15.04.2016 |

LOGFILE No. 15/2016 – The New Annex 16 – Eight Questions for Dr. Rainer Gnibl

The New Annex 16 – Eight Questions for Dr. Rainer Gnibl

The new revision of Annex 16 of the EU GMP Guide, “Certification by a Qualified Person and Batch Release,” was published in October, 2015, and went into effect on April 15, 2016. GMP Inspector Dr. Rainer Gnibl, Regierung von Oberbayern, Munic, joined us to discuss whether or not things are better or clearer now and what impact this document will have on the daily routine of the Qualified Person (QP).




One objective of the revision was to more clearly define the responsibilities and accountabilities of the QP. Has this been accomplished?

Annex 16 is in fact very clear now with respect to what duties the QP must perform personally and what he or she can delegate. However, there are only three rather formal aspects that the certifying QP has to personally ensure, namely:

  • Certification is permitted under the terms of the manufacturing/import authorization.
  • Any additional duties and requirements of national legislation are complied with.
  • Certification is recorded in a register or equivalent document.

The other 21 certification requirements given in the Annex can be delegated to appropriately trained employees or third parties. They deal with all quality-related activities involved in manufacturing and testing pharmaceuticals in the broader sense of the word. These include documentation of the supply chain, audits, specifications, OOS/OOT investigations, starting materials, changes, technical agreements or compliance with the marketing authorization.

Is the globalization of the supply chain well represented as planned?

Yes, according to the revised Annex 16, the supply chain has to be completely mapped out. This change was implemented because of the EU Anti-Falsification Directive (2011/62/EU). It makes an important contribution to blocking the intrusion of counterfeits. The supply chain has to be documented not only for active substances and medicinal products, but also for starting materials, packaging materials and other materials that are crucial to product quality. As a result, all suppliers, including sub-contractors, now have to be disclosed. In the case of batch certification, GDP compliance is now advancing to take a prominent position beside GMP compliance. Meeting the GDP requirements for active substances is specifically mentioned.

When can the QP rely on third-party audits? What does the QP have to ensure?

The QP does not have to personally audit plants that are involved in manufacturing and testing the product or in manufacturing active substances. That can be delegated internally, or an external service provider can be engaged, as long as this provider has been prospectively qualified in accordance with Chapter 7 of the EU GMP Guide, Part I, “Outsourced Activities.” The new Annex 16 also defines minimum requirements audit reports must fulfil to retain their usefulness for the Qualified Person. In any case, the certifying Qualified Person must be informed about critical outcomes of audits. Audit reports must be available to the QP at all times.

The QP has to ensure that the pharmaceutical quality systems (PQS) of the plants involved in manufacturing and testing the product are in working order and in compliance with the plants’ own PQS. This is especially important in those cases in which the QP relies for the batch certification on the QP of a contract manufacturer to verify that production is GMP compliant (Certificate of Conformance (CoC). But this is only possible with contract manufacturing under the terms of a European manufacturing authorization.

What does the QP have to watch for in imports from third countries? Is everything different now?

The prerequisites for importation from third countries (countries outside of the EU with which there is no mutual recognition agreement (MRA) in the GMP area) have not changed. What is new, however - and this poses a new risk - is the possibility of sampling for EU reanalysis in the third country. The previously valid Annex 16 permitted sampling only within the EU or the EEA. In third countries it was only possible to take extra samples (such as sampling during filling to test for sterility). It is true that samples taken at the manufacturing site in the third country may be drawn in accordance with a technically justified approach which is documented within the company’s quality system. This includes audits of the sampling and comparative tests to ensure that the samples are fully representative. Unfortunately, however, in actual practice things are often different and the samples cannot always be proven to be fully representative. But if importers are satisfied with purely formal security to give them the advantage of time, for instance to compensate for poor internal planning for replenishments, then of course this change will offer new opportunities. As a consequence, however, the GMP principle of quality assurance and the highest measure of product safety which it strives to achieve are subordinated in this way to the new objective of “continuous supply.”

Another important aspect for the QP in certifying products from third countries is that he or she absolutely cannot rely on the verifications or CoCs of other QPs - as is the case within the EU. The QP certifying the import in this case is solely (!) and fully responsible for all manufacturing and testing steps taken in third countries. Nor can the batch record review to ensure GMP compliance take place in a third country or be verified by a QP located there, no matter how qualified that person may be.

For the first time the Annex also contains requirements for certification of the parallel importation and/or distribution of products. Are these requirements reasonable and adequate?

Contrary to the earlier version of Annex 16, for the first time, the new one now includes mention of the parallel importation and/or distribution of medicinal products. However, it does not address content that is truly relevant to quality, such as proof of GMP compliance of the starting materials used. This comes as a surprise in contrast to the draft version: The QP’s responsibility is clearly cut back. He or she must only verify that the repackaging took place in accordance with the marketing authorization and in conformity with GMP.

Consideration of unexpected deviations in the manufacturing process or with respect to control methods is also totally new. The already published “QP Discretion Paper” by the EMA was incorporated here. How helpful is the regulation in this format?

Including the content of the “QP Discretion Paper” in the Annex is advantageous for the GMP inspectorates, since it is now unequivocally made clear that only unplanned deviations can be accepted in batch certification. And that is true only as long as the specifications for active substances, excipients, packaging materials and finished products according to the marketing authorization have not been affected. Thus, the deviations concerned can only be miscellaneous deviations in batch production and testing.

This interview was conducted by our Editor Dr. Sabine Paris:

with Dr. Rainer Gnibl
GMP Inspector, Regierung von Oberbayern, Munic