Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01 Rev. 1 — May 2001) adopted by the Committee for Proprietary Medicinal Products (CPMP) and by the Committee for Veterinary Medicinal Products (CVMP) — July 2001
Date: 2001-07-01
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. 1 (cid:151) May 2001)

adopted by the Committee for Proprietary Medicinal Products (CPMP) and by the Committee for
Veterinary Medicinal Products (CVMP)

July 2001

(2001/C 286/04)

NB: This note for guidance has been revised to reflect the current scientific knowledge regarding TSE and
is offered without prejudice to future measures which Community institutions might take in this area.

This joint CPMP-CVMP note for guidance on minimising the risk of transmitting animal spongiform
encephalopathy agents via human and veterinary medicinal products
the following
guidelines:

replaces

(cid:151) CPMP note for guidance on minimising the risk of transmitting animal spongiform encepha-
lopathy agents via medicinal products, revision September 2000 (CPMP/BWP/1230/98/Rev. 1),

(cid:151) CVMP note for guidance on minimising the risk of transmitting animal spongiform encepha-
lopathy agents via veterinary medicinal products, revision June 1999 (EMEA/CVMP/145/97
Revision).

Background note

1. GENERAL REMARKS

The purpose behind this joint CPMP/CVMP note for guidance is
to set out the scientific principles which minimise the possible
risk of transmission of spongiform encephalopathy via human
and veterinary medicinal products. These principles include a
number of control measures such as sourcing and the quality
control of starting materials, and the design and control of the
manufacturing procedure. All of
these measures in combi-
nation give assurance on product safety. Particular attention
has been placed on the sourcing of material and the categori-
sation of tissues.

(TSE)

Transmissible
include
spongiform encephalopathies
scrapie in sheep and goats, chronic wasting disease in mule
deer and elk, bovine spongiform encephalopathy (BSE)
in
cattle, as well as Kuru and Creutzfeldt-Jakob Disease (CJD) in
humans. Agents causing these diseases replicate in infected
individuals generally without evidence of infection detectable
by available diagnostic tests applicable in vivo. After incubation
periods of up to several years the agents cause disease and,
finally, lead to death. No means of therapy are known.

The note for guidance has been updated to take account of
comments of Member States and other interested parties.

The note for guidance should be understood and applied
together with the EU legislation regarding TSE (1).

(1) Commission Decision 2000/418/EC defines specified risk materials;
but medicinal products, their starting materials and intermediate
products are excluded from this legislation.
However, subject to legal constraints, specified risk materials, as
defined in Decision 2000/418/EC or in any future updates, should
not normally be used in the manufacture of medicinal products,
their starting materials and intermediate products (including active
substances, excipients and reagents), unless justified.
In exceptional and justified circumstances, the use of specified risk
the manufacture of active
materials could be envisaged for
substances, when,
(as
after performing the
described in the note for guidance on minimising the risk of trans-
mitting animal spongiform encephalopathy agents via human and
veterinary medicinal products) and taking into account the intended
clinical use, a positive benefit/risk can be presented by the
marketing authorisation applicant.).

risk assessment

Diagnosis is based on clinical signs with post mortem confir-
mation of characteristic brain lesions by histopathology or
detection of the fibrillary proteins specific for the spongiform
encephalopathies. The demonstration of
infectivity by the
inoculation of suspect tissue into target species or laboratory
animals may also be used for confirmation but have an incu-
bation period of months or years. Iatrogenic transmission of
spongiform encephalopathies has been reported.
In sheep,
scrapie has been accidentally transmitted by the use of
formaldehyde
Louping Ill vaccine prepared from pooled,
treated ovine brain and spleen in which material
from
scrapie infected sheep had been inadvertently incorporated.
In man, cases of
transmission of CJD have been reported
which have been attributed to the repeated 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
transplantation of human
meninges and cornea.

and with the

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to most of

Information on the characteristics of these agents is limited.
They are extremely resistant
the chemical and
physical procedures that inactivate conventional viruses. They
do not induce a detectable immune response. There are natural
barriers, which limit the interspecies spread of infection, but
they can be crossed under appropriate circumstances. This is
usually dependent upon strain, dose, route of exposure and the
size of the species barrier. Studies on laboratory animals have
shown that intracerebral inoculation is the most efficient route.

Humans have been naturally exposed to the scrapie agent of
sheep for at least 200 years, but despite extensive epidemi-
ological studies no sign of transmission of scrapie to humans
has been detected. Bovine spongiform encephalopathy (BSE)
was first recognised in the United Kingdom in 1986. A large
number of cattle and individual herds have been affected. It is
clear that BSE is a food-borne infection. Other countries have
had some cases of BSE, either in animals imported from UK or
in indigenous animals. In so far as the biological properties of
the BSE agent differ from those of scrapie, it is conceivable that
also the species barriers may be different. There is convincing
evidence to show that the new variant of CJD is caused by the
agent that is responsible for BSE in cattle.

The appearance of a new variant form of human CJD has
raised further concerns that the BSE agent can be transmitted
to man. Therefore, due prudence continues to be warranted if
biological materials from species affected by those diseases
other
especially bovine
species, are used for the manufacture of medicinal products.

than by experimental

challenge,

Therefore the recommendations below should be followed to
minimise the risk of contamination. Notwithstanding this
guidance note it should be highlighted that
the potential
risks associated with a given medicinal product will have to
be considered individually in the light of specific circumstances
and current knowledge.

2. SCOPE OF THE NOTE FOR GUIDANCE

This note for guidance considers the implications of TSE for
human and veterinary medicinal products and measures for
minimising the risk of transmission by their use. Therefore, it
applies to materials of animal origin and particularly if they are
of ruminant origin, which are used for the preparation of:

(cid:151) active substances,

(cid:151) excipients,

(cid:151) raw or source materials and reagents used in production
(e.g. bovine
culture media
including those to prepare working cell banks or new
master cell banks).

serum albumin,

enzymes,

This note for guidance is also applicable to materials which
come into direct contact with the equipment used in manu-
facture (and therefore have the potential to allow contami-
nation), for example, in test media used in the validation of
plant and equipment.

This note for guidance relates to material of all ruminants. The
proposed measures are especially applicable for bovine material

and may need to be adapted for measures regarding material
from sheep, goats and other species known to be susceptible to
TSEs, other than by experimental challenge.

In the light of the current scientific knowledge and irrespective
of the geographical origin, milk is unlikely to present any risk
of TSE contamination (2). Therefore, milk and materials derived
only from milk are excluded from the scope of the guideline
provided milk is sourced from healthy animals in the same
conditions
for human consumption.
Derivatives of milk from ruminants prepared with the use of
other ruminant materials (e.g. pancreatic enzyme digests of
casein), are not excluded from the scope of
the guideline
because of the use of these other ruminant materials.

as milk

collected

Derivatives of wool and hair of ruminants, such as lanolin,
wool alcohols and amino acids are also excluded from the
the guideline, provided the wool and hair are
scope of
sourced from live animals. Derivatives of wool and hair from
ruminants prepared with the use of other ruminant materials
(such as pancreatic enzymes) are not excluded from the scope
of the guideline because of the use of these other ruminant
materials.

This note for guidance should be read in conjunction with the
various Commission Decisions progressively implemented since
1991. Where appropriate references to these Decisions are
given in the text.

3. MANUFACTURE (INCLUDING COLLECTION OF SOURCE

MATERIALS)

Where manufacturers have a choice to use ruminant or
non-ruminant material, the use of non-ruminant material
is
preferred. Substitution of
source materials by
from other species which are recognised to suffer
material
from TSEs, or which can be infected experimentally by the
oral route, would not normally be acceptable.

ruminant

the material

the source of

In the marketing authorisation application the applicant should
give details of
(including the
the animal) and the other measures
geographical origin of
transmission of TSE agents.
taken to minimise the risk of
The pharmaceutical manufacturer should audit
the supplier
they are sourced and
of
handled in conformity with this note for guidance and appro-
priate quality control systems.

to ensure that

these materials

The risk of transmission of infectious agents can be greatly
reduced, by controlling a number of parameters. These
parameters include:

(cid:151) source of animals,

(cid:151) nature of animal tissue used in manufacture,

(2) When assessing and minimising the risks associated with veterinary
medicinal products intended for use in ruminant species, additional
factors of
specific relevance only to these species must be
considered by the applicant and relevant competent authorities.
These factors are detailed in related position paper
(EMEA/
CVMP/121/01).

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(cid:151) production process(es).

No single approach will necessarily establish the safety of a
product and therefore the three approaches cited above may
need to be complementary to each other for minimising the
risk of contamination.

3.1. Animals as source of material

Careful selection of source materials is the most important
criterion for the safety of medicinal products.

3.1.1. The most satisfactory source of materials is from
countries which have not reported cases of BSE (3)
and have:

(cid:151) a compulsory notification, and

(cid:151) compulsory clinical and laboratory verification

of suspected cases.

certification should

Official
In
addition, it should be ensured that a risk of BSE
infection is not
introduced from the following
factors:

available.

be

(cid:151) importation of cattle from countries where high

incidence of BSE has occurred,

(cid:151) importation of progeny of affected females,

(cid:151) the use in ruminant feed of meat and bonemeal
containing any ruminant protein which orig-
inates
low
from countries with a high or
incidence of BSE, or of unknown status (2)

3.1.2. Materials may also be sourced from countries
indigenous cases have
in

in addition to the

where a low number of
occurred,
if
paragraph 3.1.1:

factors

(cid:151) carcasses of all infected animals are destroyed,

(cid:151) the progeny of affected females are not used,

(cid:151) the

feeding

to ruminants of mammalian

protein (4) is banned,

(3) Both the Office international des Epizooties (OIE) and the Scientific
Steering Committee (SSC) of the European Commission are in the
process of developing criteria for classification of countries or zone
according to their BSE status. The most recent version of the OIE
(cid:145)International annual health code chapter on BSE(cid:146) can be found on
the SSC are
the OIE website: http://www.oie.int. Opinions of
available on the Commission website: http://europa.eu.int/comm/
food/fs/bse/index_en.html.
this guideline will be
If necessary,
updated when the OIE/SSC classification has been finalised.

(cid:151) source animals should be born after the feeding
ban was imposed. If the date of birth of the
animals is not known, safety of the sourcing
should consider both the implementation date
of the ban and the incubation period of TSE,

(cid:151) herds with reported cases of BSE are not used

for sourcing.

3.1.3. Source materials should not be used from countries
where there is a high incidence of BSE (5)

Along with these measures the marketing author-
isation applicants should justify their strategy for
sourcing, in relation to the category of materials,
the quantity of source material and the intended
use of the finished medicinal product in humans.
In supplying countries, source materials from well-
monitored herds may provide an extra safety
margin (see Annex).

3.2. Parts of animal bodies, body fluids and secretions as

starting materials

scrapie, organs,

In a TSE infected animal, different organs and secretions
have different levels of infectivity. On the basis of data on
natural
tissues and fluids have been
classified into four main groups bearing different
potential risks, as shown in the table below. Although it
is now known that the distribution of infectivity in BSE
affected cattle appears to be more restricted, the classifi-
cation of
tissues and body fluids in the table should
continue to be considered for the selection of source
materials. The categories in the table are only indicative
and it is important to note the following points:

(cid:151) The classification of tissues shown in the table is based
on titration of infectivity in mice by the intracerebral
route. In experimental models using strains adapted to
laboratory animals, higher titres and a slightly different
classification of tissues may occur.

(cid:151) In certain situations there could be cross-contami-
nation of tissues of different categories of infectivity.
The potential risk will be influenced by the circum-
stances in which tissues were removed, especially by
contact of material of a low-risk group with that of a
high-risk group. Thus,
the 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
including placenta, amniotic and
foetal
or
allantoic fluids.

tissues

(4) Protein as referred to in Commission Decision 94/381/EC as

(5) Council Decision 98/256/EC of 16 March 1998 concerning

amended.

emergency measures to protect against BSE.

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(cid:151) The

risk posed by cross-contamination will be
factors

complementary

several

on

dependent
including:

(cid:151) precautions

adopted

to avoid

contamination

during collection of tissues (see above),

(cid:151) level of contamination (amount of the contami-

nating tissue),

(cid:151) amount of material to be used,

(cid:151) process to which the material will be subject

during the manufacturing process.

Manufacturers should present an assessment of
risk.

the

Relative scrapie infectivity titres in tissues and body fluids from
naturally infected sheep and goats with clinical scrapie (1)

CATEGORY I
High infectivity

CATEGORY II
Medium infectivity

CATEGORY III
Low infectivity

CATEGORY IV
No detectable infec-
tivity (2)

brain, spinal cord, (eye)

ileum,
spleen,
placenta),
adrenal

lymph nodes, proximal
tonsil,

colon,
(dura mater, pineal gland,
fluid, pituitary,

cerebrospinal

colon, nasal mucosa, peripheral
lung,

bone marrow,

liver,

distal
nerves,
pancreas, thymus

blood clot, faeces, heart, kidney, mammary
gland, milk, ovary, saliva, salivary gland,
skeletal muscle,
seminal vesicle,
serum,
foetal tissue,
testis, thyroid, uterus,
(bile,
bone (3), cartilaginous
tissue, connective
tissue, hair, skin, urine)

(1) Tissues in brackets were not titrated in the original studies, but their relative
infectivity is
indicated by other data on spongiform encephalopathies.
Materials not listed may be classified by analogy to those mentioned on the
basis of their composition.

(2) No infectivity was transmitted in bioassays involving inoculation of up to

5 mg of tissue into rodent brains.

(3) For skull and vertebrae see, also, point 3(2), second indent, relating to cross

contamination.

3.3. Process validation

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

Validation studies of removal/inactivation procedures are
difficult to interpret as it needs to take into consideration
the nature of the spiked material and its relevance to the
natural
the study (including
scaling-down of processes) and the method of detection
of the agent (in vitro or in vivo assay), after spiking and
after the treatment. Further research is needed to develop

the design of

situation,

an understanding of the most appropriate methodology
for validation studies. Therefore, validation studies are
if claims are
currently not generally required. However,
made for
to
remove or inactivate TSE agents, these will have to be
substantiated by appropriate validation studies. Validation
studies are process specific.

the ability of manufacturing processes

Beyond the particular limitations which apply to TSE vali-
dation studies and their interpretation, the major hurdle is
identifying steps which will effectively remove or inac-
tivate TSE agents during the manufacture of biological
medicinal products. Manufacturers are encouraged to
continue their investigations into removal and inactivation
methods to identify steps/processes which would have
benefit in assuring the removal or inactivation of TSE
agents.

In any event, a production process wherever possible
should be designed taking note of available information
on methods which are thought to inactivate or remove
TSE agents.

production

Certain
contribute
considerably to the reduction of the risk of TSE contami-
nation, e.g. procedures used in the manufacture of tallow
and its derivatives (see below).

procedures may

3.4. Age of animals

As the accumulation of TSE infectivity occurs over an
incubation period of several years, sourcing from young
animals may be prudent.

3.5. Specific products

Tallow used as the starting material for the manufacture
of tallow derivatives should be produced by a method at
least as robust and rigorous as those referred to in
Commission Decision 92/562/EC. Tallow derivatives,
such as glycerol and fatty acids which are manufactured
from tallow by rigorous processes have been the subject
of specific consideration and are thought unlikely to be
infectious. Examples of rigorous processes are:

(cid:151) transesterification or hydrolysis at not less than 200 (cid:176)C
for not less than 20 minutes under pressure (glycerol,
fatty acids and fatty acid esters production),

(cid:151) saponification with NaOH 12 M (glycerol and soap

production):

(cid:151) batch process: at not less than 95 (cid:176)C for not less

than three hours,

(cid:151) continuous process: at not less than 140 (cid:176)C, under
than eight minutes, or

less

pressure for not
equivalent.

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Gelatin

(cid:151) For gelatin produced from bovine bones (6), all of the
following parameters will contribute to the safety of
this product:

(cid:151) the geographical origin of the source animals,

(cid:151) skulls and spinal cords should be removed from

the starting material (7),

(cid:151) it is also recommended that vertebrae be excluded,
especially depending on the geographical origin,

option should be to avoid the use of material derived from
animals known to be susceptible (other than by experimental
challenge) to TSEs in the products produced by pharmaceutical
industry. The acceptability of a particular medicinal product
containing these materials, or which as a result of manufacture
could contain these materials, will be influenced by a number
of factors, including:

(cid:151) documented and recorded source of animals,

(cid:151) nature of animal tissue used in manufacture,

(cid:151) production process(es),

(cid:151) the current preferred manufacturing method is the

(cid:145)alkaline process(cid:146),

(cid:151) route of administration,

(cid:151) systems such as ISO 9000 certification and HACCP
should be
the
production process and for batch delineation (i.e.
definition of batch, separation of batches, cleaning
between batches etc.),

for monitoring of

in place

(cid:151) quantity of tissue used in the medicinal products,

(cid:151) maximum therapeutic dosage (daily dosage and duration of

treatment),

(cid:151) procedures should be in place to ensure traceability

and to audit suppliers of starting materials.

(cid:151) intended use of the product.

(cid:151) For bovine hide gelatin:

(cid:151) cross

contamination with possible

infectious

material should be avoided.

Manufacturers should present an assessment of
risk.

the

4. CONCLUDING REMARKS

Pharmaceutical manufacturers and producers of medicinal
products of animal origin are responsible for the selection
and justification of adequate measures. The state of science
and technology must be taken into consideration.

Notwithstanding this guidance note it should be highlighted
that
the potential risks associated with a given medicinal
product will have to be considered individually in the light
of specific circumstances and current knowledge.

The assessment of the risk associated with TSE needs careful
consideration of all of the parameters cited, and the preferred

These guidelines should also be used in the evaluation of indi-
vidual products based on a risk/benefit judgment.

in the worst case scenario,

(6) Starting material is considered as bones before degreasing.
(7) The future geographical distribution of BSE/TSEs can not be
geographical distribution of
in the
predicted. Any change
BSE/TSEs could result,
in a recall of
pharmaceuticals containing gelatin. Due to the large number of
medicinal products containing gelatin as an excipient and the
(cid:145)long life(cid:146) of gelatin from its production up to the end of the
shelf
life of the pharmaceuticals, any recall could have dramatic
consequences in terms of supply for essential medicinal products.
Therefore, skull and spinal cord should be removed from the
starting materials of bovine bone-derived gelatin whatever
the
geographical origin of the source animals.

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ANNEX

Draft requirements for sourcing from well-monitored herds materials intended to be used for the manufacture
of human and veterinary medicinal products

The scientific principle behind the concept of well-monitored herds is an attractive one, the implementation and
policing requires further consideration.

The criteria for well-monitored herds include:

(cid:151) having had no cases of TSE,

(cid:151) having never been fed mammalian derived protein (Commission Decision 94/381/EC as amended),

(cid:151) having a fully documented breeding history,

(cid:151) having introduced new genetic material only from herds with the same BSE-free status,

(cid:151) readily identifiable animals.

The additional safeguards provided by well-monitored herds would depend on:

(cid:151) establishment and supervision system put in place by both the applicant and the control authorities of the

concerned country(ies) of well-monitored herds,

(cid:151) feasibility and performance of proper inspections and controls which are dependent upon the size of the herd and

amount of material to be collected,

(cid:151) accuracy of the relevant certificates.

The above criteria are cumulative.