Appendix XV J (Vet) 2. Substances of Animal Origin for the Production of Immunological Veterinary Medicinal Products

(Ph. Eur. general texts 5.2.5)

1. Scope

Substances of animal origin (for example serum, trypsin and serum albumin) may be used during the manufacture of immunological veterinary medicinal products.

The requirements set out in this chapter apply to substances of animal origin produced on a batch basis, for use at all stages of manufacture, for example in culture media or as added constituents of products during blending. These requirements are not intended for the control of seed materials or substrates of animal origin that are covered by requirements in other pharmacopoeial texts such as the monograph Vaccines for veterinary use (0062) and chapter 5.2.4. Cell cultures for the production of veterinary vaccines.

2. General principles and requirements

Substances of animal origin comply with the requirements of the European Pharmacopoeia (where a relevant monograph exists).

Restrictions are placed on the use of substances of animal origin because of safety concerns associated with pathogens that may be present in them and epidemiological and/or regulatory concerns associated with the presence of particular antigens (either live or inactivated).

General principles:

— it is recommended to minimise, wherever practicable, the use of substances of animal origin;

— unless otherwise justified, the use of substances of animal origin as constituents in the formulation of medicinal products is not acceptable except where such substances are subject to a treatment validated for the inactivation of live extraneous agents.

General requirements:

— any batch of substance (after inactivation and/or processing, if relevant) found to contain or suspected of containing any living extraneous agent shall be discarded or used only in exceptional and justified circumstances; to be accepted for use, further processing must be applied that will ensure elimination and/or inactivation of the extraneous agent, and it shall then be demonstrated that the elimination and/or inactivation has been satisfactory;

— any batch of substance that, as concluded from the risk assessment, may induce an unacceptable detectable immune response in the target species as a consequence of contamination with inactivated extraneous agents, must not be used for the manufacture of that particular immunological veterinary medicinal product.

3. Risk management

No single measure or combination of measures can guarantee the safety of the use of substances of animal origin, but they can reduce the risk from such use. It is therefore necessary for the manufacturer of immunological veterinary medicinal products to take account of this when choosing a substance of animal origin to use in manufacture, and to conduct a risk assessment, taking into account the origin of the substance and the manufacturing steps applied to it.

In addition, risk management procedures must be applied. Any residual risk must be evaluated in relation to the potential benefits derived from the use of the substance for the manufacture of the immunological veterinary medicinal product.

3-1 Risk assessment

The risk assessment must take account of the animal diseases occurring in the country of origin of the animals used as a source of the substance, the potential infectious diseases occurring in the source species and the likely infectivity in the source organ or tissue. From this information, as part of the risk assessment, a list can be prepared of the extraneous agents that may be present in the substance.

The risk of contamination of the substance and the resultant immunological veterinary medicinal product with living extraneous agents needs to be assessed. The risk of contamination of the substance and the resultant immunological veterinary medicinal product with inactivated extraneous agents may also need to be taken into account. This would be the case if, for example, the contaminant was one from which a European country is officially free and/or is the subject of a specific disease control program in a European country and where the presence of the inactivated agent could lead to the stimulation of a detectable immune response in recipient animals.

As part of the risk assessment, the presence in the substance of antibodies that can interfere with the detection and/or inactivation of living extraneous agents must also be taken into account.

The risk assessment may need to be repeated and the risk management steps described below re-evaluated and revised in order to take account of changes:

— in the incidence of diseases occurring in the country or countries of origin of animals used as the source for the substance, including emerging diseases (new pathogens);

— in the incidence of diseases and of disease control measures applied in the European countries in which immunological veterinary medicinal products manufactured with the substance are used.

3-2 Risk control

For each of the potential extraneous agents identified by the risk assessment, and taking into account the proposed use of the substance, the risk must be controlled by the use of one or a combination of the followings measures:

— placing restrictions on the source of the material and auditing this;

— using validated inactivation procedures;

— demonstrating the ability of a production step to remove or inactivate extraneous agents;

— testing for extraneous agents.

4. Control measures

4-1 Source

All substances of animal origin used in the manufacture (including blending) of immunological veterinary medicinal products must be from a known and documented source (including species of origin and country of origin of source animals and tissues).

4-2 Preparation

Substances of animal origin are prepared from a homogeneous bulk designated with a batch number. A batch may contain substances derived from as many animals as desired but once defined and given a batch number, the batch is not added to or contaminated in any way.

The production method used to prepare the substance of animal origin from the raw material may contribute to the removal and/or inactivation of extraneous agents (see section 4-3).

4-3 Inactivation and/or other processing steps for removal of extraneous agents

The inactivation procedure and/or other processing steps chosen shall have been validated and shown to be capable of reducing the titre of potential extraneous agents described below in the substance concerned by a factor of at least 10⁶.

If this reduction in titre cannot be shown experimentally, a maximum pre-treatment titre of the extraneous agent must be set, taking into account the reduction in titre afforded by the inactivation/processing step and including a safety margin factor of 100; each batch of substance must be tested to determine the pre-treatment starting titre and confirm it is no greater than the specified limit, unless proper risk assessment, based on valid and suitable data, shows that titres will always be at least 100-fold below the titre that can effectively be inactivated.

The validation of the procedure(s) is conducted with a suitable representative range of viruses covering different types and sizes (enveloped and non-enveloped, DNA and RNA, single- and double-stranded, temperature- and pH-resistant), including test viruses with different degrees of resistance, taking into account the type of procedure(s) to be applied and the viruses that may be present in the material. The evidence for the efficacy of the procedure may take the form of references to published literature and/or experimental data generated by the manufacturer, but must be relevant to the conditions that will be present during the production and inactivation/processing of the substance.

For inactivated immunological veterinary medicinal products, the method used for inactivation of the active ingredient may also be validated for inactivation of possible contaminants from substances of animal origin used in the manufacture of this active ingredient.

4-4 Tests

Depending on the outcome of the risk assessment and the validation data available for any procedure applied, tests for extraneous agents may be conducted on each batch before and/or after the application of an inactivation/processing step. For examination of the substance for freedom from extraneous agents, any solids are dissolved or suspended in a suitable medium to provide a suitable preparation for testing. A sufficient quantity of the preparation is tested to give a suitably sensitive test, as established in the validation studies.

As well as tests for living extraneous agents, tests may need to be conducted for the presence of inactivated extraneous agents, depending on the risks identified.

Freedom from living extraneous viruses

A sample from each batch of the substance is tested for extraneous viruses by general and specific tests. These tests are validated with respect to sensitivity and specificity for detection of a suitable range of potential extraneous viruses. Suitably sensitive cell cultures are used for the tests for extraneous viruses, including primary cells from the same species as the substance to be examined.

General test The inoculated cell cultures are observed regularly for 21 days for cytopathic effects. At the end of each 7-day period, a proportion of the original cultures is fixed, stained and examined for cytopathic effects, and a proportion is tested for haemadsorbing agents.

Specific tests A proportion of the cells available at the end of the general test is tested for specific viruses. The specific viruses to be tested for are potential extraneous viruses that are identified through the risk assessment and that would not be detected by the general test. A test for pestiviruses is conducted if the source species is susceptible to these.

Bacteria and fungi

Before use, substances are tested for sterility (2.6.1), or sterilised to inactivate any bacterial or fungal contaminants.

Mycoplasma

Before use, substances are tested for freedom from mycoplasma (2.6.7), or sterilised to inactivate any mycoplasmal contaminants.