Anti-counterfeit drugs: Italy must comply with EU Regulation 2016/161 by February 9, 2025

Measures to combat counterfeit drugs work to prevent such drugs from entering the European supply chain. Delegated Regulation (EU) 2016/161 introduces new rules to halt counterfeit drugs from entering the European market and includes digital tools. As of February 9, 2025, Italy will have to comply with the provisions of the regulation, so there is not much time left to get in line with the new measures.

Regulation (EU) 2016/161

As mentioned above, the regulation implements some of the provisions of Directive 2011/62/EU, known as the falsified medicines directive. It also introduces new tools for combating the falsification of medicines. Although the regulation took effect in most European countries on February 9, 2019, Italy obtained a waiver (as did Greece) to postpone implementation of the regulation to February 9, 2025. This was possible because Italy already had a national system for drug identification and traceability (the vignette system). New obligations under the regulation apply to:

• prescription medicines that on their packaging display safety features established by Directive 2001/83/EC or safety features that enable wholesale distributors and persons authorized or entitled to supply medicines at the wholesale level to verify the authenticity of the medicine and identify individual packages and devices that indicate when the outer packaging has been manipulated;
• certain non-prescription medicines (see Annex II to the Regulations), namely 20 and 40 mg omeprazole capsules.

However, Member States may enact national legislation to expand application of the regulation to other medicines. Prescription medicines for which there are no safety feature indications (see Annex I to the Regulation), including homeopathic medicines, radionuclide generators, advanced tissue- and cell-based therapies, medicinal gases, parenteral nutrition solutions, contrast agents, and allergy tests, do not fall under the regulation.

New obligations for pharmaceutical companies to combat counterfeit medicines

The new regulation introduces a large number of obligations and regulates a range of activities to counter the purchase of falsified medicines. Many of these measures involve using digital tools to improve the efficiency of supply chain tracking.

Data Matrix identification code

One of the biggest changes introduced by the regulation is a new code for identifying medicines, the Data Matrix code. The manufacturer prints the code on the packaging. It is a series of numeric or alphanumeric characters unique to each drug package. The code makes it possible to identify:

1. The product code (at a minimum the name, common name, pharmaceutical form, strength, and size and type of packaging for the medicinal product);
2. Serial number (numeric or alphanumeric sequence of no more than 20 characters generated by a deterministic or nondeterministic randomization algorithm);
3. National reimbursement number or other national number identifying the medicinal product (if required by the Member State);
4. Lot number;
5. Expiration date.

The Data Matrix code is encoded in a two-dimensional machine-readable barcode that complies with ISO/IEC 16022:2006 standards. It is printed on a smooth, uniform, and low-reflective packaging surface. Manufacturers must assess the quality of Data Matrix code printing according to parameters in the regulation (Article 6). The manufacturer must state the product code, serial number, and national reimbursement number on medicine packaging. Prescription medicines covered under the regulation cannot have any other barcodes on their packaging (Article 9).

Unique serial numbers

Including these codes on all packages will streamline monitoring of products throughout the distribution chain. A person authorized to supply medicinal products to the public who believes that the packaging of a medicinal product has been tampered with must immediately halt supply and inform the appropriate authorities and must do the same if inspection of safety features reveals that a product is not authentic. The regulation also states that when a medicine leaves the distribution circuit (e.g., exported or recalled from the market) the identifier must be deactivated.

European Medicine Verification System (EMVS)

Another new feature in the directive is a repository of data about medicine safety and authenticity. The regulation governs the structure and main features of this repository. The EMVS is a digital archiving platform managed at the European level that enables centralized collection of data on medicines contained in the Data Matrix. The platform is centralized but linked to national or supranational (i.e., covering multiple Member States) archives. Each repository that is part of the EMVS ecosystem must be located within the EU, must be established and managed by a nonprofit legal entity established in the EU, and must be interoperable with other repositories.

Responsibility for compilation

AIC holders are responsible for uploading medicine data (and must do so before a medicine is placed on the market or distributed by the manufacturer and before checking that the information contained in the repository is up-to-date). In addition to manufacturers and MA holders, wholesalers and entities authorized to supply medicines to the public may access the platform. This centralized archiving system allows wholesalers, pharmacies, and authorities to:

• upload, assemble, process, and edit information on the safety and authenticity of medicines;
• verify the authenticity of packages in real time when dispensing them using digital interfaces for rapid and automated oversight and, if necessary, deactivating them at any point in the legal supply chain under the circumstances allowed.

Tampering prevention systems

The regulation requires manufacturers, wholesalers, and those authorized or entitled to supply medicines to the public to verify the integrity of tampering prevention systems. A drug must be protected by an anti-tampering device that ensures that the package cannot be opened without leaving obvious marks.

Implementation of the new rules

To enable Italy to meet the deadline imposed by the European regulations, Law No. 15 of February 21, 2024 was enacted. It assigned the government to adopt one or more legislative decrees to adapt the national regulatory framework to the provisions of the regulation. On August 30, 2024, the Council of Ministers preliminarily approved a draft legislative decree that currently is still being discussed at the institutional level. Eventually it needs to be approved by the government and published in the Official Gazette. For the mechanism then to be fully operational, implementing ministerial decrees and AIFA measures will need to be issued. The draft decree states that beginning February 9, 2025, all prescription-only medicines for human use, except those listed in Annex I of the regulation and non-prescription medicines listed in Annex II of the regulation (i.e., currently only 20 and 40 mg omeprazole), must bear unique identifiers encoded in two-dimensional barcodes on their packaging. Also, all medicinal products for human use authorized in Italy must bear tamper-prevention systems, including Poligrafico dello Stato high-value paper as a tamper-evident device. This requirement is particularly onerous for Italian companies, given that other Member States use tamper-evident cartons (e.g., glue point, adhesives, and interlocking cardboard systems) that guarantee the integrity of the packaging with standard tools.

A race against time

Deadlines are looming. According to the decree (and assuming that the entire regulatory system has been completed in the meantime), by November 9, 2024, an Italian company must submit a notification to the AIFA of modification of its medicines’ printed materials (pursuant to Article 78 of the Medicines Code, which provides a silence/assent mechanism after 90 days) to allow implementation of the change as of February 9, 2025 at the latest. For a (relatively) less abrupt transition to the new rules, the draft decree specifies that medicinal products for human use intended for sale in Italy that are part of batches released by February 9, 2025 and that bear pharmaceutical seals affixed to the outer packaging may be marketed, distributed, and supplied to the public in Italy until their expiration dates and need not be repackaged or relabeled. The considerable penalties introduced by the draft decree will also kick in as of February 9, 2025. Both institutions and companies are racing to comply with these new rules by the European deadline.