Packaging and labelling of ATMPs

All medicinal products placed on the European Union market are required by Directive 2001/83/EC to be accompanied by labelling and package leaflet which provide a set of comprehensible information enabling the use of the medicinal product safely and appropriately.   

The main purpose of medicinal products’ labelling and packaging is the clear and unambiguous identification of the medicines and the conditions for their safe use by the patients.    

A defect regarding the packaging and labelling of medicinal products can be either unintentional (gap or error) or intentional (falsification). It carries risks for the patients.

The required information on packaging and labelling of advanced therapy medicinal products is part of the process to obtain a marketing authorisation from the European Commission, after the assessment of the European Medicines Agency.   

In order to support marketing authorisation applicants on these aspects, the European Medicines Agency provides numerous templates and guidance, including notably some flexibilities for developers of COVID-19 treatments.  

1) Information required on the outer packaging (especially when the immediate packaging take the form of blister packs) and/or on the immediate packaging, where there is no outer packaging (Annex I of marketing authorisation application)  

• The name of the medicinal product and, if appropriate, an indication of whether it is intended for babies, children or adults; the international non-proprietary name (INN) shall be included, or, if the product has no INN, the common name;  
• A description of the active substance(s) expressed qualitatively and quantitatively, including, where the product contains cells or tissues, the statement ‘This product contains cells of human/animal [as appropriate] origin’ together with a short description of these cells or tissues and of their specific origin, including the species of animal in cases of non-human origin;  
• The pharmaceutical form and, if applicable, the contents by weight, by volume or by number of doses of the product;  
• A list of excipients, including preservative systems; 
• The method of use, application, administration or implantation and, if necessary, the route of administration. If applicable, space shall be provided for the prescribed dose to be indicated;  
• A special warning that the medicinal product must be stored out of the reach and sight of children;  
• Any special warning necessary for the particular medicinal product;  
• The expiry date in clear terms (month and year; and day if applicable);  
• Special storage precautions, if any;  
• Specific precautions relating to the disposal of unused medicinal products or waste derived from medicinal products, where appropriate, as well as reference to any appropriate collection system in place;  
• The name and address of the marketing authorisation holder and, where applicable, the name of the representative appointed by the holder to represent him;  
• Marketing authorisation number(s);  
• The manufacturer’s batch number and the unique donation and product codes referred to in Article 8(2) of Directive 2004/23/EC;  
• In the case of advanced therapy medicinal products for autologous use, the unique patient identifier and the statement ‘For autologous use only’. (Annex III and Article 11 of Regulation (EC) No 1394/2007)  
• safety features:  a unique identifier (UI) carried by a 2-D barcode and an anti-tampering device. (Directive 2011/62/EU; Commission delegated regulation (EU) 2016/161 related to safety features for sensitive medicines; and EMA, Implementation plan for the introduction of the safety features on the packaging of centrally authorised medicinal products for human use)  
• Optional for the outer packaging and the package leaflet: symbols or pictograms designed to clarify certain information mentioned above and other information compatible with the summary of the product characteristics which is useful to the patient, to the exclusion of any element of a promotional nature. (Article 62 of Directive 2001/83/EC)  

The particulars above-mentioned shall be easily legible, clearly comprehensible and indelible. (Article 56 of Directive 2001/83/EC)  

2) Information required on immediate packaging which take the form of blister packs  

• The name of the medicinal product and, if appropriate, an indication of whether it is intended for babies, children or adults; the international non-proprietary name (INN) shall be included, or, if the product has no INN, the common name;   
• the name of the holder of the authorization for placing the product on the market;  
• the expiry date,   
• the batch number. (Article 55(2) of Directive 2001/83/EC)  
• the unique donation and product codes, as referred to in Article 8(2) of Directive 2004/23/EC;  
• in the case of advanced therapy medicinal products for autologous use, the unique patient identifier and the statement ‘For autologous use only’. (Article 12 of Regulation (EC) No 1394/2007)  

The particulars above-mentioned shall be easily legible, clearly comprehensible and indelible. (Article 56 of Directive 2001/83/EC)  

3) Information required on small immediate packaging units on which requirements provided in 1) above cannot be displayed  

• The name of the medicinal product and, if appropriate, an indication of whether it is intended for babies, children or adults; the international non-proprietary name (INN) shall be included, or, if the product has no INN, the common name and, if necessary, the route of administration;  
• the method of administration,    
• the expiry date,   
• the batch number,   
• the contents by weight, by volume or by unit. (Article 55(3) of Directive 2001/83/EC)  
• the unique donation and product codes, as referred to in Article 8(2) of Directive 2004/23/EC;   
• in the case of advanced therapy medicinal products for autologous use, the unique patient identifier and the statement ‘For autologous use only’ (Article 12 of Regulation (EC) No 1394/2007)  

The particulars above-mentioned shall be easily legible, clearly comprehensible and indelible. (Article 56 of Directive 2001/83/EC)  

Relevant European Medicines Agency’s templates for outer packaging and immediate packaging:  

• Implementation plan for the introduction of the safety features on the packaging of centrally authorised medicinal products for human use, 2017  
• QRD product-information annotated template v.10.2 rev.1 (applicable as of January 1st, 2021) (Especially pages 14 to 24)  
• QRD annex A template   
• Guideline on 'Excipients in the labelling and package leaflet of medicines for human use' and its annex  
• In addition, for Advanced Therapy Medicinal Products containing genetically modified cells: Guideline on Core SmPC, labelling and package leaflet for Advanced Therapy Medicinal Products (ATMPs) containing genetically modified cells 

4) Information required on the package leaflet (Annex III of marketing authorisation application)   

• For the identification of the advanced therapy medicinal product:  
  • the name of the advanced therapy medicinal product and, if appropriate, an indication of whether it is intended for babies, children or adults. The common name shall be included;  
  • the therapeutic group or type of activity in terms easily understandable for the patient;  
  • where the product contains cells or tissues, a description of those cells or tissues and of their specific origin, including the species of animal in cases of non-human origin;  
  • where the product contains medical devices or active implantable medical devices, a description of those devices and their specific origin;  
• The therapeutic indications;  
• A list of information which is necessary before the medicinal product is taken or used, including:  
  • contra-indications;  
  • appropriate precautions for use;  
  • forms of interaction with other medicinal products and other forms of interaction (e.g. alcohol, tobacco, foodstuffs) which may affect the action of the medicinal product;  
  • special warnings;  
  • if appropriate, possible effects on the ability to drive vehicles or to operate machinery;  
  • the excipients, knowledge of which is important for the safe and effective use of the medicinal product and which are included in the detailed guidance published pursuant to Article 65 of Directive 2001/83/EC.  

The list shall also:  

• take into account the particular condition of certain categories of users, such as children, pregnant or breastfeeding women, the elderly, persons with specific pathological conditions;  
• mention, if appropriate, possible effects on the ability to drive vehicles or to operate machinery;  
• list those excipients knowledge of which is important for the safe and effective use of the medicinal product and which are included in European Union guidelines. (Article 59(2) of Directive 2001/83/EC)  
• The necessary and usual instructions for proper use, and in particular:  
  • the posology;  
  • the method of use, application, administration or implantation and, if necessary, the route of administration; and, as appropriate, depending on the nature of the product:  
  • the frequency of administration, specifying if necessary the appropriate time at which the medicinal product may or must be administered;  
  • the duration of treatment, where it should be limited;  
  • the action to be taken in case of an overdose (such as symptoms, emergency procedures);   
  • information on what to do when one or more doses have not been taken;  
  • a specific recommendation to consult the doctor or the pharmacist, as appropriate, for any clarification on the use of the product;  
• A description of the adverse reactions which may occur under normal use of the medicinal product and, if necessary, the action to be taken in such a case; the patient should be expressly asked to communicate any adverse reaction which is not mentioned in the package leaflet to his doctor or pharmacist;   
• A reference to the expiry date indicated on the label, with:  
  • a warning against using the product after that date;  
  • where appropriate, special storage precautions;  
  • if necessary, a warning concerning certain visible signs of deterioration;  
  • the full qualitative and quantitative composition;  
  • the name and address of the marketing authorisation holder and, where applicable, the name of his appointed representatives in the Member States;  
  • the name and address of the manufacturer;  
• The date on which the package leaflet was last revised.  
• The package leaflet shall reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use. (Annex IV and Article 13 of Regulation (EC) No 1394/2007)  
• The following additional statement “This medicinal product is subject to additional monitoring” followed by an appropriate standardised explanatory sentence.   
• A standardised text expressly asking patients to communicate any suspected adverse reaction to his/her doctor, pharmacist, healthcare professional or directly to the national spontaneous reporting system, and specifying the different ways of reporting available (electronic reporting, postal address and/or others). (Article 59(1) of Directive 2001/83/EC as modified by Directive 2010/84/EU)  

Relevant European Medicines Agency’s templates:  

• QRD product-information annotated template v.10.2 rev.1 (applicable as of January 1st, 2021) (Especially pages 24 to 39)  
• QRD annex A template  
• Guideline on 'Excipients in the labelling and package leaflet of medicines for human use' and its annex  
• In addition, for Advanced Therapy Medicinal Products containing genetically modified cells: Guideline on Core SmPC, labelling and package leaflet for Advanced Therapy Medicinal Products (ATMPs) containing genetically modified cells  

Exemptions to labelling and package-leaflet obligations  

When the medicine is not intended for direct delivery to the patient or when there are serious problems with the availability of the medicine, an exemption from the obligation to include certain particulars on the labelling and the package leaflet may be granted by the European Medicines Agency (Article 63.3 of Directive 2001/83/EC). 

Relevant European Medicines Agency guidance  

• Recommendations for the implementation of the exemption to the labelling and package-leaflet obligations in the centralised procedure  
• Contact details of national competent authorities for requests of translation exemptions falling under Art. 63.3 of Directive 2001/83 EC and cases of shortages  
• Labelling-exemption requests under Art. 63 of Directive 2001/83/EC examined by the QRD group 

Reviews processes at the European Medicines Agency  

European Medicines Agency’s reviews and checking process of packaging and labelling of advanced therapy medicinal products  

• The European Medicines Agency reviews drafts packaging and labelling (mock-ups and specimens of the packaging and labelling) of advanced therapy medicinal products authorised at the European level, both before the medicine is marketed and following certain changes to the medicine's authorisation.   
• The EMA operates a checking process of the printed materials used in the packaging and labelling of authorised advanced therapy medicinal products. The aim of this checking process is to improve the quality of the printed materials that patients and healthcare workers receive with a medicine. This includes the outer and inner packaging of the medicine, and the printed package leaflet.  

Relevant European Medicines Agency’s guidelines on checking process  

• Checking process of mock-ups and specimens of outer/immediate labelling and package leaflets of human medicinal products in the centralised procedure  
• Checking process of mock-ups and specimens of outer/immediate labelling and package leaflets of human medicinal products in the centralised procedure   
• Standard operating procedure for checking of mock-ups and specimens for new applications and extensions  
• Standard operating procedure for checking of mock-ups and specimens for renewals  
• Standard operating procedure for checking of mock-ups and specimens for transfer of marketing authorisation  
• Standard operating procedure for checking of mock-ups and specimens for all post-authorisation procedures other than new applications, line extensions, renewals and transfers  
• Contact details of national competent authorities for requests to use a sticker to place the Unique Identifier on the outer/immediate packaging of centrally approved products  

To go further: Detailed checking process of mock-ups and specimens in the centralised procedure available here.  

Linguistic review of packaging and labelling of advanced therapy medicinal products  

A linguistic review of product information in all EU languages is performed after the adoption of the Committee for Medicinal Products for Human Use (CHMP) Opinions to ensure high quality and consistent product information of advanced therapy medicinal products in all Member States.   

Relevant European Medicines Agency’s guidelines 

Linguistic review process:   

• Linguistic review process of product information in the centralised procedure  
• Checklist for the submission of Day 215 product information annexes for a post-opinion linguistic review  
• Member states contact points for translations review  
• Practical information on translations for referral procedures (human)  

Provision of final language versions:  

• User guide on how to generate PDF versions of the product information - human  
• Submission of day +25/235 final product information annexes (human and veterinary)  
• Quality review of Documents (QRD) convention to be followed for the EMA QRD templates  

Standard operating procedures:  

• Standard operating procedure for Product information Quality/Quality review of Documents pre-opinion review of product information for renewal procedures  
• Standard operating procedure for Quality Review of Documents post-opinion review of product information for initial applications and annex-II applications  
• Standard operating procedure for Quality Review of Documents post-opinion review of product information for post-authorisation procedures affecting the annexes, excluding annex II applications  
• Standard operating procedure for handling of financial compensation for checking of product information by the Member States   

Early contacts with the European Medicines Agency before marketing authorization application  

As part of the marketing authorisation application dossier of advanced therapy medicinal products, issues or questions related to packaging and labelling can be discussed with the European Medicines Agency during the pre-submission phase as part of early contacts with regulators (See entries "Research & Innovation", “Early contacts with regulators”)  

Assistance from the European Medicines Agency on linguistics aspects for packaging and labelling 

The Working Group on Quality Review of Documents (QRD) of European Medicines Agency provides assistance to the European Medicines Agency's scientific committees and to companies on linguistic aspects of the product information for medicines. This includes summaries of product characteristics, labelling and package leaflets.   

Published: 07/11/2022

Last updated: 11/03/2024

Authors:

Luc-Sylvain Gilbert, EuroGCT ELSI Legal Information Officer

and Aurélie Mahalatchimy, EuroGCT WP4 Convenor, UMR 7318 DICE CERIC, Aix-Marseille University, CNRS, Aix-en-Provence- France

Reviewed by:

Under internal review by EuroGCT Manufacturing Working Group.