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Questions and Answers QP Forum 2015, Berlin

Q: Is the written confirmation for the import of APIs also applicable for IMPs?
A: No. Active substances used for investigational medicinal products or for medicinal products intended for research and development trials are excluded from the rules. (Source: "Importation of active substances for medicinal products for human use, Questions and Answers / European Commission, Vers. 4.1, Question 3").
One known exception is Germany: Active substances used for IMPs are not exempted from ยง72a Arzneimittelgesetz (German Drug Law).

Q: Difference IMPs - personalised medicine: which licence will cover personalised medicine? IMP or Specials? How can the labelling be handled according Annex 13?
A: European Legislation currently permits access to personalized medicine via two routes,

  • Dir 2001/83/EC Article 3 (7) - the hospital exemption scheme for ATMPs, or
  • the "specials" scheme (Dir 2001/83/EC Article 5).
Source and further information: JD Johnston, P Feldschreiber, Br J Clin Pharmacol. 2014 Jun; 77(6): 939-946.
It is recommended to clarify with the responsible inspectorate which licence will cover the personalised medicine in the specific case.
Further specifics for labelling may be found in the EC's consultation document "GMP for ATMPs" (July 2015). An example for labelling is included in the presentation "GMP for ATMPs", K. Hoogendoorn (IMP Pre-conference 2013) and can be provided on request by the IMP Working Group.

Q: As a wholesaler we receive from time to time from the manufacturer a CoC which is not approved by a QP. A "QA authorized person" has in some way released the product for sale. Is this allowed? The manufacturer explained that in some in EU countries it is not required that the QP approves the CoC. What could we do as a wholesaler?
A: Another appropriately trained person other than the QP can release the product (transfer the product to saleable stock). This does not include the possibility to delegate the signature under the certificate. According to Annex 16 Annex II certification statements require signature of the Qualified Person.

Q: According Annex 16, 8.3, a QP should maintain knowledge and experience up to date in the light of technical and scientific process and changes in Quality Management. How can this be demonstrated?
A: Each QP should have the concept how he maintains his knowledge and experience documented based on an assessment of need dependent of the responsibilities taken. Training documentation should be available in appropriate depth to document, that the concept is followed.

Q: New Annex 16: in the case of deviations, the root cause should be corrected prior to QP certification and/or sufficient level to support certification should be provided. What is the difference? How should this be handled?
A: Chapter 3 of Annex 16 discusses the handling of unexpected deviations in relation to confirmation and certification by the QP. The deviation management system should ensure that deviations are thoroughly investigated and the root cause corrected. In combination with 1.7.16 All investigations pertaining to the batch being certified (including out of specification and out of trend investigations) have been completed to a sufficient level to support certification.
the confirmation or certification may be performed prior to formal close out of the deviation or complete effective correction of the root cause. This is restricted to such cases, where deviations are unexpected excluding repetitive confirmation and certification for later batches with continued open deviations or not corrected root causes.

Q: New Annex 16: Sampling in a third country now requires comparative analysis, random periodic retesting etc. Furthermore, any unexpected or confirmed OOS result has to be notified to the competent authority as a potential quality defect even if the batch was not certified and released to market. Why should the competent authority be notified if the batch will not be released?
A: Scrutiny is given on the sampling in a third country. Precondition have to be met and surveillance of the establish processes have to be ensured. These provisions intend to ensure that the importer does not receive a perfect sample but falsified product. Any signals like any unexpected result or confirmed out of specification result during the importation testing do not only indicate that the batch concerned may be falsified but also that the measures and controls in place to avoid falsification may not be sufficient. The approach is comparable with handling of unexpected results in the stability programme.

Q: From my experience, FDA is "not amused" if inspectors from the EU competent authority are present during an FDA inspection. What is your experience?
A: Normally we [EU Inspectors] are informed from our companies about the FDA inspection. Amused or not, if we want to participate we will participate. But I did not have the impression that they do not like it if we accompany them.

Q: Ambient transport (15 - 25°C): do you think that it is justified to predefine tolerance for temperature excursions (for example 24h between 25 and 30°C or 6h between 30 and 35°C) without handling an occurrence as a deviation? Might the Mean Kinetic Temperature evaluation help?
A: This might be an option if competent authority agrees, but ONLY if all temperature excursions from end of production are summarized. As a consequence you need all excursions from the whole supply chain. Whether it is a deviation or not depends on the criticality and your QA-System. In any case it must be assessed.

Q: Annex 16, 1.7 (additional pre-requisites to be fulfilled prior to batch certification): how should a QP behave if a Q-System of a company is not capable to provide all the requested data like for example assurance of appropriate GMP requirements for excipients (risk assessment missing). Should I refuse final batch certification? Should I inform senior management and certify the batch? Or anything else?
A: : From 21 March 2016 Excipient Guideline is in operation. From then requirements need to be fulfilled. Guideline was published one year in advance, though there was/is enough time for at least defining excipient-risk-profile and defining appropriate GMP by medicinal product manufacturer. This must be taken into consideration for batch certification. Enforcement of defined appropriate GMP requirements at excipient manufacturers might take some more time.

Q: According Annex 16, 8.3, a QP should maintain knowledge and experience up to date in the light of technical and scientific process and changes in Quality Management. What do authorities expect?
A: E.g. detailed product and process knowledge. Knowledge on new implemented regulatory guidelines. Participation in change control system.

Q: As a virtual company, do we need access to the "Medicines Verification System"? Can we delegate this to our CMO (contract manufacturing organization)? Do I need to verify serialisation at release stage?
A: As a virtual company you do not have to perform this. The verification of serialisation should normally be included at the release stage from the manufacturer, which also includes CMO.

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