This presentation was delivered during the “go-home-meeting” hosted by Pharmakon on Sept 9th, 2020. We shared our insights and thoughts on the impact of Brexit on medicinal products – in the pre-and post-approval phase, from the EU and the UK perspective.

1. 1
Velkommen
1

2. 22
How to overcome the regulatory
challenges due to
BREXIT
9 September 2020
09/09/20

3. 33
Kulminder Nowacki - Director of Regulatory
Science Drugs and Biologics at VCLS
Barbara Christensen – Senior Regulatory Science
Specialist at IWA Consulting
Who are we?
The VCLS Family:
+200 life sciences professionals providing Regulatory Science Services to privat and
public clients within Biotech, Pharma and Medtech.

4. 44
To share with others the knowledge/experiences we have gained together with our
clients throughout the past few years
Brexit is a ”super-hot subject” - MHRA Brexit guidances recently withdrawn and
being replaced by updated guidance (+20 guidance documents published within
last 1-2 weeks)
We are currently studying the updated guidance in more detail. The process of
gaining a thorough understanding of all implications is ongoing. Some guidance
still pending → We don’t have all the answers
Why this meeting? What to expect?

5. 55
Meeting originally planned as a ”go-home-meeting” early summer 2020 –
changed to a ”stay-home-meeting”
Please pose questions in writing during the presentation and we will try to answer
some of them at the end of the meeting
Any Qs not answered during today, please reach out to us following the meeting.
We may not be able to answer all questions but we wish to understand what are
the challenges faced by industry
Please consider, while listening to the presenters today, if it could be relevant for
you if Pharmakon would arrange a more in-depth Brexit course
Why this meeting? What to expect?
(cont.)

6. 66
Agenda
Kulminder Nowacki:
• Current status
• Brexit Readiness
• Challenges facing stakeholders
• Regulatory Impact of Brexit
• Continuity of supply to EU
• MHRA post-transition guidance for Industry and Organizations to
follow from 1st January 2021
Barbara Christensen:
• Consequences of Hard Brexit:
• Life cycle management
• Manufacturing of medicinal products to the EU market
• Pharmacovigilance
• Non-clinical and clinical trials conducted in the UK
• Medical Devices

7. Brexit - Current Status
January 31, 2020
• The UK stopped being a member of EU and became a third country.
December 31, 2020
• The transition period will come to an end by December 2020
• During the transition period UK will continue to follow EU’s rules
From 01 January 2021 onwards...
• If a trade deal has been agreed and ratified:
• The UK will either start a new relationship with the EU
• Or exit the transition period without a trade deal
Negotiations are still ongoing between UK Government and EU Commission,
details yet to be defined

8. Brexit Readiness
• EMA moved from London to Amsterdam
• Centralized Procedures:
o UK (Co)-Rapporteurs for CAPS have been re-assigned one of the EEA MSs
• MRP/DCP:
o UK Reference Member States MRP or DCP have been re-assigned to one of the EEA
MSs
• MHRA
o UK Portal set up for post Brexit Applications/Submissions
o MHRA published extensive guidance (1st Sept) on the regulation of medicines and
medical devices in readiness for the end of the Transition Period in both a negotiated
and non-negotiated outcome with the EU. To help ensure continuity of supply of
medicines and medical devices from 1 January 2021, especially in a non-negotiated
outcome with the EU
The UK will unilaterally recognise certain EU regulatory processes for a time limited
period. This recognition is known as ‘Standstill’.
8

9. Challenges facing EU, UK and Pharma Industry
• Brexit is a big question mark for everybody including the
Pharmaceutical Industry, we can see that EU Commission, Member
States and of course the UK government face challenges to find a
compromise on the main topics
• Each industry –not only Pharmaceutical- is facing these
challenges given there is still no clear guidance/agreement at least
on some key aspects between EU and UK
• The Pharmaceutical Industry hopes there will be a sense of
reciprocity in the procedures between EU and UK, meaning UK will
not impose something deleterious to EU and conversely EU will not
impose something that is impossible for the UK to meet.
• If UK Government and consequently MHRA is forced to adopt
stringent requirements, thus setting the bar too high for drug
developers, Applicants may deprioritize UK in their development
and registration plans.

11. Continuity of supply in the EU
1
1

12. Continuity of supply to EU (1/2)
UK becomes a third country:
• As a consequence of this third country status, MAHs & Applicants of CAPs need to
make sure necessary changes are made by 31 December 2020 and activities moved
from the UK to the European Union, so that products may still be marketed in the EU:
MAH/Applicant located in UK
• Any MAH established in the UK will needs to be changed to a non-UK MAH established
in the Union (EEA) before 31 December 2020.
UK Sponsor of Orphan Designation(s)
• Any UK Sponsor of an Orphan Designation will need to transfer the designation to a
holder established in the Union (EEA) before transferring the MAH
Batch release site located in UK
• Any proposed UK batch release site(s) should be removed from the MA application and
replaced with a site(s) located in the EEA by 31 December 2020.

13. Continuity of supply to EU (2/2)
Site for Batch control testing located in UK
• Any UK-based site designated for batch control of the release of finished products should be
removed from the EU MA application and replaced with another site located in the EEA or in a
country that has signed a mutual recognition agreement (MRA) with the EU. To date, the UK is
not on the EMA’s list of MRAs
Site for Secondary packaging of finished product located in UK
• A secondary packaging site located in UK will require the designation of an authorised site
responsible for physical importation established in the Union (EEA). Alternatively, the applicant
can relocate the secondary packaging activity to a site in the Union EEA
Site for Physical importation located in UK
• Any proposed site responsible for physical importation into the Union (EEA) located in UK should
be removed from the MA application and replaced with another authorized in the Union (EEA)
QPPV located in UK
• The UK QPPV details should either be amended or a new QPPV residing in the EEA appointed
by 31 December 2020.
PSMF located in UK
• The location should be moved to a Member State within the Union (EEA) by 31 December 2020.

14. MHRA post-transition period
information
Guidance for industry and organisations to
follow from 1 January 2021
1
4

15. UK Medicines & Healthcare products
Regulatory Agency (MHRA)
• From 1 January 2021, the MHRA will be the UK’s standalone
medicines and medical devices regulator, and stakeholders need to
get ready for new rules from 1 January 2021.
• Please note that there will be some different requirements for
products placed on the market in the UK with respect to Great Britain
(England, Wales and Scotland) and Northern Ireland
• The National Institute for Biological Standards and Control (NIBSC),
one of the three centres of the MHRA, has published a guidance
on information for manufacturers of biological medicines.
1
5

16. Converting Centrally Authorised Products (CAPS) to UK Marketing
Authorisations (MAs)
• All existing CAP MAs will automatically be converted into GB MAs effective in
GB (only), known as “grandfathering and issued with a GB MA number on 1
January 2021. MAHs can choose to opt-out of the conversion process for all
or some of their CAPs by notifying the MHRA by 21 January 2021.
• These GB MAs are referred to in guidance as “converted EU MAs”. Existing
CAPs will remain valid for marketing products in Northern Ireland
• Applicants will need to submit baseline data as an eCTD sequence together
with certain other related MA-specific information for each converted EU MA.
• MAHs will have a period of one year from 1 January 2021 to submit this
baseline. Until these initiating sequences are submitted and processed, it will
not be possible to submit a variation for the converted EU MA unless there are
exceptional circumstances relating to public health.

17. Handling Applications submitted via CP (Guidance still
pending)
The company will have two options:
1. To apply to MHRA in parallel with the application for an EU MA. The approach
of the MHRA will be to take into account any assessment that has already
been reported on before 1 January 2021 with a view to completing the
application no later than the issue of the EU Commission Decision.
2. To wait for EMA CHMP positive opinion and then apply for a GB MA. The
application will be determined when the EC decision has been confirmed.
In all cases, applicants will need to submit an application and supporting dossier
to the MHRA accompanied by all CHMP assessment reports.

18. GB Conditional /Exceptional Circumstances Marketing Authorisations
(MAs) & Sunset Clause
GB Conditional MA:
o A national Conditional Marketing Authorisation scheme will be introduced for new
medicinal products (applicable to GB only)
GB Exceptional Circumstances MA:
• Applications for UK marketing authorisations under exceptional circumstances need
to be discussed with the MHRA prior to submitting the Marketing Authorisation
Application
Sunset Clause
• MAs for CAPs that are not currently marketed in the EU or UK can still be converted
to GB MAs. The period of three years during which the product has not been
marketed in GB will be restarted from the date of conversion to a Great Britain
MA.

19. Legal Presence for MAs Converted to UK MAs (Grandfathering)
Converted MAs with a non-UK MAH will need to establish a MAH in the UK within 24
months of 1 January 2021 (by 1 January 2023).
MAHs have two options:
Option 1
• Submit a Change of Ownership application (COA) after the submission of the
baseline initiating sequence within 21 months after the transition period
Option 2 – MHRA preference
• Include the COA in the initiating sequence as if it had already been approved by the
MHRA and state in the cover letter that this option had been adopted.
There will be no fee in either case.
Further change of ownership published on the MHRA website.
1
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20. Scientific advice
• The MHRA will continue to offer its national scientific advice service after 1 January 2021.
• The procedure for requesting scientific advice is described in further detail (see MHRA
website)
• From 1 January 2021, applications for scientific advice submitted by UK-based Small and
Medium-sized Enterprises (SME) will be exempt from the fee. Applicants will be
required to submit evidence of their SME status together with the scientific advice form.
• Requests for advice that is purely regulatory in nature will remain free of charge.
This guidance will apply from 1 January 2021.
2
0

21. Procedures for UK Paediatric Investigation Plan (PIPs) from 1 January 2021
1. MHRA will simplify the PIP application process for applicants by offering an expedited
assessment where possible, and by mirroring the submission format and terminology of
the EU-PIP system.
2. The scientific content and assessment required will be kept in line with EMA
guidance documents.
3. Applicants should include information relevant specifically to the UK, particularly any
areas of unmet therapeutic need that the product intends to cover in the UK
4. Further step by step information on the process of submitting PIPs via the new MHRA
submissions portal including the format and submission procedure for UK-PIP
applications will be published separately.
5. Northern Ireland will continue to be part of the EU’s system for paediatric medicines
2
1

22. Further Guidance on PIPs available on the MHRA Website
1.General approach to UK Paediatric Investigation Plans
2.Section 1: PIP submissions
3.Section 2: PIP Modifications
4.Section 3: Class Waivers
5.Section 4: Compliance Check
6.Section 5: Paediatric Study Plans (PSP)
7.Section 6: Unmet needs in the UK paediatric population
8.Queries about paediatric submissions
2
2

23. GB will be recognised as a Third Country for the export of Active Substances to the EEA
• Active substances manufactured in GB for use in EEA will need Written Confirmation for
each shipment exported to the EEA or Northern Ireland.
• A Written Confirmation confirms that, for a third country exporting Active Substances to the
EEA have met the standards of GMP equivalent to those in the EU/EEA
• You will not need to provide any information to the MHRA to allow the Written Confirmation
to be generated. All the information required for the Written Confirmations is available
within MHRA systems.
• From 1 January 2021 GB will continue to accept importation of active substances into
Great Britain without a Written Confirmation from the same list of countries as currently
listed as well as from Northern Ireland.
Active Substances manufactured in Great Britain

24. Registering new packaging information for medicines from 1 January 2021
24 months from 1st Jan 2021
EU MA to GB MA:
New administrative info to be
registered:
• name and address of Marketing
Authorisation Holder (MAH) or
representative
• Great Britain MA number
• name and address of product
manufacturer for batch release
Actions to take once you have been
issued an MA
You will have a further 12 months (36
months in total from 1 January 2021)
to ensure all stock released to
market is in compliant packaging.
Packs containing the Falsified
Medicines Directive (FMD) safety
features would still be accepted in
the UK, provided that they are in line
with other UK packaging
requirements
Multi-language packs
The MHRA will continue to allow multi-country packs,
including packs with more than one language on the pack
and/or in the PIL, provided that the entirety of the
information is compliant with the UK requirements.

25. MHRA Portal for future applications
How to submit the application
• Except for applications made through European procedures to market in
Northern Ireland, the MHRA does not expect to be able to receive submissions
through the Common European Submission Portal (CESP).
• MHRA have developed a new national portal to be ready by 1 January 2021 and
expect that submissions will be made via this portal.
• Information on the use of this portal will be published in advance of 1 January
2021.

26. How the MHRA will manage UK orphan medicinal products after Brexit –
GUIDANCE WITHDRAWN (1of 2)
10-year market exclusivity
• Orphan (rare disease) medicines are currently regulated through the EU
system where an ‘orphan designation’ may be given during development if
the criteria are met
• Orphan products currently have access to the central EU authorisation
system and if an orphan MA is granted, the product benefits from a 10-year
period of marketing exclusivity from competition from similar products.
• After Brexit there will be a UK system for rare disease medicinal products
with orphan status determined at the point of MA
• The EU pre-marketing authorisation of orphan designation will not be
replicated in the UK
• Overall, the orphan criteria would still be based on the current EU criteria,
but UK-specifics will be incorporated. These will be based on the
prevalence of the rare disease in the UK, the availability of satisfactory
alternative treatment methods in the UK and the significant benefit of the
product.
2
6

27. How the MHRA will manage UK orphan medicinal products after
Brexit – GUIDANCE WITHDRAWN (2 of 2)
Fee reductions
• Where a medicine receives orphan status the initial MA application,
fee will be refunded at 100% for SMEs, and 10% for all other
manufacturers.
• The 10 years market exclusivity from competition from similar
products in the approved orphan indication would be retained.
• If criteria for orphan status are met, this incentive would be awarded
following grant of a UK orphan MA

28. 2828
Consequences of Hard Brexit on Life
cycle management

29. 2929
eCTD Dossier Split – MRP/DCP
Current UK licenses are valid as they are issued at national level.
Future variations to be submitted via MHRA portal via National procedure.
eCTD dossier to be converted into GB MA Dossier.
Resubmission of current documents via MHRA portal – 4 options:
1) Start a completely new lifecycle and reference to the existing MRP
sequences.
2) Reuse all existing MRP sequences to UK to continue new lifecycle.
3) Clone all existing sequences as a new set for UK.
4) Create a baseline from “current view”.
Detailed guidance is still pending!

30. 3030
eCTD Dossier Split – CP
MAH Obligations of converted EU MAs:
• 1 year to submit (starting on exit day) initiating sequence
• Initiating sequence must reflect only what is relevant for GB
• Single, technically valid eCTD sequence 0000 of the converted EU MA
• There is no fee for the grandfathering process but an annual service fee
• Must include all currently approved information that has previously been
submitted in the eCTD format
• Two-step process possible - minimal initiating sequence containing at least
the mandatory documents at an early point following 1 January 2021.
The date on which the minimal or full initiating sequence is received is
referred to as “the data submission date”.
Submission package (defined in MHRA GU):
Cover letter, declaration, Summary of historical regulatory activities, Initial
MAA eAF, Launch status in UK, Common EN 1.3.1, etc.

31. 3131
CP - ongoing variations/renewals
Submission Type Positive Opinion
before exit day
Include in Initiating
Sequence
Type IA
Submitted before exit day and not rejected
N/A Yes
Type IB
Submitted but not granted before exit day
Yes/No Yes
Type II
Submitted but not granted before exit day
Yes Yes
Type II before or in clock stop
Submitted but not granted before exit day
No No
Type IB/II variations
Submitted to EMA after exit day
N/A No
Renewal before or in clock stop
Submitted but not granted before exit day
No No
Renewal
Submitted but not granted before exit day
Yes Yes

32. 3232
CP - ongoing new MAAs
Ongoing MAAs expecting approval after the end of the
transition period, the…
• QPPV,
• PSMF,
• Batch release site,
• Batch control sites and
• local representatives for Member States (other than
UK) must be located in the Union/EEA
Changes to be made during the procedure!
Documents to be submitted as part of Response to
Day 120 or Day 180!

33. 3333
MRP/DCP - ongoing variations/renewals
Variation procedures that are pending on exit day will be processed by MHRA to its
conclusion as a purely national variation for UK.
Procedural timelines will be followed to the extend possible.
Guidance on ”Handling Variations” will follow soon according to MHRA.
The current EU variations classification guideline, is expected to continue to apply.
Brexit related Type IA (“do and tell”) to be implemented before exit day;
submission no later than within 2 months after exit day ~ end Feb 2021.
Renewals:
• Resubmission is not needed if submitted before 1 Jan 2021.
• After 1 January 2021, follow the same requirements as EU.

34. 3434
MRP/DCP - ongoing new MAAs
Ongoing MAAs with future..
• MAH
• batch release site
• batch control site
• local representative
• QPPV
• PSMF
located in the UK after exit day, can be processed until EoP.
However, changes to be submitted with Day 106 or Day 160
response document.
If batch release and batch control sites are still located in the UK
on Day 210 – procedure will be closed negatively due to an invalid
batch release/control site.

35. 3535
Generic/hybrid application
EU:
Generic/hybrid MAs granted before Brexit based on UK reference product will remain valid in EU
BE-studies with UK reference product can only be used in generic applications if MA approval
is granted before Brexit (exceptions may occur)
Advised to contact relevant HA to ensure BE-studies with UK reference product can support new
MAAs after Brexit.
UK:
Reference Medicinal Product – needs to be UK RMP (pending applications based on ERMP
remain valid).
Comparator product – for bioequivalence and therapeutic equivalence studies, if not sourced
from the UK market, the applicant should provide evidence that it is representative of the
reference medicinal product.
Northern Ireland:
The EU medicines legislation will remain applicable in Northern Ireland.

36. 3636
Consequences of Hard Brexit on
manufacturing of medicinal products to
the EU market

37. 3737
Manufacturing sites in UK
Manufacturing sites of drug substance and drug product
located outside EEA must be GMP certified by an
EEA competent authority or a country covered by a
mutual recognition agreement.
At the end of the transition period, EEA competent
authority to decide when GMP inspections of UK sites will
be required, to confirm/re-confirm GMP compliance.
For DP manufactured in UK an authorised importation
site in EEA will need to be introduced.

38. 3838
Quality control & Batch release
Medicinal products imported into the EEA have to undergo a full quality
control testing (‘batch testing’) in the EEA.
The QP of the manufacturing and importation authorisation holder (MIAH) is
responsible to certify that each batch placed on the EU market was manufactured
in accordance with EU GMP requirements.
Qualified Person to be identified in the marketing authorisation and located
in the EEA.
These requirements apply to medicinal products imported from UK to EU by the
end of the transition period.
UK:
QP for MP manufactured in UK or directly imported into UK, from a country not on
an approved country list.
QP must reside and operate in UK.

39. 3939
Common Brexit related manufacturing
variations
Manufacturing process for a chemical product Type of variation application
Addition or replacement of site
The UK site is only a batch release site and/or
importation site for the finished product
Type IAIN (B.II.b.2.c.1)
The UK site is a batch release and quality control site of
the finished product
Type IAIN (B.II.b.2.c.2)
The UK site is only a quality control site of the finished
product
Type IA (B.II.b.2.a)
At the same UK batch release site, primary and/or
secondary packaging also takes place
Type IAIN (B.II.b.1a and b)
Deletion of a manufacturing site
Deletion of site(s) for batch release, packaging, batch
control
Type IA (A.7)
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/practical-
guidance-procedures-related-brexit-medicinal-products-human-veterinary-use-within_en.pdf

40. 4040
Consequences of Hard Brexit on
Pharmacovigilance

41. 4141
Pharmacovigilance System Master File
(PSMF)
The PSMF must be located within the EU.
Therefore, if a PSMF is located in UK it has to be moved to EU before the end of the
transition period i.e. 31 December 2020.
Changes to the location of PSMF (address) can be updated via the Article 57 database
only with no need for a variation application.
UK:
The UK PSMF must be located in, or accessible electronically from, the UK at the
same site at which adverse reaction reports may be accessed.
Guidance on QPPV and PSMF to be issued soon according to MHRA.
Continue to accept EU versions of PSURs and RMPs (UK specific annexes)

42. 4242
Qualified Person’s for
Pharmacovigilance (QPPV)
The QPPV must reside and carry out his/her tasks in a Member State of the EU.
Therefore, QPPV’s currently residing/carrying out their tasks in UK have to transfer
to the EU or a new QPPV residing and carrying out tasks in the EU will need to be
appointed, before the end of the transition period i.e. 31 December 2020.
Changes in the QPPV can be updated via the Article 57 database only with no
need for a variation application.
UK:
A Qualified Person for Pharmacovigilance (QPPV) should be established in the UK
on day one.
However, a temporary exemption will allow companies until 31 July 2021.
This temporary exemption will allow an EU QPPV to assume responsibility for UK
MAs until a QPPV who resides and operates in the UK can be established.

43. 4343
Consequences of Hard Brexit on non-
clinical and clinical trials conducted in
the UK

44. 4444
Non-Clinical studies
How will the UK’s withdrawal affect GLP status of non-clinical studies
conducted in the UK?
GLP compliant non-clinical studies conducted in the UK,
are not affected by Brexit.
Non-clinical tests on pharmaceutical products are to be carried out in
accordance with the principles of Good Laboratory Practice (GLP).
The laboratories carrying out the tests shall certify that the tests
have been carried out in conformity with the GLP principles.
In accordance with the OECD principles of GLP, data generated in
an OECD country (including UK), are accepted in other OECD
Member Countries.

45. 4545
Clinical Trials
Clinical trials conducted in UK:
Marketing authorisation application to include statement to the effect that clinical trials carried out
outside the European Union meet the ethical requirements of Directive 2001/20/EC.
GCP inspection by UK Authority:
Risk based approach to request a GCP inspection by an EEA competent authority when an application
rely on clinical studies for which GCP inspections have been conducted by UK authorities.
Testing and certification of IMPs:
For EU trials a QP certification of IMP must be undertaken within the EEA.
Sponsor / Legal representative:
A sponsor established in the United Kingdom and conducting a clinical trial in the EU has to ensure that
a sponsor or a legal representative is established in the EU.
The change of the sponsor or of the sponsor's legal representative is typically a substantial amendment.
UK:
For IMPs coming into the UK, the UK will recognise the QP certification done in an approved country
(EEA countries), meaning IMPs will not need UK QP certification, if it has already been certified in one of
the approved countries.

46. 4646
Consequences of Hard Brexit on Medical
Devices

47. 4747
Medical Devices - EU
From 1. January 2021 UK notified bodies will lose their status as EU notified
bodies.
Apply for a new certificate issued by an EU NB or arrange for transfer of
the file and the UK certificate to an EU NB, taking over the responsibility for
that certificate.
The transfer of certificates from a UK Notified Body to an EU Notified Body
needs to take place before the end of the transition period.
Change of NB supporting the CE marking is a Type IAIN (B.IV.1.a)
A medical device forming a single integral product with the medicinal product
does not require a CE mark, therefore no submission of a new CE marking
documentation is required.

48. 4848
Medical Devices - UK
CE marking recognised until 30 June 2023
New route to market and product marking (UK CA) after
1. Jan 2021
Registration of all MD with the MHRA – grace period of 4
– 12 months depending on the medical device class
UK responsible person for non-UK manufactured MD
placed on UK market
MDR / IVDR will not automatically apply in GB