This week, the Therapeutic Goods Administration (TGA) announced that they will be adopting version 16 of the PIC/S Guide to GMP on 3rd June 2024 (PIC/S Guide to GMP for medicinal products – version 16 | Therapeutic Goods Administration (TGA)).

The differences between version 15 and 16 of PIC/S are:

·         Update of Annex 13 – Manufacture of Investigational Medicinal Products

·         New Annex 16 – Authorised Person and Batch Release.

There are no changes to Part I or Part II of the guide in version 16.

This article will take a comprehensive look at the new Annex 16, in relation to the current TGA release for supply guidances (Release for supply of medicines | Therapeutic Goods Administration (TGA)), and what it may mean for your Australian operations.

Why the New Annex 16?

In February 2022, PIC/S released version 16 of the Guide to Good Manufacturing Practice (GMP) for Medicinal Products with the revised Annex 13 and new Annex 16.

Annex 16 was a PIC/S adaptation of the European Union (EU) Annex 16, which was originally not adopted by PIC/S.

The PIC/S announcement states, “Initially PIC/S considered this annex to be EU-specific and difficult to transpose for PIC/S… in particular, since the PIC/S GMP Guide is limited to the manufacture of medicinal products and not to import and distribution. Following a consultation of PIC/S Participating Authorities in 2017, it was agreed to make an attempt to transpose EU Annex 16, considering that a PIC/S adaptation could offer added benefit to better convey expectations associated with product release. … PIC/S also agreed that elements in Annex 16 related to imported medicinal products would be voluntary, dependent on national law.” (see full announcement here News (picscheme.org)).

Not only is Annex 16 a comprehensive guidance on the Authorised Person’s (AP) duties and completing release for supply (RFS), it also includes detailed GMP guidance on finished product batch transport, import and export, and the relationship between multiple sites within the supply chain.

Overview of Annex 16

All of the requirements of the current TGA guidance in their technical papers on RFS and multisite RFS are covered within Annex 16.

There are some terminology differences, most notably Release For Further Processing (RFFP) is not used in Annex 16. The RFFP activities completed by an AP at one site in the supply chain for partial batch manufacture is referred to as Confirmation.

The annex is comprised of the following sections:

·         Scope

·         General Principles

·         1. The Process of Certification

·         2. Relying on GMP Assessments by Third Parties e.g. Audits

·         3. Handling of Unexpected Deviations

·         4. The Release of a Batch

·         Glossary

·         Appendix I – Recommended content of the confirmation of the partial manufacturing of a medicinal product

·         Appendix II – Recommended content of the Batch Certificate for Medicinal Products

What is the RFS Process?

Annex 16 states that the process of RFS is comprised of:

1.      Checking manufacture and testing of the batch meets release procedures i.e. often referred to as batch review

2.      Certifying by the AP that the batch complies with GMP and the requirements of the Marketing Authorisation (MA) i.e. the quality release of the batch, and

3.      The transfer to saleable stock and/or export of the batch that should take into account the certification performed by the Authorised Person. 

Section 1. The Process of Certification includes comprehensive GMP requirements specifying expectations for the AP. These meet the intent of the current TGA technical guidance for RFS, even though the TGA guidance is not as specific for some of the situations included in PIC/S Annex 16.

Some additional requirements include:

·         The AP must be able to prove their continuous training regarding the product type, product processes, technical advances and changes to GMP (Clause 1.2). This is easily demonstrated by having an Authorised Person module within the PQS training system.

·         For medicinal products manufactured outside the jurisdiction of [TGA], physical importation and certification are the final stages of manufacturing, which precede the transfer of saleable stock of the batch (depending on national law) (Clause 1.5).

·         The AP is responsible for ensuring that the finished medicinal product batch has undergone testing required upon importation (according to national law) (Clause 1.5.4)

Requirements for Samples and Transport

Annex 16 is also very prescriptive in terms of ensuring the compliance of samples and the transport of samples taken before importing a batch. Clauses 1.5.5 and 1.5.6 ensure that any samples are representative of the batch. If samples are taken prior to importation and they are transported with, or separately, from the batch, then a technical approach must be documented within the PQS, or within a quality agreement (if different companies).

When sampling is performed by the manufacturer located in another jurisdiction, then the technical justification must include a Quality Risk Management process to identify and manage any risks. Clause 1.5.6 outlines the minimal requirements that include:

1.      Conducting audits of the manufacturing activities including sampling

2.      Completing a scientific study with data to support conclusions that samples are representative of the batch after importation i.e. a detailed transport study

3.      Providing random periodic analysis of samples taken after importation to justify relying on samples taken in another jurisdiction

4.      Reviewing any unexpected results or confirmed out of specification (OOS) results, particularly if they implicate issues with relying on the sampling from another jurisdiction.

Requirements for Imported Batches from the Same Bulk Product Batch

Different imported finished product batches originating from the same bulk product batch may be required to be tested upon importation. In this case, the AP certifying the finished product batches may base their decisions on the QC testing of the first imported finished batch. This is provided there is a documented justification based on Quality Risk Management. Refer to Clause 1.5.7 for further details.

RFS Checklist Activities

Clauses 1.7.1 to 1.7.21 include activities required to be checked as part of RFS and available to the AP completing the batch certification. These are summarised below:

1.      All activities comply with GMP.

2.      The entire supply chain of active substances and medicinal product up to certification must be documented in a comprehensive diagram showing each party, including sub-contractors. This must be available for the AP. This includes all starting materials and packaging materials and any other materials critical to the manufacturing process (as deemed by quality risk management).

3.      All audits of sites involved in finished product or API manufacture and testing are complete and audit reports are available to the AP.

4.      All manufacture, analysis and certification meet the requirements of the MA for the intended jurisdiction.

5.      All manufacturing activities and testing are consistent with the MA.

6.      The source and specifications of starting materials and packaging materials used in the batch must comply with the MA. Supplier PQS/QMS must be in place to ensure the required product/material quality.

7.      APIs for finished products must be manufactured according to GMP and distributed according to Good Distribution Practices (GDP).

8.      APIs for medicinal products for human use must only be imported if the API manufacture and transport meets GMP and GDP, and that there is evidence that the  manufacturer complies with GMP if from a different jurisdiction.

9.      Excipients for medicines have been manufactured with appropriate GMP and should meet the PIC/S guidelines for risk assessment for excipients (PH 4/97 (picscheme.org)).

10.  The Transmissible Spongiform Encephalopathy (TSE) status of materials for a batch must comply with the terms of the MA.

11.  All records are complete and approved. All in-process controls and checks have been completed.

12.  All manufacturing and testing processes must remain in the validated state. Personnel must be trained and qualified as appropriate.

13.  QC test data complies with specifications described in the MA or the authorised Real Time Release Testing programme.

14.  Any regulatory post-marketing commitments relating to manufacture or testing have been addressed. Ongoing stability data continues to support the certification.

15.  The impact of any change to product manufacturing or testing has been evaluated and any checks and tests are complete.

16.  All investigations for a batch (including OOS and OOT) have been completed to support certification.

17.  A batch must not be certified if there are on-going complaints, investigations or recalls impacting the batch.

18.  The required technical agreements must be in place.

19.  The self-inspection programme is active and current.

20.  The appropriate arrangements for distribution and shipment are in place.

21.  Any required safety features have been attached to packaging, to enable wholesalers / distributors to verify authenticity of the medicine, identify individual packs, and verify if outer packaging has been tampered with.

Relying on GMP Assessments by Third Parties

This section in Annex 16 highlights the need for transparency and accuracy in audits of suppliers and manufacturing sites in relation to the ability of the AP to confidently certify the batch, especially when audits are completed by a third party. To do this, the AP must be confident in the audit outcomes before certifying any impacted batches.

Although this section details typical activities that should not be a surprise to anyone in the industry who understands Chapter 7 of Part I of PIC/S Guide to GMP, this annex formalises the requirements specifically for RFS. Clause 2.2 requires the following for the approval of audit reports:

·         Audit reports must address general GMP requirements associated with the PQS, production and QC related to the supply of product. All areas audited must be accurately described resulting in a detailed audit report.

·         Confirmation of whether the manufacture and QC of the API and/or medicine meets GMP, or at least equivalent GMP to that expected by TGA.

·         For outsourced activities, verify compliance with the MA.

·         The AP must ensure that a written assessment and approval of third party audit reports has been made. The AP must have access to all documents used in the review of the audit outcome and have continued reliance on the outsourced activity.

·         Outsourced activities with critical impact to product quality must be defined according to Quality Risk Management as per Annex 20 of PIC/S Guide to GMP. The AP must be aware of the outcome of an audit with critical impact to product quality before certifying relevant batches.

Handling Unexpected Deviations

Likewise, this section does not contain any surprises but again prescribes the requirements for deviation investigations with respect to RFS. Some key points are:

·         Investigations must be completed before certifying the batch. If root cause correction impacts the MA, then a variation may be required to release the batch.

·         Impact of deviations must be assessed according to Quality Risk Management and include evaluation of impact to product quality, efficacy and safety.

·         In the situation of shared responsibilities for RFS such as for partial manufacture, the AP completing the final batch certification must be aware of, and take into consideration, any deviations with the potential to impact compliance with GMP or the MA.

Release, Quarantine and Transfer

As per the current TGA RFS guidances, Annex 16 requires that uncertified batches either remain at the manufacturing site or be shipped under quarantine to another site with an appropriate TGA GMP license for this manufacturing step (and be included on the MA).

However, Annex 16 also stipulates further details:

·         Quarantine of uncertified batches is either via physical or electronic means to prevent a mix-up with saleable stock. These requirements also apply if the batch is moved to another registered site to prevent uncertified release.

·         Sites holding quarantined batches should receive formal, unambiguous notification from the AP of batch certification (and when the batch can be moved from quarantine). The steps required for notification should be included in a technical agreement. The notification from the AP must meet the GMP documentation compliance requirements described in Chapter 4 of Part I, PIC/S Guide to GMP.

Conclusions

This annex is a prescriptive guide to the GMP requirements for RFS. Where the current TGA technical guidances are high-level, Annex 16 resolves some applications of the GMPs in situations where the supply chain is complex or with multi-site scenarios.

There will be no surprises for anyone familiar with PIC/S GMP and the pharmaceutical industry, as this Annex is a natural extension of what we find in Part I of the PIC/S Guide to GMP. However, each facility should review the clauses in detail in light of their specific situations, particularly for complex supply chains and distribution pathways.

Need More?

Quality System Now has recently launched a new, premium course - Authorised Person Training – covering both the current TGA guidance requirements and those captured in Annex 16.

You can learn more about this training or contact us about getting ready for version 16 of PIC/S Guide to GMP, by clicking the link below:

Authorised Person Training