Position paper on risk assessment of the use of starting materials of ruminant origin in veterinary medicinal products intended for use in ruminant species

(EMEA/CVMP/121/01 - February 2001)

adopted by the Committee for Veterinary Medicinal Products (CVMP)

July 2001

(2001/C 286/05)

Introduction

When assessing the risk of the use of veterinary medicinal products intended for use in ruminant species, a number of factors need to be taken into account which are additional to those detailed in the "Note for guidance for minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products" (the joint CPMP/CVMP note for guidance). Ruminants are susceptible to BSE by the oral route and the risk of transmission is greatest when animals are exposed to infectious material derived from the same species. Transmission of infectivity to food producing species represents a risk of amplifying TSE infectivity in a form that is readily transmissible to man. It therefore follows that manufacturers should demonstrate that they have addressed the additional considerations that relate to ruminant species when analysing, and minimising, the risk of transmission of TSEs by veterinary medicinal products intended for use in ruminants.

Although particular attention is paid in this position paper to milk and milk products due to their exclusion from the note for guidance, it is important to note that the scope of this position paper extends beyond milk to cover all substances of ruminant origin when used in products intended for ruminants.

Manufacturers of products intended for use in non-ruminant species, whether food producing or not, i.e. pigs, poultry, horses, dogs, fish, rabbits and cats, need only address the factors detailed in the joint CPMP/CVMP note for guidance(1).

This position paper details under what circumstances an additional risk assessment should be carried out, and the factors that should be taken into account, when minimising the risks of transmission of TSEs to ruminant species. Manufacturers have the option of obtaining a certificate of compliance from the EDQM to demonstrate compliance of starting materials of animal origin that fall within the scope of the joint CPMP/CVMP note for guidance. The risk assessment referred to in this document is a separate requirement from the certification procedure. The additional risk assessment is required for all products intended for ruminant species, irrespective of whether or not a certificate is available for one or more starting materials used in their production and should be carried out by the marketing authorisation holder or applicant.

As indicated in the joint CPMP/CVMP note for guidance, applicants for marketing authorisations should take account of the latest available scientific information when preparing a risk assessment. In the event of a change in the state of knowledge or the disease situation, the risk posed should be reassessed. Likewise, this position paper will be updated in line with future changes to the joint CPMP/CVMP note for guidance.

Scope

This document relates to the use of:

(i) substances of animal origin that fall within the scope (Section 2) of the joint CPMP/CVMP note for guidance when used in the manufacture of veterinary medicinal products intended for administration to ruminant species, i.e. cattle, sheep, goats and deer;

(ii) milk and milk derivatives under the following defined circumstances:

Whereas milk and milk derivatives are specifically excluded from the joint CPMP/CVMP note for guidance provided, the milk is obtained from healthy cows and is fit for human consumption, these materials fall within the scope of this position paper when used under the following conditions, both of which must apply:

- the veterinary medicinal product is intended for parenteral administration to a ruminant,

AND

- the milk or milk derivative is used as a source of the active substance, as an excipient, stabiliser or component of the final formulation (i.e. not when used as a component of a medium or solution used during the production of one of the final ingredients).

Risk assessment

Manufacturers should perform a risk assessment and justification for use of substances falling within the scope of this document taking into account the following factors.

Where possible, manufacturers should use substances of non-ruminant origin for products intended for ruminant species. Where this is not possible, a justification should be provided for the use of ruminant-derived material.

When milk and milk derivatives fall within the scope of this document (see section "Scope", above), full compliance with joint CPMP/CVMP note for guidance should be demonstrated in terms of the origin of the milk and, where relevant, the treatment applied (such as removal of cells).

Use of specified risk materials (SRMs) as a starting material at any stage of the production process will be unacceptable to competent authorities in all but the most exceptional cases. Only where a risk-benefit analysis clearly shows that it is in the interests of public and animal health for a particular veterinary medicinal product to be made available would use of SRMs be permitted. In these circumstances, manufacturers shall demonstrate that the use of all other possible sources of starting materials has been explored and eliminated and that every possible measure to minimise risk has been taken. Such measures would include sourcing starting materials from a country officially classified as being free from animal TSEs, use of animals less than one year old, pre-mortem inspection and, where relevant, testing for the presence of infectivity.

The presence of SRMs as contaminants of other starting materials of animal origin is of particular concern in products intended for ruminants. Particular attention should be given to ensuring, and describing, that measures and quality systems are in place to ensure that contamination with SRMs does not occur.

The risk of transmission will be related both to the route of administration and the quantity of risk material that might be present in the final product.

Attention must be paid to minimising the potential risk of transmission of scrapie by sourcing materials of small ruminant origin that fall within the scope of this position paper from a country free from scrapie or by taking other measures to ensure that the herds of origin from which the source animals are derived are adequately monitored and controlled for freedom from TSEs. These requirements do not therefore apply to substances such as lanolin that fall outside the scope of the joint CPMP/CVMP note for guidance and this position paper.

All of the factors listed above should be specifically addressed when carrying out a risk assessment of seed materials for use in a vaccine intended for ruminants, as described in the CVMP position paper EMEA/CVMP/019/01.

Practical outcomes

The basis of demonstrating compliance of starting materials used in the production of veterinary medicines should rely, where possible, on the issue of a certificate of compliance by the European Department for the Quality of Medicines, following assessment of a data package submitted by the manufacturer of the raw material to demonstrate that the requirements of the joint CPMP/CVMP note for guidance have been met.

When a marketing authorisation holder is seeking to demonstrate compliance of a veterinary medicinal product intended for ruminant species for which EDQM certificates are available for all relevant raw materials, the certificates should be presented together with a risk assessment that addresses the additional risk factors listed in this position paper.

When a marketing authorisation holder is seeking to demonstrate compliance of a veterinary medicinal product intended for ruminant species for which EDQM certificates are not available for all relevant substances, certificates could be presented for those substances for which they are available. For those raw materials (including milk derivatives, where relevant) for which certificates are not available the applicant should submit the data necessary to demonstrate compliance of the raw materials with the joint CPMP/CVMP note for guidance together with a risk assessment that addresses the additional risk factors listed in this position paper for the veterinary medicinal product as a whole.

(1) Cats and other felidae have also been shown to be susceptible to TSEs when exposed to infectivity by the oral route. Although there are no additional requirements for products intended for use in these species, manufacturers should address, where relevant, any particular issues related to the TSE risk for felidae.