The revised Annex 16 on QP  Certification and Batch  Release, are you prepared?

#The revised Annex 16 on QP Certification and Batch Release, are you prepared?

As far as changes in GMP legislation effect our daily work, the revised Annex 16 might prove to be quite a transformation. To account for rapid changes in the pharmaceutical landscape, the revision has been adapted substantially to include just about every development in the last fourteen years as well as new legislation coming into force. Especially the Qualified Persons (QP) will most likely see their workload increase to be able to ensure that batches are certified in a GMP compliant manner prior to their release. Because schedules are tight as it is, we have summarized some significant changes to the revised Annex 16 to get you up to speed.


After considerable time, on 15 April 2016 the revised version of Annex 16 will replace the one that has been in effect since January 2002. The revision process started back in October 2011 with an EMA Concept Paper on Revising Annex 16  followed by a Public Consultation from 5 July to 5 November 2013 for which no less than 30 reactions have been received. Finally resulting in a document which should probably last for quite some time.

Structure of the document

One of the changes that is difficult to miss, is the restructuring of the document. Sections containing different scenarios related to the origin of manufacture and possible existence of a mutual recognition agreement (MRA) have been omitted and the order has been changed to reflect 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.

Complexity of the supply chain and falsified medicines

Supply chains can be increasingly complex as more and more countries are involved, even in the EU. Each manufacturing site in the EU is obliged to have at least one QP (1.4) and Appendix I is added to prescribe the contents of the confirmation statement on the partial manufacturing (transfer of QP responsibilities between sites). The contents of a batch certificate needed for the certification are described in Appendix II.

The entire supply chain has to be documented, in a diagram for example (1.7.2).  Risks should be determined through risk assessments and safeguards should be built in to reduce the risks of falsified medicines finding their way into the supply chain ( 1.5.7). All arrangements between sites and parties should be in the form of written agreements.

For companies operating outside of the EU Annex 16 has another effort at hand. For medicinal products manufactured outside the EU and destined for release in the EU or for export, the complexity of the supply chain and locations of manufacturing sites is even higher. So basically the same process of certification is applicable, however with additional requirements (1.5). Mentioned specifically, are the storage and transport of a batch and any samples taken at the manufacturing site, for instance. This is allowed as long as these samples are fully representative for the batch. Formal quality risk management is required to support this assumption and the procedure should also be justified and documented (1.5.6).

New legislation for active pharmaceutical ingredients and excipients

In 2013, the import of active pharmaceutical ingredients (APIs) from outside the EU has been subjected to additional measures according to the ‘falsified medicines directive’ (2011/62/EU).  APIs can only be imported if they are accompanied by a written confirmation from the competent authority of the exporting third country stating compliance of the manufacturing process and the manufacturing site with EU GMP.  

Also in 2013 the revised GDP guidelines (2013/C 343/01) came into force,  containing requirements for GDP to cutback the number of falsified drug substances and drug products and requiring additional tasks for the supply chain that should be covered in quality agreements. Recently, legislation for excipients has been issued (Guidelines 2015/C 95/ 02). It is now required to carry out formalised risk assessment for ascertaining the appropriate GMP for excipients of medicinal products for human use.

The QP has to assure compliance with all legal requirements mentioned above.

Investigational medicinal products

The revised version specifically mentions inclusion of investigational medicinal products (IMPs) whereas the previous Annex 16 may be applied for IMPs.

Responsibilities of the QP

The revision specifies the responsibilities in much more detail. According to section 1.6, the QP must now personally ensure that several operational responsibilities are fulfilled prior to certification of a batch. These comprise of:

  • permission for certification under the terms of the manufacturing and importation authorisation (MIA)
  • compliance with national legislation
  • use of a register to record the certification.

In addition, the QP has the responsibility for ensuring that 21 points  are secured. In comparison to section 8 of Annex 16 of July 2001, at least 10 additional items have been added:

  • supplier management of starting materials and excipients (1.7.6)
  • GMP and GDP compliance of APIs (1.7.7) 
  • importation of APIs (1.7.8)
  • manufacturing of excipients (1.7.9)
  • TSE status (1.7.10)
  • finished product quality control (1.7.13)
  • regulatory post-marketing commitments (1.7.14)
  • technical agreements (1.7.18)
  • self-inspection programmes (1.7.19)
  • arrangements for distribution and shipment (1.7.20)
  • safety features of the packaging (1.7.21)

It is evident that all these duties may be delegated to other (trained) personnel or third parties. As a result of this the QP should have on-going assurance that reliance on the pharmaceutical quality system is well founded. In case third parties are involved this assurance should be done in accordance with Chapter 7 of Volume 4. Special attention is given to audits and the use of risk assessments to determine the critical aspects to be audited and the frequency of repeated audits (2).

Continuous training

More emphasis is placed on the requirement for the QP to have detailed knowledge of the product(s) and the processes as well as technical developments and GMP and should be able to prove continuous training regarding these aspects (1.2).

Handling of unexpected deviations

New to Annex 16 is the inclusion of the EMA 2009 reflection paper on dealing with unexpected deviations and the effect on batch certification. The QP may consider certification of the batch only when all specifications present in the MA are met, the impact has been assessed via a quality risk management process, a thorough investigation has been carried out and the root cause has been corrected. In other words: the manoeuvring space for the QP is limited, but clear.

What has not changed?

The principles of Annex 16 have not changed regarding the role of the QP in certification and subsequent batch release of medicinal products for human or veterinary use holding a MA or made for export. As always, the QP is still responsible for ensuring that each individual batch has been manufactured and checked in compliance with national laws of the Member State where certification takes place, in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP). Emphasised in the revised version of Annex 16 is that the marketing authorisation holder (MAH) has the ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, as also laid down in Chapter 1 of Volume 4 

In conclusion

Several new aspects have been added to the revised edition of Annex 16, next to the restructuring of the entire Annex. As a consequence there is an increase of the  responsibilities of the QP within the EU to ensure compliance of the pharmaceutical quality system  with the requirements laid down in the MA, GMP and national legislation. To be able to do that is a challenge for pharmaceutical companies. So again, are you prepared?

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