Effect of the new Annex 13 on Labelling of IMPs

Recommendation

10/11 October 2023

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As previously reported the final "Detailed Commission guidelines on GMP for IMPs for human use" have been published in December 2017 in Annex 13 of the EU GMP-Guidelines.

The previous Annex 13 contained detailed requirements and guidance for IMP (investigational medicinal product) labelling together with a summary of labelling details provided in Table 1 of Annex 13. This table is not provided in the Detailed Commission Guidieline and requirements and guidance for labelling have been moved from GMP to GCP as they are now part of Regulation (EU) No 536/2014 (Clinical Trials Regulation, CTR) including its Annex VI. For unauthorized IMPs it has been amended, for example, that "in the case of blind clinical trials the name of the substance is to appear with the name of the comparator or placebo on the packaging of both the unauthorized IMP and the comparator or placebo".

Furthermore, some of the particular requirements have been amended in the CTR in regard to limited labelling of immediate packaging (i.e. in cases where primary and secondary packaging are provided together or small primary packaging systems like blister packs or small units such as ampoules are used) in comparison with the previous Annex 13. According to the CTR the period of use (expiry date or re-test date as applicable), in month and year format and in a manner that avoids any ambiguity has to be provided on the primary packaging.

Additionally, replacing of information and providing this information by other means, e.g. by using a centralized electronic randomization system / centralized information system, is only allowed in specific cases for specific parts of information (for example particulars on the main contact like sponsor, contract research organization or investigator).  

In Detail, Section 6.6. Labelling of the Detailed Commission Guideline states:

• Labelling of IMPs shall comply with the requirements of Chapter X Labelling of the CTR. A list of information which shall appear on the labelling is set out in Annex VI (Labelling of IMPs and auxiliary medicinal products) to the CTR. The labelling operation should be performed at an authorized manufacturing site that complies with the requirements of Article 61 of the CTR.
• If it becomes necessary to change the expiry date, an additional label should be affixed to the IMP. This additional label should state the new expiry date and repeat the batch number and clinical trial reference number. It may be superimposed on the old expiry date, but for quality control reasons, not on the original batch number. The re-labelling operation should be performed by appropriately trained staff in accordance with GMP principles and specific standard operating procedures (SOPs) and should be checked by a second person. This additional labelling should be properly documented in the batch records. To avoid mistakes the additional labelling activity should be carried out in an area which is partitioned or separated from other activities. A line clearance at the start and end of activity should be carried out and label reconciliation performed. Any discrepancies observed during reconciliation should be investigated and accounted for before release. The re-labelling operation may be performed by authorized personnel at a hospital, health centre or clinic that meet the requirements of Article 61 of the CTR.

Chapter X Labelling of the CTR contains the following information on what shall appear on the outer packaging (secondary packaging) and on the immediate packaging (primary packaging):

• Unauthorized IMPs and unauthorized auxiliary medicinal products (Article 66, more details are provided in section A & B of Annex VI of the CTR):

(a) information to identify contact persons or persons involved in the clinical trial;
(b) information to identify the clinical trial;
(c) information to identify the medicinal product;
(d) information related to the use of the medicinal product.

The information which is to appear on the primary and secondary packaging shall ensure subject safety and reliability and robustness of the data generated in the clinical trial, while taking account of the design of the clinical trial, whether the products are investigational or auxiliary medicinal product, and whether they are products with particular characteristics. The information which is to appear on the primary and secondary packaging shall be clearly legible.

• Authorized IMPs and authorized auxiliary medicinal products (Article 67, more details are provided in section C of Annex VI of the CTR) shall be labelled:

(a) in accordance with Article 66 of the CTR (a-d, see above); or
(b) in accordance with Title V of Directive 2001/83/EC.

Where the specific circumstances, provided for in the protocol, of a clinical trial so require in order to ensure the safety of the subject or the reliability and robustness of data generated in a clinical trial, additional particulars relating to the identification of the clinical trial and of the contact person shall appear on the primary and secondary packaging of authorized IMPs.

• Radiopharmaceuticals used as IMPs or as auxiliary medicinal products for a medical diagnosis:

The products shall be labelled appropriately in order to ensure the safety of the subject and the reliability and robustness of data generated in the clinical trial (Article 68).

• Language: "The language of the information on the label shall be determined by the Member State concerned. The medicinal product may be labelled in several languages" (Article 69).

The CTR and the Detailed Commission Guideline are expected to become applicable in the second half of 2019. More information on Annex 13 and the Detailed Commission Guideline can be found in EudraLex, Volume 4.