Edition: BP 2025 (Ph. Eur. 11.6 update)
DEFINITION
Veterinary Vaccines for use in Emergency Situations are preparations containing antigenic substances and administered for the purpose of inducing a specific and active immunity against disease provoked by bacteria, toxins, viruses, fungi or parasites. The vaccines are for use under conditions of a need for vaccination in the face of an outbreak of infectious disease in animals for which there are no fully authorised vaccines available and that meet the criteria of an emergency situation as defined by a competent authority. The intention of this monograph is to provide in one place an indication of how certain mitigations could be introduced to accelerate development of a vaccine for authorised provisional use during an emergency whilst generating in the longer term data on long term efficacy, safety and robustness to support full authorisation.
The vaccines, live or inactivated, confer active immunity that may be transferred passively via maternal antibodies against the immunogens they contain and sometimes also against antigenically related organisms. They may contain bacteria, toxins, viruses or fungi, living or inactivated, parasites, or antigenic fractions or substances produced by these organisms and rendered harmless whilst retaining all or part of their antigenic properties; vaccines may also contain combinations of these constituents. The antigens may be produced by recombinant DNA technology. Suitable adjuvants may be included to enhance the immunising properties of the vaccines.
Terminology used in monographs on vaccines for veterinary use is defined in Appendix XV A(Vet).
BACTERIAL VACCINES AND BACTERIAL TOXOIDS
Bacterial vaccines and bacterial toxoids are prepared from cultures grown on suitable solid or liquid media, or by other suitable means; the requirements of this section do not apply to bacterial vaccines prepared in cell cultures or in live animals. The strain of bacterium used may have been modified by genetic engineering as defined in the monograph for Veterinary Vaccines. The identity, antigenic potency and purity of each bacterial culture used is controlled appropriately.
Bacterial vaccines contain inactivated or live bacteria or their antigenic components; they are liquid preparations of various degrees of opacity or they may be freeze-dried.
Bacterial toxoids are prepared from toxins by diminishing their toxicity to a very low level or by completely eliminating it by physical or chemical means whilst retaining adequate immunising potency. The toxins are obtained from selected strains of specified micro-organisms grown in suitable media or are obtained by other suitable means, for example, chemical synthesis.
The toxoids may be:
— liquid,
— precipitated with alum or other suitable agent,
— purified and/or adsorbed on aluminium phosphate, aluminium hydroxide, calcium phosphate or other adsorbent prescribed in the monograph.
Bacterial toxoids are clear or slightly opalescent liquids. Adsorbed toxoids are suspensions or emulsions. Certain toxoids may be freeze-dried.
Unless otherwise indicated, statements and requirements given below for bacterial vaccines apply equally to bacterial vaccines, bacterial toxoids and products containing a combination of bacterial cells and toxoids.
VIRAL VACCINES
Viral vaccines are prepared by growth in suitable cell cultures, Appendix XV J (Vet)1, in tissues, in micro-organisms, in fertilised eggs, or by other suitable means, or, where no other possibility is available, in live animals. The strain of virus used may have been modified by genetic engineering as defined in the monograph for
Veterinary Vaccines. They are liquid or freeze-dried preparations of one or more viruses or viral subunits or peptides.
Live viral vaccines are prepared from viruses of attenuated virulence or of natural low virulence for the target species. Inactivated viral vaccines are treated by a validated procedure for inactivation of the virus. Both live and inactivated antigens may be purified and concentrated.
PRODUCTION
The methods of preparation, which vary according to the type of vaccine (and include preparation of any vector used as part of a recombinant product), are such as to maintain the identity and immunogenicity of the antigen and to ensure freedom from contamination with extraneous agents. Where the vaccine is a combination of multiple strains the maximum number of antigens that can be included in the vaccine and the quantity for each antigen must be specified.
Substances of animal origin used in the production of vaccines for veterinary use comply with the requirements of Appendix XV J(Vet)2. Other substances used in the preparation of vaccines for veterinary use comply with requirements of the Pharmacopoeia (where a relevant monograph exists) and are prepared in a manner that avoids contamination of the vaccine.
It is recognised that an accelerated development schedule may lead to limited manufacturing data and therefore it may be necessary to introduce mitigating actions such as a higher level of process control and final product inspection. This may mean there is a wider variety and more in-process and final product tests when compared to a fully developed product with a highly defined consistency approach.
SUBSTRATES FOR PRODUCTION
Cell cultures used in the production of vaccines for veterinary use comply with the requirements of Appendix XV J (Vet)1. The testing of extraneous agents can be reduced if the applicant can provide a valid risk assessment and a valid risk management plan that show the absence of risk related to the use of starting materials of biological origin. This should include an assessment of the capacity of the inactivation procedure.
If embryonated eggs are used as a production substrate for live vaccines, these should be sourced from chicken flocks free from specified pathogens (SPF), where the flocks comply with the requirements prescribed in Appendix XV H(Vet). For the production of inactivated vaccines in embryonated eggs these must be sourced either from chicken flocks free from specified pathogens (SPF) or from healthy chicken flocks which comply with the requirements prescribed in Appendix XV H(Vet).
Where it is unavoidable to use animals or animal tissues in the production of veterinary vaccines, such animals shall be free from specified pathogens, as appropriate to the source species and the target animal for the vaccine. For inactivated vaccines it may be possible to demonstrate that the inactivation process is effective against specified potential contaminants.
MEDIA
The qualitative composition of media used for seed culture preparation and for production should be recorded. Information about the grade of each named ingredient is specified. Where media or ingredients are claimed as proprietary, this is indicated and an appropriate description recorded.
Ingredients that are derived from animals are specified as to the source species and country of origin, and must comply with the criteria described in Appendix XV J(Vet)2. Substances of animal origin (for example, serum, trypsin and serum albumin) may be used during the manufacture of veterinary immunological products as ingredients of culture media. It is recommended to reduce, wherever practicable, the use of such substances. Certain restrictions are placed upon the use of such substances to minimise the risk associated with pathogens that may be present in them.
Substances of animal origin used during production are either subjected to a suitable validated sterilisation or inactivation procedure or the substance is tested for the absence of extraneous organisms in accordance with the requirements in Appendix XV J(Vet)2. For inactivated vaccines, the method used for inactivation of the vaccine strain may also be validated for inactivation of possible contaminants from substances of animal origin.
PREPARATION
Processes for media used, including sterilisation procedures, are documented. The addition of antibiotics during the manufacturing process is normally restricted to cell culture fluids and other media, egg inocula and material harvested from skin or other tissues. Antibiotics with maximum residue limits appropriate to the target species should be prioritised and only trace amounts should remain in the final vaccine.
Bacterial and Virus Seed Lots
In general the requirements of the monograph for Veterinary Vaccines apply.
Inactivation
Inactivated vaccines are subjected to a validated inactivation procedure. The testing of the inactivation kinetics described below is carried out once for a given production process.
In general the requirements of the monograph for Veterinary Vaccines apply. It should be noted that when conducting tests for inactivation, it is essential to take account of the possibility that under the conditions of manufacture organisms may be physically protected from the inactivant. The inactivation kinetics and tests for complete inactivation should be provided for all strains separately, unless justification is provided that the inactivation process and/or the tests for complete inactivation are valid for other strains.
Choice of vaccine composition and choice of vaccine strain
For the choice of vaccine composition and choice of vaccine strain, important aspects to be considered include safety, efficacy and stability. General requirements for evaluation of safety and efficacy are given in Appendix XV K(Vet)1 and Appendix XV K(Vet)2 and should be considered in the context of the emergency vaccine use.
For live vaccines, a maximum virus titre or bacterial count acceptable from the point of view of safety should be established by basic development studies. This is then used as the maximum acceptable titre for each batch of vaccine at release.
Potency and immunogenicity
The minimum acceptable vaccinating capacity for all vaccines within the scope of the definition should be established using a well-controlled test in experimental conditions. For most vaccines, the tests cited under Potency or Immunogenicity are not suitable for the routine testing of batches.
For live vaccines, the minimum acceptable virus titre or bacterial count that gives satisfactory results in the Potency test and other efficacy studies is established during the basic development.
For inactivated vaccines, if the test described under Potency is not used for routine testing, a batch potency test is established during development. The aim of the batch potency test is to ensure that each batch of vaccine would, if tested, comply with the test described under Potency or Immunogenicity. The acceptance criteria for the batch potency test are therefore established by correlation with the test described under Potency. It is recognised that an accelerated development procedure may mean that aspects of tests validation are not available and the overall suitability of the test should be considered in the context of the emergency vaccine use.
The potency test of a multi-strain vaccine cannot be elaborated in the way normally required for normal vaccines because of all the possible combinations of antigens. The following is given as a general example. Mono-strain vaccines are manufactured for each of the available Master Seed viruses (MSVs), and a validated potency test elaborated for each of these mono-strain vaccines. The validations and specifications established through the potency testing of each mono- strain vaccine can then be extrapolated to any multi-strain vaccine containing a combination of these antigens (within the maximum number of antigens previously established). The potency test for each mono-strain vaccine should be conceived in such a way that cross-reaction between strains will be limited as much as possible when the potency tests is applied to multi-strain vaccines containing these strains. If cross-reaction cannot be avoided in an in vivo potency test, additional in vitro tests (e.g. serotype- or strain specific antigen-ELISAs on finished product of the complete antigen bulk) may be introduced.
Stability
Evidence of stability is investigated to justify a period of validity suitable for the purpose of emergency use. This evidence takes the form of the results of virus titrations, bacterial counts or potency tests carried out at regular intervals on material representative of batches of vaccine kept under appropriate storage conditions. Information to demonstrate that the moisture content in freeze-dried products, adjuvant constituents and preservatives and pH remain stable should also be provided.
Where applicable, the stability of the reconstituted vaccine should be investigated, using the product reconstituted in accordance with the proposed recommendations.
FINAL BULK VACCINE
In general the monograph for Veterinary Vaccines applies. It is accepted that, given the circumstances of minimum development time for an emergency use product, that full antimicrobial efficacy may not have been demonstrated.
Batch
The final bulk vaccine is distributed aseptically into sterile, tamper-evident containers which are then closed so as to exclude contamination.
Only a batch that complies with each of the requirements given below under Identification, Tests and Potency may be released for use.
With the agreement of the competent authority, certain of the batch tests may be omitted where in-process tests give an equal or better guarantee that the batch would comply or where alternative tests validated with respect to the Pharmacopoeial method have been carried out.
It is recognised that, in accordance with the General Notices, Part III (1.1. General statements), the routine application of the safety test is no longer required for vaccines. However, for a vaccine developed in an accelerated manner there may be a need to conduct a batch safety test over a limited number of batches unless there is sufficient data from developmental safety studies and data demonstrating consistency of the manufacturing process. Significant changes to the manufacturing process may require resumption of routine testing to re-establish consistency. Without prejudice to the decision of the competent authority in the light of information available for a given vaccine, testing of ten consecutive batches is likely to be sufficient for most products. Likewise if there are insufficient batches to demonstrate the consistency approach then it may be necessary to conduct a final product inactivation test on a batch basis in addition to the in process test.
TESTS
In general the requirements of monograph for Veterinary Vaccines apply. In terms of extraneous agents testing the monograph for Veterinary Vaccines elaborates the series of measures that can be taken to give an acceptable degree of reassurance that the final product does not contain infectious extraneous agents. Given the short timeline for developing an emergency product it may not be possible to demonstrate that these measures can be put in place and therefore it is the competent authority’s decision as to whether extraneous agents testing on a batch basis is necessary.
Mycoplasmas
Where appropriate the vaccine complies with the test for absence of mycoplasmas (culture method), Appendix XVI B(Vet)3.
Safety
If a batch safety test is deemed necessary then in general, 2 doses of an inactivated vaccine and/or 10 doses of a live vaccine are injected by a recommended route. It may be necessary to reduce the prescribed number of doses under certain circumstances or amend the method of re-constitution and injection, for example for a combined vaccine, where it is difficult to reconstitute 10 doses of the live component in 2 doses of the inactivated component. The animals are observed for 14 or 21 days. No abnormal local or systemic reaction occurs. Where several batches are prepared from the same final bulk, the safety test is carried out on the first batch and then omitted for further batches prepared from the same final bulk. During development studies, the type and degree of reactions expected with the vaccine are defined in the light of safety testing. This definition is then used as part of the operating procedure for the batch safety test to evaluate acceptable and unacceptable reactions.
The immune status of animals to be used for the safety test should fall into one of the 3 following categories below as appropriate:
1) the animals must be free from antibodies against the virus/bacterium/toxin etc. contained in the vaccine;
2) the animals are preferably free from antibodies but animals with a low level of antibody may be used as long as the animals have not been vaccinated and the administration of the vaccine does not cause an anamnestic response;
3) the animals must not have been vaccinated against the disease the vaccine is intended to prevent.
As a general rule, category 1 is specified for live vaccines. For other vaccines, category 2 is usually specified but where most animals available for use in tests would comply with category 1, this may be specified for inactivated vaccines also. Category 3 is specified for some inactivated vaccines where determination of antibodies prior to testing is unnecessary or impractical. For poultry vaccines, as a general rule the use of SPF birds is specified.
Animal Tests
In accordance with the provisions of the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, tests must be carried out in such a way as to use the minimum number of animals and to cause the least pain, suffering, distress or lasting harm. The criteria for judging tests in monographs must be applied in the light of this. For example, if it is indicated that an animal is considered to be positive, infected etc. when typical clinical signs occur, then as soon as it is clear that the result will not be affected, the animal in question shall be either humanely killed or given suitable treatment to prevent unnecessary suffering. In accordance with the General Notices, alternative test methods may be used to demonstrate compliance with the monograph. The use of such tests is particularly encouraged when this leads to replacement or reduction of animal use or reduction of suffering.
Potency
The requirements of the monograph for Veterinary Vaccines apply.
Storage
The requirements of the monograph for Veterinary Vaccines apply.
Labelling
The requirements of the monograph for Veterinary Vaccines apply.
