Parenteral Preparations

(Ph. Eur. monograph 0520)

Ph Eur

The requirements of this monograph do not necessarily apply to products derived from human blood, to immunological preparations, or radiopharmaceutical preparations. Special requirements may apply to preparations for veterinary use depending on the species of animal for which the preparation is intended.

DEFINITION

Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation into the human or animal body.

Parenteral preparations may require the use of excipients, for example to make the preparation isotonic with respect to blood, to adjust the pH, to increase solubility, to prevent deterioration of the active substances or to provide adequate antimicrobial properties, but not to adversely affect the intended medicinal action of the preparation or, at the concentrations used, to cause toxicity or undue local irritation.

Containers for parenteral preparations are made as far as possible from materials that are sufficiently transparent to permit the visual inspection of the contents, except for implants and in other justified and authorised cases.

Where applicable, the containers for parenteral preparations comply with the requirements for Materials used for the manufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Parenteral preparations intended for chronic use or total parenteral nutrition should have appropriate limits for specific components or elements, taking long-term toxicity into account.

Parenteral preparations are supplied in glass containers (3.2.1) or in other containers such as plastic containers (3.2.2, 3.2.2.1 and 3.2.9) and prefilled syringes. The tightness of the container is ensured by suitable means. Closures ensure a good seal, prevent the access of micro-organisms and other contaminants and usually permit the withdrawal of a part or the whole of the contents without removal of the closure. The plastic materials or elastomers (3.2.9) used to manufacture the closures are sufficiently firm and elastic to allow the passage of a needle with the least possible shedding of particles. Closures for multidose containers are sufficiently elastic to ensure that the puncture is resealed when the needle is withdrawn.

Several categories of parenteral preparations may be distinguished:

— injections;

— infusions;

— concentrates for injections or infusions;

— powders for injections or infusions;

— gels for injections;

— implants.

PRODUCTION

During the development of a parenteral preparation, the formulation for which contains an antimicrobial preservative, the effectiveness of the chosen preservative shall be demonstrated to the satisfaction of the competent authority. A suitable test method together with criteria for judging the preservative properties of the formulation are provided under Efficacy of antimicrobial preservation (5.1.3).

Parenteral preparations are prepared using materials and methods designed to ensure sterility and to avoid the introduction of contaminants and the growth of micro-organisms. Recommendations on this aspect are provided in the text Methods of preparation of sterile products (5.1.1).

Water used in the manufacture of parenteral preparations complies with the requirements of water for injections in bulk stated in the monograph Water for injections (0169).

TESTS

Particulate contamination: sub-visible particles (2.9.19)

For preparations for human use, solutions for infusion or solutions for injection comply with the test.

In the case of preparations for subcutaneous or intramuscular injection, higher limits may be appropriate. Radiopharmaceutical preparations are exempt from these requirements. Preparations for which the label states that the product is to be used with a final filter are exempt from these requirements, providing it has been demonstrated that the filter delivers a solution that complies with the test.

For preparations for veterinary use, when supplied in containers with a nominal content of more than 100 mL and when the content is equivalent to a dose of more than 1.4 mL per kilogram of body mass, solutions for infusion or solutions for injection comply with the test for particulate contamination: sub-visible particles.

Sterility (2.6.1)

Parenteral preparations comply with the test for sterility.

STORAGE

In a sterile, airtight, tamper-proof container.

LABELLING

The label states:

— the name and concentration of any added antimicrobial preservative;

— where applicable, that the solution is to be used in conjunction with a final filter;

— where applicable, that the preparation is free from bacterial endotoxins or that it is apyrogenic.

Injections

DEFINITION

Injections are sterile solutions, emulsions or suspensions. They are prepared by dissolving, emulsifying or suspending the active substance(s) and any added excipients in water, in a suitable non-aqueous liquid, that may be non-sterile where justified, or in a mixture of these vehicles.

Solutions for injection, examined under suitable conditions of visibility, are clear and practically free from particles.

Emulsions for injection do not show any evidence of phase separation. Suspensions for injection may show a sediment which is readily dispersed on shaking to give a suspension which remains sufficiently stable to enable the correct dose to be withdrawn.

Multidose preparations Multidose aqueous injections contain a suitable antimicrobial preservative at an appropriate concentration except when the preparation itself has adequate antimicrobial properties. When a preparation for parenteral administration is presented in a multidose container, the precautions to be taken for its administration and more particularly for its storage between successive withdrawals are given.

Antimicrobial preservatives Aqueous preparations which are prepared using aseptic precautions and which cannot be terminally sterilised may contain a suitable antimicrobial preservative in an appropriate concentration.

No antimicrobial preservative is added when:

— the volume to be injected in a single dose exceeds 15 mL, unless otherwise justified;

— the preparation is intended for administration by routes where, for medical reasons, an antimicrobial preservative is not acceptable, such as intracisternally, epidurally, intrathecally or by any route giving access to the cerebrospinal fluid, or intra- or retro-ocularly.

Such preparations are presented in single-dose containers.

PRODUCTION

In the manufacture of injections containing dispersed particles, measures are taken to ensure a suitable and controlled particle size with regard to the intended use.

Single-dose preparations The volume of the injection in a single-dose container is sufficient to permit the withdrawal and administration of the nominal dose using a normal technique (2.9.17).

TESTS

Uniformity of dosage units

Single-dose suspensions for injection comply with the test for uniformity of dosage units (2.9.40) or, where justified and authorised, with the test for uniformity of content shown below. Herbal drugs and herbal drug preparations present in the dosage form are not subject to the provisions of this paragraph.

Uniformity of content (2.9.6)

Unless otherwise prescribed or justified and authorised, single-dose suspensions for injection with a content of active substance less than 2 mg or less than 2 per cent of the total mass comply with test A for uniformity of content of single-dose preparations. If the preparation contains more than one active substance, the requirement applies only to those substances that correspond to the above conditions.

Bacterial endotoxins - pyrogens

A test for bacterial endotoxins (2.6.14) is carried out or, where justified and authorised, the test for pyrogens (2.6.8). Recommendations on the limits for bacterial endotoxins are given in general chapter 5.1.10.

Preparations for human use The preparation complies with a test for bacterial endotoxins (2.6.14) or with the test for pyrogens (2.6.8).

Preparations for veterinary use When the volume to be injected in a single dose is 15 mL or more and is equivalent to a dose of 0.2 mL or more per kilogram of body mass, the preparation complies with a test for bacterial endotoxins (2.6.14) or with the test for pyrogens (2.6.8).

Any preparation Where the label states that the preparation is free from bacterial endotoxins or apyrogenic, respectively, the preparation complies with a test for bacterial endotoxins (2.6.14) or with the test for pyrogens (2.6.8), respectively.

Infusions

DEFINITION

Infusions are sterile, aqueous solutions or emulsions with water as the continuous phase. They are usually made isotonic with respect to blood. They are principally intended for administration in large volume. Infusions do not contain any added antimicrobial preservative.

Solutions for infusion, examined under suitable conditions of visibility, are clear and practically free from particles.

Emulsions for infusion do not show any evidence of phase separation.

PRODUCTION

In the manufacture of infusions containing dispersed particles, measures are taken to ensure a suitable and controlled particle size with regard to the intended use.

The volume of the infusion in the container is sufficient to permit the withdrawal and administration of the nominal dose using a normal technique (2.9.17).

TESTS

Bacterial endotoxins - pyrogens

They comply with a test for bacterial endotoxins (2.6.14) or, where justified and authorised, with the test for pyrogens (2.6.8). For the latter test inject 10 mL per kilogram of body mass into each rabbit, unless otherwise justified and authorised.

Concentrates for injections or infusions

DEFINITION

Concentrates for injections or infusions are sterile solutions intended for injection or infusion after dilution. They are diluted to a prescribed volume with a prescribed liquid before administration. After dilution, they comply with the requirements for injections or for infusions.

TESTS

Bacterial endotoxins - pyrogens

They comply with the requirements prescribed for injections or for infusions, after dilution to a suitable volume.

Powders for injections or infusions

DEFINITION

Powders for injections or infusions are solid, sterile substances distributed in their final containers and which, when shaken with the prescribed volume of a prescribed sterile liquid rapidly form either clear and practically particle-free solutions or uniform suspensions. After dissolution or suspension, they comply with the requirements for injections or for infusions.

Freeze-dried products for parenteral administration are considered as powders for injections or infusions.

PRODUCTION

The uniformity of content and uniformity of mass of freeze-dried products for parenteral administration are ensured by the in-process control of the amount of the solution prior to freeze-drying.

TESTS

Uniformity of dosage units

Powders for injections or infusions comply with the test for uniformity of dosage units (2.9.40) or, where justified and authorised, with the tests for uniformity of content and/or uniformity of mass shown below. Herbal drugs and herbal drug preparations present in the dosage form are not subject to the provisions of this paragraph.

Uniformity of content (2.9.6)

Unless otherwise prescribed or justified and authorised, powders for injections or infusions with a content of active substance less than 2 mg or less than 2 per cent of the total mass, or with a unit mass equal to or less than 40 mg comply with test A for uniformity of content of single-dose preparations. If the preparation contains more than one active substance, the requirement applies only to those substances that correspond to the above conditions.

Uniformity of mass (2.9.5)

Powders for injections or infusions comply with the test for uniformity of mass of single-dose preparations. If the test for uniformity of content is prescribed for all the active substances, the test for uniformity of mass is not required.

Bacterial endotoxins - pyrogens

They comply with the requirements prescribed for injections or for infusions, after dissolution or suspension in a suitable volume of liquid.

LABELLING

The label states the instructions for the preparation of injections and infusions.

Gels for injections

DEFINITION

Gels for injections are sterile gels with a viscosity suitable to guarantee a modified release of the active substance(s) at the site of injection.

Implants

DEFINITION

Implants are sterile, solid preparations of a size and shape suitable for parenteral implantation and release of the active substance(s) over an extended period of time. Each dose is provided in a sterile container.

TESTS

A suitable test is carried out to demonstrate the appropriate release of the active substance(s).

Ph Eur