APVMA guideline for autogenous vaccine permit

This is a guideline about the sorts of information an applicant can submit to address APVMA requirements for autogenous vaccine permits. It also provides guidance on how the information might be presented and analysed. For further information on the safety, efficacy and trade criteria, refer to Make an application.

An autogenous vaccine is a vaccine prepared from a microorganism(s) isolated from a sick or dead animal, which the attending veterinarian believes is the causative agent(s) of the disease affecting the flock or herd.  A permit for an autogenous vaccine is generally issued for an inactivated vaccine.

An autogenous vaccine can only be used on the herd or flock from which the microorganism(s) was isolated. Consideration may be given in situations where animals are vaccinated one stage ahead in the production cycle of where the problem starts—for example, pigs on grow-out farms are often best vaccinated while still in the weaner unit.

This type of vaccine is prepared in response to a specific and immediate need, usually when a disease problem arises that is not amenable or responsive to the usual therapeutic measures or when registered products are not available or are found to be ineffective.

An autogenous vaccine permit is generally issued to cover the manufacture of a single microorganism and its subtypes only. A manufacturer that holds permits for two or more microorganisms and wishes to combine them into a single multivalent autogenous vaccine should submit a separate permit application.

A permit allows a vaccine manufacturer that is the permit holder to manufacture the vaccine for more than one farm, using the microorganism isolated from the farm. For example, a manufacturer who holds a permit for an autogenous Escherichia coli vaccine can produce E. coli autogenous vaccine for multiple farms. In all cases, the E. coli should be isolated from the affected farm and the vaccine should be used in the herd or flock of origin. It would be illegal for the manufacturer to manufacture, for example, an Actinobacillus pleuropneumoniae autogenous vaccine, unless it holds a valid permit to produce Actinobacillus pleuropneumoniae autogenous vaccine.

A farm in this guideline is defined as a site or facility under a common management and serviced by a common workforce and within a geographic area defined by a common boundary (fence). An exception to this restriction is the vaccination of stock imported into a problem area where there is a high risk of the new stock being infected with a disease endemic on the farm.

The statutory criteria that the APVMA must be satisfied of to issue an autogenous vaccine permit relate to product quality and safety as well as trade. In addition to these legislative requirements, it is our general policy not to issue a permit for an autogenous vaccine if there is a suitable registered product available for that purpose, unless there is sufficient justification to support the technical advantages of the proposed vaccine or other reasons why the registered product cannot be used. Justifications based on cost (a cheaper alternative) are generally not acceptable.   A suitable or sufficient justification may include well documented claims of ineffectiveness of the registered product. We may also consider advice from our Compliance Section, registrants, state or territory departments, or the Adverse Experience Reporting Program on claims of ineffectiveness or adverse reaction of a registered product or in situations where the registered product is unavailable. This policy ensures that the permit system will not circumvent the normal registration processes. Consequently, at the time of renewal of an autogenous vaccine permit, we take into consideration the availability of a registered vaccine with similar claims.

1. Applying for an autogenous vaccine permit

You can apply for a permit online through the APVMA portal.

1.1. Types of information that can be submitted to support your application

The APVMA evaluates each application on its merits, and therefore these guidelines should be interpreted flexibly. We may accept valid scientific argument in lieu of data as appropriate.

1.2. Information you should provide

You should provide information on the immunological properties of the vaccine, including the diseases and/or conditions that the product is designed to control and the type of immune response and correlation with protection. Information on efficacy claims is not mandatory.

You should also provide the clinical particulars of the vaccine, including target species, indications for use, contra-indications, undesirable effects (with reference to frequency and seriousness), precautions for use, dosage and method of administration, overdose studies, special warnings for each target species, major and minor incompatibilities (if appropriate), withholding periods, special precautions for the user/administrator of the product, and first aid and safety directions.

2. Chemistry and manufacture

2.1. GMP status of the manufacturing facility

Evidence that the product will be manufactured in a GMP facility licensed by the APVMA

2.2. Formulation or composition of the product

Full details of the product formulation must be provided.  This should include the active constituent(s) and the excipients.  Information on the maximum and minimum release titres as well as end-of-shelf-life titre should be provided on the active constituent.

All excipients should be listed and adequate information provided on their physio-chemical nature and properties. The quantity of each constituent in the formulation should be expressed in appropriate units.  For example the active constituent quantity should be expressed as pfu,TCID50, CID mg/dose or mL)

The function of each constituent and the reference to standards should be stated

2.3. Containers

Specifications for the immediate container and the stoppers or closures (including acceptable tolerances), method of sterilisation and reference to standards should be provided.  The method of closure and opening should also be specified.

The choice of material should take into consideration the potential for toxicity, because some materials are known to have the potential to leach and/or react with the product and produce substances that can be toxic to the target species.

2.4. Manufacturing process of the final product

A flow chart of the manufacturing process, showing each step from production of the active constituent to formulation of the final product in final containers, including any critical in-process control testing steps, such as  amplification/culture, harvesting, purification, inactivation procedures, blending, adjuvanting, bulk antigen storage, filling or lyophilisation, as relevant should be submitted.

2.5. Production, control and testing of starting materials

Starting materials means all components used in the production of the autogenous vaccine. The European pharmacopoeia (Eur Ph.), British pharmacopoeia (BP), United States pharmacopeia (USP) and Title 9 of the United States Code of Federal Regulations (9CFR) standards, where appropriate monographs exist, should apply to all substances in the product. Documentation from suppliers, such as certificates of analysis and/or raw material specifications, should be provided.

2.6. Raw materials

Specifications and functions of all raw materials as well as the manufacturer(s) and origin of the raw material should be provided.

Where imported biological raw materials are used in the production of the vaccine, from the initial isolation to the manufacture of the finished product, a copy of a Department of Agriculture and Water Resources (DA) current biological import permit should be provided.

2.7. Starting materials listed in a pharmacopoeia

The name and code identifying the starting material, title of monograph, year of publication, preferably together with a copy of the monograph and certificate(s) of analysis must be submitted.

2.8. Starting materials of biological and non-biological origin, not listed in a pharmacopoeia

The name of each starting material (trade name, scientific synonyms), description, function, material specification including identification and purity should be provided.
Controls and tests performed on the starting material, certificates of analysis and a DA current biological import permit should be provided.

2.9. Master seed organism

A record of the origin, date of isolation, storage conditions and passage history of all seed materials (eg cell, virus, bacterium, fungus, protozoa and rickettsia ), including identification, purification and characterisation of the microorganism down to the level of subtype or serotype should be provided.
Other information that should be submitted is listed below:

  • growth characteristics and  environmental distribution
  • a brief description of the methods of identifying each strain by biochemical, serological and morphological characteristics and distinguishing it as far as possible from related strains
  • tests to demonstrate that the master seed lot is pure and free from extraneous agents as per EP, BP, USP or 9 CFR, where monographs exist
  • minimum and maximum number of passage levels from master seed to production level (these should be specified and should not exceed five unless justified by data)
  • target animal safety/pathogenicity
  • target animal immunogenicity of the master seed lot  
  • substrates used, quality control testing and storage of seed lots
  • release specification of the master seed organism

2.10. Working seed organism

The method of preparation and description of the working seed lot and the range of passage levels to be used for production, controls applied, tests carried out on working seed lot and storage conditions must all be supplied.  Release specification for the working seed organism should be stated.

2.11. Cell substrate or production medium

The following information should be provided on the cell substrate or production medium

  • details of the cell substrate or production medium (name and source of the master cell seed)
  • method of preparation and sterilisation
  • test for freedom from Mycoplasma, extraneous agents and specific adventitious virus contamination, and evidence of current DA  import permit as appropriate

Where specific pathogen free (SPF) eggs are used in production, they should be sourced locally.

2.12. Media preparation

The methods of preparation and sterilisation of media, including the controls applied, the testing carried out should be adequately described. Certificates of analysis of ready-to-use media should be provided as appropriate.

2.13. Production and in-process control tests during production

Adequate description should be provided on the amplification or culture, harvesting, purification, inactivation procedure, blending, adjuvanting, bulk antigen storage, filling, lyophilisation, as well as methods and results of in-process control tests during production.

2.14. Inactivation process

A validated method should be used to inactivate the product.  Inactivation kinetics and test used to confirm complete inactivation and inactivation results should be provided.

2.15. Batch release analysis

Batch release analysis should include the following:

  • potency
  • sterility
  • safety as per 9CFR, BP or Eur. Ph
  • moisture (as appropriate)
  • endotoxin (as appropriate)
  • extraneous agents (as appropriate)
  • mycoplasmas (as appropriate)  

For each test, provide information on:

  • title and company test code (specify monographs where appropriate)
  • timing and frequency
  • function of the test
  • brief description of the test (a detailed description should be given as an annex  with details and results of the validation studies where appropriate)
  • Specify monographs (where appropriate), limits of detection of the assay and criteria for acceptance of results   
  • The fate of material that has failed the test (eg any re-test provisions)

2.16. Stability of the finished product

The APVMA may grant an expiration date of up to 18 months.  A longer shelf life may be granted if appropriate supporting stability data is presented.

3. Toxicology

You should consider submitting toxicology data and/or valid scientific argument where applicable (for example vaccines containing oil or novel adjuvants).

4. Metabolism and kinetics

You should consider submitting metabolism and kinetics data and/or valid scientific argument where applicable (for example vaccines containing oil or novel adjuvants).

5. Residues and trade

The APVMA may accept valid scientific argument in lieu of data where the autogenous vaccine contains adjuvants and/or excipients that are already approved for other registered vaccines. Applications for vaccines containing novel adjuvants and/or excipients should be accompanied by data.

6. Occupational health and safety

You should address potential occupational health and safety risks associated with the manufacture and use of the product in the application. This may include, as appropriate:

  • safety instructions
  • use of personal protective equipment
  • first aid instructions
  • information for medical practitioners.

Adequate information should be provided on the adjuvant to assist the APVMA determine the nature of the chemical and the type of mandatory user safety information that should be on the product label.

Additional information may be requested on accidental self- injection depending on the product antigen/adjuvant combination

7. Environment

Information should be provided on the extent of exposure of the product, its active constituents or relevant metabolites to the environment, and proposed disposal methods for unused or waste product.

8. Efficacy

The association between the disease to be treated and the selection of the agent used for incorporation into the autogenous vaccine need not be demonstrated.
It is the responsibility of the prescribing veterinarian to ensure that the vaccine is effective in target animals.

If there is a registered product available, you should provide evidence to support the claim that the currently registered vaccine is ineffective at combating the disease in the flock or herd concerned or is unavailable.

9. Safety

Safety tests should be carried out on each batch of vaccine in the target species to show the risks from use of the product.  This should include:

  • safety of the administration of one dose
  • safety of one administration of an overdose (2x the recommended dose) in the most sensitive group, such as animals of the youngest age, and pregnant animals if appropriate.
  • Safety of the repeated administration of one dose

Interactions with other products administered simultaneously should be established and adequately addressed.

10. Label

You should provide a copy of the proposed label that will be attached to the container with your application. The label should contain all of the relevant particulars. It should also carry the APVMA permit number, a statement that the product is not registered, the name and address of the farm from which the microorganism(s) was isolated, and a statement that the APVMA has not assessed the efficacy of the product and that it is the responsibility of the prescribing veterinarian to ensure that the vaccine is effective in target animals.

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