WHAT ARE THE SAFETY FEATURES?
The safety features consist of two elements placed on the packaging of a medicinal product:
(1) a unique identifier, a unique sequence carried by a two-dimensional barcode allowing the identification and authentication of the individual pack on which it is printed; and
(2) a device allowing the verification of whether the packaging of the medicinal product has been tampered with (anti-tampering device).
WHEN DO THE RULES ON THE SAFETY FEATURES APPLY?
They apply as of 9th February 2019. Belgium, Greece and Italy have the option of deferring the application of the rules by an additional period of up to 6 years.
DO THE SAFETY FEATURES NEED TO BE APPLIED ON ALL MEDICINAL PRODUCTS FOR HUMAN USE?
No. The safety features should only be applied on the packaging of the following medicinal products for human use:
(1) medicinal products subject to prescription which are not included in the list set out in
Annex I to of Regulation (EU) No 2016/161;
(2) medicinal products not subject to prescription included in the list set out in Annex II
of Regulation (EU) No 2016/161.
(3) medicinal products to which Member States have extended the scope of the unique identifier or the anti-tampering device to in accordance with Article 54a(5) of Directive
ARE THERE EXCEPTIONS FROM THE REQUIREMENTS FOR CERTAIN MEDICINAL PRODUCTS TO BEAR OR NOT THE SAFETY FEATURES?
Yes. The list of categories of medicinal products subject to prescription which shall not bear the safety features are set out in Annex I of Regulation (EU) No 2016/161, while the list of medicinal products not subject to prescription which shall bear the safety features are set out in Annex II of the same Regulation.
DO THE RULES ON THE SAFETY FEATURES ALSO APPLY TO VETERINARY MEDICINAL PRODUCTS?
No. The rules apply only to medicinal products for human use.
DO THE RULES ON THE SAFETY FEATURES APPLY TO MEDICINAL PRODUCTS INTENDED FOR RESEARCH AND DEVELOPMENT TRIALS?
Medicinal products intended for research and development trials and not yet granted a marketing authorisation are excluded from the rules on the safety features.
Authorised medicinal products have to fulfil the requirements of Directive 2001/83/EC and Regulation (EU) No 2016/161 up to the moment it becomes known which batch/unit will be used for research and development trials. In practice, a batch of an authorised investigational medicinal product or an authorised auxiliary medicinal product is excluded from the rules on the safety features if it is known at the time of manufacture that the whole batch is manufactured for use in clinical trials.
In addition, unique identifiers on authorised investigational medicinal products and authorised auxiliary medicinal products bearing the safety features should be decommissioned in accordance with Articles 16 and 24(4)(c) of Regulation (EU) No
ARE THE SAFETY FEATURES REQUIRED WHERE THE MEDICINAL PRODUCT MANUFACTURED IN THE EU IS DESTINED FOR EXPORTATION ONLY?
IN THE CASE OF A MEDICINAL PRODUCT BEARING THE SAFETY FEATURES IS BROUGHT INTO THE TERRITORY OF A MEMBER STATE IN ACCORDANCE WITH ARTICLE 5(1) OF DIRECTIVE 2001/83/EC, DO THE RULES ON THE SAFETY FEATURES APPLY?
When a medicinal product is brought into the territory of a Member State in accordance with Article 5(1) of Directive 2001/83/EC, the rules on the safety features do not apply.
In practical terms, when an medicinal product is brought into the territory of a Member State in accordance with Article 5(1), the “importer” of that product is not required to (re)place safety features on its packaging (e.g. through labelling/relabelling operations).
However, in case the medicinal product brought into the territory of a Member State in accordance with Article 5(1) already bears the safety features, pharmacies, healthcare institutions and other relevant stakeholders in that Member State are strongly encouraged to verify the authenticity of and decommission the medicinal product before supplying it to the public.
DOES AN OBLIGATION TO BEAR "THE SAFETY FEATURES" IMPLY AN OBLIGATION TO BEAR BOTH A UNIQUE IDENTIFIER AND AN ANTI-TAMPERING DEVICE?
ONCE REGULATION (EU) NO 2016/161 APPLIES, CAN MANUFACTURERS PLACE THE SAFETY FEATURES, ON A VOLUNTARY BASIS, ON MEDICINAL PRODUCTS NOT REQUIRED TO BEAR THE SAFETY FEATURES?
No. Once Regulation (EU) No 2016/161 applies, manufacturers cannot place the safety features on medicinal products not required to bear the safety features, unless the Member States have extended the scope of application of the unique identifier or of the anti-tampering device to those medicinal products in accordance with Article 54a(5) of Directive 2001/83/EC.
CERTAIN MEDICINAL PRODUCTS ARE CURRENTLY BEARING AN ANTI- TAMPERING DEVICE ON A VOLUNTARY BASIS. ARE THOSE PRODUCTS ALLOWED TO MAINTAIN THE ANTI-TAMPERING DEVICE ONCE REGULATION (EU) NO 2016/161 APPLIES, IF THEY ARE NOT REQUIRED TO BEAR THE SAFETY FEATURES?
Once Regulation (EU) No 2016/161 applies, medicinal products can only bear an anti-tampering device if they are in the scope of Article 54a(1) of Directive
2001/83/EC (i.e. if they are medicinal products subject to prescription or medicinal products listed in Annex II of Regulation (EU) No 2016/161) or if the Member State(s) where they are placed on the market extended the scope of the anti-tampering device to those medicinal products.
DOES REGULATION (EU) NO 2016/161 LIMIT THE LENGTH OF THE UNIQUE IDENTIFIER TO 50 CHARACTERS?
No. Only the length of the product code, one of the data elements of the unique identifier, is limited to 50 characters.
WOULD IT BE POSSIBLE TO INCLUDE, ON A VOLUNTARY BASIS, A TWO- DIMENSIONAL BARCODE ON THE PACKAGING OF MEDICINAL PRODUCTS FOR HUMAN USE NOT HAVING TO BEAR THE SAFETY FEATURES IF THE INFORMATION CARRIED BY THE BARCODE DOES NOT SERVE THE PURPOSES OF IDENTIFICATION AND AUTHENTICATION OF THE MEDICINAL PRODUCT AND DOES NOT INCLUDE A UNIQUE IDENTIFIER?
Yes, provided that the relevant labelling provisions of Title V of Directive
20014/83/EC are complied with.
Examples may include two-dimensional barcodes encoding price indications, reimbursement conditions, etc.
IS A PRINTING QUALITY OF 1.5 ACCORDING TO ISO/IEC 15415 MANDATORY?
No. Manufacturers are required to use a printing quality which ensures the accurate readability of the Data Matrix throughout the supply chain until at least one year after the expiry date of the pack or five years after the pack has been released for sale or distribution in accordance with Article 51(3) of Directive 2001/83/EC, whichever is the longer period.
The use of a printing quality of 1.5 or higher gives a presumption of conformity, i.e. manufactures using a printing quality of 1.5 or higher will be presumed to have fulfilled the requirement mentioned in the first paragraph without need to prove that it is actually the case.
If a printing quality lower than 1.5 is used, manufacturers may be asked to prove that requirements mentioned in the first paragraph are met.
IS IT COMPULSORY TO PRINT THE NATIONAL REIMBURSEMENT NUMBER IN HUMAN-READABLE FORMAT?
No. The national reimbursement number or other national number should be printed in human readable format only if required by the national competent authorities of the relevant Member State and not printed elsewhere on the packaging. It should be printed adjacent to the two-dimensional barcode if the dimensions of the packaging allow it.
IS IT COMPULSORY FOR THE HUMAN-READABLE DATA ELEMENTS OF THE UNIQUE IDENTIFIER TO BE PLACED ADJACENT TO THE TWO-DIMENSIONAL BARCODE?
Yes, whenever the dimensions of the packaging allow it.
WHAT IS THE SMALLEST FONT SIZE THAT CAN BE USED TO PRINT THE UNIQUE IDENTIFIER IN HUMAN-READABLE FORMAT?
The font size of the unique identifier should be in accordance with the “Guideline on the readability of the labelling and package leaflet of medicinal products for human use” published in Eudralex – Notice to Applicants – Volume 2C (http://ec.europa.eu/health/files/eudralex/vol-
SHOULD THE DATA ELEMENTS OF THE UNIQUE IDENTIFIER IN HUMAN- READABLE FORMAT BE PRINTED ON THE PACKAGING (PRODUCT CODE, SERIAL NUMBER AND, WHERE APPLICABLE, NATIONAL REIMBURSEMENT NUMBER) IN AN ESTABLISHED ORDER
Yes. The order of printing is set out in the QRD template and is the same as set out in Regulation (EU) No 2016/161: Product code, Serial number, National reimbursement number or other national number identifying the medicinal product (where required).
REGULATION (EU) NO 2016/161 DOES NOT MENTION BATCH NUMBER AND EXPIRY DATE AS MANDATORY COMPONENTS OF THE HUMAN READABLE CODE. IS IT MANDATORY TO PRINT THE BATCH NUMBER AND THE EXPIRY DATE IN A HUMAN-READABLE FORMAT AND ADJACENT TO THE TWO DIMENSIONAL BARCODE
Batch number and expiry date are mandatory components of the labelling of all medicinal products – regardless of whether they bear the safety features – and should be printed on the packaging in accordance with Article 54 (h) and (m) of Directive
2001/83/EC. There is no obligation to place batch number and expiry date adjacent to the two dimensional barcode.
HOW SHOULD THE UNIQUE IDENTIFIER BE DECOMMISSIONED IF THE TWO-DIMENSIONAL BARCODE IS UNREADABLE OR DETERIORATED?
The unique identifier in human readable format should be recorded by any suitable method allowing the subsequent manual querying of the repository system in order to verify and decommission the unique identifier.
WHERE THE BARCODE CARRYING THE UNIQUE IDENTIFIER CANNOT BE READ, OR IN CASE THE VERIFICATION OF THE UNIQUE IDENTIFIER IS TEMPORARILY IMPEDED, IS IT POSSIBLE TO SUPPLY THE MEDICINAL PRODUCT TO THE PUBLIC?
Article 30 of Regulation (EU) No 2016/161 prohibits supply to the public if there is reason to believe that the packaging of the medicinal product has been tampered with, or the verification of the safety features of the medicinal product indicates that the product may not be authentic.
In all other cases, the supply of medicinal products to the public is regulated by national legislation.
Without prejudice to national legislation, in the case where it is permanently impossible to read the unique identifier and verify the authenticity of the medicinal product, for example because both the data matrix and the human readable code are damaged, it is recommended that the medicinal product is not supplied to the public.
IS IT ALLOWED TO PLACE A QR CODE ON THE PACKAGING OF A MEDICINAL PRODUCT BEARING THE SAFETY FEATURES?
Regulation (EU) No 2016/161 does not prohibit the placing of a QR code as far as it is not used for the purposes of identification and authentication of medicinal products.
Marketing authorisation holders are however encouraged, wherever technically feasible, to exploit the residual storage capacity of the Data Matrix to include the information they would otherwise include in the QR code. This would minimise the number of visible barcodes on the packaging and reduce the risk of confusion as regard the barcode to be scanned for verifying the authenticity of the medicinal product.
WOULD IT BE POSSIBLE TO PLACE A UNIQUE IDENTIFIER ON THE PACKAGING OF A MEDICINAL PRODUCT DURING THE 3 YEARS PERIOD BETWEEN THE PUBLICATION OF REGULATION (EU) NO 2016/161 AND ITS APPLICATION?
Yes, on a voluntary basis. It is recommended that, whenever possible, unique identifiers are placed on the packaging only once a functional national/supranational repository allowing the storage, verification of the authenticity and decommissioning of those identifiers is in place. Unique identifiers which are placed on medicinal products before such repository is in place are expected to be uploaded in the repository as soon as it becomes operational.
WILL THE MANDATORY CHANGES TO THE PACKAGING DUE TO THE PLACING OF THE UNIQUE IDENTIFIER AND OF THE ANTI-TAMPERING DEVICE REQUIRE THE SUBMISSION OF VARIATIONS TO MARKETING AUTHORISATIONS?
The regulatory requirements to be followed to notify the EMA of the placing of the unique identifier and/or the anti-tampering device on centrally authorised products are detailed in an implementation plan developed by the EMA and the European Commission and published in the “product information templates” section of the EMA
The regulatory requirements for nationally authorised products will be made available by the CMDh on their website.
ARE THERE ANY MANDATORY SPECIFICATIONS FOR THE ANTI- TAMPERING DEVICE?
In accordance with Article 54(o) of Directive 2001/83/EC and Article 3(2)(2) of Regulation (EU) No 2016/161, an anti-tampering device has to allow the verification of whether the packaging of the medicinal product has been tampered with.
There are no other mandatory specifications. The CEN standard EN 16679:2014 “Tamper verification features for medicinal product packaging” is available for manufacturers to consider.
IS IT ALLOWED TO SIMULTANEOUSLY VERIFY THE AUTHENTICITY OF OR DECOMMISSION MULTIPLE UNIQUE IDENTIFIERS BY SCANNING AN AGGREGATED CODE?
Yes, it is possible to verify the authenticity of or decommission multiple unique identifiers by scanning an aggregated code rather than scanning each individual pack, provided that the requirements of Regulation (EU) No 2016/161 are complied with.
WHERE ON THE PACKAGING SHOULD THE UNIQUE IDENTIFIER BE PLACED?
Where Member States have extended the scope of application of the unique identifier in accordance with Article 54a(5), the unique identifier should be placed for centrally authorised medicinal products in the so called “blue box”. In all other cases, the placement is to be approved by national competent authorities.
DO THE RECORDS REFERRED TO IN ARTICLE 15 OF REGULATION (EU) NO 2016/161 HAVE TO BE STORED IN THE REPOSITORIES SYSTEM?
No. The manufacturers can decide how and where to keep the records of every operation he performs with or on the unique identifier.
ARTICLES 18, 24 AND 30 OF REGULATION (EU) NO 2016/161 REQUIRE THAT MANUFACTURERS, WHOLESALERS AND PERSONS AUTHORISED OR ENTITLED TO SUPPLY MEDICINAL PRODUCTS TO THE PUBLIC IMMEDIATELY INFORM NATIONAL COMPETENT AUTHORITIES IN CASE OF SUSPECTED FALSIFICATION OF MEDICINAL PRODUCTS. HOW SHOULD THIS INFORMATION BE NOTIFIED?
The delegated Regulation does not specify how this information should be notified to competent authorities. However, Article 117a of Directive 2001/83/EC requires that Member States have in place a system aiming at preventing medicinal products that are suspected to present a danger to health from reaching the patient, including suspected falsified medicinal products. Manufacturers, wholesalers and persons authorised or entitled to supply medicinal products to the public may therefore inform authorities by means of such system.
HOW SHOULD THE EXPRESSION "THE SAME LEGAL ENTITY" REFERRED TO IN ARTICLES 21(B) AND 26(3) OF REGULATION (EU) NO 2016/161 BE INTERPRETED?
This expression should be interpreted in accordance with national legislation. As general guidance, and without prejudice to national legislation, a legal entity may be considered the same when it has the same registration number in the national company registry or, if no national registration is required, the same number for tax purposes (i.e. VAT number).
MEMBER STATES MAY HOLD STOCKS OF CERTAIN MEDICINAL PRODUCTS FOR THE PURPOSE OF PUBLIC HEALTH PROTECTION. HOW SHOULD THE UNIQUE IDENTIFIERS ON THOSE PRODUCTS BE VERIFIED AND DECOMMISSIONED?
In accordance with Article 23(f) of the delegated Regulation No 2016/161, Member States may request wholesalers to verify the safety features of and decommission the unique identifier of medicinal products which are supplied to governmental institutions maintaining stocks of medicinal products for the purposes of civil protection and disaster control.
CAN A MEDICINAL PRODUCT WHICH CANNOT BE AUTHENTICATED BE RETURNED, AND TO WHOM? WHO SHOULD PAY FOR THE RETURN?
See the answer to Q20. It should be noted that Regulation (EU) No 2016/161 does not change the national provisions in place regulating returns of medicines from pharmacies and hospitals. The regulation of returns of medicinal products, including their financial aspects, remains a national competence.
IN-PATIENTS IN A HOSPITAL MAY BE ADMINISTERED MEDICINAL PRODUCTS DURING THEIR STAY, THE COSTS OF WHICH MAY BE CHARGED TO THEIR INSURER, WHICH CONSTITUTES A SALE. IN THIS CASE, WOULD THE HOSPITAL (OR ANY OTHER HEALTHCARE INSTITUTION) BE ALLOWED TO VERIFY THE SAFETY FEATURES AND DECOMMISSION THE UNIQUE IDENTIFIER OF THOSE PRODUCTS EARLIER THAN THE TIME OF SUPPLY TO THE PUBLIC, IN ACCORDANCE WITH ARTICLE 25(2)?
Yes. In the case described, the charging of the medicinal products costs to the patient’s insurer happens as a consequence of the administration of that product to the patient (regardless of whether the sale takes place before or after the actual administration). Consequently, it is considered that the charging of the cost of the medicinal product to the patient’s insurer (or to the patient himself, for the matter) does not preclude hospitals from applying the derogation provided for in Article 25(2).
MANY HOSPITALS AND OTHER HEALTHCARE INSTITUTIONS SUPPLY THE CONTENTS OF PACKAGES OF A MEDICINAL PRODUCT TO MORE THAN ONE PATIENT. WHERE ONLY PART OF A PACK OF A MEDICINAL PRODUCT IS SUPPLIED, WHEN SHOULD THE DECOMMISSIONING OF THE UNIQUE IDENTIFIER BE PERFORMED?
The unique identifier should be decommissioned when the packaging is opened for the first time, as required by Article 28 of Regulation (EU) No 2016/161.
DOES AUTOMATED DOSE DISPENSING REQUIRE THE PLACING OF NEW SAFETY FEATURES ON THE INDIVIDUAL PATIENT DOSES/PACKS?
No. Automated dose dispensing falls in the scope of Article 28 of Regulation (EU) No 2016/161. Consequently, it is not necessary to place new safety features on the individual patient’s dose/pack.
HOW SHOULD THE EXPRESSION "MANUFACTURERS OF MEDICINAL PRODUCTS BEARING THE SAFETY FEATURES", AS REFERRED TO IN ARTICLE 31(5) OF REGULATION (EU) NO 2016/161, BE INTERPRETED?
For the purposes of Regulation (EU) No 2016/161, “manufacturer” means the holder of a manufacturing authorisation in accordance with Article 40 of Directive
2001/83/EC. The expression “manufacturers of medicinal products bearing the safety features” encompasses any holder of the said authorisation performing partial or total manufacture of a medicinal product bearing the safety features.
WHAT IS A SUPRANATIONAL REPOSITORY?
In practice, a repository serving as “national” repository for more than one
HOW SHOULD THE EXPRESSIONS "APPLICATION PROGRAMMING INTERFACE" OR "GRAPHICAL USER INTERFACE" REFERRED TO IN ARTICLES 32(4) AND 35(1) OF REGULATION (EU) NO 2016/161 BE INTERPRETED?
The expression “application programming interface” refers to a software/software interface consisting of a set of programming instructions and standards used by a piece of software to ask another piece of software to perform a task. The programming instructions and standards are set by the software being called upon. In the context of Regulation (EU) No 2016/161, the expression refers to the programming instructions and standards allowing the software of pharmacies, wholesalers and national competent authorities to query the repository system.
The expression “graphical user interface” (GUI) refers to a human/computer interface that allows users to interact with software or a database through graphical icons and visual indicators without the need of using complex programming language.
Article 35(1)(i) limits the use of the GUI by wholesalers and persons authorised/entitled to supply medicines to the public to the very specific case of failure of their own software. In practice, it can be considered that:
- wholesalers and persons authorised or entitled to supply medicines to the public are expected to use their own software to connect to their national repository and verify the authenticity of/decommission the unique identifier; and
- they should use the GUI for the above purposes exclusively when their software fails.
ARTICLE 33(1), SECOND SUBPARAGRAPH, REQUIRES THAT INFORMATION REFERRED TO IN PARAGRAPHS 2(A) TO 2(D) OF THAT ARTICLE, WITH THE EXCEPTION OF THE SERIAL NUMBER, IS STORED IN THE HUB. DOES THIS MEAN THAT THE SERIAL NUMBER CANNOT BE UPLOADED TO THE HUB?
No, the provision only regulates which information is to be stored in the hub.
ARTICLES 34(4), 35(4) AND 36(N) REFER TO THE LINKING OF THE INFORMATION ON UNIQUE IDENTIFIERS REMOVED OR COVERED TO THE INFORMATION ON THE EQUIVALENT UNIQUE IDENTIFIERS PLACED FOR THE PURPOSES OF COMPLYING WITH ARTICLE 47A OF DIRECTIVE 2001/83/EC. IS THE LINKING REQUIRED TO BE AT THE LEVEL OF INDIVIDUAL UNIQUE IDENTIFIERS? HOW DOES THE LINKING WORK IN PRACTICE?
No, it is not necessary to link individual unique identifiers. The link can be made at batch level by linking the list of decommissioned unique identifiers in the “old” batch (the batch to be repacked/relabelled) and the list of new unique identifiers placed on packs in the “new” batch (the repacked batch). The provision does not require the linking to be done at the level of individual unique identifiers, since the number of packs in the
batch to be repacked/relabelled (and consequently the number of unique identifiers in that batch) may not correspond to the number of packs (and of unique identifiers) in the new batch – making a one-to-one link between unique identifiers impossible.
IN ARTICLE 35(1)(F), DOES THE UPPER LIMIT OF 300 MS FOR A REPOSITORY TO RESPOND TO QUERIES ALSO APPLY WHEN MULTIPLE REPOSITORIES ARE IMPLICATED IN THE QUERY, FOR EXAMPLE IN CASE OF CROSS- BORDER VERIFICATION?
300 ms is the maximum response time of an individual repository. When the verification/decommissioning operation requires the querying of multiple repositories in the repositories system, for example in case of cross-border verification, the overall response time – that is the sum of the response times of each repository queried – may be higher than 300 ms.
IN ARTICLE 38, DOES THE SENTENCE "WITH THE EXCEPTION OF THE INFORMATION REFERRED TO IN ARTICLE 33(2)" REFER TO DATA ACCESS ONLY, OR ALSO TO DATA OWNERSHIP?
It refers to data access only.
SITUATIONS ARISE WHERE, FOR THE SAME BATCH OF PRODUCT, COMPETENT AUTHORITIES FROM DIFFERENT MEMBER STATES ISSUE DIFFERENT LEVELS OF RECALL, E.G. PATIENT LEVEL VS WHOLESALER LEVEL, OR NO RECALL AT ALL. HOW WILL ARTICLE 40 OF REGULATION (EU) NO 2016/161 WORK IN THIS TYPE OF SCENARIO?
Article 40 of Regulation (EU) No 2016/161 would not apply to recalls at patient level as the scope of the delegated act does not extend beyond the supply of the medicinal product to the end consumer. Where a medicinal product is recalled at pharmacy level in a Member State and at wholesale level in another, the marketing authorisation holder should customise the information he needs to provide in the relevant national/supranational repositories in accordance with Article 40(c).
CERTAIN MEMBER STATES HAVE NATIONAL SYSTEMS MANAGING RECALLS AND WITHDRAWALS OF MEDICINAL PRODUCTS IN PLACE. WOULD IT BE POSSIBLE TO INTERFACE THOSE NATIONAL SYSTEMS WITH THE REPOSITORIES SYSTEM FOR THE VERIFICATION OF THE SAFETY FEATURES?
The delegated Regulation No 2016/161 does not provide for the connection between the national systems for recalls/withdrawal of medicinal product and the repositories system. Such connections may be considered by the legal entities managing the relevant repositories in the repositories system, on a voluntary basis.
HOW SHOULD THE TERM "KITS" REFERRED TO IN ANNEX I TO REGULATION (EU) NO 2016/161 BE INTERPRETED?
The term “kit” is defined in Article 1(8) of Directive 2001/83/EC. It refers to “any preparation to be reconstituted or combined with radionuclides in the final radiopharmaceutical, usually prior to its administration”.
ARTICLE 31 OF REGULATION (EU) NO 2016/161 ALLOWS WHOLESALERS AND PERSONS AUTHORISED OR ENTITLED TO SUPPLY MEDICINAL PRODUCTS TO THE PUBLIC TO PARTICIPATE IN THE LEGAL ENTITY/IES SETTING UP AND MANAGING THE REPOSITORIES SYSTEM, AT NO COSTS. CAN THE TERMS OF SUCH PARTICIPATION BE REGULATED BY STAKEHOLDERS, FOR EXAMPLES THROUGH THE STATUTES OF ESTABLISHMENT OR INCORPORATION OF THE LEGAL ENTITY/IES?
Yes, it is possible, provided that the terms do not contradict what is enshrined in legislation. In case of discrepancy, the provisions of Regulation (EU) No 2016/161 and Directive 2001/83/EC prevail.