Good Manufacturing Practices (GMP) - questions and answers

Updated 06 March 2018

Here you may find answers to frequently asked questions regarding Annex 13 on medicinal products in clinical trials in the European guidelines on GMP.

For comments and further questions, please contact Head of Department Annette Byrholt Hansen on: abh@dkma.dk


Can a medicine batch be placed outside the EU/EEA when released?

No. A medicine batch must always be located physically within the EU/EEA when released by a qualified person (QP), cf. 1.1 of EU GMP Annex 16.


Is it a mistake that there are no longer any requirements for destruction of empty and half empty medicinal product packets?

By close reading you will find that what used to be indicated under paragraph 49 “unused investigational medicinal products” is now indicated under paragraph 53 as “unused and/or returned investigational medicinal products” in the revised Annex. Hence, the requirement is not reduced in the new Annex, as returned packets include empty and half empty packets.


Must the name of the investigator appear directly from the labelling or is it sufficient if it appears in code?

Under paragraph 26, it is not a requirement that the name of the investigator appears directly from the packet. However, it should always be considered closely, e.g. it is recommended where patients bring home trial medicine. If the investigator is chosen to be the person responsible for information (cf. point 26a: “main contact for information on the product, clinical trial and emergency unblinding”), his or her name must appear from the labelling.

To this we have received the following comment: If it, in the country where the study will be carried out, is accepted to use the Trial Reference Code, as described in paragraph 26d of Annex 13, and the patient also holds a leaflet or a card, as described in paragraph 27, it is not deemed necessary that trial medicine is marked with the doctor’s name in cases where the patient brings home trial medicine.

As a starting point, the Danish Medicines Agency maintains its decision that the name of the investigator should appear when patients bring home trial medicine. Paragraph 27 only allows that the address and telephone number need not appear on the label where the subject is given a leaflet or card which provides this detail. There must be a reasonable explanation if this is omitted.


Must medicinal products for clinical trials (IMP) imported from countries outside the EU/EEA be reassessed?

It is not obligatory to reassess IMP within the EU. In pursuance of the GMP rules (cf. Annex 13, Table 2), the specialist is, however, expected to prepare a statement if the reassessment lacks.


Can private pharmacies label medicinal products for clinical trials?

Private pharmacies must not label medicinal products for clinical trials as a contractual part for a pharmaceutical company, cf. the Danish Act on Pharmacy Practice. Pharmacies must only carry out labelling provided that it is a non-interventional trial of marketed medicinal products and that the pharmacy does exactly as it does usually, i.e. to label medicinal products with the usual usage label with the information specified by the doctor on the prescription.


Is it still permitted to write: “investigator:­­­­­ and Subject no.:­­­­­” on the label, so that the staff at the clinical site fills in the two fields in handwriting?

Release of medicinal products, hereunder control that the labelling is correct, is the responsibility of the specialist. If the name of the investigator and the number of the trial subject is not indicated prior to the release, the following labelling must at least be carried out by qualified and authorised staff within the quality control system. It must be double-checked and batch documentation must be drawn up for the labelling. As a point of departure, the information mentioned must appear from the packets when they are received at the site.


Section 23(3) of the GMP executive order provides that all critical manufacturing processes must be validated regularly. Must validation be conducted exactly as for medicinal products with a marketing authorisation or should the stage of development of the product be taken into consideration?

In paragraph 17 of Annex 13, it is indicated that validation is not expected to the same extent as for routine manufacturing of medicinal products. The term critical manufacturing processes in the executive order refers to particularly critical processes, such as those specifically mentioned in paragraph 17 of Annex 13, e.g. virus inactivation and sterilisation processes. Such particularly critical processes are expected to be validated for all medicinal products, even at the earliest stages of development of a product. The extent of additional validation is expected to increase with the product development, so that for medicinal products for stage III clinical trials, full validation is usually carried out so that it corresponds to the level of medicinal products with marketing authorisation. Incidentally, the formulation has been changed in the current executive order on GMP/GDP.


Should the responsible person be continuously contactable?

According to section 30 of the GMP executive order, pharmaceutical manufacturers are obliged to introduce an effective system for the processing of complaints, which makes it possible to initiate recall operations of medicinal products in the distribution network promptly and at any time.

We expect companies to be continuously contactable to be able to perform a recall, if required. It is not a requirement that the responsible person or the qualified person can be contacted directly. But it must be ensured that the responsible person is informed about any enquiries that are relevant to his responsibilities, and the company should have relevant procedures for how to handle such calls.

We also expect that contact details are made readily available to citizens as well as the Danish Medicines Agency. If the company can be contacted on a special phone number outside opening hours, we expect that a call to your main phone number will inform about the possibility to call the relevant phone number. Any unanswered calls should be returned as soon as possible.

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