EUROPEAN PHARMACOPOEIA 6.

0 Substances for pharmaceutical use

Standard preparations are calibrated by spectroscopic in other ways. Processing with addition of excipients is
measurements and stored in a state suitable for use over permitted only where this is specifically stated in the
an extended period of time. Definition of the individual monograph.
— Hybridisation conditions. The stringency of hybridisation Substance for pharmaceutical use of special grade.
conditions is such as to ensure specific hybridisation Unless otherwise indicated or restricted in the individual
between probes and standard DNA preparations and the monographs, a substance for pharmaceutical use is intended
drug substances must not interfere with hybridisation for human and veterinary use, and is of appropriate quality
at the concentrations used. for the manufacture of all dosage forms in which it can be
used.
Sequence-independent techniques
Polymorphism. Individual monographs do not usually
Suitable procedures include : detection of sulphonated specify crystalline or amorphous forms, unless bioavailability
cytosine residues in single-stranded DNA (where DNA is is affected. All forms of a substance for pharmaceutical use
immobilised on a filter and cytosines are derivatised in situ, comply with the requirements of the monograph, unless
before detection and quantitation using an antibody directed otherwise indicated.
against the sulphonated group) ; detection of single-stranded
DNA using a fragment of single-stranded DNA bound to a PRODUCTION
protein and an antibody of this protein. Neither procedure
requires the use of specific host or vector DNA as an assay Substances for pharmaceutical use are manufactured
standard. However, the method used must be validated to by procedures that are designed to ensure a consistent
ensure parallelism with the DNA standard used, linearity of quality and comply with the requirements of the individual
response and non-interference of either the drug substance monograph or approved specification.
or excipients of the formulation at the dilutions used in the The provisions of general chapter 5.10 apply to the control
assay. of impurities in substances for pharmaceutical use.
Whether or not it is specifically stated in the individual
IDENTIFICATION, TESTS AND ASSAY monograph that the substance for pharmaceutical use :
The requirements with which the final product (bulk material — is a recombinant protein or another substance obtained
or dose form) must comply throughout its period of validity, as a direct gene product based on genetic modification,
as well as specific test methods, are stated in the individual where applicable, the substance also complies with the
monograph. 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
01/2008:2034 challenge, where applicable, the substance also complies
with the requirements of the general monograph on
Products with risk of transmitting agents of animal
SUBSTANCES spongiform encephalopathies (1483) ;
FOR PHARMACEUTICAL USE — is a substance derived from a fermentation process,
whether or not the micro-organisms involved are modified
by traditional procedures or recombinant DNA (rDNA)
Corpora ad usum pharmaceuticum technology, where applicable, the substance complies
with the requirements of the general monograph on
The statements in this monograph are intended to be read Products of fermentation (1468).
in conjunction with individual monographs on substances
in the Pharmacopoeia. Application of the monograph If solvents are used during production, they are of suitable
to other substances may be decided by the competent quality. In addition, their toxicity and their residual level
authority. are taken into consideration (5.4). If water is used during
production, it is of suitable quality.
DEFINITION If substances are produced or processed to yield a certain
Substances for pharmaceutical use are any organic or form or grade, that specific form or grade of the substance
inorganic substances that are used as active substances complies with the requirements of the monograph. Certain
or excipients for the production of medicinal products for functionality-related tests may be described to control
human or veterinary use. They may be obtained from natural properties that may influence the suitability of the substance
sources or produced by extraction from raw materials, and subsequently the properties of dosage forms prepared
fermentation or synthesis. from it.
This monograph does not apply to herbal drugs, herbal drug Powdered substances may be processed to obtain a certain
preparations or extracts, which are the subject of separate degree of fineness (2.9.12).
general monographs [Herbal drugs (1433), Herbal drug Compacted substances are processed to increase the particle
preparations (1434), Extracts (0765)]. size or to obtain particles of a specific form and/or to obtain
a substance with a higher bulk density.
Where medicinal products are manufactured using
substances for pharmaceutical use of human or animal Coated active substances consist of particles of the active
origin, the requirements of chapter 5.1.7. Viral safety apply. substance coated with one or more suitable excipients.
Substances for pharmaceutical use may be used as such or Granulated active substances are particles of a specified
as starting materials for subsequent formulation to prepare size and/or form produced from the active substance by
medicinal products. Depending on the formulation, certain granulation directly or with one or more suitable excipients.
substances may be used either as active substances or as If substances are processed with excipients, these excipients
excipients. Solid substances may be compacted, coated, comply with the requirements of the relevant monograph or,
granulated, powdered to a certain fineness or processed where no such monograph exists, the approved specification.

General Notices (1) apply to all monographs and other texts 703
Substances for pharmaceutical use EUROPEAN PHARMACOPOEIA 6.0

CHARACTERS of general relevance for substances subject to microbial

The statements under the heading Characters (e.g. contamination. Depending on the nature of the substance
statements about the solubility or a decomposition point) and its intended use, different acceptance criteria may be
are not to be interpreted in a strict sense and are not justified.
requirements. They are given for information. Sterility (2.6.1). If intended for use in the manufacture
Where a substance may show polymorphism, this may be of sterile dosage forms without a further appropriate
stated under Characters in order to draw this to the attention sterilisation procedure, or if offered as sterile grade, the
of the user who may have to take this characteristic into substance for pharmaceutical use complies with the test for
consideration during formulation of a preparation. sterility.
IDENTIFICATION Bacterial endotoxins (2.6.14). If offered as bacterial
endotoxin-free grade, the substance for pharmaceutical use
Where under Identification an individual monograph complies with the test for bacterial endotoxins. The limit
contains subdivisions entitled First identification and and test method (if not gelation method A) are stated in the
Second identification, the test or tests that constitute the individual monograph. The limit is calculated in accordance
First identification may be used in all circumstances. The with Test for bacterial endotoxins : guidelines (2.6.14),
test or tests that constitute the Second identification may unless a lower limit is justified from results from production
be used for identification, provided it can be demonstrated batches or is required by the competent authority. Where a
that the substance is fully traceable to a batch certified to test for bacterial endotoxins is prescribed, a test for pyrogens
comply with all the other requirements of the monograph. is not required.
TESTS Pyrogens (2.6.8). If the test for pyrogens is justified rather
Polymorphism (5.9). If the nature of a crystalline or than the test for bacterial endotoxins and if a pyrogen-free
amorphous form imposes restrictions on its use in grade is offered, the substance for pharmaceutical use
preparations, the nature of the specific crystalline or complies with the test for pyrogens. The limit and test
amorphous form is identified, its morphology is adequately method are stated in the individual monograph or approved
controlled and its identity is stated on the label. by the competent authority. Based on appropriate test
validation for bacterial endotoxins and pyrogens, the test for
Related substances. Unless otherwise prescribed or justified bacterial endotoxins may replace the test for pyrogens.
and authorised, organic impurities in active substances are
to be reported, identified wherever possible, and qualified Additional properties. Control of additional properties (e.g.
as indicated in Table 2034.-1. physical characteristics, functionality-related characteristics)
may be necessary for individual manufacturing processes
Specific thresholds may be applied for impurities known or formulations. Grades (such as sterile, endotoxin-free,
to be unusually potent or to produce toxic or unexpected pyrogen-free) may be produced with a view to manufacture of
pharmacological effects. preparations for parenteral administration or other dosage
If the individual monograph does not provide suitable forms and appropriate requirements may be specified in an
control for a new impurity, a suitable test for control must individual monograph.
be developed and included in the specification for the
substance. ASSAY
The requirements above do not apply to biological and Unless justified and authorised, contents of substances for
biotechnological products, peptides, oligonucleotides, pharmaceutical use are determined. Suitable methods are
radiopharmaceuticals, products of fermentation and used.
semi-synthetic products derived therefrom, to crude products
of animal or plant origin or herbal products. LABELLING
Residual solvents are limited according to the principles In general, labelling is subject to supranational and national
defined in chapter 5.4, using general method 2.4.24 regulation and to international agreements. The statements
or another suitable method. Where a quantitative under the heading Labelling therefore are not comprehensive
determination of a residual solvent is carried out and a test and, moreover, for the purposes of the Pharmacopoeia
for loss on drying is not carried out, the content of residual only those statements that are necessary to demonstrate
solvent is taken into account for calculation of the assay compliance or non-compliance with the monograph are
content of the substance, the specific optical rotation and mandatory. Any other labelling statements are included
the specific absorbance. as recommendations. When the term ‘label’ is used in the
Pharmacopoeia, the labelling statements may appear on the
Microbiological quality. Individual monographs give container, the package, a leaflet accompanying the package
acceptance criteria for microbiological quality wherever or a certificate of analysis accompanying the article, as
such control is necessary. Table 5.1.4.-2. – Acceptance decided by the competent authority.
criteria for microbiological quality of non-sterile
Where appropriate, the label states that the substance is :
substances for pharmaceutical use in chapter 5.1.4.
Microbiological quality of pharmaceutical preparations — intended for a specific use ;
gives recommendations on microbiological quality that are — of a distinct crystalline form ;
Table 2034.-1. – Reporting, identification and qualification of organic impurities in active substances
Use Maximum daily Reporting Identification Qualification
dose threshold threshold threshold
Human use or human and ≤ 2 g/day > 0.05 per cent > 0.10 per cent or a daily > 0.15 per cent or a daily
veterinary use intake of > 1.0 mg (whichever intake of > 1.0 mg (whichever
is the lower) is the lower)
Human use or human and > 2 g/day > 0.03 per cent > 0.05 per cent > 0.05 per cent
veterinary use
Veterinary use only Not applicable > 0.1 per cent > 0.2 per cent > 0.5 per cent

704 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 6.0 Vaccines for human use

— of a specific degree of fineness ; Viral vaccines are prepared from viruses grown in animals,
— compacted ; in fertilised eggs, in suitable cell cultures or in suitable
— coated ; tissues or by culture of genetically engineered cells. They
are liquids that vary in opacity according to the type of
— granulated ; preparation or may be freeze-dried. Liquid preparations
— sterile ; and freeze-dried preparations after reconstitution may be
— free from bacterial endotoxins ; coloured if a pH indicator such as phenol red has been used
— free from pyrogens ; in the culture medium.
— containing gliding agents. PRODUCTION
Where applicable, the label states :
General provisions. The production method for a given
— the degree of hydration, product must have been shown to yield consistently batches
— the name and concentration of any added substance (for comparable with the batch of proven clinical efficacy and
example, an antimicrobial preservative or an antioxidant). safety in man. Requirements for production including
Where an active substance is processed with addition of an in-process testing are included in individual monographs.
excipient or excipients, the label states the excipient(s) used Where justified and authorised, certain tests may be omitted
and the content of active substance and excipient(s). where it can be demonstrated, for example by validation
studies, that the production process consistently ensures
compliance with the test.
01/2008:0153
Unless otherwise justified and authorised, vaccines
are produced using a seed-lot system. The methods of
VACCINES FOR HUMAN USE preparation are designed to maintain adequate immunogenic
properties, to render the preparation harmless and to
Vaccina ad usum humanum prevent contamination with extraneous agents.
Where vaccines for human use are manufactured
For a combined vaccine, where there is no monograph using materials of human or animal origin, the general
to cover a particular combination, the vaccine complies requirements of chapter 5.1.7. Viral safety apply in
with the monograph for each individual component, with conjunction with the more specific requirements relating to
any necessary modifications approved by the competent viral safety in this monograph, in chapters 5.2.2. Chicken
authority. flocks free from specified pathogens for the production and
DEFINITION quality control of vaccines, 5.2.3. Cell substrates for the
production of vaccines for human use and 2.6.16. Tests for
Vaccines for human use are preparations containing extraneous agents in viral vaccines for human use, and in
substances capable of inducing a specific and active individual monographs.
immunity in man against an infecting agent or the toxin or
the antigen elaborated by it. They shall have been shown Unless otherwise justified and authorised, in the production
to have acceptable immunogenic activity in man with of a final lot of vaccine, the number of passages of a virus, or
the intended vaccination schedule. They may contain an the number of subcultures of a bacterium, from the master
adjuvant. seed lot shall not exceed that used for production of the
Vaccines for human use may contain : organisms inactivated vaccine shown in clinical studies to be satisfactory with
by chemical or physical means that maintain adequate respect to safety and efficacy.
immunogenic properties ; living organisms that are naturally Vaccines are as far as possible free from ingredients known
avirulent or that have been treated to attenuate their to cause toxic, allergic or other undesirable reactions in
virulence whilst retaining adequate immunogenic properties ; man. Suitable additives, including stabilisers and adjuvants
antigens extracted from the organisms or secreted by them may be incorporated. Penicillin and streptomycin are not
or produced by genetic engineering ; the antigens may be used at any stage of production nor added to the final
used in their native state or may be detoxified by chemical product ; however, master seed lots prepared with media
or physical means and may be aggregated, polymerised or containing penicillin or streptomycin may, where justified
conjugated to a carrier to increase their immunogenicity. and authorised, be used for production.
Terminology used in monographs on vaccines for human use Consistency of production is an important feature of vaccine
is defined in chapter 5.2.1. production. Monographs on vaccines for human use give
Bacterial vaccines are suspensions of various degrees of limits for various tests carried out during production and on
opacity in colourless or almost colourless liquids, or may the final lot. These limits may be in the form of maximum
be freeze-dried. The concentration of living or inactivated values, minimum values or minimum and maximum
bacteria is expressed in terms of International Units of tolerances around a given value. While compliance with
opacity or, where appropriate, is determined by direct cell these limits is required, it is not necessarily sufficient to
count or, for living bacteria, by viable count. ensure consistency of production for a given vaccine. For
Bacterial toxoids are prepared from toxins by diminishing relevant tests, the manufacturer must therefore define for
their toxicity to a non-detectable level or by completely each product a suitable action or release limit or limits to
eliminating it by physical or chemical procedures whilst be applied in view of the results found for batches tested
retaining adequate immunogenic properties. The toxins clinically and those used to demonstrate consistency of
are obtained from selected strains of micro-organisms. The production. These limits may be subsequently refined on a
method of production is such that the toxoid does not revert statistical basis in the light of production data.
to toxin. Toxoids may be liquid or freeze-dried. They may be Substrates for propagation. Substrates for propagation
purified and adsorbed. Adsorbed toxoids are suspensions comply with the relevant requirements of the Pharmacopoeia
of white or grey particles dispersed in colourless or pale (5.2.2, 5.2.3) or in the absence of such requirements with
yellow liquids and may form a sediment at the bottom of the those of the competent authority. Processing of cell banks
container. and subsequent cell cultures is done under aseptic conditions

General Notices (1) apply to all monographs and other texts 705