Guideline for the transfer of a manufacturing site for immunobiological products

The guideline supplements the tailored guidance material for manufacturing site transfer.

This guideline aims to provide clarity and consistency on data requirements for manufacturing site transfers of primary and secondary manufacturing steps for registered immunobiological products.

Definitions of manufacturing site transfers

A transfer (which includes addition of a site) of a manufacturing site(s) for an immunobiological product is classified as:

1. transfer and/or addition of a manufacturing site of an immunobiological product from a local (Australian) or overseas manufacturing site to a local manufacturing site
2. transfer and/or addition of a manufacturing site of an immunobiological product from a local or overseas manufacturing site to an overseas manufacturing site

For the purposes of this guidance for variation applications for registered immunobiological products, manufacturing site changes are classified into the following:

a) site transfer of primary* manufacturing steps for immunobiologicals
b) site transfer of secondary* manufacturing steps for immunobiologicals
c) administrative changes—name or address change without any physical relocation.

*Primary and secondary manufacturing steps are defined as follows:

A primary step includes all steps in the manufacturing process that result in direct contact with the veterinary chemical product. For immunobiological products, this would include production from the master seed(s) through to the final product filled into the primary container.

Secondary manufacturing steps are defined as those manufacturing steps that do not result in direct contact with the veterinary chemical product released to market:

• labelling or relabelling or secondary/supplementary labelling
• secondary packaging
• storage
• release for supply
• analysis and testing (Quality Control [QC]).

Primary and secondary manufacturing categories are not defined under the APVMA code of Good Manufacturing Practice (GMP). Therefore, the manufacturing steps described in this guidance should be used only for the purposes of submitting manufacturing site transfer applications for registered immunobiologicals.

For immunobiologicals, a manufacturing site transfer is defined as the transfer of some or all manufacturing operations and/or in process (IP) and final product (FP) testing. Examples of such transfers include:

Primary manufacturing steps for immunobiologicals

• some or all manufacturing steps for a registered product (from master seed through to final filled product in the primary container)
• some or all manufacturing steps for an active constituent (from master seed through to final bulk antigen)
• any intermediate manufacturing step (bulk antigen or final formulation prior to filling or freeze-drying)
• change of site for formulation and filling operations for a registered product.

Secondary manufacturing steps for immunobiologicals

• a change of site for labelling, re-packaging, storage and release
• change of site of analysis and testing for In-Process (IP) and Finish Product (FP) tests for a registered product and/or active constituent.

Variations for manufacturing site transfers

Transfer of a primary manufacturing site for immunobiologicals

Primary manufacturing site transfers for immunobiologicals can potentially affect the quality, safety and efficacy profile of a registered product. Therefore, this requires the submission of data to support the transfer and a technical assessment to ensure it meets APVMA standards. Thus, primary manufacturing transfers from/to a local or overseas site will be assessed under an Item 14 application.

Where the proposed transfer affects an active constituent, in addition to an Item 14 application for the transfer of the product, APVMA legislation requires the submission of an additional application to cover the transfer of an active ingredient. An Item 17 or an Item 18 application will be required for each antigen associated with a product transfer under Item 14.

If undertaking a site transfer for the final product and active, it is necessary to submit an Item 14 for the product and an Item 18 for the active. The Item 18 will include a separate data list cross-referencing the data package included in the Item 14.

Alternatively, you have the option to submit concurrently an Item 17, with a chemistry package, with an Item 14 if the intention is to register a new source with the relevant particulars to be included in the record.

Applications for transfer of a primary manufacturing site for an immunobiological product under an Item 14 will require the following modules.

Pre-Application Advice (PAA) can be used to determine the optimum route and data requirements for specific transfers. The acceptance of International data is another option that could be considered to facilitate manufacturing site transfers.

Data requirements for transfer of a primary manufacturing site

A transfer of primary manufacturing site for immunobiologicals for both overseas and local sites will fall under an Item 14 variation.

For a primary manufacturing site transfers the variation should be specific for the site transfer and not include other variations to the particulars of the registered product or label. For site transfers of primary manufacture, a chemistry data package is required demonstrating physicochemical equivalence between the existing site and new site of manufacture.

Additional safety and efficacy data to support the transfer of primary manufacture will only be requested for immunobiologicals that are released without a validated potency assay and therefore additional in vivo test data may be required to support the transfer.

Data requirements applicable for the transfer of primary manufacturing steps from master seed(s) through to antigen and final product:

• results of at least two consecutive antigen batches at the new site according to the registered manufacturing process
• results of at least two consecutive vaccines batches at the new site according to the registered manufacturing process
• transfer validation reports for critical manufacturing steps eg centrifugation, purification, filtration or other evidence demonstrating production equivalence
• validation reports of IP and FP tests eg potency tests (eg ELISAs, serological tests, and sterility tests) unless the test is a pharmacopeia standard
• a manufacturing flow chart for the new manufacturing site
• evidence of satisfactory GMP compliance for the new QC site
• a commitment to undertake stability studies on the final product

For inactivated antigens/products additional requirements:

• inactivation kinetics at industrial or pilot scale at the new site
• inactivation test validation
• inactivation tests results for at least two consecutive antigen batches.

Note: In all cases involving the import of immunobiological from an overseas site of manufacture, an import permit from the Department of Agriculture, Fisheries and Forestry will be a condition of approval of the site change application if not accompanying the application.

Transfer of a secondary manufacturing site for immunobiologicals

The transfer of the secondary manufacturing steps (labelling, repackaging, storage or release) does not require technical assessment.

The transfer to a local (Australian) site or an overseas site for secondary production is carried out under an Item 13A. A GMP certificate does not need to be submitted in the application, however the holder will be required to make a declaration that the site has appropriate GMP certification. The declaration must state that the proposed new site has appropriate GMP licensing for the relevant steps for Australian sites or overseas sites. Please use the wording below in your declaration:

I declare that as the product holder, I have evidence that each secondary step in the manufacture of this chemical product by the manufacturer at the new site of manufacture conforms to a standard that the APVMA has determined is comparable to the manufacturing principles and the Australian GMP Code.

Transfer of a site for analysis and testing (QC site)

For immunobiologicals, QC site transfers may be classified as prescribed variations (Item 13A) or technical variations (Item 14) depending on the test:

The transfer of biological assays (eg microbiological, or immunological potency assays) will be considered as technical variations for both local and overseas sites and requires an Item 14 application.

For technical transfers of biological assays (Item 14) the following data requirements apply:

• validation reports for the transfer of the QC assays to the new site
• confirmation that the specifications for the methods of analysis are identical/equivalent to those approved for the registered product, or a justification for any changes to the specification that does not impact safety and efficacy
• evidence of satisfactory GMP compliance for the new QC site.

The transfer of a site for analysis and testing where the test is a physical or chemical test will be considered as a prescribed variation (Item 13A) for both local and overseas sites. For this type of variation, the new site must hold appropriate GMP certification for the relevant tests (whether Australian or overseas) and the applicant must provide a declaration to this effect. Please use the words below in the declaration:

I declare that as the product holder, I have evidence that each secondary step in the manufacture of this chemical product by the manufacturer at the new site of manufacture conforms to a standard that the APVMA has determined is comparable to the manufacturing principles and the Australian GMP Code.

Name change of a manufacturing site

A variation to the name of either local or overseas manufacturing sites requires an Item 13A application.

Apply now

NOTE: For Item 13A applications, the application form is being updated to incorporate this type of prescribed variation. Until the form is updated, applicants should select the ‘Start Application’ button below which will say the purpose of the application is to vary the name and/or address of an Australian manufacturer of the chemical product (even though the variation is for an overseas site of manufacture).

Start Item 13A application

Start Item 14 application

You will be redirected to online services to log in. You will be able to select the appropriate modules once you have generated the decision ID.