Release for supply scenarios when manufacturing at multiple sites

These scenarios relate to medicines manufactured at multiple manufacturing sites.

The scenarios provided:

• aim to demonstrate how RFFP and RFS steps relate to each other
• do not represent all possible scenarios
• are designed to be updated, where additional information is requested from industry.

We describe the following scenarios:

Scenario 1 – RFS from a secondary packaging site

In this scenario, release for supply occurs at a secondary packaging site (Site 2). The primary packaging occurs at a different site (Site 1) and is released for further processing.

Scenario 2 – Two consecutive RFS steps

In this scenario, release for supply occurs twice. After RFS, the product requires relabelling or additional secondary packaging, requiring a second RFS step.

We provided an additional scenario for medicinal gases in our medicinal gas guidance.

Scenario 1 - RFS from a secondary packaging site

In this scenario:

Manufacturing steps that occur at site(s) 1 include:

• bulk product manufacture and primary packaging
• release for further processing, performed by authorised person 1 (AP1)

Manufacturing steps that occur at site 2 include:

• labelling and/or secondary packaging
• release for supply of the finished product, performed by authorised person 2 (AP2)

Specific examples of labelling or secondary packaging steps include:

• a bottle is placed in a carton
• the consumer medicine information (CMI) is added to the product
• the medicine is over-labelled or relabelled
• a carton is added or replaced
• the pack size is changed without changing the primary pack, e.g. changing the number of blister cards in a pack

Text description of flow chart

Flow chart for release for supply from a secondary packaging site:

• Bulk product manufacture and primary packaging occurs at site(s) 1.
• Release for further processing is performed by authorised person 1 at site(s) 1.
• Labelling and/or secondary packaging occurs at site 2.
• Release for supply by authorised person 2 occurs at site(s) 2.

Description of specific issues

In this scenario:

• The labelling and/or secondary packaging performed at the secondary site did not alter the primary packaging or the stability profile.
• Additional stability would not normally be required, as the stability profile is not changed.
• Site 1 would be required to take responsibility for:
  • ongoing stability for the primary packaged product
  • compiling the full PQR
• Authorised person 1 at site 1 performing RFFP has:
  • certified that the bulk and primary packaging was manufactured in accordance with the market authorisation, where applicable
  • provided authorised person 2, conducting RFS at site 2, with the complete RFFP documentation

Meeting GMP compliance

RFFP authorised person

The authorised person performing RFFP is to perform all duties of an authorised person as outlined in RFFP authorised person responsibilities.

In this scenario, authorised person 1, performing RFFP, is required to provide the minimum RFFP documentation to the RFS authorised person 2, including:

• a Certificate of Analysis for the batch
• a batch specific certification for compliance to the Australian marketing authorisation for the steps of manufacture covered. This should include, for example but not limited to:
  • assurance that the batch has been manufactured in accordance with the marketing authorisation
  • assurance that any deviations that may impact medicine quality, efficacy, safety and shelf life have been resolved
  • verification that product storage has met requirements
• a declaration that the PQR and ongoing stability data have been performed, are current, and meet specifications, GMP requirements and the marketing authorisation

RFS authorised person

The authorised person performing RFS at Site 2 is to performing all duties of an authorised person for RFS as outlined in release for supply of medicinal products

In this scenario, authorised person 2 performing RFS is required to rely on the RFFP documentation package from authorised person 1 at site(s) 1.

Risk assessment

In this scenario, we expect a formal risk assessment to be completed, prior to the secondary packaging steps, to demonstrate that the:

• additional steps represent no further risk to the product
• modifications being performed either:
  • have no impact on stability
  • has an impact on stability, in which case, authorised person 2 is expected to verify the suitability of the secondary packaging process

Ongoing stability

The manufacturer performing release for supply and the sponsor need to fulfil the requirements detailed in their GMP agreement.

In this scenario:

• all applicable aspects of manufacture, up to the step of RFFP from site(s) 1, were completed in accordance with PIC/S Guide to GMP requirements
• the additional steps at Site 2:
  • represent no further risk to the product
  • do not change the product expiry date

Product quality review

The PQR is required to cover all relevant steps of manufacture, including the packaging steps. The manufacturer performing RFS and the sponsor need to fulfil the requirements detailed in their GMP agreement.

In this scenario, the established GMP agreement could specify that:

• authorised person 1 at site 1 is responsible for compiling the full PQR
• authorised person 2 at site 2 communicates any information from the secondary packaging step, relevant to compiling the PQR, to authorised person 1 at site 1
• full PQR information will be accessible to authorised person 2 performing RFS at site 2, as required e.g. inspection, recalls, complaints etc.

Information for TGA inspectors

In this scenario, during an inspection of Site 2, the TGA inspector will need access to ongoing stability data and PQRs.

Scenario 2 – Two consecutive RFS steps

In this scenario, RFS occurs twice. Following the first RFS, the product undergoes relabelling or additional secondary packaging steps. These extra steps require an additional RFS step.

The following manufacturing steps occur at site(s) 1:

• the bulk product manufacture, primary and secondary packaging
• release for supply is conducted by authorised person 1 (AP1)

The following manufacturing steps occur at site 2:

• re-labelling and/or secondary packaging
• release for supply conducted by authorised person 2 (AP2)

A secondary RFS step due to relabelling or secondary repackaging may occur, in examples such as but not limited to, when:

• the product is modified following a change to marketing authorisation, requiring:
  • addition of changed CMI
  • over-labelling or relabelling
  • carton change or add an additional carton
  • change or add an additional carton

Flow chart

Text description of flow chart

Flow chart for two consecutive RFS steps:

• Bulk product manufacture, primary and secondary packaging occurs at site(s) 1.
• Release for supply conducted by authorised person 1, at site(s) 1.
• Re-labelling and/or secondary packaging occurs at site 2.
• Release for supply conducted by authorised person 2, at site 2.

Description of specific issues

In this scenario:

• the primary packaging is not altered between the two RFS steps, so there is no change to the stability profile
• no changes are made to the product expiry date between the first RFS step and the second RFS step
• at the first RFS step, the authorised person certified that manufacturing of the product occurred in accordance with both:
  • the marketing authorisation
  • the PIC/S Guide to GMP requirements.

In this situation, it is acceptable that the authorised person 2, performing the RFS from site 2, relies on the certification and supporting documentation from the first RFS step from site 1.

Addressing GMP compliance

First RFS

The authorised person performing RFS is to performing all duties of an authorised person for RFS as outlined in release for supply of medicinal products

In this scenario, authorised person 1, conducting RFS from site 1, provides the RFS certification to the authorised person at site 2, as the product had already been released.

Second RFS

The authorised person 2, performing RFS from site 2:

• is also required to perform all the duties of an authorised person outlined in release for supply of medicinal products
• requires receipt of the initial RFS certification from site 1
• is required to address the issues below

Risk assessment

In this scenario, a formal risk assessment is required, prior to the repackaging steps, clearly demonstrating that the:

• modifications being performed have either:
  • no impact on stability
  • an impact on stability and the suitability of the secondary packaging process is verified by authorised person 2
• information generated is suitable for:
  • verifying the consistency of the existing process
  • verifying the appropriateness of current specifications for both starting materials and finished product
  • highlighting any trends
  • identifying possible product and process improvements

The additional steps should create no extra risk.

Ongoing stability data

The manufacturer performing release for supply and the sponsor need to fulfil the requirements detailed in their GMP agreement.

In this scenario, the established GMP agreement could specify that ongoing stability data will be accessible to authorised person 2 at the site conducting secondary re-packaging and undertaking release for supply, as required e.g. inspection, recalls, complaints etc.

Product quality review

The PQR is required to cover all relevant steps of manufacture, including the packaging steps. The manufacturer performing RFS and the sponsor need to fulfil the requirements detailed in their GMP agreement.

In this scenario, the established GMP agreement could specify that:

• authorised person 1 is responsible for compiling the full PQR
• the secondary re-packaging manufacturer prepares the PQR for their step of manufacture and provides this to authorised person 1 to prepare the full PQR

Information for TGA inspectors

During an inspection of Site 1 or Site 2, the TGA inspector needs access to ongoing stability data and PQRs.