Position paper on the assessment of the risk of transmission 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) — July 2001
Date: 2001-07-01
Institutions: European Commission
Subjects: bovine spongiform encephalopathy, health risk, pharmaceutical legislation, vaccine, veterinary drug

C 286/12

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Official Journal of the European Communities

12.10.2001

Position paper on the assessment of the risk of transmission of animal spongiform encephalopathy
agents by master seed materials used in the production of veterinary vaccines

(EMEA/CVMP/019/01 (cid:151) February 2001)

adopted by the Committee for Veterinary Medicinal Products (CVMP)

July 2001

(2001/C 286/06)

BACKGROUND

SCOPE OF THE DOCUMENT

animal

immunological

spongiform encephalopathy

Since 1993, manufacturers of
veterinary
medicinal products (IVMPs) have been required to comply
with the (cid:145)Note for guidance for minimising the risk of trans-
mitting
via
veterinary medicinal products(cid:146), as adopted and periodically
updated by the Committee for Veterinary Medicinal Products
(CVMP). Commission Directive 1999/104/EC gave this note for
guidance the force of Community law. To ensure consistency in
terms of the requirements imposed on manufacturers, Member
States need to have a harmonised position on TSE risk
assessment for starting materials used in the manufacture of
IVMPs.

agents

In January 2001, the CPMP and CVMP agreed to harmonise the
separate notes for guidance into one note for guidance for
medicinal products for human and veterinary use. The CVMP,
having considered that
the exclusion of milk and milk
derivatives would be inappropriate for veterinary medicinal
products administered to ruminants, have added the proviso
that, 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.

This position paper therefore makes reference to the note for
guidance on minimising the risk of transmitting animal spon-
giform encephalopathy agents via human and veterinary
medicinal products (the joint CPMP/CVMP note for guidance).

Seed materials used to produce vaccines lodged for registration
after 1 October 2000 should fully comply with the
requirements of the joint CPMP/CVMP note for guidance, in
accordance with Directive 1999/104/EC (new seeds). This
position paper is therefore restricted to consideration of seed
materials used to produce vaccines with marketing authoris-
ations lodged before this date (established seeds).

the

that

paper

assumes

compliance with

This
joint
CPMP/CVMP note for guidance eliminates, as far as possible,
the risk of introducing TSE infectivity into an IVMP during the
process of manufacture through the use of materials of
biological origin which are used in routine production (e.g.
serum and blood products, tissue or tissue extracts).
If this
assumption is correct, then the only risk that remains to be
addressed is that posed by the seed materials, i.e. master and
working seeds.

This paper considers the factors that should be addressed when
assessing the risk posed by established seed materials so that a
systematic and consistent risk assessment can be made. Seed
materials (SM) are defined as master seeds and working seeds
for viruses, micro-organisms, parasites and cells. The individual
risk factors are identified and the likelihood of their occurrence
is discussed in relation to different types of vaccines. Where
relevant, the potential consequences of the risk are assessed.

1. RISK THAT SEED MATERIALS ARE CONTAMINATED WITH

TSE INFECTIVITY

LIKELIHOOD OF OCCURRENCE

Contamination of seed material could arise from either the
original source of the agent/cell
line or from materials used
in the production and/or storage of the seed.

at

risk of

contamination either

The
source or during
production of a seed with TSE infectivity can be assessed by
reference to the joint CPMP/CVMP note for guidance in relation
to the source of the animal of origin, the nature of the material
and the process used to derive or treat the seed or any material
used in its production. Particular attention should be paid to
the species of origin in relation to both TSE risk at source and
in relation to the intended species of use. As much information
as possible should be gathered about the nature and source of
substances of animal origin used in the isolation, passage and
storage of the seed material.

In relation to seed materials, the following factors should be
considered in particular:

(cid:151) the time that the seed was isolated/laid down in relation to
the history of BSE in the country of origin of the material
concerned. This is particularly relevant for seed materials
laid down before the emergence of BSE. The FDA considers
1980 to be the cut-off date after which a risk assessment
should be carried out on materials of animal origin sourced
from European countries,

(cid:151) in the case of other TSEs, such as scrapie, the history of the
material should be reviewed in relation to the history of the
TSE concerned, the origin of the material and the suscep-
tibility of the target species,

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isolation/laying down of

(cid:151) the passage history of the material and whether or not
infectivity could have been introduced subsequent to the
original
is
the
particularly relevant
to working seeds which may have
been laid down later than master seeds at a time when
the risk of
infectivity in the starting materials used in
media production etc. was higher,

seed. This

(cid:151) cell cultures may be used either as the substrate for master
or working seed viruses or as master or working cell seeds
themselves. In either case the risk of contamination will
usually be increased if primary cell cultures are used and
reference should be made to the joint CPMP/CVMP note for
guidance in relation to the source of origin of the cell
culture,

(cid:151) it is likely that for old master seed material some of the
required information will not be available either because it
was never recorded or because it has been lost. In such
cases an assessment
the potential
significance of this missing data in terms of overall risk
of TSE infectivity. Factors such as the country in which
the material was handled at the time and the actual or
likely sources of any substances of animal origin used
should be taken into account, together with any relevant
history of TSEs in the countries or species concerned.

shall be made of

CONSEQUENCES

In many cases, the risk of contamination will be judged to be
low or extremely low, due to either the time that the seed
materials were laid down or due to the species of origin of
the materials used to produce them. However, unless full
compliance with the joint CPMP/CVMP note for guidance can
be certified and justified, then the overall risk of transmission
that the seed represents should be assessed taking into account
the following factors.

2. RISK THAT TSE INFECTIVITY COULD BE PROPAGATED

DURING THE MANUFACTURING PROCESS

it

is difficult

Scientific evidence to date indicates that
to
establish, and to maintain, TSE infectivity in vitro. In general,
high titres of infectious material have been required to initiate
the in-vitro changes that are correlated with infectivity and
lines and in vitro conditions are required to
specialised cell
maintain these presumed correlates of
infectivity. There are
currently no published reports which demonstrate transmission
of disease through the use of (cid:145)infectious(cid:146) material generated in
vitro.

the risk of

Taking into account
the above factors,
in-vitro
propagation of TSE infectivity during vaccine manufacture is
likely to be low in the majority of cases. However, TSE infec-
tivity can be passaged by experimental
inoculation between
species, whether or not the recipient species is susceptible to
the particular TSE concerned. A risk assessment taking into
account this uncertainty shall therefore be carried out where
the production process itself involves inoculation of animals

and harvest of material from those animals. In addition, an
assessment of risk shall be carried out in those exceptional
cases where a particular cell type capable of in-vitro propa-
gation of TSE infectivity (e.g. a neuronal cell
is used
either as a seed material or to propagate other seed materials.
to the
In these
joint
CPMP/CVMP note for guidance and,
in very exceptional
cases, it may be necessary to require additional data to assess
directly whether or not there is a risk of propagation of TSE
infectivity.

should be made

reference

cases

line)

3. RISK THAT INFECTIVITY PRESENT IN THE MASTER SEED
MATERIAL COULD STILL BE PRESENT IN THE FINAL
PRODUCT AND TRANSMIT INFECTION

the amount of original material

This risk is relatively straightforward to estimate and will vary
according to the method of manufacture. For bacterial vaccines,
a dilution estimate can usually be made of how much seed
in the final harvest. For viral
material might be present
vaccines,
remaining will
depend on the method used for passage (e.g. dilution v
adsorption followed by washing off of the original material).
It should be possible to estimate approximately how much of
the original volume of inoculum could remain in the final
harvest. This estimation should take into account the effect
that any subsequent purification steps might have on the
amount of
infectivity remaining, e.g. washing of bacterial
harvests, centrifugation, purification, concentration steps, and
dilution of the antigen concentrate for final formulation. For
vaccines blended from different bulks, the amount of potential
residual infectivity could vary on a batch-by-batch basis.

low. This will often result

For the majority of vaccines the dilution factors are likely to be
high and the amount of possible infectivity present in the seed
material
in incalculably small
amounts of possible infectivity potentially remaining in the
final product. However, until such time as the infectious
doses for the various TSEs are established, the risk posed by
residual
In
addition, for vaccines, there is at least a theoretical risk of
accumulated infectivity as they are often administered on
more than one occasion to the same animal.

completely overlooked.

infectivity cannot be

The risk of
transmission of a TSE due to any residual,
contaminated seed material present in the final vaccine will
depend principally on the species to which the product
is
administered and the route of administration. The species of
origin of any potential infectivity should be assessed in relation
to the recipient species of the vaccine and the consequent
presence or absence of (cid:145)species barriers(cid:146) to infectivity. Suscep-
tibility to experimental TSEs varies according to the route of
administration of
the infectious material. The relative effi-
ciencies of transmission, ranked in decreasing order are; intra-
subcutaneous/intra-
cerebral,
dermal and oral/intragastric. Efficiency by the intramuscular
route is thought to be similar to that of the intra-peritoneal
route. The risk of
transmission is also related to the dose
administered but, relative to the other factors involved, this is
unlikely to be a major factor in the overall risk assessment.

intra-peritoneal,

intra-venous,

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OVERALL RISK ASSESSMENT

By combining the assessments of
factors it
should be possible to arrive at an overall risk assessment for
the seed materials contained in a vaccine.

the individual

PRACTICAL OUTCOMES

This position paper does not address the requirements for seed
materials used for the production of vaccines for which auth-
orisations are lodged after 1 October 2000. All materials used
in the storage and passage of such seed materials shall fully
comply with the requirements of the joint CPMP/CVMP note
for guidance. In the case of establishing a new master seed, the
joint CPMP/CVMP note for guidance should be followed to
minimise the risk of contamination at source. Full attention
should be given to factors such as the TSE history of the
animal, herd and country of origin,
the type of material
from which the strain is isolated and any possible measures
that can be taken to minimise the risk following subsequent
processing.

For established master seed materials, marketing authorisation
holders (MAHs) should demonstrate that they have assessed the
risk posed by these materials by reference to this position
paper. Conversely, competent authorities should refer to this
position paper in their assessment as to whether or not these
risk/benefit
risks are considered acceptable in the overall
analysis of the product.

In view of (i) the factors described in this position paper; (ii)
the control measures indicated below that can be put in place
to minimise the risks associated with working seeds; and (iii)
the likely history of the safe use of the product over several
years, it is likely that only in exceptional circumstances might
the competent authority consider the risk represented by the
use of a master seed material to be unacceptable.
In these
exceptional
discuss with the
the MAH should
competent authority how this risk might be reduced to an
acceptable level, possibly through a procedure of manipulation
through replacement by an equivalent but compliant master
seed or, if no other alternative ultimately exists, by removal
of the product from the market.

cases,

Use of working seeds should only be accepted by competent
authorities if full compliance with the joint CPMP/CVMP note
for guidance can be certified and justified. In situations where
full compliance of working seeds cannot be certified, a
commitment should be received from the MAH that
they
will submit a variation to their authorisation to replace such
materials with working seeds produced using starting materials
fully compliant with the joint CPMP/CVMP note for guidance
as soon as possible and within a specific time scale agreed with
the competent authority. Unless new information or events
result in a substantially revised risk assessment for the estab-
lished working seeds, competent authorities should generally
allow sale of vaccines produced using these seeds up to the
end of their shelf life.