GMP requirements when manufacturing at multiple sites

The information presented in this section aims to help you understand how to apply the RFS requirements when complex manufacturing occurs, such as manufacturing at multiple sites and how release for further processing fits into the RFS process.

On this page: Sponsor responsibilities | Sponsor and manufacturer - joint RFFP responsibility | Manufacturer responsibilities | RFS authorised person responsibilities | RFFP authorised person responsibilities | GMP agreementS | RFFP documentation requirements

Sponsor responsibilities

The responsibilities listed here are in addition to all of the sponsor responsibilities, and joint responsibilities with the manufacturer, outlined in the release for supply of medicines guidance.

The sponsor is responsible for ensuring that:

• each ARTG entry has at least one TGA approved manufacturer (i.e. licensed or holding a current GMP clearance) responsible for each manufacturing step, including the RFS manufacturing step.

Traceability of release for supply

Where the ARTG entry of a medicine allows more than one RFS site of the finished product batch, the Australian sponsor is responsible for ensuring:

• the ability to identify:
  • the site at which any particular batch has been released for supply
  • the name of the authorised person responsible for releasing each batch
• inclusion in the batch records (for review by the authorised person conducting RFS) both the RFS site and RFS authorised person

Statements related to the shelf life and stability data

Sponsors are responsible for ensuring the authorised person performing RFS receives signed and dated written statements regarding the shelf life and stability for:

• Finished product:
  • a statement that summarises current approved shelf life allocated to the market authorisation and the current status of the ongoing stability testing for the finished product

    OR

  • a statement that summarises initial stability data of the finished product used to define the shelf life of the batch of finished product

    OR

  • a statement that justifies the applied shelf life of the finished product when initial long-term stability testing of listed medicines is being undertaken
• Intermediate or bulk product stored for more than three months:
  • a statement that summarises the initial stability data of the intermediate or bulk product used to define the shelf life and the current status of the ongoing stability testing of the intermediate or bulk product

    OR

  • a statement that justifies the applied shelf life of the intermediate or bulk product when undertaking initial long term stability testing of the intermediate or bulk product

Sponsor and manufacturer - joint RFFP responsibility

The PIC/S Guide to GMP identifies shared responsibilities between the sponsor (marketing authorisation holder) and the manufacturer.

Provide RFFP authorised person access to information

Where manufacture occurs across multiple sites the authorised person, performing RFFP to the next manufacturer in the supply chain, requires access to all information that is relevant to the manufacturing steps for which they are responsible.

Provide the authorised person(s) performing RFFP full access to all relevant aspects of:

• the marketing authorisation, including details in the ARTG and other matters agreed on in writing between TGA and the Australian sponsor
• the manufacturing steps, if a TGA-licenced manufacturer, including:
  • the licence to manufacture therapeutic goods
  • all authorisations and conditions under the licence
  • the steps in manufacture granted under section 38, Therapeutic Goods Act 1989 and conditions of licences as imposed under section 40, Therapeutic Goods Act 1989
• the manufacturing steps, if an overseas manufacturer:
  • the TGA GMP certificate and GMP clearances
  • all authorisations and conditions, as imposed under sections 25(1)(g), 26(1)(g) and 26A(3, Therapeutic Goods Act 1989
• the PIC/S Guide to GMP as specified in the current manufacturing principles
• default standards under section 10 of the Therapeutic Goods Act 1989
• all applicable Therapeutic Goods Orders

Manufacturer responsibilities

In addition to the manufacturer RFS responsibilities, for medicines manufactured at more than one site, each manufacturer in the supply chain is to ensure their PQS contains:

• detailed procedures and responsibilities for RFFP to the next manufacturer in the supply chain, where applicable
• detailed release for supply procedures, where applicable

RFS authorised person responsibilities

Release for supply of medicines outlines the responsibilities of an authorised person performing RFS. When manufacture occurs at multiple sites, the authorised person performing RFS of the finished product batch is allowed to rely on decisions of delegated authorised persons.

Delegated authorised persons

A delegated authorised person can either be working:

• within the same company (on the same site or on a different site)

  OR

• with another manufacturer

A delegated authorised person has specific responsibilities when performing RFFP.

Additional responsibilities of RFS authorised persons

When manufacture occurs at multiple sites, there are additional responsibilities for the authorised persons performing RFS, including:

• reviewing the complete RFFP documentation
• relying on decision of other authorised persons

Relying on decisions of other authorised person(s)

The authorised person performing release for supply can only rely on decisions by other authorised persons when all necessary steps have been completed through an appropriate PQS and all of the following conditions are met:

1. All authorised person(s) have full access to all parts of the marketing authorisation that are relevant for the manufacturing steps performed at the site for which they are the authorised person.
2. All partial manufacturers must be covered by valid GMP agreements that define RFFP to the next manufacturer in the supply chain.
3. The PQS at each manufacturing site has detailed information on the release procedures.
4. All decisions on RFFP to the next manufacturer in the supply chain are recorded through a legally valid signature. For example, a full written signature either:
   1. on a paper document

      OR

   2. an electronic signature in a validated electronic environment (note Annex 11 of the PIC/S Guide to GMP)
5. The authorised person performing RFS has accepted the PQS used for RFFP, for example through the supplier qualification program.
6. The authorised person at each site performing RFFP is required to fulfil the RFFP authorised person responsibilities described below.

The level of evidence required for the authorised person responsible for RFS to be confident of compliance with these conditions depends on the type of products manufactured.

RFFP authorised person responsibilities

All RFFP decisions are made by an authorised person, or delegate, including a review of the supporting documentation package.

The responsibilities of the RFFP authorised person are to:

• have access to the all parts of the marketing authorisation that are relevant for the steps in manufacture performed at the site for which they are the authorised person
• follow the release procedures described in the PQS
• record all decisions regarding RFFP through a legally valid signature, for example:
  • full written signature on a paper document
  • electronic signature in a validated electronic environment (note Annex 11 of the PIC/S Guide to GMP)
• complete the RFFP documentation requirements
• ensure the RFS authorised person receives all RFFP documentation prior to RFS by:
  • sending all RFFP documentation for each batch, including RFFP documents from previous manufacturing steps, to the authorised person at the next manufacturing site
  • providing all relevant product quality review (PQR) data to the manufacturer performing RFS

Where two consecutive RFS steps occur, refer to scenario 2.

GMP agreements

Sponsors and manufacturers are required to establish valid GMP agreements to cover all partial manufacturers in the supply chain, in accordance with the PIC/S Guide to GMP.

Valid GMP agreements

Valid GMP agreements are to:

• clearly define the RFFP to the next manufacturer in the supply chain, as applicable
• clearly establish responsibilities for all GMP related activities at each licenced or certified site.
• specify how the RFS authorised person ensures that each batch has been manufactured and checked for compliance with the marketing authorisation, where applicable
• include an obligation on all providers of bulk or intermediate product to notify the recipient(s) of any:
  • significant deviations from the agreed production process
  • out-of-specification results
  • non-compliance with GMP
  • investigations
  • complaints
  • other matters that should be taken into account by the RFS authorised person.

Ongoing stability programs

The manufacturer(s) performing release for supply and the sponsor share the responsibility to ensure an ongoing stability program of the finished product is conducted.

GMP agreements are to detail these mutual responsibilities, by ensuring:

• a mechanism is described for how the authorised person conducting RFS obtains access to the ongoing stability data as required, e.g. inspections, recalls, complaints
• a mechanism is described for how the TGA inspector obtains access to the ongoing stability data during an inspection of the RFS manufacturer, if the RFS manufacturer is not the compiler of stability data

Product quality reviews (PQR)

GMP agreements are to detail the mutual responsibilities concerning the PQR, ensuring:

• which manufacturer in the supply chain, or the sponsor, is responsible for compiling the PQR data into the complete PQR
• the process for communicating all the relevant PQR information to the compiler
• a mechanism to ensure that the full PQR is accessible by the authorised person at the site undertaking RFS, as required, e.g. inspections, recalls, complaints
• a mechanism for the TGA inspector to obtain the PQR during an inspection of the RFS manufacturer, if the RFS manufacturer is not the PQR compiler.

Arrangements for collecting PQR data

Where multiple manufacturers are involved in the manufacture of a product:

• each (contract) manufacturer will normally:
  • prepare the data for the PQRs of the manufacturing steps performed by that manufacturer
  • submit the relevant PQR data to the manufacturer performing RFS of the finished product batch
• the manufacturer responsible for RFS is responsible for:
  • collating the data into complete PQRs
• the authorised person performing RFS must consider the results within the context of the PQR findings

You can consider other arrangements, as long as all the relevant data are provided to one manufacturer in the supply chain or to the sponsor who prepares complete PQRs. In that case, you must clearly define the arrangements in all applicable GMP agreements.

RFFP documentation requirements

This information is relevant when manufacture of a batch of product occurs at more than one manufacturing site.

The authorised person at each manufacturing site is required to:

• complete an identical minimum RFFP documentation package
• send the RFFP documentation package to the next authorised person in the chain of manufacture
• accumulate all of the RFFP documents so that the authorised person performing RFS can review the full set of RFFP documents

Minimum RFFP documentation package

The minimum RFFP documentation package is to be printed showing the company letterhead and signed and dated by the authorised person. If you are using computer systems to record RFFP decisions, take note of Annex 11 of the PIC/S Guide to GMP.

The RFFP documentation package comprises:

• product name
• product code
• batch number
• assurances that:
  • the step(s) in manufacture for the batch have been undertaken in compliance with Australian marketing authorisation, where applicable
  • any deviations that may impact medicine quality, efficacy or shelf life have been resolved
  • there are no investigations, complaints or other matters that may impact product quality, efficacy or shelf life that should be taken into account by the authorised person responsible for RFS
  • the storage conditions on the label are consistent with the shelf life of the finished product
  • quality risk management principles were applied to develop an approach tailored to the risk situation
  • the information and data relating to manufacture of the batch has been added to the PQR program at the site and that an annual review of that information and data is part of that program
• Acknowledgement that a mechanism has been established to allow relevant PQR and ongoing stability data and reviews to be provided to the authorised person at the site performing the RFS step in manufacture.

The sponsor is responsible for ensuring that the authorised person conducting RFS receives appropriate information about shelf life and stability data.

Certificate of Analysis

The entity with GMP responsibility for compiling the testing results of the batch is also responsible for adding the relevant Certificate of Analysis for each batch to the accumulating RFFP documentation package.