The Impact of Annex 16 Adoption by PIC/S in Australia

The Therapeutic Goods Administration (TGA) is part of the Australian Federal Government’s Department of Health and regulates the supply, import, export, manufacturing, and advertising of therapeutic goods, including medicines in Australia.

As a Pharmaceutical Inspection Convention / Pharmaceutical Inspection Co-operation Scheme (PIC/S) member, the TGA has adopted the PIC/S Guide to Good Manufacturing Practice for Medicinal Products. However, the TGA and other PIC/S members, may not automatically adopt versions and annexes released by PIC/S. One such discrepancy exists with Annex 16 (referring to Qualified Person and Batch Release).

The current version of the PIC/S Guide adopted by the TGA (PE009-15) has an asterisk (*) marked against Annex 16, which denotes that “This Annex is specific to the EU GMP Guide and has not been adopted by PIC/S”.

In February 2022, PIC/S revised PE 009 from version 15 to version 16 to include Annex 16 on the Certification by the Authorised Person and Batch Release.

So, what does this all mean?

The European Union (EU) adopted its own GMP in 1989, equivalent to the PIC/S GMP guide regarding GMP requirements. That same year, the Therapeutic Goods Act 1989 was passed into Law in Australia. Since then, the EU and the PIC/S GMP Guides have been developed in parallel. The guides are practically identical, but not quite.

Prior to PE 009 version 16, PIC/S considered Annex 16 to be EU-specific and difficult to transpose for PIC/S purposes. Part of the reason was that PIC/S GMP Guide is limited to manufacturing medicinal products while the EU GMP includes import and distribution.

Q: Why did PIC/S not adopt Annex 16 initially?

A: EU Annex 16 entered into force in 2002; however, PIC/S did not deem it necessary to adopt the annex as it was EU-specific – in 2002 PIC/S had 24 inspectorates of which over a third were outside of the EU. However, when Annex 16 was revised in 2016, PIC/S re-assessed whether to transpose Annex 16 in the interest of international harmonisation for product release, as such the PIC/S Sub-Committee on GM(D)P Harmonization was mandated to transpose a PIC/S version of EU GMP Annex 16.

Q: What is the TGA’s current position on Annex 16?

A: The TGA currently has two guidance documents on Release For Supply, which explain the TGA’s interpretation and expectations for compliance with the release for supply requirements of the PIC/S Guide to GMP. These guidance documents are:
Release for supply of medicines
Technical guidance on the interpretation of the PIC/S Guide to GMP Version 3.0, February 2019*
and 
Releasing medicines manufactured at multiple sites 
Technical guidance on the interpretation of the PIC/S Guide to GMP Version 2.0, February 2019*
(* Guidances are not legal mandates)

PIC/S released PE 009-15 in May 2021, and on 1 July 2022, the TGA adopted PE 009-15 of the GMP Guide; the TGA doesn’t automatically adopt new versions of the PIC/S Guide for medicinal products, so although PE 009-16 was released in Feb 2022 companies currently inspected by the TGA are inspected for compliance to version 15 which does not include Annex 16.  The TGA is currently performing a gap analysis on the technical requirements of Annex 16; they will then consult with relevant stakeholders and assess the feedback received.

Q: What are the main differences between PIC/S Annex 16 and the TGA Guidance on Release For Supply?

A: Mainly just terminology, the intent of Annex 16 and the TGA Release For Supply Guidance are essentially the same - that the purpose of controlling batch release is to meet the Marketing Authorisation, GMP and other legal requirements. For terminology differences, Annex 16 states Conformation which is equivalent to Release for Further Processing from the TGA; Annex 16 states Certification which is equivalent to Release For Supply from the TGA.

However, there are some differences:

• Section 1.5 of the Annex states “For medicinal products manufactured outside the jurisdiction of a National Competent Authority, physical importation and certification are the final stages of manufacturing which precede the transfer to saleable stock of the batch, depending on national law.” For the TGA, this is currently not applicable unless specifically required in the Marketing Authorization
• Section 1.9 of Annex 16 states the requirements for parallel importation and parallel distribution, which is not applicable to the TGA as Australia does not permit parallel importation
• Section 3 of Annex 16 states the requirements for Handling of Unexpected Deviations, which permits a batch with unexpected deviations to be released if registered specifications are met, however, in Australia, the Therapeutics Goods Act includes penalties for the supply of products not conforming to standards and consent must be obtained from the TGA.
• A few sections are more detailed/explicit, such as Section 1.7 (List of Authorised Persons (AP’s) responsibilities) and section2 (Relying on GMP Assessments by Third Parties). The TGA is assessing the expectations based on a risk approach.
• Note that the scope of the Annex applies to medicines for human or veterinary use – in Australia veterinary medicines are currently under the Australian Pesticides and Veterinary Medicines Authority (APVMA) for veterinary medicines sold within Australian Territory.

It is not known when the TGA will adopt version 16 of the GMP Guide (which includes Annex 16 and revised Annex 13 Manufacture of Investigational Medicines), and to note that PIC/S have just published version 17 on their website, to come into effect on 25 August 2023 with the new Annex 1.

SeerPharma is routinely called to provide guidance on Release for Supply activities in Australia and address the expected requirements of QPs in Europe.

In addition, we have been engaged by companies to provide training on the requirements laid out by PIC/S and the approaches adopted by Australia and the EU.

Contact us to address any concerns you may have.