Koteze, Sokola 1 st., 83-200 Starogard Gdanski, Poland
Phone/Fax: (+48) 58 531 02 59
Phone: (+48) 606 93 82 51

ASE Pharma Solutions

On 12 October 2015, the European Commission published revised version of Annex 16: Certification by a Qualified Person and Batch Release of the EU GMP Guide. The new annex will become effective on 15 April 2016.

General principles

Revised version of the annex states that: The ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, lies with the marketing authorisation holder (MAH). However, the QP is responsible for ensuring that each individual batch has been manufactured and checked in compliance with laws in force in the Member State where certification takes place, in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP). (…)


New Annex 16 clarifies issues related to sampling of imported products.

(…) Samples may either be taken after arrival in the EU, or be taken at the manufacturing site in the third country in accordance with a technically justified approach which is documented within the company’s quality system. Responsibilities in relation to the sampling should be defined in a written agreement between the sites. (…)

Where sampling is performed at a third country manufacturing site, revised annex requires the technical justification including a formal Quality Risk Management process to identify and manage any risks associated with this approach. This should be fully documented and include for example the following elements:

  • Audit of the manufacturing activity including any sampling activity at the third country site;
  • Evaluation of subsequent transportation steps of both the batch and samples to ensure that the samples are representative of the imported batch;
  • Provision for random periodic analysis of samples taken after importation to justify ongoing reliance on samples taken in a third country;
  • A review of any unexpected result or confirmed out of specification result (such an occurrence should be regarded as a potential quality defect and investigated in line with the guidance in Chapter 8 of EudraLex, Volume 4, Part I).

There are some duties/tasks which must be personally ensured by QP and the others (twenty-one), which may be delegated to appropriately trained personnel or third parties.

The QP must personally ensure that the following operational responsibilities are fulfilled prior to certification of a batch for release to market or for export:

  1. Certification is permitted under the terms of the MIA.
  2. Any additional duties and requirements of national legislation are complied with.
  3. Certification is recorded in a register or equivalent document.

In addition, the QP has responsibility to ensure, for example, that:

  • the entire supply chain of the active substance and medicinal product up to the stage of certification is documented and available for the QP; this should include the manufacturing sites of the starting materials and packaging materials for the medicinal product and any other materials deemed critical through a risk assessment of the manufacturing process,
  • all audits of sites involved in the manufacture and the testing of the medicinal products and in the manufacture of the active substance have been carried out and that the audit reports are available to the QP performing the certification,
  • finished product quality control (QC) test data complies with the Finished Product Specification described in the MA, or where authorised, the Real Time Release Testing programme,

although these tasks may be delegated (as mentioned above).


In some cases the QP will rely on the correct functioning of the pharmaceutical quality system of sites involved in the manufacture of the product and this may be derived from audits conducted by third parties.

Relying on assessment by third parties, e.g. audits, should be in accordance with Chapter 7 of the GMP Guide in order to appropriately define, agree and control any outsourced activity.


This is very important section of the new Annex 16. It implements the position and solution proposed by EMA related to certification and releasing of the batches where minor deviation concerning the manufacturing process and/or the analytical control methods from details described in the MA occurs Doc. Ref. EMEA/INS/GMP/227075/2008.

Revised Annex 16 states that: Provided registered specifications for active substances, excipients, packaging materials and medicinal products are met, a QP may consider confirming compliance or certifying a batch where an unexpected deviation concerning the manufacturing process and/or the analytical control methods from details contained within the MA and/or GMP has occurred. The deviation should be thoroughly investigated and the root cause corrected. This may require the submission of a variation to the MA for the continued manufacture of the product.

The impact of the deviation should be assessed in accordance with a quality risk management process using an appropriate approach. The quality risk management process should include evaluation of the potential impact of the deviation on quality, safety or efficacy of the batch(es) concerned and conclusion that the impact is negligible.


Batches of medicinal products should only be released for sale or supply to the market after certification by a QP. Until a batch is certified, it should remain at the site of manufacture or be shipped under quarantine to another site which has been approved for that purpose by the relevant Competent Authority.

All details you will find in the revised version of Annex 16: Certification by a Qualified Person and Batch Release.