Monographs: Dosage forms: General monographs: Parenteral preparations

Definition

Parenteral preparations are sterile, pyrogen-free liquids (solutions, emulsions, or suspensions) or solid dosage forms containing one or more active ingredients, packaged in either single-dose or multidose containers. They are intended for administration by injection, infusion, or implantation into the body.

Preparations such as vaccines, human blood and products derived from human blood, peritoneal dialysis solutions, and radioactive pharmaceuticals require special formulation, methods of manufacture, or presentation appropriate to their particular use and may not comply with certain parts of this monograph.

There are four main forms of parenteral preparations: injections, intravenous infusions (large volume parenterals), powders for injections, and implants. Certain injections and intravenous infusions may be presented in the form of sterile concentrated solutions, which must be suitably diluted before use.

Parenteral preparations may contain excipients such as solvents, suspending agents, buffering agents, substances to make the preparation isotonic with blood, stabilizers, or antimicrobial preservatives. The addition of excipients should be kept to a minimum. When excipients are used, they should not adversely affect the stability, bioavailability, safety, or efficacy of the active ingredient(s), or cause toxicity or undue local irritation. There must be no incompatibility between any of the components of the dosage form.

Water for injections is used as the vehicle for aqueous injections. It should be freshly distilled by the process described under "Aqua pro Injectione", be free from carbon dioxide, and comply with 3.4 Test for bacterial endotoxins. Sterilization at this stage may be omitted, provided that the solution or preparation is immediately sterilized upon finalization. For non-aqueous injections, fixed oils of vegetable origin are used as vehicles.

Unless otherwise specified in the individual monograph, sodium chloride or other suitable substance(s), may be added to an aqueous solution for injection in order to render the preparation isotonic.

Manufacture

The manufacturing process should meet the requirements of Good Manufacturing Practice. The following information is intended to provide very broad guidelines concerning the main steps to be followed during production, indicating those that are the most important.

The quality of starting materials, the design and maintenance of the equipment, and the method of manufacture must be such as to ensure the stability of the active substance and the final product which is sterile and free of pyrogens and particulate matter. From the clinical viewpoint all parenteral preparations must be pyrogen-free. For practical purposes, however, certain categories of parenteral preparations may be exempted from the test for bacterial endotoxinsor or the test for pyrogens as specified in the individual monograph.

For the sterilization of parenteral preparations follow 5.8 Methods of sterilization. Heating in an autoclave is the method of choice for aqueous preparations and should therefore be used whenever possible.

When a parenteral preparation is liable to deterioration due to oxidation, the operation of filling may be performed in an atmosphere of suitable inert gas, such as nitrogen, whereby the air in the container is replaced by this gas.

Throughout manufacturing, certain procedures should be validated and monitored by carrying out appropriate in-process controls. These should be designed to guarantee the effectiveness of each stage of production. In-process controls during production of parenteral preparations should include monitoring of environmental conditions (especially with respect to particulate and microbial contamination), bacterial endotoxins, pH and clarity of solution, freedom from particulate matter, and integrity of container (absence of leakage, etc.). For dispersions controls should also include the particle size of the dispersed phase, and for powders for injections the uniformity of content and mass, moisture content, and the ease of reconstitution of a solution or suspension. The presence of preservatives or other additives should be determined as these can influence the choice of assay method.

Visual inspection

Inspect the solutions, reconstituted solutions, and intravenous infusions (except dispersions). They should be clear and free from visible particulate matter.

Test for sterility

Parenteral preparations comply with 3.2 Test for sterility.

Test for bacterial endotoxins / pyrogens

All intravenous infusions and those injections and powders for injections where the volume to be injected in a single dose is 15 ml or more must comply with 3.4 Test for bacterial endotoxins or, where justified, with 3.5 Test for pyrogens. In addition, where specified in the individual monographs for certain preparations where the active ingredients are of biological origin, injections and powders for injections must comply with the appropriate test, irrespective of the volume to be injected in a single dose.

For injections, the amount to be tested should relate to the volume of the dose and should be specified in the individual monograph.

For powders for injections, the amount of powder to be tested and the nature and volume of the liquid in which it is to be dissolved or suspended should be specified in the individual monograph.

Containers

Parenteral preparations are usually supplied in glass ampoules, bottles or vials, plastic bottles or bags, and prefilled syringes, which are coloured in the case of light-sensitive substances.

Except where otherwise indicated in individual monographs, these containers should be made from material that is sufficiently transparent to permit the visual inspection of the contents. They should not adversely affect the quality of the preparation, allow diffusion of any kind into or across the material of the container, or yield foreign substances into the preparation.

Closures

Closures for parenteral preparation containers should be equipped with a firm seal to prevent entry of microorganisms and other contaminants while permitting the withdrawal of a part or the whole of the contents without removal of the closure. They should not be made of components that react with the contents, nor should they allow foreign substances to diffuse into the preparation. Plastic materials or elastomers of which the closure is composed should be sufficiently firm and elastic to allow the passage of a needle with the least possible shedding of particles. Closures for multidose containers should be sufficiently elastic to allow the puncture to reseal when the needle is withdrawn and protect the contents from airborne contamination. A tamper-evident container is fitted with a device that reveals clearly whether it has ever been opened.

Labelling

Every pharmaceutical preparation must comply with the labelling requirements established under Good Manufacturing Practice.

The label should include:

(1) the name of the pharmaceutical product;

(2) the name(s) of the active ingredient(s); INNs should be used wherever possible;

(3) the amount of the active ingredient(s) in a suitable dose volume and the volume in the container; for powder for injections: the amount of the active ingredient(s) in the container;

(4) the batch (lot) number assigned by the manufacturer;

(5) the expiry date and, when required, the date of manufacture;

(6) any special storage conditions or handling precautions that may be necessary;

(7) directions for use, warnings, and precautions that may be necessary; and

(8) the name and address of the manufacturer or the person responsible for placing the product on the market.

For parenteral preparations that are solutions or dispersions, the concentration of the active ingredient(s) should be given in terms of mass or biological activity per volume. For concentrated solutions, labels should state the composition and the dilution to be carried out before use.

Requirements for specific types of parenteral preparations

Injections

Definition

Injections are sterile, pyrogen-free solutions or dispersions (emulsions or suspensions) of one or more active ingredients in a suitable vehicle.

Whenever possible, an injection should be prepared using an aqueous vehicle. If necessary, suitable non-aqueous solvents are indicated in the individual monographs. Injections that are dispersions should remain sufficiently stable so that, after shaking, a homogeneous dose can be withdrawn.

The use of single-dose injections is to be preferred and is essential when the preparation is intended for administration by routes where, for medical reasons, an antimicrobial preservative is not acceptable, e.g. intracisternal, intrathecal.

Single-dose preparations

Single-dose preparations should contain a sufficient quantity of the injection readily to permit the withdrawal and administration of the volume specified on the label.

Multidose preparations

Multidose preparations should contain a suitable antimicrobial preservative in appropriate concentrations, except in cases where the preparations themselves have adequate antimicrobial properties. The containers should be equipped to ensure adequate protection of the contents after partial withdrawal. In order to minimize the risk of contamination resulting from multiple penetrations of the closure, the contents of a multidose preparation should normally not exceed 30 ml.

Intravenous infusions

Definition

Intravenous infusions are sterile, pyrogen-free aqueous solutions or emulsions with water as continuous phase, usually prepared to be isotonic. They are intended for administration in large volumes (usually 100 ml or more), and should not contain any antimicrobial preservatives.

On visual inspection, emulsions for intravenous injection should show no evidence of phase separation. The particle size of the dispersed phase should be controlled by the manufacturer.

Powders for injections

Definition

Powders for injections are solid substances (including freeze-dried materials), distributed in their final containers and which, when shaken with the prescribed volume of the appropriate sterile liquid, rapidly form either clear and practically particle-free solutions or uniform suspensions. Powders for injections, after dissolution or suspension, comply with the requirements for injections or intravenous infusions, as appropriate.

Uniformity of mass

Powders for injections (single-dose use) comply with the test for 5.2 Uniformity of mass for single-dose preparations, unless otherwise specified in the individual monograph.

Uniformity of content

A requirement for compliance with the test for 5.1 Uniformity of content for single-dose preparations is specified in certain individual monographs where the active ingredient is less than 40 mg. In such cases, compliance with the test for 5.2 Uniformity of mass for single-dose preparations may not be required.

Implants

Definition

Implants are solid preparations containing one or more active ingredients. They are of a size and shape suitable for parenteral implantation, and provide release of the active ingredient(s) over an extended period of time. They are presented in individual sterile containers.

All requirements for these specialized dosage forms are given in the individual monographs.

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