Understanding Annex 16 Changes for Qualified Persons and Batch Release

In the U.S. and Europe, the approach to ensuring drug quality has many more similarities than differences. But one key difference has always been the additional responsibilities placed upon the role of a Qualified Person or QP in ensuring the quality of a drug product. The European Union (EU) recently put in place new legislation under Annex 16¹, broadening the role and accountability of the QP with regard to responsibilities for batch release. The new legislation reflects the European Medicines Agency’s (EMA) efforts to introduce new quality control strategies that address today’s complex global pharmaceutical supply chain which includes new technologies such as Process Analytical technology (PAT), Real Time Release Testing (RTRT), and the growing problem of falsified medicines. This new directive has been in development since 2011 and replaces the old Annex 16 in effect since 2002. The changes are extensive and went into law in April 2016.

Core principles unchanged

The principles underlying the role of the QP have not changed as they relate to certification and subsequent batch release of medicinal products for human or veterinary use holding a market authorization (MA) or made for export. Each manufacturing site in the EU is obliged to have at least one QP (§1.4). Appendix I describes the contents of the confirmation statement for partial manufacturing (transfer of QP responsibilities between sites) while Appendix II describes what is needed for batch certification.

The QP must still ensure that each individual batch has been manufactured in compliance with the national laws of the member state where certification takes place, verify that they are compliant with GMPs and in accordance with the MA requirements. This new revision does however reinforce that despite the QP’s responsibilities it does not release the market authorization holder (MAH) from the ultimate responsibility for the performance and safety of a medicinal product over its lifetime.

Supply chain focus

The revised directive has been restructured to more directly address the challenges introduced by a global supply chain and the complexities of preventing distribution of adulterated or falsified medicines. It also clearly states that it applies to both commercial and Investigational Medicinal Products (IMP). The previous directive only suggested that Annex 16 may apply to IMPs. The new directive now focuses on the process of certification of a batch followed by GMP assessment by third parties, handling of unexpected deviations, and finally the release of a batch and has eschewed the previous discussion regarding the role of Mutual Recognition Agreements and the origin of manufacture. This new Annex 16 structure clearly is intended to emphasize the QP’s responsibilities in ensuring the drug’s suitability across the entire supply chain.

One sweeping new requirement is the formal requirement to document the entire supply chain. The directive cites a preference to capture the supply chain diagrammatically (§1.7.2). Practically this could be a set of Value Stream Maps (VSMs) starting at the highest level of the supply chain then drilling down to cover the more tactical VSMs. Along with each VSM there should be a corresponding risk assessment or threat assessment and the countermeasures designed to minimize the potential for falsified medicines to be introduced into the supply chain (§1.5.7). Mapping of the supply chain is applicable to the whole supply chain and should include the API, high and medium risk excipients, intermediates, bulk and finished product transportation, storage and distribution facilities, and associated activities. It should ensure facilities are licensed appropriately for the activities involved, such as temporary storage.

The roles and responsibilities between all parties within the supply chain should be formally captured in written agreements. These would likely be the Quality and Supply Agreements between the MAH and any third party or contract service provider.

Non-EU manufacturers

One of the most significant changes in the directive pertains to companies operating outside of the EU on products that are destined for release within the EU or for export (§1.5). For these MAHs the same level of certification is applicable, but there is an additional requirement to certify the storage and transport of a batch and any samples taken at the manufacturing site. This is allowed as long as the samples are fully representative of the batch. Formal quality risk management procedure is required to support this assumption along with a documented justification (1.5.6).

Batch release requirements clarified

The new directive provides greater detail regarding the batch release process. Specifically, it describes three key elements:

The QP is responsible for verifying the manufacture and testing of the batch. This practical application of the requirement can be shared with the quality assurance function to demonstrate compliance with all specified requirements
The QP is responsible for certification of the finished product
Sampling and importation testing requirements. These include the new specifics already discussed regarding risk assessments and verification of sample storage and transport conditions

Escalating QP responsibilities-Annex 16 and beyond

The revised directive much more clearly states the primary responsibilities of the QP (§ 1.6) and has added several more specific responsibilities. In total, the specific elements which are the responsibility of the QP have increased from ten to 21 key elements (§ 8). However, it is important to remember that Annex 16 isn’t the only directive for which a QP must ensure compliance. The Falsified Medicines Directive (2011/62/EU) has imposed additional requirements for importing APIs from outside the EU that must be verified by a QP. The Good Distribution Practices (GDP) guidelines (2013/C343/01) also specify additional requirements that must be included in quality agreements to address the risks pertaining to falsified medicines. Finally, the recent legislation issued for excipients (2015/C95/02) requiring formalized risk assessments to determine suitability for use must also be verified by the QP before certifying a batch.

Conclusion

The role of the QP in ensuring the safety and efficacy of medicinal products has grown considerably with the issuance of the revised Annex 16 directive. MAHs looking to operate within the EU will have to address the convergence of the quality management system and applicable directives including Annex 16 across the entire supply chain if they are to facilitate their QP certifying product for use in the EU.

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