Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01 Rev. 2 — October 2003) adopted by the Committee for Proprietary Medicinal Products (CPMP) and by the Committee for Veterinary Medicinal products (CVMP)
Date: 2004-01-28
Institutions: European Commission
Subjects: animal disease, bovine spongiform encephalopathy, health risk, medicinal product, pharmaceutical legislation, veterinary drug

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Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy
agents via human and veterinary medicinal products (EMEA/410/01 Rev. 2 — October 2003)
adopted by the Committee for Proprietary Medicinal Products (CPMP) and by the Committee
for Veterinary Medicinal products (CVMP)

(2004/C 24/03)

the TSE (Transmissible Spongiform Encephalopathy) note for guidance has been
This revision of
undertaken to introduce,
inter alia, risk assessment into the regulatory compliance process, to provide
clarification on a variety of terms and classifications, and to take into account advances in scientific
knowledge, Community legislation and rules affecting the authorisation of medicinal products for
human or veterinary use. It replaces the previous revision of the note for guidance (EMEA/410/01 Rev.
1 published in the Official Journal of the European Communities C 286, 12.10.2001, p. 4). The date of
application of this note for guidance is 1 July 2004.

1. INTRODUCTION

1.1. SCIENTIFIC BACKGROUND

Transmissible Spongiform Encephalopathies (TSEs) are chronic
degenerative nervous diseases characterised by the accumu-
isoform of a cellular glycoprotein
lation of an abnormal
isoform of
known as PrP or prion protein). The abnormal
PrP (PrPSc) differs from normal PrP (PrPc)
in being highly
resistant to protease and heat denaturation treatments. PrPSc
is considered to be the infective agent responsible for trans-
mitting TSE disease.

TSE diseases in animals include:

— bovine spongiform encephalopathy (BSE) in cattle,

— scrapie in sheep and goats,

— chronic wasting disease (CWD) in cervids (deer and elk),

— transmissible mink encephalopathy (TME) in farmed mink,

— feline

spongiform encephalopathy

(FSE)

in

felidae

(specifically domestic cats and captive large cats), and

— spongiform encephalopathy of exotic ungulates in zoos.

spongiform encephalopathies

In humans,
include different
forms of Creutzfeldt-Jakob disease (CJD), kuru, Gerstmann-
familial
Sträussler-Scheinker
insomnia (FFI).

syndrome

(GSS),

fatal

and

Interspecies TSE transmission is restricted by a number of
natural barriers, transmissibility being affected by the species
in
of origin, the prion strain, dose, route of exposure and,
some species, the host allele of the PrP gene. Species barriers
can be crossed under appropriate conditions.

Bovine spongiform encephalopathy (BSE) was first recognised
in the United Kingdom in 1986 and a large number of cattle
and individual herds have been affected. It is clear that BSE is a
food borne disease associated with feeding meat and bone meal
derived from TSE affected animals. Other countries have
experienced cases of BSE, either in animals imported from
the United Kingdom or
in indigenous animals. There is
convincing evidence to show that the variant form of CJD
(vCJD) is caused by the agent which is responsible for BSE in
cattle. Therefore,
to be
warranted if biological materials
from species naturally
affected by TSE diseases, especially bovine species, are used
for the manufacture of medicinal products.

approach continues

cautious

a

It has

the highest

Scrapie occurs worldwide and has been reported in most
European countries.
incidence in the
United Kingdom. While humans have been exposed to
naturally occurring scrapie for over 200 years, there is no
epidemiological evidence directly linking scrapie to spongiform
encephalopathies in humans. However, there remains a theor-
etical
some
BSE-contaminated protein supplement may have been fed to
sheep. If such feed causes a recurrent BSE infection in sheep, it
may be diagnosed as scrapie and might as such pose a risk of
human TSEs. Further, it should also be assumed that any BSE
ruminant population via
agent
contaminated feed is likely to be recycled and amplified.

introduced into the small

unquantifiable

currently

that

and

risk

Iatrogenic transmission of spongiform encephalopathies has
been reported. In sheep, scrapie has been accidentally trans-
mitted by the use of Louping Ill vaccine prepared from pooled
formaldehyde treated ovine brain and spleen in which material
from scrapie-infected sheep had been inadvertently incor-
porated.
transmission of CJD have been
reported which have been attributed to the parenteral adminis-
tration of growth hormone and gonadotropin derived from
human cadaveric pituitary glands. Cases of CJD have also
been attributed to the use of contaminated instruments in
brain surgery and with the transplantation of human dura
mater and cornea.

In man, cases of

1.2. REGULATORY COMPLIANCE

Risk assessment — Since the use of animal-derived materials
is unavoidable for the production of some medicinal products
and that complete elimination of risk at source is rarely
possible, the measures taken to manage the risk of transmitting
animal TSEs via medicinal products represent risk minimisation
rather than risk elimination. Consequently, the basis for regu-
latory compliance should be based on a risk assessment, taking
into consideration all pertinent factors as identified in this note
for guidance (see below).

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Legal aspects — This note for guidance has been given the
force of law by virtue of Annex I to European Parliament and
Council Directives 2001/82/EC and 2001/83/EC (as amended
by Commission Directive 2003/63/EC (1)) governing the
veterinary and human medicinal products, respectively. These
directives require that applicants for marketing authorisation
for human and veterinary medicinal products must demon-
strate that medicinal products are manufactured in accordance
with the latest version of this note for guidance published in
the Official Journal of the European Union. This is a continuing
obligation after the marketing authorisation has been granted.

By definition, the principle of specified risk materials as defined
in Regulation (EC) No 999/2001 of the European Parliament
and of the Council (2) does not apply to medicinal products.
The use of substances derived from high infectivity tissues must
be
benefit/risk
following
justified
evaluation (see further below).

an appropriate

fully

instruments

This note for guidance should be read in conjunction with the
various European Community legal
including
Commission decisions progressively implemented since 1991.
Where appropriate, references to these decisions are given in
the text. Position statements and explanatory notes made by
the Committee for Proprietary Medicinal Products (CPMP) and
Committee for Veterinary Medicinal Products (CVMP) are still
applicable for the purpose of regulatory compliance unless
otherwise superseded by this note for guidance.

spongiform encephalopathies’

‘Products with risk of trans-
A general monograph entitled:
mitting agents of animal
is
included in the European Pharmacopoeia. This monograph
refers to a general chapter of the European Pharmacopoeia,
which is identical to this note for guidance. The monograph
forms the basis for issuing certificates of suitability as a
procedure for demonstrating TSE compliance for substances
and materials used in the manufacture of human and veterinary
medicinal products.

Clarification of note for guidance — As the scientific under-
standing of TSEs, especially the pathogenesis of the diseases, is
evolving,
from time to time CPMP and its Biotechnology
Working Party in collaboration with CVMP and its Immuno-
logicals Working Party may be required in the future to
develop supplementary guidance in the form of position
statements or explanatory notes for the purpose of clarifying
this note for guidance. The supplementary guidance shall be
the
published by the Commission and on the website of
European Agency for the Evaluation of Medicinal Products
(EMEA) and taken into consideration accordingly in the
scope of the certification of the European Directorate for the
Quality of Medicines (EDQM).

Implementation of this revised note for guidance — All
authorised medicinal products in the EU have demonstrated
compliance with the note for guidance on minimising the
risk of transmitting animal spongiform encephalopathy agents

(1) OJ L 159, 27.6.2003, p. 46.
(2) OJ L 147, 31.5.2001, p. 1.

via human and veterinary medicinal products (EMEA/410/01
— Rev. 1) in line with the legal requirement as inscribed in
Annex I to Directives 2001/82/EC (veterinary medicines) or
Directive 2001/83/EC as amended by Directive 2003/63/EC
(medicines for human use). This revised note for guidance is
to be applied prospectively, i.e. for all medicinal products that
will be authorised or whose marketing authorisation will be
renewed after the time of coming into operation of this revised
note for guidance.

2. SCOPE OF THE NOTE FOR GUIDANCE

TSE-relevant animal species — Cattle, sheep, goats and
animals that are naturally susceptible to infection with trans-
missible spongiform encephalopathy agents or susceptible to
infection through the oral route other than humans (3) and
non-human primates are defined as
‘TSE-relevant animal
species’ (4).

Materials — This note for guidance is concerned with
materials derived from ‘TSE-relevant animal species’ that are
used for the preparation of:

— active substances,

— excipients and adjuvants,

— raw and starting materials and reagents used in production
(e.g. bovine
culture media
including those used to prepare working cell banks, or
new master cell banks for medicinal products which are
subject to a new Marketing Authorisation).

serum albumin;

enzymes;

This note for guidance is also applicable to materials that come
into direct contact with the equipment used in manufacture of
the medicinal product or that come in contact with the
medicinal product and therefore have
for
contamination.

the potential

Materials used in the qualification of plant and equipment, such
as culture media used in media fill experiments to validate the
aseptic filling process, shall be considered in compliance with
the constituent or
this note for guidance provided that
constituents are derived from tissues with no detectable infec-
tivity (category C tissues), where the risk of cross-contami-
nation with potentially infective tissues has been considered
(see section 3.3) and where the materials are sourced from a
GBR I/II country (see section 3.2). Such information shall be
provided in the dossier for a marketing authorisation and
verified during routine inspection for compliance with good
manufacturing practice (GMP).

(3) Regulatory guidance and position papers have been issued by the
Committee for Proprietary Medicinal Products and its Biotechnology
Working Party on human tissue derived medicinal products in
relation with CJD and vCJD. Such guidance can be found on
http://www.emea.eu.int

(4) Pigs and birds, which are animal species of particular interest for
the production of medicinal products, are not naturally susceptible
to infection via the oral route. Therefore they are not TSE-relevant
animal species within the meaning of this note for guidance. Also
dogs, rabbits and fish are non TSE-relevant animal species within
the meaning of this note for guidance.

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such as

cleaning agents,

softeners and
Other materials
lubricants that come into contact with the medicinal product
during its routine manufacture or in the finishing stage or in
the primary packaging are considered in compliance with this
note for guidance if they are derived from tallow under the
conditions described in section 6.

working cell banks, the applicant must demonstrate that they
fulfil the requirements of this note for guidance.

3. GENERAL CONSIDERATIONS

3.1. SCIENTIFIC PRINCIPLES FOR MINIMISING RISK

cell

and

lots,

banks

routine

Seed
fermentation/
production (5) — For the purpose of regulatory compliance,
master seeds or master cell banks in marketing authorisation
applications lodged after 1 July 2000 (for human medicinal
products) or 1 October 2000 (for veterinary medicinal
products) are covered by this note for guidance.

Master seeds and master cell banks,

(a)

for vaccine antigens;

(b) for a biotechnology-derived medicinal product within the
meaning of Part A of the Annex to Council Regulation (EC)
No 2309/93; and

(c)

for other medicinal products using seed lots or cell banking
systems in their manufacture,

that have already been approved for the manufacture of a
constituent of an authorised medicinal product
shall be
considered in compliance with this note for guidance even if
they are incorporated in marketing authorisation applications
lodged after 1 July 2000 (for human medicinal products) or 1
October 2000 (for veterinary medicinal products).

Master cell banks and master seeds established before 1 July
2000 (for human medicinal products) or 1 October 2000 (for
veterinary medicinal products), but not yet approved as a
constituent of an authorised medicinal product shall demon-
strate that they fulfil the requirements of this note for guidance.
If, for some raw or starting materials or reagents used for the
establishment of these cell banks or seeds, full documentary
evidence is not/no longer available,
should
present a risk assessment as described in Section 4 of this
note for guidance.

the applicant

Established working seeds or cell banks used in the manu-
facture of medicinal products authorised before 1 July 2000
(human medicines) or 1 October 2000 (veterinary medicines),
which have been subjected to a properly conducted risk
assessment by a competent authority of the Member States
or the EMEA and declared to be acceptable, shall also be
considered compliant.

However, where materials derived from the ‘TSE-relevant
animal species’ are used in fermentation/routine production
in the establishment of working seeds and
processes or

(5) See also: Position paper on the assessment of the risk of trans-
mission of animal spongiform encephalopathy agents by master
seed materials used in the production of veterinary vaccines (EMEA/
CVMP/019/01 — February 2001) adopted by the Committee for
Veterinary Medicinal products (CVMP) in July 2001, Official Journal
of the European Communities C 286 of 12 October 2001, p. 12.

When manufacturers have a choice the use of materials from
‘non TSE-relevant animal species’ or non-animal origin is
preferred. The rationale for using materials derived from
‘TSE-relevant
from
‘non-TSE-relevant species’ or of non-animal origin should be
given. If materials from ‘TSE-relevant animal species’ have to be
the necessary
used, consideration should be given to all
measures to minimise the risk of transmission of TSE.

instead of materials

species’

animal

Readily applicable diagnostic tests for TSE infectivity in vivo are
not yet available. Diagnosis is based on post mortem confir-
mation of
characteristic brain lesions by histopathology
and/or detection of PrPSc by Western Blot or immunoassay.
The demonstration of
inoculation of
suspect tissue into target species or laboratory animals is also
used for confirmation. However, due to the long incubation
periods of all TSEs, results of in vivo tests are available only
after months or years.

infectivity by the

in vitro diagnostic tests capable of detecting PrPsc in
Several
brain samples from infected animals have been approved for
use but in the main they are less sensitive than in vivo infec-
tivity assays. Nonetheless, screening of source animals by in
vitro tests may prevent the use of animals at late stages of
incubation of the disease and may provide information about
the epidemiological status of a given country or region.

Minimising the risks of transmission of TSE is based upon
three complementary parameters:

— the source animals and their geographical origin,

— nature of animal material used in manufacture and any
procedures in place to avoid cross-contamination with
higher risk materials,

— production process(es)

including the quality assurance
system in place to ensure product consistency and tracea-
bility.

3.2. SOURCE ANIMALS

The source materials used for the production of materials for
the manufacture of medicinal products shall be derived from
animals fit for human consumption following ante- and post
mortem inspection in accordance with Community or
equivalent
for materials
derived from live animals, which should be found healthy
after clinical examination.

(third country) conditions, except

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3.2.1. GEOGRAPHICAL SOURCING

3.2.1.1. Bovine materials

are

currently two organisations

There
involved in the
assessment of the BSE status of a specified country or zone.
Firstly, the Organisation Internationale des Epizooties (OIE) (6)
lays down the criteria for the assessment of
the status of
countries in the chapter of the International Animal Health
spongiform encephalopathy. OIE also
Code on bovine
provides a list of notified BSE cases worldwide. Secondly, the
European Commission Scientific Steering Committee (SSC) (7)
has established a system for classifying the countries according
to their geographical BSE risk (GBR).

Regulation (EC) No 999/2001 of the European Parliament and
of the Council laying down rules for the prevention, control
and eradication of certain transmissible spongiform encepha-
lopathies (TSE Regulation) (2) entered into force on 1 July
2001. While medicinal products, medical
and
cosmetics are excluded from the scope of this regulation, the
principles for the determination of BSE status should be taken
into account in the categorisation of the BSE status of a given
country or region.

devices

For the purposes of this note for guidance the SSC GBR classi-
fication should be used as the indicator of the status of a given
country. However, when countries are categorised according to
Regulation (EC) No 999/2001, this categorisation should be
used.

European Commission Scientific Steering Committee
Classification

Where there is a choice, animals should be sourced from
countries with the lowest possible GBR level unless the use
of material from higher GBR countries is justified. Some of
the materials identified in Section 6,
‘Specific conditions’ can
be sourced from GBR Category III and, in some cases, Category
IV countries, provided that the controls and requirements as
specified in the relevant sections below are applied. Apart from
these exceptions, animals must not be sourced from Category
IV countries, and justifications for the use of animals from
Category III countries must always be provided.

3.2.1.2. Sheep and goats (small ruminants)

Naturally occurring clinical scrapie cases have been reported in
a number of countries worldwide. As BSE in sheep could
possibly be mistaken for scrapie, as a precautionary measure,
sourcing of materials derived from small ruminants shall take
into account the prevalence of both BSE and scrapie in the
country and the tissues from which the materials are derived.

The principles related to ‘BSE negligible risk (closed) bovine
herds’
(see section 3.2.2) could equally be applied in the
context of small ruminants in order to develop a framework
to define the TSE status of a flock of small ruminants. For
sheep, because of the concern over the possibility of BSE in
sheep,
to
BSE/scrapie infection shall be considered in establishing TSE
free flocks. However, goats have not been studied sufficiently
with regard to a genotype specific sensitivity.

the use of a genotype(s) shown to be resistant

The European Scientific Steering Committee classification for
geographical BSE risk (GBR) gives an indication of the level of
likelihood of the presence of one or more cattle clinically or
pre-clinically infected with BSE in a given country or region. A
definition of the four categories is provided in the table:

Material of small ruminant origin should preferably be sourced
from countries with a long history of absence of scrapie, such
as New Zealand or Australia or from proven TSE-free flocks.
Justification shall be required if the material is sourced from
some other origin.

GBR level

Presence of one or more cattle clinically or pre-clinically
infected with BSE in a geographical region/country

I

II

III

IV

Highly unlikely

Unlikely but not excluded

Likely but not confirmed or confirmed at a lower level

Confirmed at a higher level (1)

(1) ‡ 100 cases/1 million adult cattle per year.

Reports of the GBR assessment of the countries are available
on the SSC website (8). If the BSE status of a country has not
been classified by the SSC, a risk assessment shall be submitted
taking into account the SSC criteria for the GBR classification.

(6) http://www.oie.int
(7) The Scientific Steering Committee established by Commission
Decision 97/404/EC shall assist
the Commission to obtain the
best scientific advice available on matters relating to consumer
health. Since May 2003,
its tasks have been taken over by the
European Food Safety Agency (EFSA): http://www.efsa.eu.int

(8) http://europa.eu.int/comm/food/fs/sc/ssc/outcome_en.html

3.2.2. BSE NEGLIGIBLE RISK (CLOSED) BOVINE HERDS

The safest sourcing is from countries where the presence of
BSE is highly unlikely, i.e. GBR I. Other countries may have or
have had cases of BSE at some point in time and the practical
concept of
‘Negligible risk (closed) bovine herds’ has been
developed by the SSC and endorsed by the CPMP and CVMP.
Criteria for establishing and maintaining a ‘BSE negligible risk
(closed) bovine herd’ can be found in the SSC opinion of 22-23
July 1999 (9).

For the time being it is not possible to quantify the reduction
of the geographical BSE risk for cattle from BSE negligible risk
(closed) bovine herds. However,
it is expected that this risk
reduction is substantial. Therefore, sourcing from such closed
bovine herds shall be considered in the risk assessment in
conjunction with the GBR classification of the country.

(9) SSC scientific opinion on the conditions related to ‘BSE negligible
risk (closed) bovine herds’ adopted at the meeting of 22-23 July
1999, http://europa.eu.int/comm/food/fs/sc/ssc/out56_en.html

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3.3. ANIMAL PARTS, BODY FLUIDS AND SECRETIONS AS
STARTING MATERIALS

account the tissue classification tables in the Annex to this note
for guidance (12).

In a TSE infected animal, different organs and secretions have
different levels of infectivity (10). The tables in the Annex of this
note for guidance (11)
the
distribution of infectivity and PrPSc in cattle with BSE, and in
sheep and goats with scrapie.

summarise current data about

The information in the tables is based exclusively upon obser-
vations of naturally occurring disease or primary experimental
infection by the oral route (in cattle) but does not include data
on models using strains of TSE that have been adapted to
experimental animals, because passaged strain phenotypes can
differ significantly and unpredictably from those of naturally
occurring
and/or
western blot detection of misfolded host protein (PrPSc) have
proven to be a surrogate marker of infectivity, PrPSc testing
results have been presented in parallel with bioassay data.
Tissues are grouped into three major infectivity categories,
irrespective of the stage of disease:

immunohistochemical

disease. Because

Category A: High-infectivity tissues: central nervous system
(CNS) tissues that attain a high titre of infectivity
in the later stages of all TSEs, and certain tissues
that are anatomically associated with the CNS.

Category B:

Lower-infectivity tissues: peripheral
tissues that
have tested positive for infectivity and/or PrPSc
in at least one form of TSE.

Category C: Tissues with no detectable infectivity: tissues that
have been examined for infectivity, without any
infectivity detected, and/or PrPSc, with negative
results.

Category A tissues and substances derived from them shall not
be used in the manufacture of medicinal products, unless
justified (see section 5).

Although the category of lower risk tissues (category B tissues)
almost certainly includes some (e.g. blood) with a lower risk
than others (e.g. lymphoreticular tissues), the data about infec-
tivity levels in these tissues are too limited to subdivide the
category into different levels of risk. It is also evident that the
placement of a given tissue in one or another category can be
disease and species specific, and subject to revision as new data
emerges.

For the risk assessment (see section 4), manufacturers and/or
take into
marketing authorisation holders/applicants

shall

(10) If materials from ‘TSE-relevant animal species’ have to be used,
consideration should be given to use of materials of the lowest
category of risk.

(11) The tissue classification tables are based upon the most recent
‘WHO guidelines on transmissible spongiform encephalopathies
in relation to biological and pharmaceutical products’ (February
2003) WHO/BCT/QSD/03.01.

The categories in the tables are only indicative and it
important to note the following points:

is

— In certain situations there could be cross-contamination of
tissues of different categories of infectivity. The potential
risk will be influenced by the circumstances in which
tissues were removed, especially by contact of
tissues
with lower-infectivity tissues or no detectable infectivity
(Categories B and C tissues) with high-infectivity tissues
(Category A tissues). Thus, cross-contamination of some
tissues may be increased if infected animals are slaughtered
by penetrative brain stunning or if the brain and/or spinal
cord is sawed. The risk of cross-contamination will be
decreased if body fluids are
collected with minimal
damage to tissue and cellular components are removed,
and if
foetal blood is collected without contamination
from other maternal or foetal tissues including placenta,
amniotic and allantoic fluids. For certain tissues, it is very
difficult or impossible to prevent cross-contamination with
Category A tissues (e.g. skull). This has to be considered in
the risk assessment.

— For certain classes of substances the stunning/slaughtering
in minimising the
techniques used may be important
potential risk (13) because of the likelihood of disseminating
the brain particles into the peripheral organs, particularly to
the lungs. Stunning/slaughtering techniques
should be
described as well as the procedures to remove high infec-
tivity tissues. The procedures to collect the animal tissues/
organs to be used and the measures in place to avoid
cross-contamination with a higher risk material must also
be described in detail.

— The risk of contamination of

tissues and organs with
BSE-infectivity potentially harboured in central nervous
material as a consequence of the stunning method used
for cattle slaughtering depends on the following factors:

— the amount of BSE-infectivity in the brain of

the

slaughtered animal,

— the extent of brain damage,

— the dissemination of brain particles in the animal body.

These factors must be considered in conjunction with the
GBR classification of the source animals, the age of the
animals in the case of cattle and the post mortem testing
of the cattle using a validated method.

(12) The introduction of the three-category tissue classification system
does not invalidate the risk-assessments based on the previously
used four-category tissue classification, performed for authorized
medicinal products.

(13) SSC opinion on stunning methods and BSE risk (The risk of
dissemination of brain particles into the blood and carcass when
applying certain stunning methods), adopted at the meeting of
10-11 January 2002, http://europa.eu.int/comm/food/fs/sc/ssc/
out245_en.pdf

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The underlying principles indicated above would be equally
applicable to sheep and goats.

The risk posed by cross-contamination will be dependent on
several complementary factors including:

— measures adopted to avoid contamination during collection

of tissues (see above),

— level of contamination (amount of

the contaminating

tissue),

— amount and type of materials collected at the same time.

holders/
Manufacturers
applicants should take into account the risk with respect to
cross-contamination.

the marketing

authorisation

or

reduction or elimination of TSE contamination should be
discussed. Whenever
are
different manufacturing
involved,
the steps performed at each site shall be clearly
identified. The measures in place in order to ensure traceability
of every production batch to the source material should be
described.

sites

Cleaning process — Cleaning of process equipment may be
difficult to validate for the elimination of TSE agents.
It is
reported that after exposure to high titre preparations of TSE
agent, detectable infectivity can remain bound to the surface of
stainless steel. The removal of all adsorbed protein by the use
of sodium hydroxide or chlorine releasing disinfectants (e.g.
20 000 ppm. chlorine for 1 hour) have been considered
acceptable
cannot be
replaced has been exposed to potentially contaminated
material.
In the case of using Category A materials in the
manufacture of a product, dedicated equipment shall be used,
unless otherwise justified.

approaches where

equipment

that

3.4. AGE OF ANIMALS

As the TSE infectivity accumulates in bovine animals over an
incubation period of several years, it is prudent to source from
young animals.

3.5. MANUFACTURING PROCESS

The assessment of the overall TSE risk reduction of a medicinal
product shall take into account the control measures instituted
with respect to:

— sourcing of the raw/starting materials, and

— the manufacturing process.

Controlled sourcing is a very important criterion in achieving
acceptable safety of
the product, due to the documented
resistance of TSE agents to most inactivation procedures.

A quality assurance system, such as ISO 9000 certification,
HACCP (14) or GMP, must be put in place for monitoring the
production process and for batch delineation (i.e. definition of
batch,
cleaning between batches).
Procedures shall be put in place to ensure traceability as well
as self-auditing and auditing suppliers of raw/starting materials.

separation of batches,

Certain production procedures may contribute considerably to
the reduction of the risk of TSE contamination, e.g. procedures
used in the manufacture of tallow derivatives (see section 6). As
such rigorous processing cannot be applied to many products,
processes involving physical removal, such as precipitation and
filtration to remove prion-rich material, are likely to be more
treatments. A description of the
appropriate than chemical
manufacturing process,
including in-process controls applied,
shall be presented and the steps that might contribute to

(14) Hazard Analysis Critical Control Point.

If risk materials are used in the manufacture of a product,
cleaning procedures, including control measures, shall be put
in place in order to minimise the risk of cross-contamination
between production batches. This is especially important if
materials from different risk categories are handled in the
same plant with the same equipment.

for TSEs are difficult

Removal/Inactivation validation — Validation studies of
removal/inactivation procedures
to
interpret. It is necessary to take into consideration the nature
of the spiked material and its relevance to the natural situation,
the design of the study (including scaling-down of processes)
and the method of detection of the agent (in vitro or in vivo
assay). Further research is needed to develop an understanding
for validation
of
studies. Therefore,
currently not
validation studies
generally required. However, if claims are made for the safety
of the product with respect to TSEs based on the ability of
manufacturing processes to remove or inactivate TSE agents,
they must be substantiated by appropriate validation studies.

the most appropriate ‘spike preparation’
are

sourcing, manufacturers

In addition to appropriate
are
encouraged to continue their investigations into removal and
inactivation methods to identify steps/processes that would
have benefit in assuring the removal or inactivation of TSE
agents. In any event, a production process wherever possible
shall be designed taking account of available information on
methods which are thought to inactivate or remove TSE agents.

4. RISK ASSESSMENT OF MATERIALS OR SUBSTANCES USED
IN THE MANUFACTURE AND PREPRATATION OF A MEDI-
CINAL PRODUCT IN THE CONTEXT OF REGULATORY
COMPLIANCE

The assessment of the risk associated with TSE needs careful
consideration of all of the parameters as outlined in section 3.1
(Scientific Principles for Minimising Risk).

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As indicated in the introduction to this note for guidance,
regulatory compliance is based on a favourable outcome
from a risk assessment. The risk assessments, conducted by
the manufacturers and/or the marketing authorisation holders
or applicants for the different materials or substances from
‘TSE-relevant animal species’ used in the manufacture of a
medicinal product shall show that all TSE risk factors have
been taken into account and, where possible, risk has been
minimised by application of the principles described in this
note for guidance. TSE Certificates of suitability issued by the
EDQM may be used by the marketing authorisation holders or
applicants as the basis of the risk assessments.

by

for

the marketing

risk assessment

the medicinal product,
An overall
conducted
authorisation holders or
applicants, shall take into account the risk assessments for all
the different materials from ‘TSE-relevant animal species’ and,
where appropriate, TSE reduction or inactivation by the manu-
facturing steps of the active substance and/or finished product.

The final determination of regulatory compliance rests with the
competent authority.

It is incumbent upon the manufacturers and/or the marketing
authorisation holders or applicants
for both human and
veterinary medicinal products to select and justify the control
measures for a given ‘TSE-relevant animal species’ derivative,
taking into account the state of the art of science and tech-
nology.

5. BENEFIT/RISK EVALUATION

In addition to the parameters as mentioned in sections 3 and 4,
the acceptability of a particular medicinal product containing
materials derived from a ‘TSE-relevant animal species’, or which
as a result of manufacture could contain these materials, shall
take into account the following factors:

— route of administration of the medicinal product,

of this note for guidance, and taking into account the intended
clinical use, a positive benefit/risk assessment can be presented
by the marketing authorisation applicant. Substances from
Category A materials,
justified, must be
produced from animals of GBR I countries.

their use is

if

6. SPECIFIC CONSIDERATIONS

The following materials prepared from ‘TSE-relevant animal
species’ are considered in compliance with this note for
guidance provided that
the conditions
specified below. The relevant information or a certificate of
suitability granted by the EDQM shall be provided by the
Marketing Authorisation applicant/holder.

they meet at

least

6.1. COLLAGEN

Collagen is a fibrous protein component of mammalian
connective tissue.

For collagen, documentation to demonstrate compliance with
this note for guidance needs to be provided taking into account
the provisions
In addition,
listed in sections 3 to 5.
consideration should be given to the following:

— For collagen produced from bones, the conditions specified

for gelatin are applicable (see below).

— Collagen produced from tissues such as hides and skins do
not usually present a measurable TSE risk provided that
contamination with potentially infected materials,
for
example spillage of blood and/or central nervous tissues,
is avoided during their procurement.

6.2. GELATIN

Gelatin is a natural, soluble protein, gelling or non-gelling,
obtained by the partial hydrolysis of collagen produced from
bones, hides and skins, tendons and sinews of animals.

— quantity of animal material used in the medicinal product,

— maximum therapeutic dosage (daily dose and duration of

treatment),

For gelatin, documentation to demonstrate compliance with
this note for guidance needs to be provided taking into
account the provisions listed in sections 3 to 5. In addition,
consideration should be given to the following:

— intended use of

the medicinal product and its clinical

(i) The source material used

benefit.

High-infectivity tissues (Category A tissues) and substances
derived thereof
shall not be used in manufacture of
medicinal products, their starting materials and intermediate
products (including active substances, excipients and reagents),
unless justified. A justification why no other materials can be
In these exceptional and justified
used shall be provided.
circumstances,
the use of high-infectivity tissues could be
envisaged for the manufacture of active substances, when,
after performing the risk assessment as described in section 4

Gelatin used in medicinal products can be manufactured
from bones or hides.

— Hides as the starting material — On the basis of current
knowledge, hides used for gelatin production represent
a much safer source material as compared to bones.
However,
is highly recommended that measures
should be put in place to avoid cross-contamination
with potentially infected materials during procurement.

it

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skulls and spinal cords

— Bones as the starting material — Where bones are used
to manufacture gelatin, more stringent production
conditions shall be applied (see below). In any case,
the removal of
from the
starting material is considered as a first precautionary
measure, which largely affects the safety of the product.
As far as practicable, bones should be sourced from
countries classified as GBR I and II. Bones
from
Category GBR III countries can be used if the gelatin
is manufactured under defined conditions as indicated
below and if vertebrae from cattle over 12 months of
age are removed from the raw/starting materials (15).

(ii) Manufacturing methods

No specific measures with regard to the processing
conditions are required for gelatin produced from hides
provided that control measures are put in place to avoid
cross-contamination both during the procurement of the
hides and during the manufacturing process.

6.3. BOVINE BLOOD DERIVATIVES

Foetal bovine serum is commonly used in cell cultures. Foetal
bovine serum should be obtained from foetuses harvested in
abattoirs from healthy dams fit for human consumption and
the womb should be completely removed and the foetal blood
harvested in dedicated space or area by cardiac puncture into a
closed collection system using aseptic technique.

New born calf serum is obtained from calves under 20 days old
and calf serum from animals under the age of 12 months. In
the case of donor bovine serum, given that it may be derived
from animals less than 36 months old, the TSE status of the
donor herd shall be well defined and documented. In all cases,
serum shall be collected according to specified protocols by
personnel trained in these procedures to avoid cross-contami-
nation with higher risk tissues.

For bovine blood derivatives, documentation to demonstrate
compliance with this note for guidance needs to be provided
taking into account the provisions listed in sections 3 to 5. In
addition, consideration should be given to the following:

However, the mode of manufacture must be taken into
account where bones are used as the starting material.

(i) Traceability

— Bones

for

(including vertebrae)

the production of
gelatin using acid treatment shall be sourced only
from GBR Category I or II countries. An additional
alkaline treatment (pH 13, 1 hour) of the bones/ossein
may further increase the TSE safety of acid-derived
bone gelatin.

Traceability to the slaughterhouse must be assured for each
batch of serum or plasma. Slaughterhouses must have
available lists of farms from which the animals are orig-
inated. If serum is produced from living animals, records
must be available for each serum batch which assures the
traceability to the farms.

For bones sourced from a GBR Category III country, the
alkaline process shall be applied. However, this manu-
facturing method is optional for bones coming from
GBR Category I and II countries.

(ii) Geographical origin

— For a typical alkaline manufacturing process, bones are
finely crushed, degreased with hot water and deminer-
alised with dilute hydrochloric acid (at a minimum of
4 % and pH < 1,5) over a period of at least two days to
produce the ossein. This is followed by an alkaline
treatment with saturated lime solution (pH at
least
12,5) for a period of at least 20 days. The gelatin is
extracted, washed, filtered and concentrated. A ‘flash’
heat treatment (sterilisation) step using 138-140 °C for
4 seconds is applied. Bovine hide gelatin can also be
produced by the alkaline process. Bovine bones may
also be treated by an acid process. The liming step is
then replaced by an acid pre-treatment where the ossein
is soaked overnight at pH < 4.

laying down health rules

(15) Regulation (EC) No 1774/2002 of the European Parliament and of
animal
the Council
intended for human consumption shall apply
by-products not
unless
justified. Regarding the manufacturing of gelatin and
collagen or import of raw material for such manufacturing for
use in pharmaceutical products, only material from animals fit
for human consumption shall be used. The use of vertebrae
from such animals from Category II countries, which according
to the risk assessment is safe, shall continue to be allowed.

concerning

Whilst tissue infectivity of BSE in cattle is more restricted
than scrapie, as a precautionary measure bovine blood
must be sourced from countries classified GBR I and II,
unless otherwise justified.

(iii) Stunning methods

It has been demonstrated that

importance to assure the safety of

If it is sampled from slaughtered animals, the method of
the
slaughter is of
material.
stunning by
captive bolt stunner with or without pithing as well as
by pneumatic stunner, especially if
injects air, can
destroy the brain and disseminate brain material into the
blood stream. Negligible risk can be expected from a
non-penetrative stunner and from electro-narcosis (16).
The stunning methods must therefore be described for
the bovine blood collection process.

it

(16) SSC opinion on stunning methods and BSE risk (The risk of
dissemination of brain particles into the blood and carcass when
applying certain stunning methods) adopted at
the meeting
on 10-11 January 2002, http://europa.eu.int/comm/food/fs/sc/ssc/
out245_en.pdf

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If sourcing is allowed from countries where cases of BSE
have been detected (GBR III) a non-penetrative stunner
shall be used for slaughter.

6.4. TALLOW DERIVATIVES

the

starting material

Tallow is fat obtained from tissues including subcutaneous,
abdominal and inter-muscular areas and bones. Tallow used
tallow
as
derivatives shall be Category 3 material or equivalent, as
defined in Regulation (EC) No 1774/2002 (17) of
the
European Parliament and of the Council of 3 October 2002
laying down health rules concerning animal by-products not
intended for human consumption.

the manufacture of

for

Tallow derivatives, such as glycerol and fatty acids, manu-
factured from tallow by rigorous processes are thought
unlikely to be infectious and they have been the subject of
specific consideration by CPMP and CVMP. For this reason,
such materials manufactured under the conditions at least as
rigorous
considered in
those given below shall be
the
compliance for this note for guidance,
geographical origin and the nature of the tissues from which
tallow derivatives are derived. Examples of rigorous processes
are:

irrespective of

as

— trans-esterification or hydrolysis at not less than 200 °C for
not less than 20 minutes under pressure (glycerol, fatty
acids and fatty acid esters production),

— saponification with NaOH 12 M (glycerol and soap

production)

otherwise justified, the starting material for the manufacture
of animal charcoal shall be Category 3 material or equivalent,
as defined in Regulation (EC) No 1774/2002 of the European
Parliament and of the Council of 3 October 2002 laying down
health rules concerning animal by-products not intended for
human consumption. Irrespective of the geographical origin
and the nature of the tissue, for the purpose of regulatory
compliance, animal charcoal shall be considered in compliance
with this note for guidance.

Charcoal manufactured according to these conditions are
unlikely to present any TSE risk and shall
therefore be
considered compliant with this note for guidance. Charcoal
produced using other conditions must demonstrate compliance
with this note for guidance.

6.6. MILK AND MILK DERIVATIVES

In the light of the current scientific knowledge and irrespective
of the geographical origin, milk is unlikely to present any risk
of TSE contamination.

Certain materials, including lactose, are extracted from whey,
the spent liquid from cheese production following coagulation.
Coagulation can involve the use of calf rennet, an extract from
ruminants. The
rennet derived from other
abomasum, or
CPMP/CVMP have performed a risk assessment
for lactose
and other whey derivatives produced using calf rennet and
concluded that the TSE risk is negligible if the calf rennet is
produced in accordance with the process described in the risk
assessment report (18). The conclusion was endorsed by the
SSC (19), which has also performed an assessment of the TSE
risk of rennet in general (20).

— batch process: at not less than 95 °C for not less than 3

hours

Milk derivatives manufactured according to the conditions
below are unlikely to present any TSE risk and shall
therefore be considered compliant with this note for guidance.

— continuous process: at not

less than 140 °C, under

pressure for not less than 8 minutes, or equivalent,

— The milk is sourced from healthy animals in the same
conditions as milk collected for human consumption, and

— distillation at 200 °C.

Tallow derivatives manufactured according to these conditions
are unlikely to present any TSE risk and shall therefore be
considered compliant with this note for guidance.

Tallow derivatives produced using other conditions must
demonstrate compliance with this note for guidance.

6.5. ANIMAL CHARCOAL

Animal charcoal is prepared by carbonisation of animal tissues,
such as bones, using high temperature at > 800 °C. Unless

(17) OJ L 273, 10.10.2002, p. 1.

— no other ruminant materials, with the exception of calf
rennet, are used in the preparation of such derivatives
(e.g. pancreatic enzyme digests of casein).

(18) Committee for Proprietary Medicinal Products and its Biotech-
nology Working Party conducted a risk and regulatory assessment
of lactose prepared using calf rennet. The risk assessment included
the source of the animals, the excision of the abomasums and the
availability of well-defined quality assurance procedures. The
quality of any milk replacers used as feed for the animals from
which abomasums are obtained is particularly important. The
report can be found on http://www.emea.eu.int

(19) Provisional statement on the safety of calf-derived rennet

for
the manufacture of
its mee-
ting of 4-5 April 2002 (http://europa.eu.int/comm/food/fs/sc/ssc/
out255_en.pdf).

lactose. Adopted by the SSC at

(20) The SSC issued an opinion on the safety of animal rennet in regard
to risks from animal TSE and BSE in particular, adopted at its
meeting of 16 May 2002 (http://europa.eu.int/comm/food/fs/sc/
ssc/out265_en.pdf).

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Milk derivatives produced using other processes or rennet
derived from other
species must demonstrate
compliance with this note for guidance.

ruminant

6.8. AMINO ACIDS

Amino acids can be obtained by hydrolysis of materials from
various sources.

6.7. WOOL DERIVATIVES

Derivatives of wool and hair of ruminants, such as lanolin and
wool alcohols derived from hair
shall be considered in
compliance with this note for guidance, provided the wool
and hair are sourced from live animals.

Unless otherwise justified, the starting material for the manu-
facture of amino acids
shall be Category 3 material or
equivalent, as defined in Regulation (EC) No 1774/2002 of
the European Parliament and of the Council of 3 October
2002 laying down health rules concerning animal by-products
not intended for human consumption.

Wool derivatives produced from wool, which is sourced from
slaughtered animals declared ‘fit for human consumption’ and
the manufacturing process in relation to pH, temperature and
duration of
the stipulated
processing conditions listed below are unlikely to present any
TSE risk and shall therefore be considered compliant with this
note for guidance.

treatment meets at

least one of

— Treatment at pH ‡ 13 (initial; corresponding to a NaOH
concentration of at least 0,1 M NaOH) at ‡ 60 °C for at
least 1 hour. This occurs normally during the reflux stage
of the organic-alkaline treatment,

— molecular distillation at ‡ 220 °C under reduced pressure.

in

Amino acids prepared using
following processing
accordance with Commission Decision
conditions,
98/256/EC (21) and Commission Decision 2001/376/EC (22),
are unlikely to present any TSE risk and shall be considered
compliant with this note for guidance.

the

— Amino acids produced from hides and skins by a process
which involves exposure of the material to a pH of 1 to 2,
followed by a pH of > 11, followed by heat treatment at
140 °C for 30 minutes at 3 bar,

— the resulting amino acids or peptides must be filtered after

production, and

— analysis

is performed using a validated and sensitive
intact macromolecules,

method to control any residual
with an appropriate limit set.

Wool derivatives produced using other
demonstrate compliance with this note for guidance.

conditions must

Amino acids prepared using other conditions must demon-
strate compliance with this note for guidance.

(21) OJ L 113, 15.4.1998, p. 32.
(22) OJ L 132, 15.5.2001, p. 17.

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ANNEX

MAJOR CATEGORIES OF INFECTIVITY

The tables below are adapted from the ‘WHO Guideline on Transmissible Spongiform Encephalopathies in Relation to
Biological and Pharmaceutical Products’ (February 2003).

Data entries are shown as follows:

+

–

Presence of infectivity or PrPTSE (1)

Absence of detectable infectivity or PrPTSE

NT Not tested

?

Controversial or uncertain results

Category A: High-infectivity tissues

Tissues

Cattle

BSE

Sheep and goats

Scrapie

Infectivity (1)

PrPTSE

Infectivity (1)

PrPTSE

Brain

Spinal cord

Retina, optic nerve

Spinal ganglia

Trigeminal ganglia

Pituitary gland (2)

+

+

+

+

+

–

Dura mater (2)

NT

+

+

NT

NT

NT

NT

NT

+

+

NT

NT

NT

+

NT

+

+

+

+

+

NT

NT

(1) Infectivity bioassays of cattle tissues have been conducted in either cattle or mice (or both); and most bioassays of sheep and/or goat

tissues have been conducted only in mice. In regard to sheep and goats not all results are consistent for both species.

(2) No experimental data about infectivity in human pituitary gland or dura mater have been reported, but cadaveric dura mater patches,
and growth hormone derived from cadaveric pituitaries have transmitted disease to scores of people and therefore must be included
in the category of high-risk tissues.

Category B: Lower-infectivity tissues

Tissues

Cattle

BSE

Sheep and goats

Scrapie

Infectivity

PrPTSE

Infectivity

PrPTSE

Peripheral nervous
system

Peripheral nerves

Enteric plexuses (1)

Lymphoreticular
tissues

Spleen

Lymph nodes

Tonsil

–

NT

–

–

+

NT

+

–

–

NT

+

NT

+

+

+

NT

+

+

+

+

(1) In the main body of this note for guidance the abnormal isoform of the prion protein is referred to as PrPSc. However, as these tables
are transcribed directly from the WHO guideline mentioned above, the WHO nomenclature for the abnormal prion protein (PrPTSE)
has been maintained.

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Tissues

Cattle

BSE

Sheep and goats

Scrapie

Infectivity

PrPTSE

Infectivity

Nictitating membrane

NT

Thymus

Alimentary tract

Esophagus

Fore-stomach (2)
(ruminants only)

Stomach/abomasum (2)

Duodenum

Jejunum

Ileum (3)

Large intestine

Reproductive tissues

Placenta

Other tissues

Lung (*)

Liver

Kidney (*)

Adrenal

Pancreas

Bone marrow

Blood vessels

Olfactory mucosa

Gingival tissue (*)

Salivary gland

Cornea (4) (*)

Body fluids

CSF

Blood (5)

–

–

–

–

–

–

+

–

–

–

–

–

NT

–

+

–

–

NT

–

NT

–

–

–

NT

NT

NT

NT

NT

NT

+

NT

NT

NT

NT

–

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

+

NT

NT

NT

NT

NT

+

+

+

–

+

–

+

+

+

NT

+

NT

+

NT

+

+

PrPTSE

+

NT

+

+

+

+

+

+

+

+

NT

NT

–

NT

NT

NT

+

NT

NT

NT

NT

NT

–

(1) In cattle, limited to the distal ileum.
(2) Ruminant forestomachs (reticulum, rumen, and omasum) are widely consumed, as is the true stomach (abomasum). The abomasum

of cattle (and sometimes sheep) is also a source of rennet.

(3) In cattle and sheep, only the distal ileum has been bioassayed for infectivity.
(4) Because only one or two cases of CJD have been plausibly attributed to corneal transplants among hundreds of thousands of
recipients, cornea is categorised as a lower-risk tissue; other anterior chamber tissues (lens, aqueous humor, iris, conjunctiva) have
been tested with a negative result both in vCJD and other human TSEs, and there is no epidemiological evidence that they have been
associated with iatrogenic disease transmission.

(5) Early reports on the transmission of disease to rodents from the blood of patients with sCJD have not been confirmed, and evaluation
of the ensemble of experimental and epidemiological data relevant to TSE transmission through blood, blood components, and
therapeutic plasma products fails to suggest transmission from blood of patients with any form of ‘classical’ TSE. Not enough data has
accumulated to be able to make the same statement about blood from patients with vCJD. Foetal calf blood contains no detectable
infectivity, but in genotypically susceptible sheep with natural scrapie or experimentally induced BSE, transfusion of large blood
volumes has transmitted disease to healthy sheep. Infectivity has also been demonstrated in studies of rodent-adapted strains of TSE.
(*) These tissues have been classified under Category B — Lower-infectivity tissues, because infectivity and/or PrPTSE have been found in

human CJD (vCJD or other).

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Category C: Tissues with no detected infectivity

Tissues

Cattle

BSE

Sheep and goats

Scrapie

Infectivity

PrPTSE

Infectivity

PrPTSE

Reproductive tissues

Testis

Prostate/Epididymis/
Seminal vesicle

Semen

Ovary

Uterus (Non-gravid)

Placenta fluids

Foetus (1)

Embryos (1)

Musculo-skeletal
tissues

Bone

Skeletal muscle (2)

Tongue

Heart/pericardium

Tendon

Other tissues

Trachea

Skin

Adipose tissue

Thyroid gland

Mammary gland/udder

Body fluids,
secretions and
excretions

Milk (3)

Colostrum (4)

Cord blood (4)

Saliva

Sweat

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

NT

–

–

NT

–

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

–

–

NT

–

–

NT

–

?

NT

–

NT

–

NT

NT

–

NT

–

–

–

–

NT

–

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

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Tissues

Cattle

BSE

Sheep and goats

Scrapie

Infectivity

PrPTSE

Infectivity

PrPTSE

Tears

Nasal mucus

Urine (4) (5)

Faeces

NT

NT

–

–

NT

NT

NT

NT

NT

NT

NT

–

NT

NT

NT

NT

(1) Embryos from BSE-affected cattle have not transmitted disease to mice, but no infectivity measurements have been made on foetal
calf tissues other than blood (negative mouse bioassay). Calves born of dams that received embryos from BSE-affected cattle have
survived for observation periods of up to seven years, and examination of the brains of both the unaffected dams and their calves
revealed no spongiform encephalopathy or PrPTSE.

(2) Intracerebral inoculation of muscle homogenates has not transmitted disease to (1) primates from humans with sCJD; (2) mice or
cattle from cattle with BSE; and (3) mice from sheep and goats with natural or experimentally-induced scrapie. However, older reports
described single instances of transmission from goat and hamster muscle, and a more recent report described transmission from the
muscle of wild type and transgenic mice, but as each of these studies were conducted with passaged strains of TSE, their relevance to
natural disease remains undetermined. A recent human case report described a patient with CJD and inclusion body myositis with
abundant PrPTSE in diseased muscle. After much deliberation, the committee nevertheless elected to retain muscle in the ‘no detected
infectivity’ tissue category until more information about uncomplicated natural infections becomes available.

(3) Evidence that infectivity is not present in milk includes temporo-spatial epidemiologic observations failing to detect maternal trans-
mission; clinical observations of over a hundred calves nursed by infected cows that have not developed BSE; and experimental
observations that milk from infected cows has not
transmitted disease when administered intracerebrally or orally to mice.
Experiments are in progress in which large volumes of milk from experimentally infected cows are concentrated and tested for
the presence of PrPTSE.

(4) Single reports of transmission of CJD infectivity from human cord blood, colostrum, and urine have never been confirmed and are

considered improbable.

(5) A previously unreported PrP type, termed PrPu, has been identified in the urine of sporadic and familial CJD patients, but its

significance for transmission risk remains to be determined.

Notice of the expiry of certain anti-dumping measures

(2004/C 24/04)

Further to the publication of a notice of impending expiry (1), following which no request for a review was
received, the Commission gives notice that the anti-dumping measures mentioned below will shortly
expire.

This notice is published in accordance with Article 11(2) of Council Regulation (EC) No 384/96 of 22
December 1995 (2) on protection against dumped imports from countries not members of the European
Community.

Product

Country(ies) of origin
or exportation

Measures

Reference

Date of expiry

Hardboard

Bulgaria
Estonia
Latvia
Lithuania
Poland
Russia

Bulgaria
Estonia
Lithuania
Poland

Duty

Regulation (EC) No 194/1999
(OJ L 22, 29.1.1999, p. 16)
as last amended by
Regulation (EC) No 1899/2001
(OJ L 261, 29.9.2001, p. 1)

29.1.2004

Undertaking Decision 1999/71/EC

(OJ L 22, 29.1.1999, p. 71)
as last amended by
Decision 2001/707/EC
(OJ L 261, 29.9.2001, p. 65)

(1) OJ C 100, 26.4.2003, p. 11.
(2) OJ L 56, 6.3.1996, p. 1, as last amended by Council Regulation (EC) No 1972/2002 (OJ L 305, 7.11.2002, p. 1).