Brexit − Regulatory and supply chain considerations

Converted centrally authorised procedure MAs to Great Britain MAs

All existing centrally authorised procedure (CAP) marketing authorisations (MAs) were automatically converted into UK MAs effective in Great Britain (GB) only (England, Scotland and Wales). These were issued with a new MA number on 1 January 2021, unless the MHRA were otherwise advised. This process was referred to as grandfathering. The MHRA issued product licence numbers to CAPs with a format of PLGB, which are only valid in GB. As a result of the implementation of the Northern Ireland Protocol, existing CAPs will remain valid for marketing products in Northern Ireland. Future EU marketing authorisations will continue to include Northern Ireland. It is important to note that this has created two parallel licences; one for the EU, including Northern Ireland, and a new separate GB licence. The MHRA now acts as a stand-alone sovereign regulator outside of the European regulatory network. Therefore, the MHRA does not have access to the same repositories as it did prior to Brexit. The MHRA required essential baseline data to be submitted in the form of an initiating eCTD sequence, together with certain other related MA-specific information for each grandfathered product. This process had a deadline of one year and concluded at the end of 2021. As with all national MAs, annual service fees are required for converted EU MAs. 

Ongoing CAP procedures

For pending CAP procedures, the MHRA provided two alternate routes for a UK authorisation:

• Companies can apply for an ‘in-flight assessment’ for a GB MA, in parallel with the EU review. The MHRA will consider any assessment that has already been reported on or before 1 January 2021, with a view to completing the application no later than the issue of the European Commission (EC) decision

or

• Wait until the product has received a positive opinion from the CHMP to follow the new reliance route. The application will be determined when the EC decision has been confirmed.

The MHRA would need a strong justification for not granting a licence based on the EC decision, which should be within 67 days.There is potential for a faster route by having an in-flight assessment, but there is the possibility of a divergence of opinion between the MHRA and the current rapporteurs for the EU license.

MRP/DCP existing licenses

For existing mutual recognition procedure (MRP) or decentralised procedure (DCP) products, marketing authorisation holders (MAHs) have a choice regarding the management of their MAs:

A. Maintain a UK-wide marketing authorisation and retain UK(NI) (the UK in respect of Northern Ireland) as a concerned member State (CMS). In this case, the authorisation will continue to be a UK-wide MA, with Northern Ireland as a CMS and Great Britain aligned with, but not part of, the DCP/ MRP. This will be the default position and no action will be required by the MAH

B. Request that separate MAs are issued for UK(NI) as a CMS, and Great Britain (England, Wales and Scotland)

C. Notify the UK and the reference member state (RMS), in writing, that they wish to remove UK(NI) as a CMS from the DCP/MRP and maintain a national MA in Great Britain only.

Option A is the default position, and there is no action required for companies when this route is taken. Options B and C may be utilised, if the MHRA cannot agree to an EU decision, and then the dossier diversion would be required.

MRP/DCP products: new products

MRDC reliance procedure

The MHRA can use approval of marketing authorisations submitted via the MRP or DCP in EU member states, with a view to granting the MA in UK or GB. This route is called the MRDC reliance procedure. The MAH submits the MRP/DCP marketing authorisation application (MAA) as usual. When approval is received, the entire dossier is then submitted to the MHRA via the MHRA submissions platform.

Unfettered access procedure

Northern Ireland can continue to be included as a CMS for new MAAs. If the MAH is established in NI and the product qualifies as a qualifying NI good, a second route for GB authorisation, called the unfettered access procedure (UAP), is an option. This is very similar to the MRDC reliance procedure and requires the fully approved NI dossier to be submitted to the MHRA via the submissions platform. For both procedures the assessment is expected to take 67 days from validation.

MRP/DCP: variations

For licenses maintaining the default option A, variations may continue to be submitted and managed as part of the relevant MR/DC procedure with NI as CMS, to maintain a UK-wide authorisation. The RMS will communicate the outcome of the procedure directly to the MHRA. So, there is no requirement for the applicant to send the RMS decisions to the MHRA for UK-wide licenses. There is a 30-day period, when the MHRA may raise objections at the end of the procedure. This relates to those variations where CMS input is expected. This primarily relates to major Type II variations, where the applicant will already be aware of the UK’s position throughout the procedure. If the MHRA is the only country with objections at the end of the procedure, a referral cannot be triggered by NI as CMS, so a split of the MA may be triggered. Such situations are expected to be very rare. Regarding implementation, as far as the current variations and similar variations in future are concerned, the changes can be immediately implemented on approval by the RMS. Type II variations can only be implemented 30 days after approval by the RMS, where the MHRA also issues an approval letter. For Type IB variations, the MHRA will not issue a separate approval notification. For UK or GB MAs attained under a reliance route, the variations also need to be submitted to the MHRA. Type IA notifications need to be submitted and processed by the MHRA. Type IB and Type II can be submitted after RMS approval.

National licenses: variations

Following the UK’s exit from the EU, the UK continues to rely on EU guidance documents. Where existing EU law refers to various pieces of EU guidance, those references are inserted into the UK’s Human Medicines Regulations 2012 (HMRs). The relevant version of the EU guidance is the version as it stood immediately before the end of the transition period. Any specific request for an article 5 classification for a UK change will need to be submitted directly to the MHRA, who will then issue its own recommendation. Specific changes may have differing or additional requirements. These changes include:

1. change to the location of the pharmacovigilance system master le (PSMF) or quali ed person for pharmacovigilance (QPPV)

2. implementation of the outcome of referrals and procedures concerning periodic safety update report (PSUR) or post authorisation safety study (PASS)

3. submission of protocols and study reports for PASS

4. submission of paediatric study reports for assessment.

Supply chain arrangements

Over the last several years, concerns have been raised by companies that are dependent on the supply of medicinal products into Northern Ireland from the UK. These concerns have centred on the ability of economic operators to comply with all provisions of the acquis for medicines, after the end of the transition period provided for in the Brexit Withdrawal Agreement. Following the terms and conditions of the Northern Ireland Protocol, the UK government issued a command paper in July 2021. The paper explains their desire for significant changes to the Northern Ireland Protocol and for agreement of a new balance with the EU in how the Protocol operates. To provide a level of certainty and stability to businesses, pending the discussions between the UK and the EU, the UK government announced on 6 September 2021 that it would maintain standstill arrangements.

The purpose of the standstill agreement was to ensure the continued supply of goods from the UK into Northern Ireland. Pursuant to the Protocol on the withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union, medicines placed on the Northern Ireland market must follow the EU acquis for medicinal products. The medicines must also be covered by a valid MA, issued by the Commission (EU-wide authorisations) or the UK in respect of Northern Ireland, with a pragmatic approach to the application of EU importation and unique identifier requirements. This detail is set out in the draft EU Unilateral Declaration in the Withdrawal Agreement Joint Committee.^[1], ^[2]

Under the terms of the Agreement, batch testing and qualified person (QP) certification performed in GB enabled the supply of medicines with a valid MA to Northern Ireland. Batch testing and QP certification performed in the EU/ EEA also allowed supply to Northern Ireland via GB. Medicines continued to be supplied from the GB market to Northern Ireland without requiring additional regulatory importation. This also permitted wholesale dealers to continue to supply medicines from GB into Northern Ireland.

The serialisation requirements of EU delegated regulation 2016/161 continued to remain in place for Northern Ireland.^[3] Medicines with a MA valid in Northern Ireland (PL and PLNI) still required a unique identifier and a tamper-evident device on each pack. The unique identifiers on packs with a marketing authorisation valid in Northern Ireland (PL and PLNI) supplied by a manufacturer or wholesaler in the EEA will not require decommissioning when exported to the UK until the 31 December 2024. Unique identifiers on these packs must be decommissioned in Northern Ireland as required by EU Delegated Regulation 2016/161.

Medicines with a MA valid in GB only and labelled as Product Licence GB (PLGB) do not require a unique identifier. PLGB medicines cannot be supplied to Northern Ireland unless specifically approved by the MHRA. In December 2021, an advancement in political discussions between the EU and UK saw the publication of a communication on the proposal, to ensure the continued supply of medicines to Northern Ireland.

The UK government presented before Parliament the Human Medicines (Amendment) (Supply to Northern Ireland) Regulations 2021 (SI 2021/1452) on 16 December 2021, which came into force on 1 January 2022.^[4] This saw amendments to the Human Medicines Regulations 2012^[5] , as amended, to establish the Northern Ireland MHRA Authorised Route (NIMAR^[6]) for the lawful supply of prescription-only medicines from GB to Northern Ireland, where licensed alternatives are not available in Northern Ireland. Medicines will only be supplied under the NIMAR if they are a “listed NIMAR product”, which are prescription-only products with a UKMA (UK) or UKMA (GB) marketing authorisation from the MHRA.

Updates providing clarity have been issued from the MHRA on Importing medicines into Northern Ireland in January this year (2022) on the proposed amendments.^[7]

On 12 December 2021, the EU published a communication on the approval of the content of the draft commission notice, on the application of the Union’s pharmaceutical acquis in markets historically dependent on medicines supply from or through parts of the UK other than Northern Ireland. It also updated directives 2001/20/EC, 2001/83/EC^[7], regulation 536/2014^[8] and delegated regulation 2016/161.

As regulatory importation requirements will be removed for all medicines moving between NI and GB, the proposed EU legislation changes will ensure patients in NI have access to medicines from the UK. This access will be on the same basis that currently occurs, whereby medicines move freely into Northern Ireland from the UK.

Further stability regarding the FMD requirements was provided by the extension to the existing derogation on all medicines for three years.^[9] For regulatory functions relating to a MA or QP, further clarification is provided:

• A MAH may be established in parts of the UK other than Northern Ireland
• the manufacturing and importation authorisation (MIA) may be located in parts of the UK other than Northern Ireland
• batch testing may be performed in parts of the UK other than Northern Ireland
• the QP and QPPV for batch testing and pharmacovigilance may be located in parts of the UK other than Northern Ireland
• an EU wholesaler located in Northern Ireland may purchase and obtain medicines from a third country (parts of the UK other than Northern Ireland) without holding a MIA and without re-testing the products
• suppliers of generic medicines within Northern Ireland can choose to license either through the EU or UK processes
• suppliers of new medicines in Northern Ireland will be able to use a new bridging mechanism, to ensure that their product is licensed for the whole of the UK, if the MHRA licences a product before the EMA.

The grace period that ends on 1 January 2022 will be extended by 12 months so the EU can make necessary changes to the law to support the points above. It is expected that these changes will be made before the end of the extended grace period. This is since the proposal for a directive amending the EU Medicines Directive, which is now open for feedback from stakeholders and the general public by way of a public consultation, will end on 14 February 2022. Brexit has posed several challenges to the pharmaceutical industry, which require robust actions and swift resolution, to maintain compliance with the changing regulatory landscape in the UK. Negotiations between the EU and UK are still ongoing to define their future relationship.

References

^[1] HM Government. (2020). Unilateral declarations by the European Union and the United Kingdom of Great Britain and Northern Ireland in the Withdrawal Agreement Joint Committee on human and veterinary medicines. (online). Available at: Microsoft Word - Unilateral declarations by the European Union and the United Kingdom of Great Britain and Northern Ireland in the Withdrawal Agreement Joint Committee on human and veterinary medicines.docx (publishing.service.gov.uk) (Accessed 1 February 2022).

^[2] HM Government (December 2020). Unilateral declarations by the European Union and the United Kingdom of Great Britain and Northern Ireland in the Withdrawal Agreement Joint Committee on human and veterinary medicines

^[3] Official Journal of the European Union (2015). 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 4. The Human Medicines (Amendment) (Supply to Northern Ireland) Regulations 2021

^[4] The Human Medicines (Amendment) (Supply to Northern Ireland) Regulations 2021. Available from: The Human Medicines (Amendment) (Supply to Northern Ireland) Regulations 2021 (legislation.gov.uk) (Accessed 1 February 2022).

^[5] Legislation.gov.uk. 2012. The Human Medicines Regulations 2012. [online] Available at: The Human Medicines Regulations 2012 (legislation.gov.uk)(Accessed 1 February 2022).

^[6] Legislation.gov.uk. 2021. Medicines eligible for Northern Ireland MHRA Authorised Route. [online] Available at: Medicines eligible for Northern Ireland MHRA Authorised Route - GOV.UK (www.gov.uk) (Accessed 1 February 2022).

^[7] Legislation. European Union. 2021.Directive 2001/20/EC, 2001/83/EC.

^[8] Legislation. European Union. 2021 Clinical trials - Regulation EU No 536/2014 [online] Available at: REGULATION (EU) No 536/•2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL - of 16 April 2014 - on clinical trials on medicinal products for human use, and repealing Directive 2001/•20/•EC - CHAPTER ICHAPTER IICHAPTER IIICHAPTER IVCHAPTER VCHAPTER VICHAPTER VIICHAPTER VIIICHAPTER IXCHAPTER XCHAPTER XICHAPTER XIICHAPTER XIIICHAPTER XIVCHAPTER XVCHAPTER XVICHAPTER XVIICHAPTER XVIIICHAPTER XIX (europa.eu) (Accessed 1 February 2022).

^9. Legislation.European Union. Falsified Medicnes Directive. 2011. Available at: 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 productsText with EEA relevance (europa.eu) (accessed 1 February 2022).