The Windsor Framework is a political agreement between the European Commission and the U.K. government to ensure that, in the wake of Brexit, Northern Ireland continues to receive critical supplies such as food and medicines. This past week, the MHRA provided guidance on labeling of medicines destined for Northern Ireland, with provisions to ensure that medicines only move into Northern Ireland market and don’t re-enter E.U. member states.
- The U.K.’s official exit from the E.U. on February 1, 2020 started a year-long transition period; the E.U. pharmaceutical law ceased to apply to the U.K. as of January 1, 2021. The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) has been releasing guidance for the pharmaceutical and medical device industry to aid product development and approval after the separation. The European centralized marketing authorization procedure is no longer a valid medicines approval pathway for the U.K.
- The U.K. includes England, Scotland, Wales, and Northern Ireland, but not Ireland. The Protocol on Ireland and Northern Ireland preserves the integrity of the E.U.’s single market. This agreement also aims to prevent the establishment of a “hard border” between Ireland and Northern Ireland, while ensuring the integrity of the single market, including protection of public health and consumers. These came into effect on January 1, 2021.
- The MHRA implemented the European Commission Reliance Procedure (ECDRP) to ensure swift approval of new medicines. The European Commission Decision Reliance Procedure (ECDRP) allows MHRA to rely on EC approval decisions for marketing authorization applications; the procedure is available for E.U. medicines authorized through the centralized procedure seeking a marketing authorization in Great Britain. When the ECDRP is invoked, the MHRA will ensure a product’s compliance with applicable regulatory requirements, but will generally perform a less detailed review of the application, relying in part on the decision taken by the EC. This reliance procedure was implemented on January 1, 2021, for a planned two-year span, but last September, MHRA extended the effective period for the procedure to the end of 2023. [See AgencyIQ’s analysis of the ECDRP.]
- Sponsors who submit an application to MHRA soon after an EMA opinion is issued will see faster marketing authorization assessment for Great Britain. MHRA’s guidance highlights that marketing authorization applicants should submit their application immediately upon receipt of a positive opinion from EMA’s Committee for Medicinal Products for Human use (CHMP).
- The Windsor Framework is a political agreement that aims to address the challenges posed for Northern Ireland by the U.K.’s withdrawal from the E.U. The agreement between the European Commission (EC) and the U.K. government was put in place on February 27, 2023 and includes a number of proposed regulations to address trade relations between the E.U. and the U.K. in areas such as customs, agri-food, and medicines. To supplement the Windsor Framework, the EC recently released a new Regulation (EU) 2023/1182 that specifically provides additional safeguards for medicines supply to Northern Ireland; it was published in the Official Journal of the E.U. on June 20, 2023 and will apply starting January 1, 2025.
- Basically, the new regulations “ensure that all medicines, including novel medicines, will be available in Northern Ireland at the same time as in the UK,” according to a May 30 press release announcing the medicines regulation, which was adopted along with other rules addressing agri-food, plants and pets, as well as some steel products. At the same time, the framework also includes measures to “ensure the integrity of the EU’s Single Market, to which Northern Ireland has unique access.” The aim is to make sure that medicines that receive marketing authorization in the UK become available simultaneously in Northern Ireland, without then passing into the E.U. by means of the “soft” Northern Ireland-Ireland border.
First: all medicines for Northern Ireland must be approved by the MHRA
- The new regulation (EU) 2023/1182 applies to medicines that require marketing authorization. The document specifically notes that it applies to “medicinal products for human use intended to be placed on the market in Northern Ireland in accordance with Article 6 of Directive 2001/83/EC,” the current European pharmaceutical legislation.
- Broadly, the new regulation carves out exceptions to the provisions of the Protocol on Ireland/Northern Ireland, also known as “the Northern Ireland Protocol,” which will otherwise still apply. The provisions in Annex 2 of the Brexit legislation will also apply unless the new regulation changes those. Definitions from the existing E.U. pharmaceutical legislation and regulation (in Article 1 and Article 2 of the respective documents), will also apply.
- The MHRA may allow importation of medicines into Northern Ireland through wholesale distribution authorization holders. These don’t need to possess the manufacturing authorization that would ordinarily be required under Article 40(1a) of the existing E.U. Pharmaceutical Directive. However, the medicinal product must still meet several requirements, according to the new legislation: First, it must have undergone quality control testing. Second, a qualified person must have completed the batch release. Third, a marketing authorization has to have been issued either in the E.U. or through the MHRA for medicines destined for Northern Ireland. And fourth, medicines can only be made available for patients and end-consumers in Northern Ireland.
- There are some provisions that limit requirements for wholesale distribution authorization holders. These are provisions from Articles 80-82 of the existing pharmaceutical legislation that otherwise would apply. They don’t need to verify the safety features (more on those below) to ensure medicines are not falsified. Additionally, they don’t need to keep records on batch numbers, and don’t need to include a document that would make identification of the batch number possible.
- Medicinal products authorized through the centralized procedure in the E.U. will now require a marketing authorization by the MHRA. Articles 3(1) and 3(2) of the current European pharmaceutical regulation (EC) No 726/2004 set out requirements for medicinal products that must use the centralized procedure, rather than national approval pathways. Generally, these products can’t be placed on the market unless three conditions have been fulfilled: First, the product has been authorized by the U.K. competent authority; Second, the medicinal product follows the labeling requirements provided in Article 5 of the new Regulation (EU) 2023/1182 (see below); and third, the U.K. provides the EC with written guarantees that labeling requirements are followed and that the monitoring, enforcement and controls of the new regulation have been followed (Article 8).
Specific labeling requirements aim to ensure medicines are only used in the U.K. market
- Safety features must be fully removed or covered up. Article 54(o) of the existing E.U. pharmaceutical directive would ordinarily require the inclusion of safety features to enable wholesale distributors to verify the authenticity of the medicine and identify individual packs. However, Article 3 of the new regulation governing medicines importation to Northern Ireland now requires those to be removed or covered. These features should not be included on outer packaging or immediate packaging, if there is no outer packaging. The qualified person is responsible for making sure that the safety features have not been attached.
- The label must state the words “UK only.” Article 5 of the new regulation requires that the label must be conspicuously attached to the medicinal product so that it is “easily visible, clearly legible and indelible.” Other pictorial matter or material should not hide the label or interrupt it.
- However, medicines already on the Northern Ireland market before application of the new regulation do not require relabeling. Article 12 of the new regulation states that products that were already lawfully on the Northern Ireland market can remain on the market without repackaging or relabeling until their expiry date. This transitional provision ensures that medicines remain available without the need to comply with provisions in Article 3 through 5.
- But: Medicinal products can’t be moved from Northern Ireland to an E.U. Member State. Article 7 notes that member states are responsible for applying “effective, proportionate and dissuasive penalties” to prevent entry of Northern Ireland medicines into the E.U. market.
Last week, the MHRA provided a roadmap for upcoming labeling requirements, based on license type
- The Windsor Framework allows the MHRA to approve medicines for U.K. use but also provides for the disapplication of the Falsified Medicines Directive. The E.U. Falsified Medicines Directive 2011/62/EU (FMD) implements safeguards to prevent the entry of illegal medicines into the E.U. market (more on this below). Beginning January 1, 2025, the MHRA will be responsible for authorizing all medicines for the U.K. market (including Northern Ireland) that currently fall under the scope of the E.U. centralized procedure. These are marketing authorization applications submitted to the EMA and authorized by the EC under Regulation (EU) No 726/2004. The “U.K. only” labeling aims to ensure that the medicines are only available in the U.K., and not in Ireland or any E.U. member state. However, labeling requirements depend on the type of license of the medicine.
- U.K.-wide license: The requirements of the E.U. Falsified Medicines Directive currently apply to most prescription drugs but not most non-prescription drugs. As a quick reminder, the U.K. includes all of Great Britain (i.e., England, Wales, Scotland) and Northern Ireland. The “U.K. only” labeling should be implemented for both these product types immediately but no later than December 31, 2024. The FMD will “disapply” for applicable prescription drugs beginning January 1, 2025. It has no bearing on non-prescription drugs, since the FMD does not apply to these. Packs with the “U.K. only” label can be released into the market immediately following the publication of the guidance. In other words, the MHRA states that the “U.K. only” label can be applied as of now, as long as the packs remain compliant with the FMD.
- Great Britain – Product License: The Falsified Medicines Directive currently does not apply. Great Britain (G.B.), as noted above, only includes England, Wales and Scotland. The FMD does not apply, but the “U.K. only” label should be implemented immediately, with a latest permitted submission date of December 31, 2024. However, the “U.K. only” labelled packages can only be released into the market beginning January 1, 2025, and not earlier. Since the FMD doesn’t currently apply, there won’t be a disapplication date. The guidance notes that G.B.-only licenses will be converted to U.K.-wide licenses, with additional guidance on this conversion to be provided at an unnamed future date. Beginning January 1, 2025, these packs will need to present the ”U.K. only” statement in addition to the G.B. license number.
- Northern Ireland – Product License: The “U.K. only” label will be required from the date of publication of the “licensing guidance.” The “U.K. only” label should be applied no later than December 3, 2024, but products can’t be released to market earlier than January 1, 2025. The FMD currently applies, but will disapply starting January 1, 2025.
- Any existing stock can be supplied as usual until the expiry date is reached. Medicines that are already on the market in Northern Ireland or G.B. and released by the qualified person before the December 31, 2024 date can remain on the market until the product’s expiration date is reached.
- Parallel import authorizations will change from the G.B. limitation to a U.K-wide authorization on January 1, 2025. “The UK parallel import licensing scheme lets a medicine authorized in the European Economic Area (EEA) Member State be marketed in the UK, as long as the imported product has no therapeutic difference from the cross-referenced UK product,” according to the MHRA guidance on parallel import licenses. The labeling guidance from last week states that all parallel import licenses that have a G.B. limitation will be converted to U.K.-wide parallel import licenses, effective January 1, 2025. Parallel imports a) don’t need the “U.K. only” labeling, b) don’t need to comply with the FMD, and c) have no application submission or assessment. Companies holding a U.K. parallel import license may apply the “U.K. only” label. However, MHRA is contemplating issuing further guidance specific to parallel imports.
- Joint E.U. – U.K. packs won’t be able to enter the U.K. supply chain. Joint packs present administrative information for the U.K. and at least one other E.U. member state. However, starting January 1, 2025, these packs need to display the “U.K. only” statement AND have all administrative information from the other E.U. country removed. Both changes can be notified to the MHRA at the same time.
- New marketing authorization applications may need to update labeling mock-ups. A label including the “U.K.-only” statement can be approved for any marketing authorization application currently under evaluation. Text provided with the original application may need updating if the statement hasn’t been included yet.
The guidance has some very specific requirements for the “U.K. only” label, which can be used for now
- There are three conditions for this special label: First, the “U.K. only” label can be affixed anywhere on the packaging. Second, type must be at least 7-point size, but no other font or style requirements apply. The MHRA further clarifies that it must conform with Article 5 of Regulation 2023/1182 (i.e., the EC regulation on Northern Ireland medicinal products) and the best practice guide. Third, the new label must be attached beginning January 1, 2024. The E.U. legacy packaging will still be acceptable until December 31, 2024.
- The previous deadline for G.B. packaging requirements was extended by one year. G.B. packaging was to have been required beginning December 31, 2023; that date has now been pushed back to December 31, 2024. This gives manufacturers one additional year to comply.
- A six-month transition period allows the “U.K. only” label to be attached as a sticker. The “U.K. only” label will be required on all packaging from January 1, 2025. However, for six months until June 30, 2025, manufacturers may use a sticker that is affixed to the packaging. But there are a few requirements to follow: 1. this sticker must be attached before the qualified person certifies and releases the product; 2. the sticker can’t cover up any of the statutorily required text (e.g., batch number, expiration date); and 3. manufacturers need to submit an updated mock-up through the notification process.
- “Artwork” changes to medicine packaging must be notified to the MHRA. The “U.K. only” label will require updated artwork, and therefore notification, before December 31, 2024. The MHRA offers two processes for this notification: 1. Manufacturers may include the artwork notification with other change applications through a variation. The cover letter should note the manufacturer’s intent to bring the artwork into compliance. 2. A self-certification notification can be submitted at any time. Any change proposed will apply as soon as the self-certification has been submitted, without the need to wait for approval. Labeling changes must be notified according to Regulation 267 of the Human Medicines Regulation 2012.
- A “clean mock-up” will not be required as long as the only labeling change is to add the “U.K. only” statement. The MHRA notes that an “annotated mock-up indicating where this wording will be located is acceptable.” Any changes beyond adding the “U.K. only” labeling will require a clean mock-up.
Additionally, the E.U. Falsified Medicines Directive will no longer apply beginning January 1, 2025
- All U.K. safety requirements will remain in place after the Falsified Medicines Directive effect lapses. Manufacturers may choose not to no include FMD safety features beginning January 1, 2025. U.K. packaging features should be considered for inclusion. The MHRA notes that existing U.K. safety features, such as placement of the batch number, remain unchanged. However, manufacturers may also choose to include additional features such as a 2-dimensional bar code or a serial number.
- There are no special requirements for 2-dimensional bar codes, except that the bar code should be able to be decoded by common scanning equipment. The MHRA also expects that bar codes would comply with common ISO/IEC standards. The bar code may contain information such as the product, expiry date, batch number and global trade item number.
- However, the use of a barcode containing an alphanumerical sequence that has been uploaded to the European repository system is prohibited. Any such barcode would need to be fully removed or covered. Regulation (EU) 2016/161 requires all medicines to carry a 2-dimensional bar code that also encodes the unique identifier.
The European Commission can revoke some provisions if Articles 3, 4 and 5 are not followed
- The new regulation stipulates that the EC should report serious or repeated infringements of the regulation through written notification to the U.K. government. Article 3 governs the wholesale distribution, Article 4 the requirement of U.K. authorization for products approved through the centralized procedure, and Article 5 labeling requirements. Once a written notification of violation of any of these articles has been issued, the EC and U.K. government will enter into a 3-month consultation period to remedy the issues; the consultation may be extended for an additional 3 months.
- Under the new regulation, the EC may revoke some provisions, if infringements or lax oversight aren’t properly addressed. The EC will issue delegated acts under consultation with appropriate national experts according to the Better Law-Making Agreement (Article 10). The EC is required to inform the E.U. Parliament and Council of the delegated act; those bodies then have two months to object. If no objection is issued, the delegated act will enter into force. However, Article 11 also provides for an urgent procedure where the delegated act enters into force right away until an objection is issued.
- The new regulation will apply beginning January 1, 2025. In the meantime, the currently effective pharmaceutical directive does provide a pathway for medicines to enter the Northern Ireland market. Although many procedures will remain the same, some provisions, such as those relating to the centralized procedure and mutual recognition procedures, will change when the new regulation comes into effect on December 31, 2024. The proposed European pharmaceutical directive. currently being assessed by the European Parliament and Council, will also feature provisions regarding Northern Ireland in Chapter 17. Although those provisions again provide more detail on handling medicines intended for Northern Ireland, the pharmaceutical package is not likely to be finalized before the new Northern Ireland regulation (EU) 2023/1182 comes into effect. [See AgencyIQ’s analysis of the proposed directive.]
- The new regulation simplifies and streamlines some requirements. Presumably, by the time the regulation applies, the separation of the U.K. from the E.U. single market will be virtually complete, with less need for continued oversight. However, the E.U. retains the power to ensure the agreed-upon rules are followed, or adopt delegated acts to address non-compliance. The responsibility of ensuring that medicines entering the Northern Ireland market comply with E.U. single market requirements still falls to the U.K. competent authorities.
- The new regulation cements safeguards to make sure that medicinal products do not move “freely” between the U.K. and E.U. markets. A primary safeguard will be the new “U.K. only” mark, to clearly denote medicines meant for the U.K. market. Additionally, the new regulation clearly provides that medicines placed on the market in Northern Ireland can’t be moved back to the E.U. market. Presumably, patients will still be able to carry their medication with them when they cross from Northern Ireland into Ireland, and vice versa. However, medicines will not be able to be sold in the other market.
- However, manufacturers are left with some uncertainty. With the new guidance, MHRA makes it very clear that new “U.K. only” labeling will need to be applied beginning January 1, 2025; for a grace period of 6 months, that can be done by attaching a sticker to the outer box. But how does this guidance apply to Great Britain- or Northern Ireland-licensed products in practice? For G.B. products, the “U.K. only” sticker can be applied immediately, but the product can’t be “released to market” until January 1, 2025. This leaves manufacturers to evaluate and determine the product demand for the next 1.5 years in order not to waste product.
- The sticker itself could pose a security issue. The MHRA guidance allows the use of a sticker instead of permanent printed labeling for the “U.K. only” labeling requirement. However, there are currently no requirements for the sticker itself, such as a specification that the sticker must be permanent and not easily removed. A sticker that can easily be removed, like ordinary retail pricing stickers, would not serve the purpose of ensuring the medicine is only used in the U.K. market.
- Additional clarification is needed for the applicability of some labeling provisions. For example, U.K.-wide products note that release to the market with the “U.K. only” label is possible “from date of guidance publication,” presumably referring to July 28, 2023, and the guidance on labeling and packaging that contains the chart with timelines published on that date. Northern Ireland products can use the “U.K. only” label “from date of licensing guidance publication,” but no specific link is provided. Presumably the guidance on medicines supply to Northern Ireland is referenced, but the guidance should be linked to add clarity.
- Sponsors can contact the MHRA with additional questions on labeling and packing: An email can be sent to [email protected].
- Medicines shortages have been identified as a continuous issue. The Covid-19 pandemic and resulting border closures highlighted issues even within the single E.U. market. These circumstances raise questions about how medicines shortages in Northern Ireland and Ireland would be handled. Medicines ordinarily should not cross the soft border between the two countries, but the regulation would have answered some questions had it addressed what happens when Northern Ireland, in the U.K. market, has sufficient stocks of a medicine in shortage in the E.U., or vice versa.
Key Documents and Dates
- Regulation (EU) 2023/1182, published June 20, 2023, becomes applicable on January 1, 2025
- The Windsor Framework
- MHRA guidance – Labeling and packaging of medicinal products for human use following agreement of the Windsor Framework, published July 28, 2023