New TGA GMP guidance – PIC/S Guide to GMP PE009-16 

The TGA has published new guidance giving clause-by-clause comments on Good Manufacturing Practice (GMP) requirements for medicinal products: PIC/S Guide to GMP Version 16 (PE009-16), and is consistent with information that CMA previously sent members in the TGA’s Gap Analysis. However new TGA web information has caused a lack of clarity over the TGA’s expectations, which is still to be resolved as described below. 

The Therapeutic Goods (Manufacturing Principles) Amendment Determination 2024 has been published on FRL, to declare Version 16 of the PIC/S Guide to GMP (PE009-16) as the TGA’s Manufacturing Principles. It replaces Version 15 (PE 009-15). All minor clarifications in Annex 13 – Investigational Medicinal Products are in force from 3 June 2024. The most significant update is inclusion of Annex 16 (Authorised person and batch release), in effect on 3 September 2024. This delayed adoption of Annex 16 was at CMA’s request, to provide manufacturers extra time to review the changes, on the basis of TGA verbal feedback that essentially no changes to existing processes were required. This was to be explained through TGA’s publication of Interpretative Guidance in early June. 

However, the new guidance published does NOT also include the Interpretative Guidance that we were expecting the TGA to release at the same time, and it is not abundantly clear in the guidance for clause 1.7.3 what the TGA’s expectations will be for sharing of audit reports, due to some conflicting information. Therefore, CMA have followed up with the Manufacturing Quality Branch (MQB) of the TGA about whether evidence of a license or certification is sufficient for listed medicine manufacturers, or whether greater access to audit reports are required by the AP. MQB provided that further internal discussion is required, before further consultation with CMA, after which finalisation of the Interpretative Guidance will occur by September, including information on “Mechanism for access of the audit report to the Authorised Person”. 

Due to the current confusing messaging from the TGA in the guidance and new webpage, and the lack of Interpretative Guidance to provide clarity, CMA has lodged an objection with the MQB to the following TGA webpage statements: 

  1. “Steps to be completed (by) 3 September 2024: 
  • Full implementation.  
  • Mechanism for access of the audit report to the Authorised Person established. 

And 

  1. “The TGA’s expectation is that by 3 September 2024 manufacturers will have:  
  • completed their assessment of the impact of the Annex 16 on their operations; and 
  • completed updating quality systems documentation and implementing revised practices.” 

Our objection is that manufacturers cannot be expected to perform the above in the stated timeframe, in the absence of full clarity of TGA expectations through final Interpretative Guidance, particularly for clause 1.7.3. 

CMA have also re-iterated to MQB that manufacturers would not be willing or able to share their TGA audit reports with other businesses due to confidentiality issues. If the TGA eventually outline that there any other changes to processes, documentation or Quality Management Systems would be required as a result of this clause or others in Annex 16, it would require an additional 12-month transition for industry as these process changes are lengthy to implement. 

Note: This Interpretative Guidance will also later be accompanied by a future updated Release for Supply (RFS) guidance, which is also actively under review between the TGA and industry bodies including CMA. 

Published guidance summary relating to listed medicines 

The new guidance includes tables that provide a summary of the new Annex 16 requirements (pp. 29 -79) and TGA comments against each one. 

The TGA provide that their Release for Supply (RFS) guidance and Guidance for Releasing medicines manufactured at multiple sites was based substantially on the EU GMP Annex 16 that was in effect at that time, and is substantially similar to Annex 16 in the PIC/S Guide to GMP Version 16. In other words, the TGA consider that there are no major changes to TGA’s operational expectations – however as noted earlier, this is yet to be confirmed by publication of the final guidances – rather, the adoption of Annex 16 means that the expectations that were outlined as TGA guidance only are now be formalised requirements for manufacturers. 

The new guidance addresses some concerns and questions raised by CMA on behalf the complementary and listed medicine industry for Annex 16 during the Gap Analysis, however full clarification through Interpretative Guidance on sections of Annex 16, including those below, is required to ensure there is not misunderstandings of expectations between industry and TGA inspectors. 

  • Clause 1.4.2 (responsibility of the Authorised Person). The new statement relating to the responsibility of ‘Authorised Persons’ (APs) is not intended by TGA to invoke any new or additional requirements for the AP, but rather reiterates the responsibilities of Sponsors APs at manufacturing premises. CMA has confirmed with the TGA that the AP is not expected to have any new qualifications under this clause, and is still able to rely on the existing TGA guidance about releasing medicines manufactured under multiple sites. The guidance for this clause (p37) includes: 

Annex 16 uses the existing term “Certification” which is essentially synonymous with the TGA term “Release for Supply” as described in our existing Guidance for Release for Supply. 

Batch ‘Certification’ is usually performed by the last Authorised Person in the process of manufacturing the goods. The process ensures that each preceding step in the manufacture of the goods have has been performed in accordance with Good Manufacturing Practice, the Marketing Authorisation, (or CTA) the terms of the Technical quality agreement and any other regulations relevant to the goods.  

New text is essentially identical to text included in the TGA’s existing Guidance for Release for Supply. – e.g. refer to “Authorised person responsibilities” and the Guidance for Releasing medicines manufactured at multiple sites – e.g. refer to “RFS authorised person responsibilities” 

  • Clause 1.7.3 (audit reports are available to the AP performing the certification): CMA raised concerns that the new clause 1.7.3 requires that a person performing RFS has to have access to audit reports across supply chain, which is not feasible due to commercial-in-confidence concerns. 

The TGA has clarified that for suppliers of starting materials, current guidance would continue to apply, and that current supplier approval processes (questionnaires, testing of deliveries etc.) would be considered sufficient ‘audit’. 

The TGA also clarify that there is currently no expectation that additional audits will be conducted of listed medicine contract manufacturers in the supply chain, in addition to those inspections conducted by TGA or other approved regulator. 

The below information from the guidance also discusses acceptable evidence for clause 7.4.1 is that the contract manufacturer holds a TGA licence or certificate for the relevant steps in manufacture. While we believe this is meant to mean that the licence or certificate is adequate evidence for the AP to rely on for clause 1.7.3 without being required to share TGA audit reports with other manufacturers, it is not abundantly clear. The guidance also provides some contradictory information to the effect that “Annex 16 specifically requires audit reports to be made available to the AP” and the TGA webpage communicates manufacturers are to “Mechanism for access of the audit report to the Authorised Person established” by 3 Sep 2024. Due to this mixed messaging we have lodged the objection to the timeframes outlined on the TGA webpage as previously outlined, until such time confirmation can be received that no process changes are required (that the TGA license or certificate is sufficient evidence for the AP to perform RFS certification on steps of manufacture performed by other manufacturers licensed or certified to perform that step). 

Listed medicines are discussed specifically on p53 of the guidance: 

‘For listed medicines: 

Current guidance regarding Supplier assessment, approval and qualification for listed and complementary medicines would continue to apply for the control of starting materials used in the manufacture of listed and complementary medicines.  

The current supplier approval processes (questionnaires, testing of deliveries etc) would be considered sufficient ‘audit’ for listed medicines API manufacturer 

There is currently no expectation that additional audits will be conducted of listed medicine contract manufacturers in the supply chain, in addition to those inspections conducted by TGA or other approved regulator. It is deemed acceptable evidence for clause 7.4.1 that the contract manufacturer holds a TGA licence or certificate for the relevant steps in manufacture.  

Clause 7.14 states that an audit should be permitted. It doesn’t mandate that it must occur. 

(7.4.1) Prior to outsourcing activities, the Contract Giver is responsible for assessing the legality, suitability and the competence of the Contract Acceptor to carry out successfully the outsourced activities. The Contract Giver is also responsible for ensuring by means of the contract that the principles and guidelines of GMP as interpreted in this Guide are followed. 

The contract should permit the Contract Giver to audit outsourced activities, performed by the Contract Acceptor or their mutually agreed subcontractors. 

Duties of an authorised person performing RFS 

Before release of a production batch for supply, the authorised person is responsible for ensuring: 

  • all necessary steps have been completed in accordance with the pharmaceutical quality system (PQS), regardless of how many sites are involved 

GMP internal audits and supplier audit systems are operational 

GMP Release for supply guidance is also being prepared for medicines that are not registered medicines to meet this clause.’ 

  • Clause 1.7.8 (Importation of Active substances used in the manufacture of medicinal products for human use) 

Listed medicines are specifically mentioned on p57 of the guidance: 

‘For listed medicines: 

Current guidance regarding Supplier assessment, approval and qualification for listed and complementary medicines would continue to apply for the control of starting materials used in the manufacture of listed and complementary medicines. Confirmation of the suitability of active substances and suppliers may be provided by APs within the supply chain during batch Confirmation (RFFP). 

  • Clause 1.7.9 (The excipients used to manufacture a medicinal product have been manufactured with an appropriate good manufacturing practice.) CMA sought clarification, and similarly to 1.7.3 for starting materials, normal supplier assessment processes will continue to apply for listed medicine excipients. See p59

‘For listed medicines: 

Current guidance regarding Supplier assessment, approval and qualification for listed and complementary medicines would continue to apply for the control of starting materials used in the manufacture of listed and complementary medicines. Confirmation of the suitability of excipient and suppliers may be provided by APs within the supply chain during batch Confirmation (RFFP).’ 

  • Clause 2.0 (Relying on GMP assessments by third parties, e.g. audits). CMA raised concerns that the clause requires the AP performing RFS to have access to the audit reports for all manufacturers within the supply chain as Active pharmaceutical ingredient (API) manufacturers are not always audited, and this clause did not specifically consider the impact on listed medicines. The TGA has clarified that reliance upon third party audits is not mandatory, but the sections outlined in the guidance would apply where this practice occurs. Where the manufacturer/sponsor is relying on supplier audits, this would be sufficient for listed medicines (see above information for 1.7.3, 1.7.8 and 1.7.9). The TGA has also provided that the new text is similar in intent to text included in the TGA’s existing Guidance for RFS.  
  • Clause 2.2 (Special focus should be given to the approval of audit reports). CMA raised concerns that the new clause 2.2 required clarification to specify that audit reports may not be accessible and therefore is not practical for listed medicines. The TGA has clarified that reliance upon third party audits is not mandatory, but these sections would apply where this practice occurs; and for listed medicines, see p72 of the guidance: 

‘For listed medicines: 

The AP must hold evidence that each contract manufacturer used in the manufacture of a particular batch holds a TGA licence or certificate for the relevant steps in manufacture undertaken.’ 

If members identify any areas of the new guidance that appear to be inconsistent with current industry practice, or other areas of concern, they can provide feedback to CMA via technical@cmaustralia.org.au.    

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