Substances for Pharmaceutical Use
(Ph Eur monograph 2034)
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
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.
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
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
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.
May be processed to obtain a certain degree of fineness
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.
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.
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
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.
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
Are limited according to the principles defined in the general
chapter (5.4), using the general method (2.4.24) or other suitable methods.
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.
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.
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
Unless justified and authorised, contents of substances for
pharmaceutical use are determined. Suitable methods are used.
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
intended for a specific use,
of a distinct crystalline form,
of a specific degree of fineness,
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.