Guideline for variations to registered veterinary vaccines

1. Introduction

This guideline sets out the procedures and provides guidance on making an application to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to vary the relevant particulars or conditions of a registered veterinary vaccine where those changes may affect the quality, efficacy or safety of the formulated product. These variations include extending the shelf life of a registered veterinary vaccine.

In some instances, the proposed variation to the formulation of the product will mean that the product will become a new product with a new product number.

2. Supporting data

The information that you should provide to meet the legislative criteria should include chemistry and manufacture (part 2) data and efficacy and safety (part 8) data. The Good Manufacturing Practice (GMP) status of the manufacturing facility will also be relevant.

Further general information on supporting data for applications relating to veterinary vaccines can be found in the guideline for the registration of new veterinary vaccines.

Specific guidance on types of variations to registered veterinary vaccines which require application to and approval by APVMA is provided under the examples of variations to registered veterinary vaccines.

To facilitate the evaluation of the proposed change of a registered vaccine, you are encouraged to provide copies of relevant information that has been previously submitted to the APVMA for assessment.

3. Examples of variations to registered veterinary vaccines

This section includes examples of:

• variation applications that can be made for registered veterinary products where a new product application is not required
• variations to registered veterinary products where a new product application is required
• variations to registered veterinary products that may be assessed under permits.

3.1. Examples of variation applications for registered products where a new product application is not required

Examples of variation applications for registered veterinary products are provided below. The data or information you should provide when submitting such applications is indicated for each example. The assessment module(s) that may apply are set out in the legislative instrument.

3.2. Extension to the product claim only

• Extension of use in a new food-producing animal
• Extension of use to a new disease or pest in or on the same food-producing animal
• Extension of use to a new companion animal species
  • Applications to extend the product claim should be supported by efficacy and safety data

3.3. Formulation change: minor

• Removal, addition and/or changes to preservatives, stabilisers and other non-active excipients
  • Chemistry and manufacture data or information should be provided to support the proposed changes
• Change of adjuvant within the same class
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes

3.4. Change to site or process of manufacture of the antigen

• Change in the site of manufacture or process of manufacture without change to the pharmacopoeial grade or acceptance specification for an immunoserological product
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes

3.5. Change to in-process testing or other critical decision-making test

• Chemistry and manufacture data or information should be provided to support the proposed changes

3.6. Variation to product specifications

• Product specifications include full details of all test methods and limits for the quality assurance testing for batch release and expiry. Unless the batch release and expiry specifications are identified and described separately, the APVMA will assume they are the same.
• Chemistry and manufacture data or information should be provided to support a change to product specifications. Generally, a variation to product specifications should be accompanied by stability data as a minimum to support the proposed variation.
• Further data parts and modules may be relevant in addition to validation data if variations to product specifications involve changes to purity or potency test limits. If the variation to batch release or expiry specifications involves a change which has the potential to affect product safety or efficacy, efficacy and safety data or information should be submitted with the application.
• For those products that use a reference batch, applicants should submit chemistry and manufacture and efficacy and safety data or information as appropriate for the vaccine components of the reference vaccine and vaccine product.

3.7. Change to product release or end of shelf life titres

This section provides guidance on what data to submit when titres (maximum release titre, minimum release titre, end of shelf life titre) of registered products are to be changed.

• Change to product end of shelf life titre: efficacy data should be provided to justify the proposed titre.
• Change to product minimum release titre (with or without request to reduce the shelf life): chemistry and manufacture data including stability data should be provided.
• Change to product maximum release titre (MRT): safety data should be provided to justify the proposed titre, unless the proposed titre is below the approved MRT. If safety data is not submitted, scientific justification should be provided.

3.8. Change to final product tests

• Change to potency testing or other critical release tests (excluding administrative changes to the final product tests, e.g. version number)
  • Chemistry and manufacture data or information should be provided to support the proposed changes
• Change to site of quality-control testing
  • Chemistry and manufacture data or information should be provided to support the proposed changes. Evidence of GMP for the nominated site(s) should also be provided

3.9. Change of site of manufacture of the final product

• Change to, or addition of, a site of manufacture of the final product using the same active constituents (master seeds and working seeds)
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes. Evidence of GMP for the nominated site(s) should also be provided
• Change of site of manufacture involving the filling step of the product
  • Chemistry and manufacture data or information should be provided to support the proposed changes. Evidence of GMP for the nominated site(s) should also be provided
• Change of site of manufacture involving only the packaging and labelling steps of the product
  • Evidence of GMP for the nominated site(s) should be provided

3.10. Other specific changes

• Change to specification testing of raw materials (including antigenic components).
• Change from non-pharmacopoeial to pharmacopoeial standard (all changes to testing specifications to update the testing of raw materials including antigenic components, to comply with the latest version of a pharmacopoeia, can be adopted without submission to APVMA).
• Deletion of existing test for raw materials
• Changes to the packaging material and/or closure of product containers (including diluent container if that is part of the product presentation)
  • where there are no implications for product stability or sterility
  • where there are implications for product stability or sterility
• Change in the expression of units of potency in the batch-release specification if it changes the registration particulars
• Change of reference batch – i.e. a new comparison batch of proven efficacy is established to determine in vivo the relative potency of the production batches
• Change of source of a non-active constituent of biological origin. Department of Agriculture, Fisheries and Forestry-current import permit should be submitted for imported non-active constituent of biological origin
  • Chemistry and manufacture data or information should be provided to support the proposed changes

3.11. In-use stability claim

Potency and stability data should be provided to support the recommended storage time and conditions after broaching.

3.12. Change to the diluent

• Change to the diluent (not sterile water) where the diluent is packaged and supplied with the vaccine
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes

4. Examples of variations where a new product application is required

Certain changes to veterinary vaccines are considered to change the properties of a registered product to such an extent that it should be considered to be a new product.

The following are examples of changes to registered products that we consider to be significant. In these cases, you should submit an application for a new product registration, rather than a variation application. The data or information that should be provided when submitting such applications is indicated for each example. The assessment module(s) that may apply are set out in the legislative instrument.

4.1. Formulation change: major

• Addition or variation to the class of adjuvant (for example, oil to water or vice versa)
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes

4.2. Major change to seed strains: change to source or site or process of manufacture of the antigen

• Change to the source or site or process of manufacture of an antigenic component(s). This may include additional passaging beyond the registered particulars
• Change in the donor source of antibody for an immunoserological product
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes

4.3. Fall-out product

• Registration of a new product that is derived from an existing registered product by removal of one or more antigens and with a reduced claim
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes

4.4. Build-up product

• Registration of a new product that is created by adding active constituents to an existing registered product. Any change to the claims for the product relate only to the new active constituents
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes

5. Examples of variations that may be assessed under permits

Examples of variations to registered products that may be assessed under permits are provided below. The data or information that should be provided when submitting such applications is indicated for each example. The assessment module(s) that may apply are set out in the legislative instrument.

5.1. Changes to batch shelf life

• Change to the expiry date for a specific batch or batches of a product
  • Chemistry and manufacture data or information should be provided to support the proposed changes

5.2. Resizing of batch

• Resizing of batches – i.e. a change to the number of doses per container based on potency tests
  • Chemistry and manufacture and efficacy and safety data or information should be provided to support the proposed changes. The chemistry and manufacture data should include potency and batch-release specifications. The efficacy and safety data should include safety data using the resized dose in the target species

5.3. Batch released below the approved titre and associated change in shelf life

• Batch of product to be released with a decreased minimum release titre and associated reduction in shelf life
  • Chemistry and manufacture data or information should be provided to support the proposed changes

5.4. Batch released above the approved titre and associated change in shelf life

• Batch of product to be released with potency above the maximum release titre
  • Efficacy and safety data or information should be provided to support the proposed changes

6. Extension of shelf life of veterinary vaccines

This section provides guidance on extending the shelf life of a registered veterinary vaccine beyond the period approved at the time of product registration.

Stability data should be provided to demonstrate that the product will meet the approved end-of-shelf-life specifications when stored under specified conditions for the duration of the proposed shelf life.

6.1. Test protocol and submission of data

The stability data provided in support of the extension of the approved shelf life should be generated as per the approved protocol used for the original stability data provided to the APVMA with the original dossier for the product registration.

Where the test employed is as per a pharmacopoeial standard – for example, European Pharmacopoeia, British Pharmacopoeia, United States Pharmacopeia or United States Code of Federal Regulations – the application should include a brief description of the test. The description should:

• contain enough information to enable APVMA to assess the adequacy of the test method and whether it is consistent with the cited monograph. Where applicable, copies of current pharmacopoeial monographs and specifications
• be supplied as part of the application.

Where the stability testing is conducted according to a manufacturer’s standard, a detailed description of the testing procedures should be submitted. The APVMA expects the submission for an extension of a product’s shelf life to be a stand-alone document. The submission should contain a statement that the methods used are the same as in the original registration dossier, or provide the reasons or justification for any deviations.

Quantitative results should be submitted wherever possible rather than a simple statement that the product complies with a particular specification. The APVMA will not accept reporting of results as only ‘pass’ and/or ‘satisfactory’. Qualitative results will be accepted for sterility tests of completely sealed glass containers, and visual tests such as appearance, colour etc.

Assay results obtained during the study should be recorded as absolute values and numerical figures and/or a description of the observations should be provided as appropriate.

6.2. Stability data

If the proposed extension of shelf life is 12 months or longer, studies should be conducted every 6 months during the first year, and annually thereafter.

In general, the stability data should have enough time points to improve the precision of any regression analysis that may be applied. Regression modelling is expected to be conducted on the stability-indicating parameters, by graphical presentation. If it is to be argued that some tests performed at batch release are not changed by storage and not relevant to the extension of shelf life, this should be discussed with the APVMA before commencing the stability studies.

Testing at T = 0 and T = END should include all the tests listed on the batch-release specifications approved for the registered product to demonstrate vaccine stability.

6.3. Product characteristics to be tested to demonstrate stability

The items listed below are not all-inclusive, but represent product characteristics that should typically be tested to adequately demonstrate product stability. The tests should be consistent with those indicated on the batch-release specification. The data should include appropriate statistical analysis and a scientific discussion of the stability results.

Stability data should be provided on at least three batches of finished product and should (where applicable) include:

• a description of the product packaging during testing
• a description of storage conditions (for example, temperature ranges, light/dark conditions)
• information on the integrity of the product container, the closure and seal
• potency studies performed at appropriate intervals as defined in the stability protocol. Results should be reported using the same units of measure that were employed when the original shelf life was determined. It is important to have an adequate number of test points, not simply at commencement and completion of the proposed shelf life

Note that T = 0 and T = END are the primary time points of interest. It is advisable for T=END to be three months beyond the proposed shelf life. Omission of an adequate number of intermediate time points will bias the statistical analysis of the data by regression analysis or other acceptable methods. It is also accepted that for some inactivated vaccines, no potency test for the active exists (for example, fowl cholera vaccine). In some instances only a ‘+/-’ result is obtainable; ie the titre or dose response is not quantifiable. In any case, you should provide justification for the type of test selected or exclusion of the test

• the visual appearance of the product (colour and opacity for solutions; cake appearance for freeze-dried products and dissolution time for powders), including visible particulates in solutions or after the reconstitution of powders or lyophilized cakes
• a vacuum test (in addition to visual inspection) for freeze-dried products (where applicable)
• pH, and residual moisture level of lyophilised products
• sterility testing at the beginning and end of shelf life, as a minimum. Alternative testing to achieve the same purpose (for example, container/closure integrity testing) will be considered for freeze-dried products
• additives (stabilisers, preservatives or excipients may degrade during the dating period of the drug product)
• safety (if included on the batch-release specification)
• preservatives (for multi-dose, not-for-immediate-use formulations, preservative efficacy testing or demonstration that the preservative levels remain in specification at the new shelf life)
• any other stability-indicating analytical test included in the final batch analysis not mentioned above, where the result may reflect product stability.

6.4. Bracketing

If the same container and closure system is used for three or more pack sizes, it is reasonable to elect to place only the smallest and largest container size into the stability program (bracketing).. The design of a protocol that incorporates bracketing assumes that the stability of the intermediate pack size represents those at the extremes. In certain cases, data may be needed to demonstrate that all samples are properly represented by data collected for the extremes.