Brexit Q&A - PharmaLex

Q: What are the origins of all of the current uncertainty in the Pharma Industry regarding Brexit?

Article 50 was triggered on the 29^th March 2017. Following this, negotiations have been thus far unsuccessful to define the details of the UK’s withdrawal from the EU. As it stands, the UK would no longer be bound by EU treaties after October 31^st, 2019 and there would be very little to replace the thousands of international agreements that stem from them. Unfortunately, it is still unclear what the UK’s future relationship, co-operation or alignment will be with the EU regulatory system for medicinal products. In the run up to the first Brexit deadline of March 29, 2019, and since that date, there have been several updates from both the MHRA and EMA to provide a degree of short-term flexibility in the divorce transition; however, the likelihood of the U.K. becoming a third country appears to increase since Boris Johnson’s election as Prime Minister. It is looking increasingly likely that the UK may leave the EU on 31^st October this year and the possibility of a withdrawal without an agreement (“Hard Brexit “) can no longer be dismissed. It is notable that the MHRA has recently published several guidelines for a possible no-deal scenario.

Q: Is the UK leaving the EU such a big deal from a medicine’s perspective?

Yes, it is.

When you consider that the UK’s regulator has been one of the key players in EU medicines regulation for decades and has had a significant role in the development of EU legislation covering the life cycle of medicinal products from their inception through to post-marketing. The prospect of the UK becoming a third country in 2019 has generated massive upheaval and cost in almost all Pharma organisations with operations in the UK. Companies have had to ensure the on-going validity of their Marketing Authorisations, the compliance and effectiveness of their supply chain, manufacturing and procurement, as well as in many cases, the integrity of their orphan medicinal product designations and SME registrations.

In addition, you get an idea of the scale for the potential disruption to medicine supply by bearing in mind the 45 million patient packs that are supplied from the UK to the EU-27/EEA countries and over 37 million patient packs that are supplied from the EU-27/EEA to the UK each month.

Q: What position has PharmaLex adopted in relation to Brexit induced uncertainty?

PharmaLex have consistently endorsed the position of regulators that concerted action should be taken to plan for the starkest of outcomes of Brexit in order to avoid medicines supply disruption both inside and outside the UK. Comprehensively assessing the business and operational implications for sustained regulatory compliance and preparing mitigation plans in readiness for the planned implementation of the UK’s prospective withdrawal remains the only responsible approach to Brexit.

Q: What elements of Pharmaceutical regulation are most affected by Brexit?

Of principal concern to our clients has been the location of marketing authorisation holders, orphan designation holders, Qualified Person for Pharmacovigilance (QPPV), Pharmacovigilance System Master File (PMSF), manufacturing site for active substance and finished product, batch release site, Reference Member State (RMS) for a Mutual Recognition (MRP) or Decentralised Procedures (DCP). In the frequently updated Q&A documents issued by the EMA, they have covered the specific considerations for organisations with regards to these elements. In PharmaLex, we have helped clients implement this guidance with tailored approaches for their specific operations.

Q: How has the Pharmaceutical industry reacted to the Brexit challenges?

Most pharmaceutical companies have planned for the realities of a “Hard Brexit” and a diverging regulatory alignment between the UK and EU. Many big pharma companies have publicly declared their prudence with regard to Brexit and revealed their medicine stock-piling plans, changes to their clinical programmes and the movement of product testing and operations within the EU. At PharmaLex, with the public health stakes being so high, we continue to share the view that there is still value in risk assessing the potential business and operational implications for sustained regulatory compliance after Brexit.

Q: Who are most affected by Brexit?

Marketing Authorisation Holders (MAHs) in the UK are clearly the entities that are directly impacted. Equally, MAHs in the EU that have operations in the UK and transit products through the UK are also significantly impacted. Brexit has served a timely reminder of the responsibilities MAHs have for the development and commercialisation of their products in their markets. MAHs in the EU must ensure that:

Clinical trials for the medicinal product are designed and developed ethically, in accordance with relevant EU regulations. Under the current clinical trial directive, the sponsor or a legal representative of the sponsor must be established in the EU. The future cooperation and coordination of Clinical trials on an EU-UK basis largely depends on whether the UK participate in the EU clinical trials system and meet its commitment to put the forthcoming EU Clinical Trial Regulation into law and remain highly aligned to the EU framework.
A Qualified Person (QP) is identified in the EU who has responsibility for checking that each individual batch has been manufactured in line with the terms of the Marketing Authorisation (MA) and with Good Manufacturing Practice (GMP).
Current and correct information is present on medicinal product labelling and packaging to ensure safe and effective use and prescribing.
Full supply chain oversight and controls in place to ensure continued availability of safe and effective medicinal products for the patient, including at least one Responsible Person (RP) who is approved by the relevant regulatory agency(s).
All medicinal product complaints and quality defects are appropriately investigated.
A pharmacovigilance system is operated to detect, assess and report adverse events associated with their medicinal products. The MAH is responsible to appoint and have at its disposal permanently and continuously in the EU, a QP for pharmacovigilance (QPPV) who is responsible for the maintenance of the MAH’s pharmacovigilance system.
Timely and regular new and revised medical information is provided to medical staff.
Promotional activities, including advertising, must comply with EU and local codes of practice for the pharmaceutical industry.
A continuous supply of the medicinal product and that potential disruption of supply is reported and actively managed in association with the relevant regulatory authority(s).
Marketing Authorisations are maintained according to technical and scientific developments.
It has appropriate controls in place and operates a Quality Management System to support the activities related to those controls.

As an MAH, it is very important to understand that the MAH retains responsibility for all MAH activities even if they have been delegated via a contractual agreement. Responsibility cannot be delegated.

Q: When it comes to Brexit, are there any high-risk categories of products?

Medicines that require certainty in supply chain timelines, for example cell and gene therapies, require special consideration by MAHs when it comes to Brexit. The risk posed by Brexit requires careful assessment and there are no guarantees that border controls will operate smoothly immediately after Brexit. Many companies have chosen to alter their supply chain and agreements with their suppliers to ensure improved robustness in their supply chain.

Q: Can a company follow a general set of Brexit readiness instructions?

Contingency planning for Brexit is unique to each company. A specific approach to MAH considerations (batch release, batch testing etc.) and licensing requirements can be developed based on the company’s supply chain and the physical product and financial product ownership flows. PharmaLex provide expert advice on the recommended supply chain flows to best meet client company’s requirements. PharmaLex also develop and implement the Quality Management Systems needed to support GxP activities and support clients through the regulatory application and inspection processes.

Q: What measures have the legislators and regulators in the UK put in place to assist with continued compliance and continuity of supply in the UK market?

In 2019, the UK government drafted legislation whereby Centrally Authorisation Product (CAP) Marketing Authorisations (MAs) in the EU will automatically convert to UK MAs in a process known as ‘grand-fathering’. In addition, the MHRA have put several arrangements in place to provide targeted assessments and acceleration of new applications for products containing new active substances. The MHRA have also: (a) extended the period until the end of 2021 to amend packaging and leaflets for a product already on the market, (b) allowed the parallel import of medicinal products that hold a marketing authorisation from the EU, (c) allowed devices, for a fixed period, that have a CE mark from an EU country to be continued to be recognised by UK law, (d) given some assurances on alignment with the EU Clinical Trials Regulation, where it applies and (e) confirmed a grace period until the end of 2020 for companies that have already established a QPPV based in the EU/EEA before they have to switch to a UK-based QPPV for the UK market.

Q: What are the current importation and batch testing requirements for medicinal products that are supplied from the UK to an EU member state?

Any EU company that physically receives finished medicinal product from the UK (originating from a UK manufacturer or wholesaler or transiting the UK without the use of the customs transit code), will be required to hold a manufacturer’s/importer’s authorisation (MIA) with the activity ‘Physical Importation’ listed on it. Medicines coming from a third country must be first physically received at the site that holds an MIA which includes the activity ‘Site of Physical Importation’.

In addition, the product imported for the EU market requires QP certification. (this can happen at any EU site of batch release that is approved under the Marketing Authorisation for that product).

Batch testing and certification should be conducted in the EU; however, the HPRA have been open to accepting requests for exemptions for Batch Testing in line with the Commission’s position of 25th Feb 2019: “Withdrawal of the United Kingdom and EU rules for batch testing of medicinal products”. Further details on the process to apply for this exemption are available on the HPRA website.

In a recent reminder by the EMA, all batch testing sites must be fully transferred to the remaining EU27 Member States and/or EEA countries by 1 January 2020. Also, the necessary regulatory submissions must be completed by then. This includes MAHs who have permission to perform quality control testing in the UK even after Brexit. The EMA has communicated that “The transfer should be completed quickly and in principle by the end of 2019 at the latest”.

Q: Can you summarise what PharmaLex has been doing to assist companies in their Brexit readiness?

PharmaLex is able to support clients at every stage of the product lifecycle and wherever they choose to pursue their business in a post-Brexit Europe. With our considerable local UK and EU quality, regulatory and pharmacovigilance expertise, we have supported clients in: