Q & A about safety features on the packaging of medicinal products

Updated 16 October 2017

The European Commission has laid down rules for safety features on the packaging of medicinal products (see Commission Delegated Regulation (EU) 2016/161). The rules enter into force on 9 February 2019 and the purpose is to prevent that falsified medicines enter the legal supply chain for medicinal products. The new requirements for safety features on the packaging of medicinal products and a common repository system will make it possible to identify and verify the authenticity of the medicinal products covered by the rules.

In addition to the below questions and answers, we recommend that you read the guidelines published by the EMA and the HMA (see section 10 below).

The new safety features

1. What do the safety features consist of?

The regulation on safety features (2016/161 of 2 October 2015) will apply from 9 February 2019. See the regulation. Pursuant to the regulation, certain medicinal products must bear safety features allowing the verification of whether the packaging of a medicinal product has been tampered with, and allowing the identification and authentication of the medicinal products. The safety features consist of a unique identifier/UI and an anti-tampering device/ATD. Both the unique identifier and the anti-tampering device must appear from the outer packaging or the immediate packaging if the medicinal product has no outer packaging.

The unique identifier must be encoded in a two-dimensional barcode and must at least contain:

  1. The product code allowing the identification of the name, the common name, the pharmaceutical form, the strength and the pack size.
  2. The serial number, which is a numeric or alphanumeric sequence (both numbers and letters) of a maximum of 20 characters.

  3. The batch number

  4. Expiry date

  5. A national reimbursement number (not relevant to medicinal products in Denmark)

This information must be encoded in the two-dimensional barcode. See Article 4. According to Article 5, manufacturers of medicinal products must print the two-dimensional barcode on the packaging. Thus, a stick-on label attached to the two-dimensional barcode cannot be used.

The product code, the serial number (and the national reimbursement number, if any) should be printed on the packaging in human-readable format. These requirements do not apply if the sum of the longest dimensions of the packaging equals or is less than 10 centimetres. Where the dimensions of the packaging allow it, the human-readable features must be adjacent to the two-dimensional barcode. See Article 7.


2. Do the new requirements for safety features replace the usual requirements for labelling etc.?

No. The new requirements for safety features introduced by the regulation on safety features apply in addition to the usual requirements for labelling etc. Please note that the pharmaceutical manufacturer is responsible for ensuring that the medicinal products covered by the requirements bear the safety features. The marketing authorisation holder continues to be responsible for the medicinal product and for ensuring that the labelling etc. of the medicinal product meets the rules applicable from time to time.

The unique identifier

3. Which medicinal products are covered by the regulation and will the Danish Medicines Agency extend the scope of application of the unique identifier to include all prescription-only medicinal products and all reimbursable medicinal products?

The regulation and the requirement for safety features apply to prescription-only medicinal products, unless they are included in the list set out in Annex I to the regulation. The regulation also applies to medicinal products not subject to prescription included in the list set out in Annex II to the regulation. Finally, the regulation applies to medicinal products to which the member states have extended the scope of application of the unique identifier or of the anti-tampering device. See Article 2. At present, we are not planning to extend the scope of application of the unique identifier. As regards the scope of application of the anti-tampering device, see the answer to question 6.


4. Will the Danish Medicines Agency increase the contents of the unique identifier to include a national reimbursement number or other national number?

At present, we have no plans of demanding that a national reimbursement number or other number (including the item number) forms part of the unique identifier. However, we believe that all parties involved would prefer that the item number is contained in the identifier. It should be noted that the applicable rules on requirements for labelling apply in addition to the new requirements introduced by the regulation.


5. Will the two-dimensional barcode replace the existing EAN barcode?

Yes.

Please see the answer to question 7.

Anti-tampering device

Anti-tampering device

6. Will the Danish Medicines Agency extend the scope of application of the anti-tampering device to include all medicinal products?

The Danish Medicines Agency has decided to extend the scope of application to include all medicinal products under certain minor conditions. The specific conditions have not been established yet, but in practice the extension will mean that anti-tampering devices can be kept or added to medicinal products generally not covered by the rules. The Danish Medicines Agency will provide more information when the conditions have been established. The voluntary use will presumably be based on the condition that the manufacturer makes a risk assessment and concludes that an anti-tampering device will provide improved safety against falsified medicinal products. A decision to voluntarily use an anti-tampering device will most likely not require prior permission from the Danish Medicines Agency.

GTIN and NTIN

7. At present, companies have major problems as to whether they should use GTIN or NTIN, including the problem that the item number cannot form part of the two-dimensional barcode when we do not share all packaging parts of the pack?

When the rules become effective on 9 February 2019, each medicinal product must bear a two-dimensional barcode containing the product code, serial number, batch number and expiry date. Consequently, many manufacturers are considering a change from NTIN to GTIN, which may pose some challenges in the supply chain, because the present systems can only handle one product line per product. In the transition period, until the systems of wholesalers, pharmacies and hospital pharmacies can handle several product lines, it is acceptable that products bear an EAN-13 barcode with an NTIN and a two-dimensional barcode with a GTIN.


8. If a company changes from NTIN to GTIN, will packs with NTIN on the market be returned to the company, because wholesalers and pharmacies do not currently have systems that can handle the presence of multiple barcodes for the same item number? The Danish Medicines Agency needs to accept a transition period so that systems suppliers can be informed, before 9 February 2019 when the new rules of the regulation take effect, that they should be able to handle multiple barcodes for the same item number.

In our opinion, this matter should be solved in collaboration between industry and the systems supplier.

Regulatory implementation

9. How should the anti-tampering device be implemented?

Where the anti-tampering device is placed on the outer packaging and the readability is not affected, and neither the immediate packaging (container), nor the closure system is affected, and no changes are to be made to the summary of product characteristics or the documents forming the basis for a marketing authorisation, a variation application or other regulatory activity should not be submitted.

We refer to the above implementation plans from the EMA and CMDh, which state as follows: ”implementation of the ATD is not expected to impact the product information. However, when the ATD is placed on the immediate packaging because there is no outer packaging, certain section(s) of the marketing authorization dossier may be impacted. (…) Concerning the ATD, in the case of medicinal products where the ATD is placed on the immediate packaging because there is no outer packaging and the ATD affects the container and its closure system(s), applicants are required to submit the appropriate variations to include the information on the ATD and how the ATD affects the container and its closure system(s). (…) If the ATD does not affect the container and its closure system, or is placed on the outer packaging, no regulatory procedure is necessary. However, if the addition of the ATD has an impact on the readability of the packaging information, MAHs are requested to submit a Notification pursuant to article 61(3) of Directive 2001/83/EC to register the change”.


10. How should the two-dimensional barcode be implemented?

The implementation of the two-dimensional barcode requires an updating of the QRD template (Annex IIIA, sections 17 and 18). In the CMDh annotated QRD template, you can read more about what to indicate under sections 17 and 18 to obtain authorisation from the Danish Medicines Agency.

An update in line with the QRD template is generally classified as a type IB variation under category C.I.z. See the CMDh Q&A 2.11.b. However, an update solely in line with sections 17 and 18 of the QRD template is classified as an article 61.3 notification.

As regards nationally authorised medicinal products, the Danish Medicines Agency follows the CMDh recommendations. The CMDh recommends that the update in line with sections 17 and 18 of the QRD template takes place in connection with the submission of another regulatory activity affecting the product information (type IA/IB/II variation or renewal). The labelling must be updated in line with sections 17 and 18 of the QRD template before the rules governing safety features become effective on 9 February 2019. If it is not possible to make the update in connection with another regulatory activity affecting the product information, an article 61.3 notification should be submitted.

Please note that the Danish Medicines Agency does not request that the updating of the labelling in line with sections 17 and 18 of the QRD template has been approved before the two-dimensional barcode is placed on the outer packaging. As long as the updating of the QRD template is made before the rules enter into force on 9 February 2019, it is possible to add the two-dimensional barcode before sections 17 and 18 of the QRD template have been approved. Please note that if you add the two-dimensional barcode before you apply for approval of the updating in line with the QRD template, the updating must be included in the first-coming regulatory activity affecting the product information, alternatively you must apply for an article 61.3 notification as described above.

See the implementation plans of the CMDh and the EMA:

The CMDh implementation plan

The EMA implementation plan


11. Which requirements apply to the submission of a variation application for the implementation of the unique identifier? If the application is submitted well in advance, e.g. together with another variation about updates of the packaging material, the deadline for implementation is usually one year. In that case, should the unique identifier also be implemented within one year or is it possible to select another time for the implementation?

As described in the CMDh and EMA implementation plans, an approval of a variation related to the updated QRD template (sections 17 and 18 of the labelling) is not the same as an implementation – regardless of the deadline for implementation approved for the remaining part of the variation. This applies to cases where updates in line with the QRD template only form part of the overall variation.

Note that the rules only apply to packs of medicinal products released for sale or distribution etc. after 9 February 2019, see the transitional measures laid down in article 48 of the regulation.

We expect the companies to update their common texts on an ongoing basis, see sections 17 and 18 of the QRD template. See the answer to question 10.


12. In the opinion of the Danish Medicines Agency, can batches without two-dimensional barcodes etc. not be released after the implementation deadline on 9 February 2019? Or does the Danish Medicines Agency define implementation in a different way than the other countries (e.g. supply to a wholesaler as for other variations)?  

According to article 48 of the regulation on safety measures, medicinal products that have been released for sale or distribution without the safety features in a member state before the date on which this regulation becomes applicable in that member state, and are not repackaged or relabelled thereafter, may be placed on the market, distributed and supplied to the public in that member state until their expiry date. Moreover, it appears from recital 43 that in order to avoid disruptions in the supply of medicinal products, transitional measures are necessary for medicinal products which have been released for sale or distribution without the safety features before 9 February 2019.

In the opinion of the Danish Medicines Agency, this means that medicinal products which are released before 9 February 2019 without the safety measures and are not repackaged or relabelled thereafter can form part of the entire subsequent distribution, including by wholesalers.


13. What will happen to the national authorisation procedure for the labelling document? Will the Danish Medicines Agency assess and approve the text document?

At present, there are no planned changes to the authorisation procedure. See the CMDh implementation plan above.


14. Today, national marketing authorisations do not have a labelling document. If there is such document, it may not necessarily be updated. What will the future procedure be like for approval of the labelling document for national marketing authorisations?

See the answer to question 13.


15. If there is no need for submitting a variation within the time frame, the change must be submitted as a notification at “an early stage”. What is at ”an early stage” – deadline for the submission of a notification?

Generally, companies can expect that the Danish Medicines Agency meets the deadlines applying to our assessment of variations, but if we suddenly receive a very large number of variation applications, this may increase assessment times. Consequently, we encourage you not to wait too long before you submit the required variations.


16. Is it acceptable to implement the safety features when the location and the NMVO are ready, and thus deviate from the usual requirements for the implementation of text changes?

If the rules on variations are complied with, it is acceptable to implement the safety features before the rules become effective on 9 February 2019. In that case, the two-dimensional barcodes should be uploaded as soon as possible.


17. What does the Danish Medicines Agency expect the marketing authorisation holder to indicate under sections 17 and 18, see the QRD text template, to obtain approval from the Danish Medicines Agency?

See the CMDh’s annotated QRD template:

Annotated QRD Template 

See the answer to question 10.


18. How should a variation be applied for in order to include the safety features in sections 17 and 18 in the QRD v10?

As regards medicinal products authorised under the purely national procedure, we will follow the CMDh implementation plan. This means that we recommend you to submit the variation together with another variation, and if no regulatory procedure occurs within the stated time frame, then you are requested to submit a notification pursuant to article 61.3.

See the answer to question 10.


19. Which documents should be attached to the application?

We expect you to submit either a variation application form, alternatively the 61.3 notification form (see the CMDh’s website).

The QRD template should also be used and submitted for medicinal products authorised under the purely national procedure. See the answer to question 10.

Any other documentation may be required if you apply for other variations at the same time.


20. The QRD template states for outer packaging, section 18: Unique identifier – human readable data. If relevant for product concerned, should ”PC, SN, NN” or ”product code, serial number, national or other national number identifying the medicinal product” be indicated?

Screenshot of the unique identifier

Under section 18, please write the text printed in black, that is ”Not applicable” or ”PC: {number} SN: etc.”. The text printed in green is meant as a help to explain which information is included in the various codes. For purely national marketing authorisations, please state ”Not applicable” under ”NN”. Please follow the same order as in the QRD template.


21. We can update the QRD template in connection with another updating of the product information, but can we also submit a grouped application and have the updates approved for all relevant products at the same time?

It is not possible to submit a grouped application, since only IA notifications can be grouped across products. This variation is not classified as an IA variation, see the CMDh implementation plan (section 8). 

We recommend that you make the change in connection with another regulatory activity, see the CMDh implementation plan. If no regulatory activity occurs within the time frame and no later than 9 February 2019, a notification pursuant to article 61.3 must be submitted. See the answer to question 10.

Item number

22. Both GTIN and NTIN are accepted and the requirement as to item number is maintained, but NTIN does not necessarily comply with the GS1 standards.

Will the Danish Medicines Agency support initiatives to introduce systems that can handle several EAN codes related to an item number or initiatives to an amendment procedure for EAN, perhaps ”set up” solutions as those introduced in Sweden or Finland?

What does the Danish Medicines Agency recommend as regards a continued link from the product code to the item number if the product code is changed?

The item number must still appear from the packaging in human-readable format, and if the item number is printed adjacent to the two-dimensional barcode in human-readable format, it does not need to be printed elsewhere on the packaging.

At present, we have no plans of demanding that a national reimbursement number or other number (including the item number) forms part of the two-dimensional barcode.

Pursuant to article 5 of the regulation, unique identifiers with a coding scheme, which conforms to the ISO/IEC 15418:2009, are presumed to fulfil the requirements. If NTIN does not comply with the standard, it cannot be used. We recommend that you contact the DMVO for more information, see www.dmvo.dk

The existing challenges regarding item numbers and Nordic packs are not affected by the requirements to implement safety features, and these challenges should be solved between the affected parties, however, in our opinion the system should preferably be able to handle several EAN codes.


23. Chapter 4 of the guideline to the executive order on labelling etc. of medicinal products specifies that the medicinal product’s name, strength, form, pack size and item number should be placed horizontally in the same visual field. Would it be acceptable to let the item number form part of the two-dimensional barcode printed on the “back of the pack” and not in the same visual field as the name, strength, form and pack size?

The item number can be placed in human-readable format on the back of the pack adjacent to the two-dimensional barcode.

Dispensing from pharmacies and hospital pharmacies

24. Can pharmacies dispense medicinal products with safety features if the repositories system is unavailable due to temporary IT problems?

Yes, on condition that verification of the authenticity and decommissioning is carried out as soon as the repositories system is available and that the integrity of the anti-tampering device is verified before the product is supplied to the public. Moreover, in case of suspected falsification of medicinal products, the recipients must be informed immediately to prevent that the medicinal product is used and to ensure that the medicinal product is returned to the pharmacy.


25. What should a pharmacy/hospital pharmacy do if a medicinal product cannot be verified in the repositories system?

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, the medicinal product must not be supplied to the public, and the pharmacy/hospital pharmacy must inform the Danish Medicines Agency immediately.


26. Can a hospital pharmacy reverse the status of a decommissioned unique identifier of a medicinal product supplied to a hospital ward that has subsequently returned the medicinal product to the hospital pharmacy? 

Yes. Manufacturers, wholesalers and persons authorised or entitled to supply medicinal products to the public, including hospital pharmacies, may only revert the status of a decommissioned unique identifier to an active status if the following conditions are fulfilled:

a) The person performing the reverting operation is covered by the same authorisation or entitlement and operates in the same premises as the person that decommissioned the unique identifier.

b) The reverting of the status takes place not more than 10 days after the unique identifier was decommissioned.

c) The pack of medicinal product has not expired.

d) The pack of medicinal product has not been registered in the repositories system as recalled, withdrawn, intended for destruction or stolen and the person performing the reverting operation does not have knowledge that the pack is stolen.

e) The medicinal product has not been supplied to the public. 

Medicinal products bearing a unique identifier which cannot be reverted to an active status because the conditions set out in paragraph 1 are not fulfilled must not be returned to saleable stock.

See article 13 of the regulation.


27. Can the pharmacy dispense a pack of medicinal product to a customer if the anti-tampering device has been tampered with but the pack was not dispensed, e.g. because the customer did not want the medicinal product?

The regulation does not prevent such dispensing, but if the pack of medicinal product has also been decommissioned in the repositories system, the dispensing must take place in accordance with article 13 of the regulation. This implies that the pharmacy must guarantee that the pack of medicinal product was opened by the pharmacy. See the answer to question 23.

Parallel import

28. Would it be against the regulation if a parallel importer replaces the anti-tampering device with another device?

On 12 October 2017, the European Commission announced that parallel importers that only add labels to medicinal products, without covering or destroying the unique identifier and/or anti-tampering device, do not have to repack or add a new unique identifier and anti-tampering device to the pack.

If parallel importers open the pack and destroy the anti-tampering device, they have to repack and add a new unique identifier and anti-tampering device to the pack as well as upload information etc.

Consequently, it would be against Article 47a of the Medicinal Product Directive if parallel importers place a new anti-tampering device on the original pack that seems to have been opened. Similarly, wholesalers etc. receiving a pack that seems to have been opened must not sell such products, see Articles 24 and 30 of the regulation.


29. Should parallel importers, just like other marketing authorisation holders, submit notifications/variations in connection with the implementation of the safety features?

Yes, parallel importers should, just like other marketing authorisation holders, submit notifications/variations in connection with the implementation of the safety features. Please use the QRD template for this purpose.

Over-the-counter medicines

30. Can over-the-counter medicines be labelled with a two-dimensional barcode as long as it is not a safety feature, i.e. contains a product code in combination with a serial number?

Yes. In the opinion of the Danish Medicines Agency, the content of the code (UI etc.) constitutes the safety feature. Consequently, over-the-counter medicines can be labelled with a two-dimensional barcode as long as it does not constitute a safety feature, i.e. contains a product code in combination with a serial number.

Miscellaneous

31. The legislation stipulates that certain types of customers should be treated in a special way in relation to the decommissioning of the unique identifier. The list includes prisons, schools, hospices and many other institutions. Can the Danish Medicines Agency prepare a similar list based on Danish conditions which outlines the institutions that should be treated in a special way?

The list contained in the regulation is exhaustive, and we have no knowledge of institutions in Denmark that should be covered by the list.


32. What are the requirements in cases where a medicinal product in one pack and a medical device in another pack are wrapped by cellophane?

Only the pack of medicinal product is considered as the outer packaging that should bear the safety features. According to Article 5, manufacturers of medicinal products must print the barcode on the packaging.


33. How do we apply for an exemption from the obligation to verify the safety features (the white list)?

The final lists adopted by the European Commission are set out in Annexes I and II to the regulation on safety features.

Based on recommendations from the member states, the European Commission decides which medicinal products should be included on the lists, taking into account the five criteria. Consequently, companies cannot apply for exemption from the list.

See article 54a of the Directive on medicinal products for human use

See also articles 46 and 47 of the regulation on safety features in the link above.

The lists apply from 9 February 2019 when the regulation enters into force. Changes to the present lists – additions or removals of medicinal products from the lists – require an amendment of the regulation to be adopted by the European Commission.

The European Commission can decide that a medicinal product should not bear the safety features (”white list” which means that the medicinal product will be included in Annex I to the regulation on safety features) but the risks of falsification must have been assessed. The assessment must, as a minimum, take into account, the criteria set out in articles 54a(b) (i)-(v) of the directive.

The Danish Medicines Agency has not yet established any practice on how and to what extent we will recommend that medicinal products are included on the ”white list”, see article 46(2) of the regulation on safety features. The first step would be a request from the marketing authorisation holder, including arguments related to the specified criteria as well as other matters that the MAH believes are of importance to an assessment of the risk of falsification.

Even if the Danish Medicines Agency decides to report a medicinal product to the European Commission on that basis, it should be noted that the European Commission makes the final decision and that this decision will apply throughout the EU. Moreover, the EU’s regulatory process is a long process and it will take some time before the medicinal product is included on Annex I.


34. Will the new rules imply that the Danish Medicines Agency will be approving the labelling of medicinal products?

No, we will not change our current practice of approving the labelling of medicinal products as a result of the new rules.


35. Where can I find additional information?

See the Commission Delegated Regulation (EU) 2016/161 on safety features

See The Commission’s Q&A on safety features

For more information about the DMVO, see www.dmvo.dk

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