Are you ready for the new pharma industry regulations?

By Matthew Cotten, BSc Manager in Regulatory Affairs PharmaLex

A wide range of major changes to pharmaceutical and medical device legislation in Europe will come into effect from January 1, 2021 when the Brexit transition period ends. These include changes that affect the UK as a whole as well as changes that relate specifically to Northern Ireland and others that relate only to Great Britain. Matthew Cotten of PharmaLex summarises these changes and outlines the actions that companies need to take to continue to operate in compliance with pharma industry legislation.

From January 1, 2021 the UK will be able to adopt an independent regulatory framework with the Medicines & Healthcare products Regulatory Agency (MHRA) positioned as the stand-alone regulator for medicines and medical devices.

Negotiations between the EU and the UK are still ongoing to define their future relationship and with little time left before the end of the transition period there has been no formal agreement. For the pharmaceutical industry this presents numerous challenges as companies prepare to continue supply of medicines that comply with new legislation. The preferred outcome for many within the industry will be to implement a mutual recognition agreement for areas such as GMP certification, batch testing, etc between the UK and EU. It is unclear at this stage if an encompassing mutual recognition agreement is achievable, so all involved parties should be preparing for a ‘no deal’ scenario and review existing guidance to understand risk exposure and mitigating actions.

The European Medicines Agency (EMA) updated the regulatory procedural guideline on the withdrawal of the UK and on EU rules for medicinal products in March 2020. The practical guidance for procedures related to Brexit for medicinal products (EMA/478309/2017) was also updated to reflect the implications of the withdrawal agreement.

From the September 1, 2020, the MHRA started to issue guidance on the post-transition period that will come into effect as of January 1, 2021.

The UK requirements will differ between Great Britain (consisting of England, Scotland and Wales) and Northern Ireland due to the Northern Ireland Protocol. The proposal for Northern Ireland will need to be agreed but the current position is that it will remain in compliance with EU legislation and comply with EU requirements with respect to medicinal products and medical devices. Separate guidance has been issued for inter-UK activities from January 1, 2021, where applicable.

Control of clinical trials/studies

The MHRA guidance confirms that from January 1, 2021, clinical trial sponsors will still need to register trials in a currently established, publicly accessible register. For trials in the UK only this can be the ISRCTN registry but for trials involving UK and EU sites, this will be recorded in the EU Clinical Trials Register.

For UK-based clinical trials, the sponsor or legal representative of a clinical trial will be required in the UK or an approved country and the approved country list will include EU/EEA countries. Where a clinical trial has a rest-of-world sponsor and a UK-based legal representative but covers sites in UK and other sites within the EU/EEA, a legal representative located in the EU/EEA should be assigned via a substantial amendment submission to the relevant competent authorities.

For investigational medicinal products (IMPs) used in UK clinical trials, the supply chain may include UK or approved country (EU/EEA) release sites from January 1, 2021. Where the IMP is supplied from a EU/EEA manufacturer, the sponsor will have 12 months from January 1, 2021 to ensure a UK MIA(IMP) holder puts in place an assurance system to confirm each batch of IMP has been certified by a QP before release to the trial. This will require a substantial amendment to be submitted to the MHRA to register the details of the UK MIA (IMP) holder performing the ‘supply chain oversight’.

Clinical trials involving EU/EEA markets will require the addition of an EU/EEA IMP release site to be included via a substantial amendment where this is currently performed by a UK IMP release site only.

Marketing authorisation holders

For medicinal products registered in the EU/EEA, Article 2 of Regulation (EC) No 726/2004 will still apply, confirming that the marketing authorisation holder (MAH) must be established in the EU/EEA. Therefore, a MAH currently established in the UK must be transferred to one in the EU/EEA before the end of the transition period.

In the UK, marketing authorisations (MAs) that were registered via the EU Centralised procedure will be transferred to a GB national licence but will remain applicable in Northern Ireland and future EU marketing authorisations will continue to include Northern Ireland. A GB presence for MAs must be registered within 24 months after the end of the transition period.

The EMA guidance confirms that at the end of the transition period, UK Notified Bodies will lose their status as EU Notified Bodies and will no longer be able to perform conformity assessment activity for medical devices. Product owners will need to apply for a new certificate from a recognized EU Notified body or arrange for a file transfer from the current UK Notified Body to an EU Notified Body that will take over responsibility.

In GB, the current EU medical devices legislation will be given effect in UK law from January 1, 2021. This will not include the EU Medical Devices Regulation nor the EU in vitro Diagnostic Medical Devices Legislation as they will not take effect until after the end of the transition period. Northern Ireland will be aligned with the EU.

Medical Devices in GB can, until June 2023, retain the CE marking and certification by EU/EEA based Notified Bodies. However, all medical devices and in vitro diagnostic medical devices (IVDs) placed on the UK market will need to be registered with the MHRA within the proposed grace period post-transition.

Companies that qualify for administrative and/or financial support from the EMA as a small or medium-sized enterprise (SME) must be established in the EU/EEA. Companies that are UK-based will fall under guidance for non-EU countries following January 1, 2021.

Oversight of manufacturing and QP release

To EU/EEA countries

Following the transition period, medicinal products manufactured in GB will be classed as imported products when transported into the EU/EEA. The supervisory authorities of medicinal products imported from third countries are the competent authorities of the Member State or Member States that granted the authorisation to the importer of the medicinal product concerned. The UK will no longer be able to undertake this supervisory role, so sites located in the UK and third countries that have been previously inspected may be re-inspected if the new EU supervisory authority deems it necessary to confirm or re-confirm GMP compliance.

Each batch of finished product must be certified by a QP via an MIA within the EU/EEA. Where quality control (QC) testing sites are only located in the UK for EU/EAA products, new sites located in the EU/EEA will need to be registered before the end of the transition period.

To the UK

Wholesale dealer’s licences issued by the MHRA will continue to be valid from January 1, 2021 for current holders. Companies currently importing medicines from the EU/EEA into GB were required to notify the MHRA in writing within six months from the January 1, 2020 of their intention to remain importing medical products from an approved country list. The approved country for import list includes EU/EEA countries.

The MHRA will accept QP-certified medicines from EU/EEA countries if checks are performed by a Responsible Person (Import) (RPi). The RPi will be responsible for implementing a system to confirm that QP certification has been performed on imported medicinal products.

Import can also be carried out by an MIA Holder through their QP, but he/she must apply to be named on the RPi register and should then follow RPi requirements.

Medicines with a marketing authorization sourced from Northern Ireland into GB will only require the presence of a RP and not a RPi.

Approved countries for batch testing of human medicines for supply to GB will include EU/EEA countries in addition to non-EEA countries with existing Mutual Recognition Agreements as per paragraph 14(1)(b) of Schedule 7 of the Human Medicines Regulations 2012.

EU labelling

Multi-country packs intended for supply to the EU/EEA that include the UK can still be used only if the product information is exactly the same for the UK and the EU and the Member State has allowed additional information labelled in the ‘blue box’.

Local Representatives based in the UK that are nominated for an EU Member State in product information must be replaced with a local representative located in the EU/EEA before the end of the transition period. Where product information contains a UK representative for the UK only, this will become obsolete, but the advice is to amend this at the earliest opportunity after the transition period (ie the next variation or renewal).

UK labelling

Multi-country packs will be allowed by the MHRA for UK supply provided that the entirety of the information is compliant with UK requirements.

Amendments to the artworks, patient information leaflet (PIL) and Summary of Product Characteristics (SPC) due to UK MAH updates will need to be submitted to the MHRA. This will be within the 24-month grace period.

Supply, distribution and RP responsibilities

Supply chain mapping to determine Brexit exposure is vital to understanding potential challenges for movement of goods via the UK. Following the transition period, there will be additional considerations for the transport of materials to/from the UK, between GB and Northern Ireland, and for goods passing through GB between the EU/EEA and Ireland.

Moving goods from GB to Northern Ireland will not be straightforward. The Northern Ireland Protocol will require HM Customs to apply EU customs rules and regulatory standards to all goods entering Northern Ireland, ensuring that tariffs are not paid on trade within the UK and that goods going onward to the Republic of Ireland pay tariffs and meet regulations when required.

Stockpiling has been proposed as a solution to alleviate initial disruption to supply chains as additional border activities come into action from January 1, 2021.

In the Republic of Ireland, the Health Products Regulatory Authority (HPRA) issued a letter to MAHs on July 2020 to promote the closure of regulatory gaps in the event of a worst-case scenario. They advise that a minimum of 8 to 10 weeks supply of medicines should be available at primary wholesalers on December 31, 2020 to ensure supply chain resilience post-transition.

In a letter issued to medicines and medical products suppliers on August 3, 2020, the UK Department of Health and Social Care advised that there will likely be disruption at the border for six months following the transition period. Whilst support has been offered in the form of express freight arrangements via specialist logistic providers, the advice is for companies to stockpile six weeks’ supply on UK soil to be prepared for potential delays in future stock arrival. This will provide a short-term solution and contingency planning for replenishing of stock in the event of longer-term disruption, and it is advised to enable continuity of supply.

In order to minimize disruption at the border, customs requirements will need to be understood and implemented for movement of goods between the EU and UK. This will require the development of in-house expertise or outsourcing to a customs broker. Considerations include:

  • applicable registrations
  • customs declarations
  • classification codes for the respective materials

Companies looking to move goods into the EU/EEA will need to acquire an Economic Operator Registration and Identification (EORI) number.

GMP considerations

Active substances manufactured in GB that are imported into the EU/EEAand Northern Ireland will need to be accompanied by written confirmation from the MHRA that confirms the manufacturing site that exported the active substance is compliant with EU good manufacturing practice and control while Quality Agreements may need to be updated depending on how GMP responsibilities are set out within current documentation.

Falsified Medicines Directive

The unique identifier and anti-tampering device required for EEA products as per the Falsified Medicines Directive (FMD) can be placed on the product by a UK manufacturing site. It is the responsibility of the importer to ensure compliance with the regulations and will be overseen by the QP (either directly, or via a suitable delegated party) at the EU/EEA batch release site. The EU MAH will be responsible for uploading the data to the respective repository systems.

The UK will not implement the FMD safety features but the MHRA has advised that packs containing these features will be accepted in GB if they are in line with UK packaging requirements.

Products entering GB, as a third country, will require decommissioning of the unique identifier at the point of exit from the EU. Therefore, moving goods to Northern Ireland from the EU/EEA via GB without an agreement may not be possible as product entering Northern Ireland will need to have an active unique identifier as per EU regulations. This will present a challenge to existing supply chains and may need arrangements for supply via the Republic of Ireland or alternative routes. Products manufactured in GB will not have this issue, as the unique identifier will only be activated at the point of entering Northern Ireland.

Northern Ireland will be regulated by the MHRA but will need to remain compliant with EU/EEA regulations to have unrestricted access to EU/EEA markets as promised in the Northern Ireland Protocol. Therefore, Northern Ireland manufacturers would need to arrange for future EU competent authority inspections to obtain the required GMP certificates and Northern Ireland importers and distributors would need to retain remote access to another EU27 NMVS to be able to carry out verification checks when moving from non-designated wholesalers and when decommissioning serialized prescription medicines.

Medical device manufacturers located outside of the UK that are planning to supply to GB must assign a UK Responsible Person that is established in the UK. The UK Responsible Person will be required to place a device on the market and act on behalf of the manufacturer, and will be a point of contact for MHRA requests.

Responsibilities for medical devices in Northern Ireland will depend on where the manufacturer is located.:

  • Manufacturers in Northern Ireland will be responsible for registering medical devices with the MHRA
  • Manufacturers located in GB will need to designate an Authorised Representative
    • Authorised Representatives based in Northern Ireland will need to register all device classes with the MHRA
    • Authorised Representatives based in the EU/EEA will register all classes except Class I devices, custom-made devices or general IVDs, as these will be required to be registered in the EU.
  • Manufacturers in the EU/EEA will be required to designate a UK Responsible Person before placing a device on the market. It is the responsibility of the UK Responsible Person to register the device.
  • Manufacturers in third countries will require a UK Responsible Person, unless they have an Authorised Representative established in Northern Ireland.

Northern Ireland based manufacturers that have registered devices with the MHRA for Northern Ireland may introduce devices to GB without further registrations.

Clinical data repository, pharmacovigilance and medical information

For medicinal products in the EU/EEA, the Qualified Person for Pharmacovigilance (QPPV) must reside and carry out tasks within the EU/EEA. Where this is currently performed in the UK, the QPPV will need to relocate to the EU or a new QPPV that resides in the EU should be appointed. The Pharmacovigilance System Master File (PSMF) for EU medicinal products must be based in an EU/EEAcountry. The supervisory authority for pharmacovigilance is the competent authority where the PSMF is located. The person responsible for clinical data repositories (CDRs) must be located within the EU/EEA.

For UK medicinal products, the MHRA will retain responsibility for pharmacovigilance. For products authorized in GB, MAHs will be required to submit pharmacovigilance data to the MHRA via the new MHRA Gateway. Products authorized in Northern Ireland will require data to be submitted in line with EU requirements. Where a product is subject to a UK MA covering GB and Northern Ireland, data will need to be submitted in accordance with the EU and UK requirements, as applicable. After the transition period, the UK will continue to follow Good Vigilance Practices as set out in the EU guidelines.

The QPPV may reside and operate in the EU/EEA or the UK. Where this is the EU/EEA, a national contact person for the UK should be nominated who resides and operates in the UK within 12 months from January 1, 2021.

The PSMF for whole of the UK or Northern Ireland must be located at the site in the EU/EEA where the main pharmacovigilance activities are performed or at the site where the QPPV operates.

For GB products, the PSMF must be accessible electronically at the same point in the UK from which the reports of suspected adverse reactions referred to in regulation 187 of the Human Medicines Regulations are accessible.

Market insight

PharmaLex has conducted a survey of its clients to obtain a snapshot of industry preparedness for Brexit. Areas where there is a positive preparedness trend include:

  • Supply chain mapping for Brexit exposure, stock management and future stock replenishment measures
  • Consideration of EU approval times
  • Transfer to EU-based MAHs and batch release sites for EU products
  • Additional responsibilities for the import of medical devices from the UK to EU/EEA

There was a split in client feedback for the following topics:

  • UK-based medicine local roles, responsibilities and future product maintenance
  • Customs activities
  • QPPV readiness

There was a negative trend for the following:

  • Relocation of EU medicine QC testing sites to an EU/EEA location
  • Northern Ireland Protocol impact
  • Medical devices Notified Body and Authorised Representative actions where this is currently based in the UK

This feedback appears to be somewhat aligned with the availability of current guidance. As further guidance is released by the MHRA and UK Government on UK expectations and movement of goods, companies will be able to take suitable actions.

A final word

Brexit will provide several challenges to the pharmaceutical industry that will require robust actions and swift resolution in order to remain in compliance once the transition phase ends. Further clarification on the implications of Brexit post-transition guidance and more information about how PharmaLex can support the management of these challenges can be obtained by contacting PharmaLex at