PIC/S PE 009-16 update, part 2: New Annex 16 vs Release For Supply

This is the second of a two-part blog covering the changes to PIC/S version 16. Previously we discussed changes to Annex 13 – Manufacture of Investigative Medicinal Products, and today I am doing a comparison of the new Annex 16Certification by the Authorised Person and Batch Release and comparing it against the TGA’s Release for Supply of Medicines guidelines (version 3, published February 2019) to see if there are any gaps that the Australian industry needs to watch out for.

Going through the new Annex 16, I have noticed that the EU GMP Annex 16 Certification by a Qualified Person and Batch Release (EudraLex, Volume 4) has been adapted for PIC/S as part of their continued effort to harmonise international requirements. This annex applies to the batch release of an authorised medicinal product as defined by its Marketing Authorisation (MA) and an investigational medicinal product as defined by its Clinical Trial Authorisation (CTA).

The terms, interpretation and application of PIC/S GMP requirements have been kept equivalent with the EU GMP Guide, for example, the PIC/S term of “Authorised Person” and the EU term of “Qualified Person” are equivalent.

Comparison of PIC/S Annex 16 with TGA’s Release for Supply of Medicines

The table below provides a comparison of the new Annex 16 with the TGA’s Release for Supply of Medicines guidelines:

PE 009-16 Annex 16Release for Supply of Medicines (version 3.0)Comments
Application: • Medicinal products for human or veterinary use. • IMPs for human use (subject to any legal differences and specific guidance published by PIC/S Participating Authorities under their national laws). • Products intended to be released within domestic markets or for export. • AP’s certification and subsequent release of medicinal products controlled on release by a National Competent Authority under national law (e.g. immunological products and certain blood).Application: All medicines on the ARTG: • Listed medicines • Registered medicines • Export-only medicines • Medicinal gases (additional information in Medicinal Gas guidance – release for supply) • Biological medicines (e.g. vaccines & biotechnology products) Phase 2 onwards clinical trials Extemporaneously compounded medicines.Equivalent principles. For veterinary products - “release for supply is the process of ensuring a batch of finished veterinary chemical product meets all required quality standards and is suitable to be released for sale”. APVMA’s website definition, “Release for Supply”.
Does not apply to: Any controls on release of medicinal products by a National Competent Authority under national law (e.g. certain blood and immunological products).Does not apply to: • Medical devices • Manufacture of API • Phase 1 clinical trials • Biologicals - Products covered under the regulatory framework for biologicals. • Specific requirements for biological medicines under Official Control Authority Batch Release.N/A
What is Certification and Batch Release? A process of controlling batch release to ensure that: • The batch has been manufactured and checked in accordance with the requirements of its MA and the principles and guidelines of GMP. • Any other applicable legal requirements are taken into consideration. • In the event of quality defects investigations or a batch recalled, the AP involved in batch certification or confirmation of compliance and any relevant records are readily identifiable. Certification is permitted under the terms of any authorisation by the National Competent Authority. Additional requirements, as applicable under the national law, are complied with.What is Release for Supply (RFS)? A process of verification of all production and quality control testing records of a batch comply with Chapters 2 & 3 of the Therapeutic Goods Act (TGA) 1989. Is mandatory for medicinal products manufactured according to GMP. Is the last manufacturing step. Is a licensable step in manufacture within Australia.N/A
Responsibilities: The Marketing Authorisation Holder (MAH): • is responsible for the performance of the medicinal product over its lifetime (safety, quality and efficacy). • can perform market release taking into consideration the certification of the finished product by the manufacturer. Manufacturer/Importer: • each manufacturing site must have at least one AP to perform batch certification. • are detailed in the MA. The Authorised Person (AP): • is responsible for ensuring that each individual finished product batch has been manufactured and checked in compliance with national requirements in accordance with: - the requirements of the marketing authorisation (MA) - Good Manufacturing Practice (GMP).Responsibilities: The Sponsor (the MAH): • is responsible for sharing information with a contracted manufacturer or AP (e.g. access to the relevant information in the MA, where applicable); • shares responsibilities with the manufacturer, as follows: - Ability to recall a batch - GMP agreements - Ongoing stability data and Product Quality Reviews (PQRs). - Provides APs access to information Sponsors wanting to conduct RFS have additional responsibilities (e.g. hold a TGA licence). Manufacturer: • Has a TGA licence or a current GMP clearance for all manufacturing steps performed. • Manufacturing is compliant with any MAs. • Has at least one AP available at each manufacturing site (in Australia or overseas). • Ensures traceability of each batch. • Has an established Pharmaceutical Quality System (PQS) • Has valid GMP agreements for any outsourced activities. • Shared responsibilities with the sponsor, as per above. The Authorised Person (AP): • must certify that each batch has been manufactured and controlled in accordance with: - Marketing Authorisation (MA) requirements, where applicable - Other regulations relevant to the production, control and release of the product.Equivalent principles.
Certification Process The AP has the responsibility for ensuring the following information is verified: As a note, because the AP depends on the PQS, there should be an ongoing assurance that the PQS is reliable. • All activities associated with manufacturing and testing of the medicinal product has been conducted following the principles and guidelines of GMP. • The entire supply chain of the active substance and medicinal product up to the stage of certification is documented and available to the AP. • All audits of sites involved in the manufacture and testing of the medicinal products and in the manufacture of the active substance have been carried out and the reports are available to the AP. • All sites of manufacture, analysis and certification are compliant with the MA for the intended jurisdiction. • The source and specifications of starting and packaging materials used are compliant with the MA. Ensures that only materials of the required quality have been supplied. • The active substances used have been manufactured in accordance with GMP and distributed in accordance with GDP, where required. • When relevant, the TSE status of all materials used in batch manufacture is compliant with the terms of the MA. • All manufacturing and testing processes remain in a validated state. Personnel are trained and qualified as appropriate. • Finished product test data complies with the Finished Product Specifications (FPS) described in the MA, or where authorised, the Real Time Release testing programme. • On-going stability data supports certification. • All investigations have been completed and the impact of any change to manufacturing or testing have been evaluated. • All records are completed and endorsed by the appropriate personnel. All required in-process checks and controls have been made. • Technical agreements, active and current self-inspection program and arrangements for distribution and shipment are in place. • Where required by the national law, safety features have been affixed to the packaging enabling wholesale distributers and persons authorised to supply medicinal products to the public to: - Verify the authenticity of the medicinal product - Identify individual packs - Verify if the outer packaging has been tampered with. • Individual relevant PE 009-16 Annexes are applied. • Where an unexpected deviation, concerning manufacturing process and/or the analytical control methods, from details contained within the MA and/or GMP has occurred, a submission of a variation to the MA for the continued manufacture of the product may be required. • The certification process must be recorded by the AP in a document provided for that purpose and in accordance with Annex 16 and national law.Release for Supply Process The information described below, and any other relevant information should be obtained and reviewed by the AP: GMP of manufacturer(s) • The current TGA-licence or GMP-clearance. • All relevant manufacturing steps are covered. • The manufacturer of the batch is included in the ARTG entry. If the product is manufactured are at multiple sites: • All manufacturers are included in the ARTG entry • All manufacturers hold a current TGA licence or GMP-clearance • All relevant steps are covered by the appropriate licence or clearance. GMP agreements • A GMP agreements in place between the sponsor (MAH) and manufacturer if they are different entities. • For multiple manufacturing sites, a GMP agreement is in place between the manufacturers and the partial manufacturers, in accordance with PIC/S. Acceptability of PQS If manufacturing takes place at multiple sites: • The PQS describes all manufacturing steps – the PQS can be accepted through the supplier qualification program. • There is an ongoing assurance that the PQS is reliable. • GMP internal audits and supplier audit systems of the manufacturers are operational. Validating processes The principal manufacturing and release testing processes (as per the finished product specifications) have been validated taking into account actual production conditions, manufacturing and test records. Batch records RFS involves verification of all production and quality control testing records of a batch. • Batch production and testing checks • Traceability • Deviations and changes • Product quality review and stability testing. Release for supply verification is performed through a legally valid and dated signature of an AP.Equivalent principles. As a note, if the “Release for Supply of Medicines” does not specifically ask for a TSE Certificate, the current industry practice is to have one.
Multiple sites If several sites are involved in various stages of manufacture, importation, testing and storage, the AP performing certification must ensure that all steps have been completed under accepted PQS to ensure compliance of the batch with GMP, the MA and any other national requirements where the certification takes place. If a site undertakes only partial manufacturing operations, then the AP at that site must at least confirm that the operations undertaken by the site have been performed in accordance with GMP and the written agreement terms. If the AP is responsible for providing confirmation of compliance for those operations with the relevant MA, the AP should have access to the necessary details of the MA. The AP(s) performing certification of a finished product batch may be shared with other AP(s) who are operating under the same MAH (Marketing Authorisation Holder) or operating under different MAHs. A written agreement must be in place for shared responsibilities between the AP(s).Multiple sitesReleasing medicines manufactured at multiple sites” is the technical guidance which completes the release for supply process as described in the “Release for Supply of Medicines”. When manufacture occurs at multiple sites, the AP at each manufacturing site is required to: • Complete an identical minimum Release for Further Processing (RFFP) documentation package • Send the RFFP documentation package to the next AP in the chain of manufacture • Accumulate all RFFP documents so that the AP performing the RFS can review the full set of RFFP documents. All partial manufacturers responsibilities must be captured in valid GMP agreements that define RFFP to the next manufacturer in the chain of manufacture.Equivalent principles.


As a summary, even though terms and viewpoints used by the new included PE009-16 Annex 16 and the TGA Release for Supply of Medicines are slightly different, the overarching process for the release of a batch are comparable.

Back to part 1 – Changes to Annex 13 in PIC/S Guidelines

Annex 16 Compliance Resources

Education resources for PIC/S Annex 16 and related guidelines:

List of public GMP training courses (Zoom-based) or onsite sessions for large groups of employees

Training presentation for compliance with PIC/S Annex 13 requirements (PIC/S V16 – PE 009-16) 

Training presentation for compliance with PIC/S Annex 16 requirements (PIC/S V16 – PE 009-16)  

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