Manufacturing of solution for injections

Plan 1.Peculiarities of manufacturing of parenteral preparations 2. Solvents for preparing of parenteral preparations 3. Equipment in manufacturing of parenteral drug 4. Process of ampouling 5. Methods of filling and soldering of ampoules 6. Quality control of parenteral drugs

All medicines for parenteral use are classified as: 1.Injection drugs; 2. Intravenous infusion drugs; 3. Concentrates for injection or intravenous infusion drugs; 4. Powders for injection or intravenous infusion drugs; 5. Implants.

Peculiarities of manufacturing of parenteral preparations 1. should be prepared in aseptic conditions (A class room by the GMP classifications of rooms cleanliness); 2. all substances should have quality “for injections”; 3. solutions can be sterilized by filtration thought deep or membrane filters; 4. some parenteral preparations can containe antimicrobial conservants (Benzalkonium Chloride, Chlorbutol, Chlorhexidine Gluconate, Thiomersal, Boric Acid, Salicylic Acid, etc.)

Observance of aseptic conditions is necessary during manufacture of all parenteral preparations.

Production begins with the preparing of manufacturing facilities: Sanitary preconditioning of production areas Preparing of sterile vent air Preparing of the process equipment and stock Preparing of technological clothes Preparing of the personnel

All solutions for parenteral administration should comply with the following requirements of stability: Microbiological Physical Chemical

Parenteral preparations, which do not expose thermal sterilization are: parenteral preparations with thermo sensitive substances (Adrenaline, Aminophylline, Hexamethylenetetramine); parenteral preparations with antimicrobial ingredients (Aminazine, Promethazine Hydrochloride (Diprazinum), etc.); suspensions for injections; emulsions for parenteral administrations (“Lypofundine” (Germany), “Lyposine” (USA), “Lipidine” (Ukraine).

The basic principle of stabilization of parenteral preparations the maximal avoiding some harmful factors of the environment the addition of several excipients using hydrolytic resistance glass for containers (type I or II) using the modern technological equipment, and especial technological receptions – unwater solvents, special methods of substances clearing manufacturing of parenteral preparations in powders and tablets forms.

Groups of solvents for preparing of parenteral preparations aqueous (water) solvents unhydrous solvents, which are divided : 1. fat oils, 2. monoatomic and polyatomic alcohols, 3. simple and complex ethers, 4. amides, 5. sulfoxides and sulfones, etc.

Requirements to water for injections sterile and match the corresponding reference document should be maximally purified free of pyrogens pH =5,0 - 6,8 Presence of ammonia should be no more than 0,00002 % solid residue - no more than 0,001 %. Expire term of water for injections is 24 hours.

1. Preparing of raw material; 2.Obtaining of solution for injection (or infusion); 3. Filtering and stabilization; 4. Ampouling; 5. Sterilisation; 6. Packaging. Technological stages at parenteral preparations production:

Preparation of injection solutions includes such stage as: dissolution of substances, isotoning, stabilization, adding of preservatives, filtering. Depending on properties of medicinal substances some operations can be excluded.

Nutsche-filters

Druck-filters

KSRChPhI (HNIHFI) filter

Ampouling of the purified and filtered solution includes Filling up the ampoules Soldering capillaries

Ways of ampoules filling 1. Vacuum way – a large number of ampoules are simultaneously filled with solution for injections 2. Syringe technique – each ampoule is filled separately by syringe 3. Type of vacuum way – vapours- condensation

Vacuum method 1.Cassettes with ampoules are placed in airtight device, where solution for filling ampoules and vacuum is created. While the air is pumped from the ampoules. 2.Then vacuum off and solution fills the ampoules. Dosage of solution in ampoules done by changing the size of rarefaction

Disadvantages of vacuum method: 1. impossibility precise dosing of solution; 2. the part of solution remains in the machine, goes for a second filtering, and this leads to additional pollution and uneconomic costs of solution; 3. While sealing (soldering) the capillaries "Black" head are formed by burning of solution at the end of the capillaries, which before sinking into the solution. 4. Between filling and sealing of ampoules is a significant amount of time, which adversely affects on the purity of the solution.

The advantages of vacuum method: 1. Method is used for ampoules of different shapes and sizes. 2. There is a group. 3. It has double pre-eminence – ampoules per hour at accuracy of dosage ± %.

Syringe method: is carried out by special dosing (piston, membrane). 1. Ampoules are blown by inert gas immediately before filling by solution, 2. Ampoules are filled by solution for injections, 3. Ampoules are blown by inert gas immediately after filling by solution.

Syringe method

Advantages of syringe technique: 1. Accuracy of dosing (2 %) 2. Short period of time between filling and sealing 5 – 10 c, more shelf life of parenteral drug; 3. Capillary is not moistened by solution, it remains clear, the process of sealing ampoules improves, it is important for thick and viscous solutions.

Disadvantages of syringe technique: 1. It requires complicated equipment 2. It requires more stringent requirements for size and shape of capillaries of ampoules. 3. It has less output but shorter cycle.

Vapours-condensating way: - a type of vacuum method of filling ampoules. Ampoules are slightly cooled before sealing the solution out from the capillaries, their ends are immersed in container with a liquid plastic and immediately removed; drops of plastic harden and clog sealed ampoule with a solution.

Now ampoule soldering is carried out with the help of gas burners in two main ways: In some unusual cases soldering by electric heating or plastic closure may be used. Melting of capillary tips Stretching of capillaries

Ampoule soldering

Melting the tips of the capillaries: the ampoule, which is continuously rotating, heated by capillary tip and glass is melted and soldered hole of capillary. Disadvantages of the method 1. Sealing of ampoules is followed by influx 2. The formation of sealing cracks in a place that leads to depressurization of ampoules 3. With a thin capillary formation is accompanied by sealing off the hook at the end of the capillary

Equipment for ampouling

4. At the large diameter of the capillary melting does not occur fully. 5. The method requires strictly for ampoules were one length. Deviation over the length of 1 ml ampoules, sealing quality has deteriorated, 6. Sealing of ampoules filled with a solution, the capillary formed a smell of burning because capillaries ampoules before sealing subjected washing. They are washed by spray nozzles, directing water spray injection holes in the capillaries ampoules.

Stretching of capillaries the capillary of ampoules are stretched while ampoules are soldered. Heating of capillaries is conducted in the middle of ampoules, which continuously rotates. Then part of capillaries with special forceps is stretched with formation filaments. Filaments is snipped off and melted off, and throw out in waste.

Stretching of capillaries

Parameters of quality of solution for parenteral administration The standards of filling (by a syringe) The tightness of containers Absence of the particulate matter (visually) Content of active substances Colour of solution Transparency

Parameters of quality of solution for parenteral administration

Packing and labeling of ampoules