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United Kingdom’s (UK) withdrawal from the Union: Risk Based Approach for u se of Compliance Letters issued by UK Authorities for 3 rd country blood establishment sites post Brexit The UK submitted on 29 th March 2017 the notification of its intention to withdraw from the Union pursuant to Article 50 of the Treaty on European Union and subsequently submitted requests for extension of duration of their Union membership. The United Kingdom (UK) formally left the European Union (EU) on 31 st January 2020 and became a third country. On the 30 th December 2020 t he trade and cooperation a greement were signed between EU and UK and a specific annex on medicinal product was included. However, the agreement doesn’t cover the r ecognition of inspections or control measures to verify compliance with requirements of the EU Blood Directive and acceptance of official documents issued by MHRA for blood establishments. Therefore, this position statement sets forward a risk-based approach for the assessment of Compliance letters issued by MHRA for blood establishments located in 3rd countries. Based on Article 8(2) of Directive 2002/98/EC inspection or control measures in blood establishments should take place at least every 2 years. Information on these inspections needs to be submitted in PMF annually. From the information currently available, plasma from donors from the UK is currently not fractionated in Europe as a precautionary measure because of the high exposure to BSE and CJD in UK. So far, there are no UK centres collection centres listed in any PMFs registered in the EU. Therefore, UK collected plasma would only be used at national level since the CJD crisis. Reference is made to the guideline on the investigation of manufacturing process for plasma derived medicinal products with regards to VCJD risk: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-manufacturing-processes-plasma-derived-medicinal-products-regard-variant_en.pdf From this perspective, the scope of the current paper is restricted only to PMF inspections carried out by UK MHRA post Brexit for sites located in third countries, e.g. USA. UK MHRA inspections of 3rd country PMF sites that are collecting, testing, processing, storing and distributing plasma as starting material until the end of the transition period will continue to be recognized as long as still valid. Therefore, inspections and control measures performed by MHRA after the end of the transition period will be used to confirm compliance by an EU Authority, as long as these inspections have equivalent EU standards for collection, testing, processing, storing and distributing of plasma. The COVID-19 pandemic has led to additional difficulties for EU Authorities to conduct on-site PMF inspections due to travel restrictions. In light of the severity of the current circumstances, the EU27/EEA Member states and the GMDP IWG have put in place additional mitigation measures to mitigate the suspension of on-site inspections of plasma collection centres. These mitigation measures include applying inspection and control measures in line with EMA recommendation EMA/INS/GMP/534269/2018, "Application of inspection and control measures to facilitate risk-based inspection planning of sites within the Plasma Master File (PMF) certification system”. On-site inspections will resume as soon as there is a consensus that the period of the public health crisis has passed. As a result, the impact to inspectional resources created by Brexit in combination with the COVID-19 pandemic is expected to lead to a backlog of inspections that will need to be carried out by EU27/EEA Authorities in the upcoming years. In this sense, it was considered necessary for EU27/EEA Supervisory Authorities to be able to rely on Compliance letters issued by MHRA for sites located in 3rd countries after the end of the transition period. This risk-based approach is based on the principle that the pharmaceutical legislation as laid out in the ‘acquis communautai re ’ applied in the UK, as a long-standing member of the European Community and Union, until the end of the transition period. Furthermore, in accordance with the EU - UK Withdrawal Agreement Protocol on Ireland/Northern Ireland (‘IE/NI Protocol’) the EU pharmaceutical law continues to apply to the United Kingdom in respect of Northern Ireland after the end of the transition period. In applying the risk-based approach, taking the above into account it is concluded that valid Compliance letters for blood establishments located in 3rd countries issued by MHRA after the end of the transition period, can be used for the purposes of verifying standards which are in compliance with the requirements Commission Directive 2002/98/EC and its amending Directives as well as Commission Directive 2003/94/EC of the European Parliament and of the Council, Annex 14 of the EU-GMP Guide, and relevant European Pharmacopeia Monograph(s) provided that: • the scope of the Compliance letters encompasses the collection, testing, processing, storing and distributing of plasma for which it is being relied upon in the EU27/EEA and • an inspection by an EU/EEA authority is not possible due to limited resources or travel restrictions due to the COVID-19 pandemic and • MHRA keep on providing information about compliance and non-compliance for such blood establishments. In addition, as part of this risk-based approach each Supervisory Authority can decide, at any moment in time, to perform an inspection of a site if it considers that there are grounds for suspecting non-compliance with the EU pharmaceutical law. The Inspection Working Group will re-assess the applicability of the above described guidance regularly and at the latest in 2022. This document and all re-assessments are presented for endorsement to the national authorities competent for the safety and quality of blood and blood components. United Kingdom’s (UK) withdrawal from the Union: Risk Based Approach for u se of Compliance Letters issued by UK Authorities for 3 rd country blood establishment sites post Brexit The UK submitted on 29 th March 2017 the notification of its intention to withdraw from the Union pursuant to Article 50 of the Treaty on European Union and subsequently submitted requests for extension of duration of their Union membership. The United Kingdom (UK) formally left t he European Union (EU) on 31 st January 2020 and became a third country. On the 30 th December 2020 t T he EU - UK trade and cooperation a greement was signed between EU and UK and a specific annex on medicinal product was included. However, the agreement does n’t cover the r ecognition of PMF inspections or control measures to verify compliance with requirements of the EU Blood Directive and acceptance of official documents issued by MHRA for blood establishments. Withdrawal Agreement provides for a transition period that began on 1st February 2020, during which EU pharmaceutical law remains applicable to the UK. This is due to end on 31st December 2020. During the transition period, the EU and the United Kingdom will negotiate an agreement on a new p artnership. However, it is not certain whether such an agreement will be concluded and will enter into force at the end of the transition period. As such, Therefore, this paper position statement covers the situation where no such agreement is in place at the end of the transition period and it will give s a guidance on sets forward a the risk-based approach for the assessment of Compliance letters issued by MHRA for sites blood establishments located in 3rd countries. Based on Article 8(2) of Directive 2002/ 98/EC inspection or control measures in blood establishments should take place at least every 2 years. Information on these inspections needs to be submitted in PMF annually. From the information currently available, plasma from donors from the UK is curre ntly not fractionated in Europe as a precautionary measure because of the high exposure to BSE and CJD in UK. So far, there are no UK centres collection centres listed in any PMFs registered in the EU. Therefore, UK collected plasma would only be used at n ational level since the CJD crisis. Reference is made to the guideline on the investigation of manufacturing process for plasma derived medicinal products with regards to VCJD risk: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-manufacturing-processes-plasma-derived-medicinal-products-regard-vari ant_en.pdf From this perspective, the scope of the current paper is restricted only to PMF inspections carried out by UK MHRA post Brexit for sites located in third countries, e.g. USA. UK MHRA inspections of 3rd country PMF sites that are collecting, testing, processing, storing and distributing plasma as starting material until the end of the transition period will continue to be recognized as long as still valid. Therefore, inspections and control measures performed by MHRA after the end of the transition period will be used to confirm compliance by an EU Authority, as long as these inspections have equivalent EU requirements of the EC standards for collection, testing, processing, storing and distributing of plasma. The COVID-19 pan demic has led to additional difficulties for EU Authorities to conduct on-site PMF inspections due to travel restrictions. In light of the severity of the current circumstances, the EU27/EEA Member states and the GMDP IWG have put in place additional mitig ation measures to mitigate the suspension of on-site inspections of plasma collection centres. These mitigation measures include applying inspection and control measures in line with EMA recommendation EMA/INS/GMP/534269/2018, "Application of inspection an d control measures to facilitate risk-based inspection planning of sites within the Plasma Master File (PMF) certification system”. On-site inspections will resume as soon as there is a consensus that the period of the public health crisis has passed. As a result, the impact to inspectional resources created by Brexit in combination with the COVID-19 pandemic is expected to lead to a backlog of inspections that will need to be carried out by EU27/EEA Authorities in the upcoming years. In this sense, it was considered necessary for EU27/EEA Supervisory Authorities to be able to rely on Compliance letters issued by MHRA for sites located in 3rd countries after the end of the transition period. This risk-based approach is based on the principle that the pharmac eutical legislation as laid out in the ‘acquis communautaire ’ applies applied in the UK, as a long-standing member of the European Community and Union, until the end of the transition period. Furthermore, in accordance with the EU - UK Withdrawal Agreement Protocol on Ireland/Northern Ireland (‘IE/NI Protocol’) the EU pharmaceutical law continues to apply to the United Kingdom in respect of Northern Ireland after the end of the transition period. In applying the risk-based approach, taking the above into ac count it is concluded that valid Compliance letters for blood establishments located in 3rd countries issued by MHRA after the end of the transition period, can be used for the purposes of verifying standards which are in compliance with the requirements C ommission Directive 2002/98/EC and its amending Directives as well as Commission Directive 2003/94/EC of the European Parliament and of the Council, Annex 14 of the EU-GMP Guide, and relevant European Pharmacopeia Monograph(s) provided that: • the scope of the Compliance letters encompasses the collection, testing, processing, storing and distributing of plasma for which it is being relied upon in the EU27/EEA and • an inspection by an EU/EEA authority is not possible due to limited resources or travel rest rictions due to the COVID-19 pandemic and • MHRA keep on providing information about compliance and non-compliance for such blood establishments. In addition, as part of this risk-based approach each Supervisory Authority can decide, at any moment in time, to perform an inspection of a site if it considers that there are grounds for suspecting non-compliance with the EU pharmaceutical law. The Inspection Working Group will re-assess the applicability of the a bove described guidance regularly and at the latest in 2022. This document and all re-assessments are presented for comments endorsement to the national authorities competent for the safety and quality of blood and blood components. Saatja: <[email protected]> Saadetud: 27.10.2022 14:07 Adressaat: <[email protected]> Koopia: VAN DER SPIEGEL Stefaan <[email protected]>; <[email protected]>; FEHILY Deirdre <[email protected]>; <[email protected]>; <[email protected]>; <[email protected]> Teema: Extension: UK-NCA Inspection certificates on 3rd countries plasma collection sites - post BREXIT Dear colleagues, dear competent authorities for safety of blood and blood components, We herewith come back to you regarding the inspections carried out by the UK authority MHRA post Brexit for (collection) sites located in third countries, e.g. USA. As you will recall from our exchange of 10/12/2020 below, it is considered necessary for EU27/EEA Supervisory Authorities to be able to rely on Compliance letters issued by MHRA for sites located in 3rd countries after the end of the BREXIT transition period (31/12/2020). You had no comments on the consultation on the relevant documents, in att, that took place end 2020. In these document it was mentioned that the applicability of this guidance was temporary, and will be regularly re-assessed, at the latest in 2022. It is therefore timely to come back to you and ask you whether you would agree with extending the applicability of this position statement, or whether you can let us know of any objections you might have. If so, we kindly ask you to send these to SANTE SOHO () by 12th of November 2022 eob. After that EMA will pursue the further extension. With kind regards, On behalf of the EMA colleagues and the SoHO team. European Commission DG SANTE (Health and Food Safety) Unit D2 Medical Products: quality, safety, innovationOffice address: Rue Breydel 2, 06/004, B-1049 Brussels/Belgium From: &lt;&gt; Sent: 10 December 2020 09:26To: Cc: VAN DER SPIEGEL Stefaan &lt;&gt;; Conocchia Roberto &lt;&gt;; FEHILY Deirdre &lt;&gt;; Moseley Jane &lt;&gt;; Cuddy Brendan &lt;&gt;; Spinei Andrei Catalin &lt;&gt;Subject: UK-NCA Inspection certificates on 3rd countries plasma collection sites - post BREXIT Dear colleagues, dear competent authorities for safety of blood and blood components, We herewith present you a draft EMA note prepared by the Inspection Working Group (IWG) relating the plasma master file (PMF) inspections carried out by the UK authority MHRA post Brexit for (collection) sites located in third countries, e.g. USA. Given the high dependency on US plasma, the expected reduction in plasma volumes, the overall reduced capacity to inspect due to BREXIT and COVID, it is considered necessary for EU27/EEA Supervisory Authorities to be able to rely on Compliance letters issued by MHRA for sites located in 3rd countries after the end of the BREXIT transition period (31/12/2020). As this concerns inspection of blood collecting facilities we believe it important that you are informed before adoption. This suggested approach is temporary, to be reassessed regularly and foresees some further limitations. As youll see we have asked EMA and the IWG also to ensure you would also have an opportunity to comment in case of future revised version. In case you would have any concerns or comments on this document, we kindly ask you to send these to SANTE SOHO () by 16th of December 2020 eob. After that EMA will pursue the further adoption of this document. With kind regards, On behalf of the EMA colleagues and the SoHO team. European Commission DG SANTE (Health and Food Safety) Unit B4 Medical Products: quality, safety, innovationOffice address: Rue Froissart 101, 08/70, B-1049 Brussels/Belgium