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EUROPEAN PHARMACOPOEIA 8.

ALLERGEN

Allergen products

07/2014:1063 by a microscopic particle count. Detectable mould spores


must not exceed 1 per cent. The contamination with particles
of plant origin other than pollen must be kept to a minimum.
PRODUCTS
The maximum allowed contamination must be justied.

Moulds. Biologically active contaminants such as mycotoxins


in moulds must be minimised and any presence justied.
Appropriate measures have to be implemented to avoid
contamination by foreign mould strains. Care must be taken
This monograph does not apply to : chemicals that are used
solely for diagnosis of contact dermatitis ; chemically synthesised to minimise any allergenic constituents of the media used for
the cultivation of moulds as source materials. Culture media
products ; allergens derived by recombinant DNA technology.
It does not necessarily apply to allergen products for veterinary that contain substances of human or animal origin must be
justied and, when required, must be suitably treated to ensure
use.
the inactivation or elimination of possible transmissible agents
of disease.
DEFINITION

Producta allergenica

Allergen products are pharmaceutical preparations derived


from extracts of naturally occurring source materials
containing allergens, which are substances that lead to and/or
provoke allergic reactions. The allergenic components are
most often of a proteinaceous nature. Allergen products are
intended for in vivo diagnosis or treatment of allergic diseases
attributed to these allergens.

The production method is validated to demonstrate that


allergen products obtained from moulds and intended for
parenteral administration, if tested, would comply with the
test for abnormal toxicity for immunosera and vaccines for
human use (2.6.9).

The content of the relevant residual solvents, heavy metals and


pesticides is determined on a number of batches according
to a justied sampling plan. Residual solvents and pesticides
are limited according to the principles dened in general
chapter 2.4.24. Identification and control of residual solvents
and 2.8.13. Pesticide residues respectively.
Pollens. Potential chemical contaminants, such as pesticides,
heavy metals and solvents, must be minimised. The content
of foreign pollen must be limited to 1 per cent of total mixed
pollens and 0.5 per cent of any individual pollen as determined

All allergen preparations are manufactured under conditions


designed to minimise exogenous and endogenous enzymatic
degradation.

Mites. Appropriate measures have to be implemented to avoid


contamination by foreign mite strains. Care must be taken to
Allergen products are available as nished products, and as
minimise any allergenic constituents of the media used for
nished products used on a named-patient basis. Allergen
the cultivation of mites as source materials. Culture media
products are generally presented as parenteral preparations,
that contain substances of human or animal origin must be
eye preparations, preparations for inhalation, preparations for justied and, when required, must be suitably treated to ensure
oral use, sublingual preparations or preparations for skin tests. the inactivation or elimination of possible transmissible agents
of disease.
For in vivo diagnostic use, allergen products are usually
prepared as unmodied extracts in a 50 per cent V/V solution Animal epithelia and outgrowths and/or dander. They
of glycerol for skin testing. For intradermal diagnosis or for
are obtained from healthy animals selected to avoid possible
provocation tests by nasal, ocular or bronchial administration, transmissible agents of disease.
suitable dilutions of allergen products may be prepared
Hymenoptera venoms. The species of hymenoptera from
by dilution of aqueous or glycerinated extracts, or by
which the venom is extracted is identied and specied.
reconstitution of unmodied freeze-dried extracts.
The methods of insect collection and venom extraction are
For specific immunotherapy, allergen products may be either
described and must ensure that the source material is of
unmodied extracts or extracts modied chemically and/or
proper quality.
by adsorption onto different carriers (for example, aluminium
Food. The scientic name (species, variety, strain etc.) of the
hydroxide, calcium phosphate or tyrosine).
animal or vegetable species is indicated and the part used is
stated, if applicable. Foods must be of a quality suitable for
PRODUCTION
human consumption. The origin of the food stuff as well as
SOURCE MATERIALS
its processing stage is stated.
Source materials for the preparation of allergen products
MANUFACTURING PROCESS
are products of animal or vegetable origin, mostly pollens,
Allergen products are generally obtained by extraction, and
moulds, mites, animal epithelia and outgrowths (such as hair
may be puried, from the source materials using appropriate
and feathers) and/or dander, hymenoptera venoms, insects
methods shown to preserve the allergenic properties of
and certain foods.
the components. Allergens for which there are not enough
Where allergen products are manufactured using materials of patients to determine the total allergenic activity in vivo
human or animal origin, the requirements of chapter 5.1.7.
or in vitro, the extraction ratio indicating the relative
Viral safety apply.
proportions (m/V) of allergenic source materials and solvents
is a minimum requirement. Allergen products presented as
The source materials are dened by their origin, nature,
method of collection or production and pretreatment. Control parenteral preparations, eye preparations, preparations for
methods and acceptance criteria relating to identity and purity inhalation and preparations for skin testing are manufactured
under aseptic conditions.
are established. The acceptance criteria must ensure the
consistency of the allergenic source material from a qualitative In the manufacture, packaging, storage and distribution of
and quantitative point of view. The source materials are stored allergen products intended for administration by other routes,
under controlled conditions justied by stability data.
suitable measures are taken to ensure their microbial quality ;
recommendations on this aspect are provided in chapter 5.1.4.
The collection or production, as well as the handling of the
source materials are such that uniform composition is ensured Microbial quality of non-sterile pharmaceutical preparations
and substances for pharmaceutical use.
as far as possible from batch to batch.

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

Any purication procedure is designed to minimise the


content of any potential irritant low molecular mass
components and non-allergenic components.
Allergen products may contain suitable antimicrobial
preservatives, the nature and concentration of which have to
be justied.

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Allergen products

The manufacturing process comprises various stages :


source material ;
active substance : it is generally a modied or an unmodied
allergen extract ; where applicable it is stored under
conditions ensuring its stability, for example freeze-dried ;
nished product.
All other stages of the manufacturing process are considered
as intermediates.
IN-HOUSE REFERENCE PREPARATION
An appropriate representative preparation is selected as
the in-house reference preparation (IHRP), characterised
and used to verify batch-to-batch consistency. The IHRP is
stored in suitably sized aliquots under conditions ensuring its
stability, for example freeze-dried.
Characterisation of the in-house reference preparation.
The extent of characterisation of the IHRP depends on the
source material, knowledge of the allergenic components and
availability of suitable reagents, as well as the intended use. The
characterised IHRP is used as the reference in the batch control
of active substances and intermediates and, if possible, in the
batch control of finished products.
The IHRP is characterised by the protein content
determination and a protein prole using appropriate
methods (such as isoelectric focusing, sodium dodecyl sulfate
polyacrylamide gel electrophoresis, immunoelectrophoresis,
capillary electrophoresis, chromatographic techniques and
mass spectrometry).
Allergenic components may be detected by appropriate
methods (for example, immunoblotting or crossed
radio-immunoelectrophoresis). Characterisation of the
allergenic components may include identication of relevant
allergens based on serological or other techniques using pooled
or individual sera from allergic patients, or allergen-specic
polyclonal or monoclonal antibodies.
Determination of the content of relevant allergens is performed
wherever possible. This determination may be made using
individual allergen-specic reference standards, when
available. The choice of the relevant allergen components
subjected to the determination must be justied. Individual
allergens are identied and named according to internationally
established nomenclature wherever possible.
The biological potency of the rst IHRP is determined in
patients by in vivo techniques such as skin testing, and
expressed in units of biological activity except when not
enough patients are available. In this case, the potency
of the rst IHRP is determined by an in vitro method.
Subsequently, the biological activity of future IHRPs is
demonstrated by in vitro methods by comparison with the
results obtained with the rst IHRP. The in vitro potency may
be measured by a suitable immunoassay (for example, an assay
based on the inhibition of the binding capacity of specic
immunoglobulin E antibodies).
IDENTIFICATION
The tests for identication are performed as late as possible in
the manufacturing process. In the case of products used on
a named-patient basis, the control is performed on the active
substance and/or at the intermediate stage between the active
substance and the nished product.
Identity is conrmed by comparison with the IHRP using
protein proling by appropriate methods (for example,
isoelectric focusing, sodium dodecyl sulfate polyacrylamide
gel electrophoresis, immunoelectrophoresis, immunoblotting,
liquid chromatography or mass spectrometry).
In exceptional cases, if no IHRP is available, a representative
batch may be used to conrm identity.
Identity may also be conrmed by comparison with individual
allergen-specic reference standards, when available.

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EUROPEAN PHARMACOPOEIA 8.2

TESTS
The tests are performed as late as possible in the manufacturing
process. In the case of products used on a named-patient
basis, the control is performed on the active substance and/or
at the intermediate stage between the active substance and the
nished product.
Various biochemical and immunological tests have been
developed in order to characterise allergens qualitatively and
quantitatively. In those cases where such methods cannot
be applied, particularly for the determination of allergenic
activity and allergen and/or protein prole, justication must
be provided.
Water (2.5.12 or 2.5.32) : maximum 5 per cent for freeze-dried
products.
In the case of oral lyophilisates, the water content may be
higher than 5 per cent, where justied and authorised.
Sterility (2.6.1). Allergen products presented as parenteral
preparations, eye preparations, preparations for inhalation or
preparations for skin testing comply with the test for sterility.
Microbial contamination. For non-sterile allergen products,
recommendations are provided in 5.1.4. Microbial quality of
non-sterile pharmaceutical preparations and substances for
pharmaceutical use.
Protein content (2.5.33) : 80 per cent to 120 per cent of the
stated content, unless otherwise justied and authorised. If
the biological potency can be determined then the test for
protein content is performed as a batch-to-batch consistency
test and the protein content is within 50 per cent to 150 per
cent of the stated content. When the nished product
contains proteinaceous excipients, the test for protein content
is performed as late as possible during production before
addition of the proteinaceous excipient.
Protein prole. The protein prole determined by suitable
methods corresponds to that of the IHRP. The presence of
relevant allergen components is veried, where possible. The
choice of relevant allergen components to be tested for must
be justied.
Various additional tests, some with increasing selectivity,
depending on the allergen product concerned can be applied,
but in any case for allergen products intended for therapeutic
use, a validated test measuring the potency (total allergenic
activity, determination of individual allergens or any other
justified tests) must be applied.
Aluminium (2.5.13) : 80 per cent to 120 per cent of the stated
amount but in any case not more than 1.25 mg per human dose
unless otherwise justied and authorised, when aluminium
hydroxide or aluminium phosphate is used as adsorbent.
Calcium (2.5.14) : 80 per cent to 120 per cent of the stated
amount when calcium phosphate is used as adsorbent.
Allergen prole. Relevant allergenic components
are identied by means of suitable techniques using
allergen-specic human or animal antibodies.
Total allergenic activity : 50 per cent to 150 per cent of
the stated amount as assayed by inhibition of the binding
capacity of specic immunoglobulin E antibodies or a suitable
equivalent in vitro method.
Individual allergens : 50 per cent to 200 per cent of the stated
amount of each relevant allergen component, determined by a
suitable method.
STORAGE
Adsorbed allergen products are not to be frozen, unless
otherwise justied and authorised.
LABELLING
The label states :
the name of the allergen product ;
See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.2

the biological potency and/or the protein content and/or


the extraction concentration ;
the route of administration and the intended use ;
the storage conditions ;
where applicable, the name and amount of added
antimicrobial preservative ;
where applicable, for freeze-dried preparations :

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

Allergen products

the name, composition and volume of the reconstituting


liquid to be added ;
the period of time within which the preparation is to be
used after reconstitution ;
where applicable, that the preparation is sterile ;
where applicable, the name and amount of adsorbent.

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