Substances for Pharmaceutical Use

(Ph Eur monograph 2034)

 

Ph Eur


 

 

The statements in this monograph are intended to be read in conjunction with individual monographs on substances in the Pharmacopoeia. Application of the monograph to other substances may be decided by the competent authority.

 

Definition

 

Substances for pharmaceutical use are any organic or inorganic substances that are used as active substances or excipients for the production of medicinal products for human or veterinary use. They may be obtained from natural sources or produced by extraction from raw materials, fermentation or synthesis.

 

Substances for pharmaceutical use may be used as such or as starting materials for subsequent formulation to prepare medicinal products. Depending on the formulation, certain substances may be used either as active substances or excipients. Solid substances may be compacted, coated, granulated, powdered to a certain fineness or processed in other ways. Processing with addition of excipients is permitted only where this is specifically stated in the Definition of the individual monograph.

 

Substance for pharmaceutical use of special grade

 

Unless otherwise indicated or restricted in the individual monographs, a substance for pharmaceutical use is intended for human and veterinary use, and is of appropriate quality for manufacture of all dosage forms in which it can be used.

 

Polymorphism

 

Individual monographs do not usually specify crystalline or amorphous forms, unless bioavailability is affected. All forms of a substance for pharmaceutical use comply with the requirements of the monograph, unless otherwise indicated.

 

Production

 

Substances for pharmaceutical use are manufactured by procedures that are designed to ensure a consistent quality and comply with the requirements of the individual monograph or approved specification.

 

Whether or not it is specifically stated in the individual monograph that the substance for pharmaceutical use:

 

is a recombinant protein or another substance obtained as a direct gene product based on genetic modification, where applicable, the substance also complies with the requirements of the general monograph on Products of recombinant DNA technology (0784);

 

is obtained from animals susceptible to transmissible spongiform encephalopathies other than by experimental challenge, where applicable, the substance also complies with the requirements of the general monograph on Products with risk of transmitting agents of animal spongiform encephalopathies (1483);

 

is a substance derived from a fermentation process whether or not the micro-organisms involved are modified by traditional procedures or recombinant DNA (rDNA) technology, where applicable, the substance complies with the requirements of the general monograph on Products of fermentation (1468).

 

If solvents are used during production, they are of suitable quality. In addition, their toxicity and their residual level are taken into consideration (5.4). If water is used during production, it is of suitable quality.

 

If substances are produced or processed to yield a certain form or grade, that specific form or grade of the substance complies with the requirements of the monograph. Certain functionality-related tests may be described to control properties that may influence the suitability of the substance and subsequently the properties of dosage forms prepared from it.

 

Powdered substances

 

May be processed to obtain a certain degree of fineness (2.9.12).

 

Compacted substances

 

Are processed to increase the particle size or to obtain particles of a specific form and/or to obtain a substance with a higher bulk density.

 

Coated active substances

 

Consist of particles of the active substance coated with one or more suitable excipients.

 

Granulated active substances

 

Are particles of a specified size and/or form produced from the active substance by granulation directly or with one or more suitable excipients.

 

If substances are processed with excipients, these excipients comply with the requirements of the relevant monograph or, where no such monograph exists, the approved specification.

 

Characters

 

The statements under the heading Characters (e.g. statements about the solubility or a decomposition point) are not to be interpreted in a strict sense and are not requirements. They are given for information.

 

Where a substance may show polymorphism, this may be stated under Characters in order to draw this to the attention of the user who may have to take this characteristic into consideration during formulation of a preparation.

 

Identification

 

Where under Identification an individual monograph contains subdivisions entitled First identification and Second identification, the test or tests that constitute the Second identification may be used instead of the test or tests of the First identification, provided it can be demonstrated that the substance is fully traceable to a batch certified to comply with all the requirements of the monograph.

 

Tests

 

Polymorphism

 

If the nature of a crystalline or amorphous form imposes restrictions on its use in preparations, the nature of the specific crystalline or amorphous form is identified, its morphology is adequately controlled and its identity is stated on the label.

 

Related substances

 

Organic impurities present in active substances at a level above 0.1 per cent must be qualified and, wherever possible, identified, unless the daily dose of the active substance exceeds 2 g where the threshold for qualification is 0.05 per cent. Toxic or pharmacologically active impurities at a level below 0.1 per cent may be controlled by a separate test. Impurities that are not qualified must be at a level not more than 0.1 per cent. For active substances that are solely intended for use in veterinary medicinal products, a qualification threshold of 0.5 per cent applies. Reporting of these impurities should be as from 0.1 per cent onward, while identification is required as from 0.2 per cent. These requirements do not apply to biological and biotechnological products, peptides, oligonucleotides, radiopharmaceuticals, fermentation products and semi-synthetic products derived thereof or to crude products of animal or plant origin.

 

Residual solvents

 

Are limited according to the principles defined in the general chapter (5.4), using the general method (2.4.24) or other suitable methods.

 

Sterility (2.6.1)

 

If intended for use in the manufacture of sterile dosage forms without a further appropriate sterilisation procedure, or if offered as sterile grade, the substance for pharmaceutical use complies with the test for sterility.

 

Bacterial endotoxins (2.6.14)

 

If offered as bacterial endotoxin-free grade, the substance for pharmaceutical use complies with the test for bacterial endotoxins. The limit and test method (if not gelation method A) are stated in the individual monograph. The limit is calculated in accordance with Test for bacterial endotoxins: guidelines (2.6.14), unless a lower limit is justified from results from production batches or is required by the competent authority. Where a test for bacterial endotoxins is prescribed, a test for pyrogens is not required.

 

Pyrogens (2.6.8)

 

If the test for pyrogens is justified rather than the test for bacterial endotoxins and if a pyrogen-free grade is offered, the substance for pharmaceutical use complies with the test for pyrogens. The limit and test method are stated in the individual monograph or approved by the competent authority. Based on appropriate test validation for bacterial endotoxins and pyrogens, the test for bacterial endotoxins may replace the test for pyrogens.

 

Additional properties

 

Control of additional properties (e.g. physical characteristics, functionality-related properties) may be necessary for individual manufacturing processes or formulations. Grades (such as sterile, endotoxin-free, pyrogen-free) may be produced with a view to manufacture of preparations for parenteral administration or other dosage forms and appropriate requirements may be specified in an individual monograph.

 

Assay

 

Unless justified and authorised, contents of substances for pharmaceutical use are determined. Suitable methods are used.

 

Labelling

 

In general, labelling is subject to supranational and national regulation and to international agreements. The statements under the heading Labelling therefore are not comprehensive and, moreover, for the purposes of the Pharmacopoeia only those statements that are necessary to demonstrate compliance or non-compliance with the monograph are mandatory. Any other labelling statements are included as recommendations. When the term "label" is used in the Pharmacopoeia, the labelling statements may appear on the container, the package or a leaflet accompanying the package, as decided by the competent authority.

 

Where appropriate, the label includes statements that the substance is:

 

intended for a specific use,

 

of a distinct crystalline form,

 

of a specific degree of fineness,

 

compacted,

 

coated,

 

granulated,

 

sterile,

 

free from bacterial endotoxins,

 

free from pyrogens,

 

containing gliding agents.

 

Where appropriate, the label indicates the degree of hydration, the nature of any added antimicrobial preservative, antioxidant or other excipient. When active substances are processed with addition of excipients, the label indicates the excipients used and the content of active substance and excipients.

 

 

 


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