Packaging and labelling (including outer packaging, the immediate packaging and the package leaflet) provide the information on an advanced therapy medicinal product to patients.
European Union law establishes the information that shall appear on packaging and labelling of every medicinal product, including advanced therapy medicinal products, and that is part of the marketing authorisation application. The structure of the packaging and labelling for Advanced Therapy Medicinal Products remains close to the rules applicable to other medicinal products, especially biologicals.
However, some specific rules apply for Advanced Therapy Medicinal Products to take into account their specificities. They are mainly linked to the presence of cells and tissues which must be described with their specific origin, to the particular case of advanced therapy medicinal products for autologous use which must be mentioned where appropriate.
The compliance with legal requirements on packaging and labelling of advanced therapy medicinal products allows the clear and unambiguous identification of the medicines and the conditions for their safe use by the patients. Any defect regarding the packaging and labelling of medicinal products carries risks for the patients.
Stakeholders
Marketing Authorisation Applicant and Marketing Authorisation holder: The people who produce Packaging and Labelling.
Users: The user is the patient to whom the information is provided. Certain categories of users (children, pregnant or breastfeeding women, the elderly, the blind and partially sighted, persons with specific pathological conditions) are specifically taken into account by the legal requirements.
Group of patients: Evaluations are carried out with target groups of patients to ensure packaging and labelling’s readability, clarity and ease of use. Their results are part of the Marketing Authorisation dossier.
Translators: Under the responsibility of Marketing Authorisation Applicant and Marketing Authorisation holder, they translate Packaging and Labelling in official language(s) of the Member States where the medicine is placed on the market, or even in several languages as long as the same particulars appear in all the languages used.
Regulatory agencies: European Medicines Agency and national competent authorities. They assess the packaging and labelling comply with regulatory requirements to grant marketing authorisation or for modification linked to packaging and labelling once the marketing authorisation is granted.
Definitions
Packaging & Labelling is a general expression which covers three different media linked to medicinal products: Immediate packaging, Outer packaging, Package leaflet.
Immediate packaging: “The container or other form of packaging immediately in contact with the medicinal product” (Article 1§23 of European Directive 2001/83/EC on the European Union code relating to medicinal products for human use).
Outer packaging: “The packaging into which is placed the immediate packaging”. (Article 1§24 of European Directive 2001/83/EC on the European Union code relating to medicinal products for human use).
Package leaflet: “A leaflet containing information for the user which accompanies the medicinal product” (Article 1§26 of European Directive 2001/83/EC on the European Union code relating to medicinal products for human use).
Labelling: “Information on the immediate or outer packaging” (Article 1§25 of European Directive 2001/83/EC on the European Union code relating to medicinal products for human use).
Challenges
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.
Opportunities and incentives
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.
Interactions with regulators
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.
Practical steps
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)
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 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:
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;
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)
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).
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
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.
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67–128, CELEX number: 32001L0083. See Title V, Articles 54 to 69 on packaging and labelling.
Directive 2001/83/EC has been amended regarding packaging and labelling by the following legal texts:
Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use (Text with EEA relevance), OJ L 136, 30.4.2004, p. 34–57, CELEX number: 32004L0027
Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products (Text with EEA relevance), OJ L 174, 1.7.2011, p. 74-87, CELEX number: 32011L0062
Commission delegated regulation (EU) 2016/161 of 2 October 2015 supplementing Directive 2001/83/EC of the European Parliament and of the Council by laying down detailed rules for the safety features appearing on the packaging of medicinal products for human use, OJ L 32, 9.2.2016, pp. 1–27.
Regulation (EU) no 1027/2012 of the European Parliament and of the Council of 25 October 2012 amending Regulation (EC) No 726/2004 as regards pharmacovigilance, OJ L 316, 14.11.2012, pp. 38–40.
Commission Implementing Regulation (EU) No 198/2013 of 7 March 2013 on the selection of a symbol for the purpose of identifying medicinal products for human use that are subject to additional monitoring, OJ L 65, 8.3.2013, p. 17–18.
Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance), OJ L 324, 10.12.2007, p. 121–137.
Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, OJ L 378, 27.12.2006, pp. 1–19.
This guideline applies to human and veterinary medicines.
This document covers the specific requirements for plastic immediate packaging materials for active substances or medicinal products. It is not intended to outline general requirements also applicable to other types of packaging materials or to properties of the container closure system, e.g., performance. Elastomeres and natural and synthetic rubber are not within the scope of this guideline.
European Commission, Directorate-General for health and food safety, Notice to applicants, Guideline on the packaging information of medicinal products for human use authorised by the Union, Final - Revision 14.6, April 2021.
This guideline provides information on the items required by some Member States under Article 57 of the Directive 2001/83/EC and also on the additional items included in the labelling pursuant to Article 62 of the Directive in order to ensure that these are in conformity with the legislative provisions and are correctly presented. This shall assist applicants and marketing authorisation holders when drawing up the labelling and package leaflet and preparing the mock-up and specimens of the sales presentation.
European Commission, Enterprise and Industry directorate-general, Consumer goods, Pharmaceuticals, Guideline on the readability of the labelling and package leaflet of medicinal products for human use, Revision 1, 12 January 2009.
This guideline provides guidance on how to ensure that the information on the labelling and package leaflet is accessible to and can be understood by those who receive it, so that they can use their medicine safely and appropriately.
The guideline also includes information on how the requirements for Braille can be met, as well as how to make the package leaflet available in formats suitable for the blind and partially-sighted patients. The guideline is intended to apply to all marketing authorisation procedures and to all medicinal products, including those available without prescription.
European Agency for the Evaluation of Medicinal Products, Working group on Quality review of Documents, Addressing the paediatric or incapacitated patient in the package leaflet, Version 1.0, 2000.
The document is a suggestion on how to address situations in which the paediatric or incapacitated patient is in the care of a parent or a carer who is not a health professional.
European Medicines Agency, 20 October 2005, EMEA/277378/2005, Operational procedure on Handling of “Consultation with target patient groups” on Package Leaflets (PL) for Centrally Authorised Products for Human Use.
Articles 59(3) and 61(1) of Directive 2001/83, as amended, require that the package leaflet shall reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use and that the results of assessments carried out in cooperation with target patient groups shall also be provided to the competent authority. The document is to guide applicants/MA with some practical/operational issues as to how ‘consultation with target patient groups’ will be handled and reviewed in the centralised procedure.
European Medicine Agency, 15 March 2011, EMA/57325/2011, rev. 8#, Compilation of QRD decisions on the use of terms.
More information on the European Medicines Agency’s website here.
Mobile scanning and other technologies in the labelling and package leaflet of centrally authorised medicinal products
In compliance with Article 62 of Directive 2001/83/EC, mobile technologies as quick response (QR) codes, two-dimensional (2D) barcodes or Near-field Communication (NFC) can be used in the outer and immediate packaging and the package leaflet to provide information to patients and health care professionals.
More information on the European Medicines Agency’s website here
Applicants and marketing authorisation holders can request the inclusion of mobile scanning and other technologies (including quick response (QR) codes) in the context of an evaluation procedure, including:
as part of the initial marketing-authorisation application;
after the medicine is authorised via Article 61(3) with the rapporteur's involvement;
as part of other procedures affecting annexes.
They should request inclusion of these technologies by submitting the following form, along with all relevant information within module 1.3.1 of the dossier:
Scientific abstract: Dans un arrêt en date du 3 juillet 2002, le Tribunal de première instance des Communautés européennes s'est prononcé sur les mentions spécifiques pouvant figurer dans le « cadre bleu » de l'emballage de produits pharmaceutiques. Contrairement à la Commission qui jugeait que l'apposition du logo du représentant local constituait une information inutile, le Tribunal a admis l'insertion de cette mention, considérant qu'un tel élément était utile pour l'éducation sanitaire des consommateurs.
Scientific abstract: Information on medicinal products is vital for enabling patients to give informed consent to the use of a specific product. Within the European Union (EU) the debate about how much information about prescription-only medicinal products should be made available to patients has gone on for the past five years with no definite conclusion yet. This contribution assesses the current legislation and the ongoing debate in order to identify the challenges and the prospect of new legislation, and consider its potential implications for the scope for advertising and for patient safety.
Circulation des marchandises – Emballage – Pietri, M., Europe n° 10, (10/2002)
Original text: Détentrice d'une autorisation de mise sur le marché (AMM) pour un médicament dénommé « Optruma », la société Eli Illy, a accordé une licence relative à ses droits sur ce produit pour l'Italie à la société requérante. Titulaire de l'AMM, la société Eli Illy a adressé à l'Agence européenne pour l'évaluation des médicaments (AEEM) la demande de son licencié italien de faire apparaître sa marque et son logo dans le « cadre bleu ». La directive 92/27/CEE du Conseil, du 31 mars 1992, concernant l'étiquetage et la notice des médicaments à usage humain (JOCE n° L 113, p. 8), dispose à son article 2, paragraphe 2, que ce « cadre bleu » sur l'emballage extérieur du médicament est destiné à faire apparaître les informations spécifiques à l'État dans lequel le médicament est commercialisé. Or l'AEEM a rejeté la demande d'insertion. Par ailleurs, le Comité pharmaceutique a décidé dans le même sens, affirmant son hostilité à faire apparaître sur l'emballage extérieur le nom du représentant local pour un médicament ayant bénéficié de la procédure centralisée d'AMM. Cela pourrait, selon le Comité pharmaceutique, introduire une confusion entre le titulaire de l'AMM qui assume l'entière responsabilité du médicament et le représentant local qui n'en assume a contrario aucune. La Commission n'a fait que réaffirmer tout cela dans une lettre du 17 avril 2000 qui fait objet de contestations en l'espèce. La première chose sur laquelle le Tribunal devait se prononcer concernait l'étendue de son contrôle sur la décision de la Commission. Si la décision est le résultat d'une appréciation complexe du domaine médico-pharmacologique, le contrôle doit être restreint (CJCE, 21 janv. 1999, Upjohn, aff. C-120/97 : Rec. I, p. 223. - (Ord.), 11 avr. 2001, Commission c/ Trenker, aff. C-459/00 P(R) : Rec. I, p. 2823 ; Europe, juin 2001, comm. 191, obs. M. Pietri). Or, la décision contestée en l'espèce ne relève pas d'une telle catégorie. Elle dépend surtout du fait de savoir « si un tel élément est ou non utile pour l'éducation sanitaire » (pt 45). Le contrôle opéré par le Tribunal peut donc être entier. Partant de là, le Tribunal rappelle que la directive a notamment pour objectif d'assurer un « haut niveau de protection des consommateurs ». Il estime que l'apposition du logo du représentant local dans le fameux « cadre bleu » participe de cet objectif. Les consommateurs peuvent, en effet, contacter plus facilement le représentant local et lui poser des questions sur le médicament dans leur langue maternelle. Sur le risque de confusion, avancé par la Commission, entre le titulaire de l'AMM et le représentant local, le Tribunal considère que le nom et l'adresse des deux entreprises apparaissent déjà sur l'emballage. Mais le titulaire de l'AMM peut accoler son logo. Quant au représentant local, ces informations apparaissent dans le « cadre bleu ». L'apposition du logo de ce dernier au même endroit n'ajoutera pas un risque de confusion et ne pourra que contribuer à améliorer la protection des consommateurs. Le Tribunal annule donc la décision de la Commission.
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European Medicines Agency, Electronic product information initiative