When in contact with water and injection solutions, sodium silicate is washed out from the surface of the glass ampoule, a film consisting of silicic acid is formed. especially strongalkaline compounds corrode glass. For medicinal formulations that are most sensitive to pH changes (e.g. alkaloids), only class 1 glass is used.
Modern pharmaceutical factories produce ampoules for injection solutions using the technology below:
- calibration of glass tubes (sorted by diameter, length and curvature);
- washing in a chamber with boiling water or in an ultrasonic bath;
- drying with hot filtered air;
- cutting tubes, forming them on a glass-forming machine or semi-automatic machine;
- heat treatment (annealing in furnaces) to eliminate residual stresses;
- a set of ampoules in cassettes, their external and internal multiple washing (syringe, shower, ultrasonic).
Control
The quality of injection solutions is checked by several parameters:
- transparency;
- color;
- lack of mechanical impurities (controlled twice - before and after sterilization);
- authenticity (chemical analysis of the quantitative composition of the main and auxiliary substances);
- pH;
- endotoxin, sterility (control of water for injection, intermediate and final drug products);
- volume of vessel filling;
- tight packaging.
Check for mechanical inclusions produced visually. Since this method is subjective, the verification error is high and amounts to about 30%. The absence of particles is controlled in turn on a black background.(glass dust, insoluble particles, fine fibers from filters) and on white (colour, 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 manufacturing stages:
- production of ampoules;
- cut capillaries;
- heat treatment.
Glass particles smaller than 1 micron 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, plastic, which is due to their ingress from the surfaces of equipment, containers, from service personnel.
At the preparatory stage, 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 technological process. Tightness, quality of sealing and capping of containers are checked in several ways:
- vacuuming;
- indicator solutions (for injection based on water);
- soap solution (oil-based injection);
- by the glow of gas inside the injection vessel as a result of ionization under the action of an electric field.
