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Who we are

Xendo is a leading consultancy and project management organisation in the fields of (bio)pharmaceutical products, medical devices and healthcare. Thanks to our multi-disciplinary, knowledge driven approach, Xendo can deliver a broad palette of services to the life sciences industry, applying the right colour to projects we participate in. For over 25 years we have successfully completed thousands of national and international assignments for start-ups as well as for the largest, established multinational companies and organisations. Over 220 experienced and highly educated professionals offer their expertise ranging from strategic advice and project management to auditing, operational support and training; providing a full-colour spectrum.

Our clients

The spectrum of our fields of expertise is as broad as the range of clients we work for, enabling us to cater to the varied needs and wishes of the Life Science industry. We bring our palette of services to companies, ranging from start-ups to multi-national organizations, to provide them with robust solutions. Whether they are a (bio)pharmaceutical or medical device company, a hospital or a pharmacy, a manufacturer or a laboratory, we match their colour.

18-10-2017
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#Pharmaco- & Medical Device Vigilance. What's the difference?

Are Pharmaco- and Medical Device Vigilance the same?

The European Medical Device Regulation 2017/745 (MDR) is published on May 5th, 2017 in order to replace the current Medical Device Directive 93/42/EEC;. Medical device vigilance (MDV) is a key element that is significantly reinforced in the new MDR. The European database on medical devices (Eudamed) will be revised to include vigilance data. These changes make the procedures similar to the Eudravigilance database and the pharmaco-vigilance (PV) process.

The MDV requirements affect the entire medical device (MD) industry with products in the EU. They will need to adjust and upgrade their quality management systems, and implement the required organisational elements and staff to comply with the MDR. The MD industry ready themselves to handle adverse events and incidents, including activities such as evaluating, trending and reporting as specified in articles 87-90 of the MDR.

Because of similarities, it might be tempting to follow PV procedures and systems in order to meet MDV requirements. However, this might not be the right approach because there are distinct differences. In this presentation, we will look at similarities and differences: what can we share and where do we need to pay attention to, in order to ensure compliance with the new regulations.

Recently Xendo colleague Jan Bart Hak presented on this at PhV Day 2017 and below you can find the slide

DOWNLOAD SLIDEDECK

&

INFO: New pharmacovigilance system (Argus)

12-10-2017
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#ARE YOU PREPARED TO JOIN THE BIOSIMILAR RACE?

It’s an exciting time for companies joining the Biosimilar race.

As we get more experienced to apply more advanced technologies, as well as new production processes for biologics, the regulatory landscape and recent strategies for the development of Biosimilars are rapidly evolving at the same time. In Biosimilar development, it isn’t easy to keep track of best development practices and regulatory expectations. Additionally, trends can be observed within leading health authority agencies to become more open for discussions and accept new scientific- and product-tailored development strategies to establish and demonstrate Biosimilar comparability. As usual, it´s all about risk assessment, impact evaluation, and scientific-based justifications, but agencies are actively paving the way for Biosimilars with new regulatory procedures and guidelines. In general, biological manufacturing processes show an inherent variation in terms of process and product. It’s important to look at the development of Biosimilars from an integrated standpoint that includes the essential quality, non-clinical and clinical elements. Obviously, there is a high demand for Biosimilar CMC development as it plays a critical role in demonstrating comparability to the reference product.

What is it about

In our latest update, you'll read more about:

  • the wave of biosimilars at the horizon
  • development challenges and biosimilar comparability
  • best practices and orthogonal approaches
  • the rapidly evolving landscape

Download the whitepaper and feel free to contact us if you have any questions regarding Biosimilar development

25-09-2017
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#NEW: XPure Systems website

Our XPure Systems team recently launched their new website to better serve new customers who are looking for a downstream processing solution using SMB technology. We invite you to have a look at www.xpure-systems.com #SMB #downstreamprocessing

12-09-2017
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#All you need to know about the EU & US MRA

All you need to know about the EU & USA MRA

March 2017 was a historical month for the pharmaceutical industry and for EU and US. The amended mutual recognition agreement (MRA) on “Pharmaceutical Good Manufacturing Practices” between the EU and the US was signed. Best case scenario, it could lead to significantly reduced inspection pressure of the FDA EU inspectorates and we might be done with re-testing of imported batches and batch certification. So let’s hope this amended MRA will actually be implemented and history doesn’t repeat itself.

Mutual Recognition Agreement

In the broadest sense of the word, a mutual recognition agreement is a bilateral trading agreement to facilitate trading between nations or regions. It facilitates market access while safeguarding consumer health, mutual acceptance of reports, and certificates, exchange of information, and encourages harmonization. An MRA covers various economic sectors including Pharmaceutical Good Manufacturing Practices. The sectoral annex of “Pharmaceutical good manufacturing practices” mentions for instance; recognition of GMP regulation, exchange of reports of inspections of manufacturers, and the possibility to rely on foreign test results for batch release, the so-called re-testing. The EU has MRAs with several countries; Australia, Canada, Japan, New Zealand, Israel, Switzerland and the US and all with different terms and conditions. All these MRAs are in force, except the one with the US. Which was first drafted in 1998, but was never actually implemented. So, what happened?

 

History of MRA events so far (link)

  • In 1994, MRA negotiations began between the EU and the US.
  • After numerous difficulties, (disclosure of inspection reports to the public and differing opinions on how to focus on post approval inspections or on post- and preapproval inspections) the negotiations finally resulted in an MRA in 1998, which already contained a “Pharmaceutical good manufacturing practices” annex.
  • Apart from the usual 18 months, the implementation period was extended to 3 years. In this period, it was recognized that legislation and implementation of this legislation were too different, to be able to mutually accept GMP inspection information at that moment. The MRA came a bit too soon. Hence, it was never implemented.
  • Despite the apparent failure of the MRA, it was recognized something should be done. The FDA expanded its reach beyond US borders by opening offices in Europe, China, India, and Latin America and conducted significantly more foreign inspections to gain more insight into the GMP compliance level of foreign companies.
  • Together with the Food and Drug Administration Safety and Innovation Act. In 2012 (FDASIA), stating that FDA cannot and should not monitor the world’s drug inventory by itself, this resulted in 2014 in Mutual Reliance Initiative (MRI). Which aims to increase strategic collaboration between the FDA and EU member states through the exchange of information.
  • Additionally, in September 2014, the FDA was invited to observe the EU’s Joint Audit Program, in which two EU nations audit the inspectorate – the regulatory authority – of another EU country.
  • These combined initiatives eventually resulted in an amended MRA on a sectoral annex of “Pharmaceutical good manufacturing practices” in March 2017.

 

Amended MRA EU and US 2017

The signed amended MRA is a major achievement, but euphoria should be tempered. Although this MRA could probably significantly cut costs for (bio) pharmaceutical companies enormously, it still contains a lot of terms and conditions. Aspects like an FDA assessment of the EU member states, an EU assessment of the FDA, and not all products are included in the annex. Depending on all these terms and conditions and assessment outcomes, parts of the MRA will come into force in time.

EU assessment of FDA

The EU’s assessment of the FDA started in September 2015. EU officials visited three FDA district offices, FDA headquarters complex, and an FDA laboratory. The EU team inspected with the same criteria that apply within EU. In late 2016, EU also observed FDA conducting an inspection as part of its evaluation. The progress in collaboration, negotiations, and assessments was found positive and finalization of the assessment in 2017 should be achievable.

FDA assessment of EU member states

  • FDA assessment started a year earlier in September 2014 with their presence at the Joint Audit Program of EU.
  • However, this is just a small part of the full capability assessment that the FDA will perform in all member states. In 2017, the FDA had already attended 14 audits of different EU member states and expects to be present at the remaining 14 before the end of 2017.
  • For this full capability assessment, the FDA requires each member state to provide a capability assessment package to FDA containing e.g. a finalized Joint audit program audit report, completed conflicts of interest questionnaire, four inspection reports including the report from the inspections observed during the Joint Audit Program audit, standard operating procedures (report finalization, training and inspector qualification, etc.) and an inventory of manufacturing facilities.
  • Eight of these packages should be assessed by FDA, before the MRA comes into force on 1 November 2017. Subsequently, the FDA and EU can and will rely on each other’s GMP inspections.
  • FDA intends to complete all of the 28 (27 after March 2019 depending on Brexit negotiations) full assessments by 15th of July 2019. After completion of all assessments, re-testing of imported batches and batch certification is no longer required. Until that moment, each imported batch and each batch to be certified is to be re-tested. The fact that delivery of capability assessment packages and their assessments are already planned and documented in the MRA, provides confidence that these milestones will be achieved.

NOTE: Not all Pharmaceutical products are included!

A wide variety of the pharmaceutical products are included in the amended MRA, but medicines derived from blood or blood plasma, human tissues and organs, immunologicals,  and veterinary products are not. for now, Medicinal products for veterinary use are expected to be included in July 2019 and Vaccines and plasma derived medicinal products in July 2022.

CONSIDERATIONS

The signed amended MRA is an important step forward. Nonetheless, it contains a significant number of terms and conditions, but it does provide a roadmap. If a positive attitude is maintained and the challenging timelines are respected, both parties will mutually accept GMP inspection information from 1 November 2017 onwards and omit the further need for import testing and batch certification after 15th of July 2019.

Until then, it is business as usual.

Blog by: Jeroen Ottens MSc, PharmD - Consultant 

04-09-2017
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#Lean Deviation Management

Within Good Manufacturing Practice (GMP), we both love and hate them. On the one hand, they are a valuable source of information on how we should arrange our processes, on the other hand managing them can be quite a challenge. More specifically: deviations. Often seen as something negative and probably one of the biggest burdens within the quality system. But what if you could increase the quality of deviation reports and reduce the time you spend resolving them? Let’s have a look at some examples on how we can apply Lean Six Sigma in achieving these goals.

Deviation Reduction

Reoccurring deviations are amongst the leading causes of losing control of a deviation management system, resulting in a build-up of deviations that are not closed in time, ultimately putting your processes, products or even patients at risk. It sounds easy: stop deviations from reoccurring. But, for example, identifying and preventing reoccurring deviations is easily forgotten in the daily routine of closing them. This is where a Green or Black Belt can help. By analysing deviations, grouping them and using Pareto charts, for instance, it becomes clear what the reoccurring issues are. To do so, besides Lean and GMP knowledge, you will need the knowledge of the Subject Matter Experts (SME), especially those who actually perform the process on a daily basis. This is where the Kaizen becomes an essential tool. The Kaizen is a multi-day workshop in order to improve a process or to solve a problem. Identifying the most reoccurring issues and solving them can be done with a multi-disciplinary team during a Kaizen of a few days, making this investment in time well worth it.

Improved root cause analysis

In order to prevent deviations from reoccurring, we need to address the underlying problem causing the deviation. This is what is called the root cause. After the root cause is identified, defining corrective and preventive actions (solving the problem) is often straight forward. However, putting CAPAs in place that aren't addressing the true root cause can result in losing control even further. Just think of a boat with a leak: pumping out the water is a great short term solution, but meanwhile, the leak is probably getting worse. In the end, the pump won’t be enough anymore to keep afloat, so we need to install a bigger pump. This is called ‘tampering’, and this also often done solving deviations. In order to improve the quality of root cause investigations and thus prevent tampering, a vast array of the 150 Lean Six Sigma tools is at your disposal. Depending on the issue just think of applying Lean group exercises with your SMEs like Process mapping, making a SIPOC,  performing Kaizens or Gemba walks (shop floor visits) in order to increase your understanding of the problem.  You can support your findings with aspect from the Six Sigma spectrum: data gathered from sampling or test runs. So defining metrics and detailed data collection plans in order to investigate the extent of the problem and identifying process variation can boost your investigations.  By applying such an approach, the quality of investigations will improve, lead times will reduce and (maybe most important) teamwork will be improved.

Backlog reduction

So what if you already have a build-up of deviations and a large backlog? Where to start? How to get activated again? Instead of looking at an endless list, we need to find a starting point. Compare it to a shop floor. If it is one big mess with lots of equipment in a room, execution of work in there won’t be efficient. Here we can apply the lean concept of 5S

  • Sort: Sort out everything that is really needed in that room and what is not (take these out of the room).
  • Set: Arrange all items at the place where they are needed
  • Shine: Clean the place since we made room to do so
  • Standardize: define a process/best practice in order to maintain the improved situation
  • Sustain: Ensure the new standards are met.

But, why not apply this to your deviation system?  One thing we have learned is that there is plenty of low-hanging fruit within most deviation systems, investigations that are almost finished or a bunch of relatively easy deviations to solve. Sorting deviations, stratifying them and giving them a place (priority/group) will give you a good starting point to reduce the backlog. Also here, by applying a Kaizen approach you will be able to achieve much in a short period of time. It can be helpful to use visual management in such a case:  for example, develop an overview of all deviations to be closed in the Kaizen and apply colour coding (red, yellow, green) to show statuses,  priority’s or deadlines. This way, you always know the status of a project and you remain in control. For a long term solution, think of a best practice to improve the process including a thorough definition of roles and responsibilities within the process. By applying these concepts, solving a backlog will be like a walk in the park.

Deviation process improvement

Altogether, a deviation handling process that is fit for purpose is what you need. Not just a procedure, but especially how it’s done in practice. It often happens that in practice we are doing additional steps compared to what is required according to a procedure. This is what we call a ‘process around the process’.  But why do we end up with such a waste in the system? Practical limitations compared to the theoretical procedure, or even tampering to make a process more efficient in the short term is what we often see as causes. This is one of the biggest causes of excessive workloads and increased lead-times related to deviation management. Situations like these can be addressed by applying the DMAIC process, which means:

Define the problem

Measure the extent

Analyse the data gathered

Improve the process

Control (check/sustain) the new situation.

Truly understanding current deviation processes facilitates working towards a much leaner situation. Standardization and visual management can prove to be your best friends in order to solve problems in a sustainable manner.

So where to start?

In the end, having deviations is not the problem in GMP.  It’s part of a healthy, working quality system. The way we handle the deviations determines whether it becomes a challenge or not.  This is where you can make a real difference by applying the basics of Lean Six Sigma on both the system as well as individual deviation investigations. See deviation management as ‘a problem’ itself: the system will only work if you really know the process behind it. Map the process, define the essential process steps, apply clear roles and responsibilities with those involved and from that, proceduralise it. Next, incorporating the DMAIC structure in your root cause investigations will leverage them and definitively solve the deviations. Finally, applying visual management will give you the edge in keeping control of your deviation management system once and for all.

If you want to learn more about applying Lean Six Sigma principles in the Life Sciences, please contact Xendo or take a look at the courses we provide together with the Biotech Training Facility (Yellow Belt & Green Belt).

Blog by: Stefan van Dam - Consultant & Green Belt

 

 

 

14-08-2017
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#Xendo welcomes Dr. Anton Franken as Scientific Advisor

Per 1st of August 2017, Dr. Anton Franken is linked to Xendo as an independent external Scientific Advisor. Dr. Franken works at the Isala hospital in the Netherlands as a consultant physician in internal medicine and endocrinology. During the past 12 years, he has been a Board Member of the MEB, specialized in the development and registration of Biosimilars. He was a board member of the Scientific Advisory Board Endocrinology and Diabetes of the European Medicines Agency (EMA) in London. He is a member of the Scientific Advisory Board at the Dutch National Healthcare Institute and is a co-founder and core member of the Initiative Biosimilars Netherlands (IBN).

20-07-2017
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#4 Strategies to manage a global pharmacovigilance system

Experiences from speaking at the DIA USA in June 2017; read about the challenges of a global pharmacovigilance system and strategies to manage it. 

Speaking at the DIA 

During the DIA USA in June 2017, I was one of the three speakers in the session: The Brave New World; The Ongoing globalisation of Pharmacovigilance (#320). The main topic of this session was how to manage a global Pharmacovigilance system. My specific contribution was sharing my experiences with growing pharmaceutical companies whose growth strategy was: entering the European Market. 

Growing EU Market

The EU market is estimated to grow to a staggering 206 billion Euro in 2022. Whether the growth of a company (and thus sales) is achieved by establishing affiliates in Europe, entering into commercial partnerships (distribution or license partners), or acquiring local companies, there is always an impact on the company’s current PV system. Changes (or upgrades) of a PV system are inevitable and need to be managed with care to avoid non-compliance with applicable regulations at any given time. This is especially challenging in the EU where regulations are among the most conservative. Particularly the requirements to have only one global PV system while working in different global environments and thus having different regulatory requirements all applicable to that one PV system. Next to that, the PV system needs to be managed by different people with their own cultural habits and languages. So how do we manage these challenges?

"Plans are nothing; planning is everything." Dwight D. Eisenhower

Experiences / Pitfalls

During my presentation I shared some pitfalls for each strategy from my personal experiences:

  • For example, an acquired company’s product portfolio can be so different, that their PV system is not able to handle a new innovative product with events under special monitoring in combination with a higher case load. The impact of the different product portfolios is often not recognised during due diligence because Subject Matter Experts for PV aren’t involved.
  • Another example is the incomplete merger of two PV systems, resulting in PV staff working according to different standards, which leads to compliance and data integrity problems as well as a lot of duplication of work.
  • Or a partner that turns out not to be as compliant as had been indicated during a qualification audit. It’s questionable how this is possible, as this should be exactly why you perform an audit in the first place. If the audit isn’t executed by experienced staff with access to the right background information the audit becomes a tick box activity and you may be in for a surprise.
  • Establishing new affiliates has its challenges, as many different priorities need to be addressed during the pioneering phase in which contractors and vendors may be used for PV system related tasks. The big questions here are: do these vendors/contractors deliver and does the staff at Head Quarters truly understand the local (EU) requirements of a compliant PV system?

4 Recommended Strategies

The three session presenters, independently from each other, came to the same conclusion on how to establish and maintain oversight on a global compliant PV system:

  1. Have a strategic goal/objective at the level of the company’s (Senior) Management: decide on a company’s goal and the route to obtain this goal. Ensure that everybody is informed on the growth strategy and understands where the company is going. For example, the company will be expanding its market into the EEA and to ensure a fast submission of the dossier, obtain approval, and launch the product, a fully functioning EU compliant PV system is a prerequisite.
  2. Implement a governance structure to manage changes and monitor the performance of the PV system throughout the transition phase. Project management principles must be implemented through comprehensive plans with explicit timelines. Ensure PV contracts, describing who is responsible for what, when and decision-making PV committees with binding charters, supplemented with global SOPs describing how tasks are executed and against what standards, are implemented.
    Following the above strategy, a vendor needs to be selected and qualified before work can be delegated. Delegating the work to a vendor means that the contractor remains responsible, so you need to “check” your vendor’s performance. Preferably in real-time and not 3 years later during an audit. Therefore, the company needs to set up a performance monitoring platform and agree on how often to measure, what to measure against (KPI), and decide on who takes the decisions. What can be decided without escalation (and what not – meaning scope and boundaries), how to monitor their performance during the project, and, most importantly, against which standards the work should be executed (e.g the GVP guidelines) should be part of the contract. This also implies that although the work is carried out by the vendor, resources are required to manage the oversight.
  3. Before any work or responsibilities are delegated, due diligence or qualification audits need to be executed by experienced staff who understands the impact of the planned changes for the PV system.
    It sounds a bit strange in a GxP environment, but do ensure that the team members involved in the Due Diligence or qualification audits are actually qualified for the job. And if this is not the case, you should add a subject matter expert to the team. For such important tasks, you may expect that at least one person with work experience in PV is involved. When the PV requirements become a checklist, the “tick boxing audit” may turn out to become a nasty surprise. Such as: “yes, there is a safety database”, but it turns out, the system is not validated and there is no E2B reporting in place. With a few hundred cases per month or even less, this is definitely not a nice surprise.
  4. Plan your activities by ensuring a structure is in place, resources and budgets are assigned and timelines (deliverables) are communicated and agreed upon.

Considerations

Let me also share the most important lessons learned over the past years: with the implementation of the new PV guidelines in 2012, the PV system interacts with roles and responsibilities from many departments throughout a company and having them “on board” from the early beginning is a challenge, which, if managed correctly will pay off. The solution to managing those involved from different departments lies not within the PV department or within the PV system alone. Having Project Management in place, ensuring these cross-divisional structures, is equally important.

With this strategic approach, any company will be more likely to remain compliant during important changes and enabled to act on deviations more rapidly. All it needs now is the human touch.

Blog by: Sandra van der Poel - Principal Consultant Pharmacovigilance

11-07-2017
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#BREXIT: Consequences and preparation tips for Biotech & Pharma

Triggering Article 50 by Theresa May has been a striking event of 2017 and will most likely be the start of a long and tedious road for all parties involved. Though the biotech and pharmaceutical industry in the UK has leaned towards remaining in the EU, legislative and operational changes are inevitable for them as well, since a large amount of regulation originates from membership of the EU.

So what’s changing? Actually, no one really knows just yet, so prepare for the worst case scenario is the EC’s recommendation. But is this really such a good idea?

Between a full Brexit and adhering to the current (EU) regulatory system (referred to as the Great Repeal Deal), there are two other likely options; adapting the European Economic Area model to which Norway, Iceland, and Liechtenstein adhere, or arrange separate sectoral agreements through the Economic Free Trade Association (EFTA) like Switzerland. Obviously, the administrative hassle increases significantly in the order as shown here below. The impact of the Brexit may be the highest for small and medium sized companies not having offices in other EU member states since their ability to move functions to other locations is limited.

 

Great Repeal

EEA

EFTA

Full Brexit

UK converts current EU law into British law (‘business as usual’)

UK participates as non-EU member (European Economic Area, like e.g. Norway)

UK develops sectorial agreements with EU (join Switzerland in European Free Trade Association)

UK develops own laws / drug approval system

General changes

Besides the administrative issues at hand, which will be present no matter what model is chosen, there will also be specific matters to be dealt with in the pharmaceutical industry. Of course, there will be the unavoidable relocation of the EMA head office, increased responsibilities of the MHRA which have to be secured into British Law, loss of EU membership benefits, and risks for continuity in several areas being compromised. But there is also a need to look into specific matters regarding Quality Assurance, Regulatory Affairs and Pharmacovigilance; all of which are regulated in the current framework.

Quality Assurance & QP

Currently, Quality Assurance and the role of the Qualified Person are stipulated in EU legislation so there will be changes anyhow. This is made even clearer in the recent statement by the EU Commission and EMA that the UK will be a ‘Third Country’ after 30 March 2019. Looking at it more specifically, you can question if the role of QP itself is about to change. Not in the EU, that is certain. For the UK it is to be expected that there will be little to no changes, even though the UK could theoretically abolish the role of the QP and adhere to the US system where QA signs off, for instance. It will be interesting to see how this will be laid down in British Law, also because there might be adaptations in sub-areas where the UK has had friction with EU regulations in the past. So will the UK keep the QP role and will it be comparable? Yes, most likely so.

EU QP

What will be the future of EU QPs is in the UK? Like most countries, the UK has some specific requirements for QPs in view of national legislation and it is most likely that this will not change unless they change the process of qualification of QPs. Since this is determined by British law, it is not very likely to be affected by consequences of the Brexit either. As communicated by the EU Commission and EMA, for companies who have their QP located in the UK, they will need to have a QP for batch release residing in the EU (EEA).

EU GMP

With regard to changes in EU GMP and whether it will continue to be applicable in the UK, one may assume that EU GMP will always be subject to updates, but should not suffer any consequences due to the Brexit. The joint cause has always been to harmonise rules governing the production of medicines, so it is not to be expected that EU GMP and whatever regulations the UK will conform, will be much different from each other. The past years EU GMP principles have been strongly embedded in the UK’s pharmaceutical industry, and form the base of inspections. Thus, making significant changes would result in a lot of administrative strain on the UK, making it seem rather unlikely as well. But then again, so did Brexit.

Importation testing & Recertification

Will importation testing and recertification be required for exports to the EU? Basically, if there is no mutual recognition agreement between the UK and EU there is a need for retesting and recertification, which would be a significant economic burden to UK located pharmaceutical companies. It would actually similar to the current situation between the EU and US.

Mutual Recognition Agreement

It is in the best interest of both the UK and the EU to get a Mutual Recognition Agreement in place to prevent economic downfall, meaning it is most likely that the UK regulations will closely mirror those of the EU.  Adoption of the FDA guidelines is less likely because they differ more from the current EU GMP, which is applied in the UK. 

Regulatory Affairs

One area that is bound to go through an administrative ordeal is Regulatory Affairs. For about 25% of  EU procedures, the MHRA is currently the (Co-)Rapporteur or RMS  and simply because they will no longer be part of the EU this workload will need to be shifted to the remaining 27 countries. This alone should cause a lot of work and consideration (proper distribution among the member states) until the ratification of Article 50 in 2019, but there is also the significant participation in EMA committees/Working Parties and the Inspection, and most likely a to be expected delay of the entire approval process.

EMA Office and Activities Relocation

The EMA will need to find a new home for its head office and about 900 expertly skilled staff. Apparently, countries are already lining up to embrace this task including The Netherlands, Denmark, Ireland, Italy, Sweden and Spain. But, as said before, MHRA also handles a large share of EU procedures meaning that a relocation of the EMA office would also mean the reallocation of Rapporteur and Co-Rapporteur activities and Reference Member State (RMS) activities. Withdrawal of concerned Member State (CMS) activities from the EU procedure will only impact on the Market Authorisation in the UK. Compensation by the remaining countries would put a burden on the existing structures which are currently suited to a specific need. This means these institutions would need to expand, which might be problematic for those who receive funding through larger organisations instead of directly receiving funds for the activities they undertake for the EMA.

Approval procedure

The current Centralized and Mutual Recognition/Decentralized procedures are forfeited by the UK by exiting the EU. Consequently, the UK needs to set up its own approval procedure for new drugs and this is best explained by looking at the 4 models mentioned earlier: Great repeal deal, EEA model, EFTA model, and Full Brexit.

The Great Repeal Deal is out of the question because being part of the EU is quite essential to the entire concept of EU procedures with equal rights between the EU countries. So the next best option would be joining Norway, Iceland, and Liechtenstein in the EEA model. This way the UK can participate in the centralised procedure, albeit with a significantly reduced influence. The UK would be able to participate in the discussions but in no way be able to vote in the CHMP (whilst before the MHRA had a major influence).

In the case of the latter models, the UK would have to implement their own national approval procedure (and legislation to place this responsibility in the hands of the MHRA). This way there will be a need for the UK to come to terms with the EU (and all other countries) through an MRA like Australia, Canada, Israel, Japan, New Zealand, Switzerland, and the US.

Marketing Authorisation Holders

We can surely assume there’s work to be done for all Market Authorisation Holders (MAHs) present in the UK. This is made very clear by the EU Commission and EMA statement mentioned earlier which also says:

“EU law requires that MAHs are established in the EU (or EEA).”

Meaning a pharmaceutical company will need a registered and licensed office or facility with a license in the EU/EEA.

That being said, all companies are recommended to look into the transfer of EU MAs (CAP: Centralised Authorisation Procedure) from UK companies to EU based companies. The UK needs to question whether existing MAs for CAPs will still be valid for the UK?  Or is there going to be a need to relicense? They need to find new (Co)Rapporteurs for existing CAPs and new Reference Member States for existing Mutual-Recognition-Procedure/DeCentralised Procedure products. And of course, all Summaries of Product Characteristics and Artwork for drugs with a UK-based MAH need to be adapted. A large number of variations is expected as a result of Brexit. All of which is most likely coupled with a huge administrative burden and accompanying costs for companies.

International companies

The EU offers many advantageous aspects to international companies which will no longer be applicable after Brexit is completed. Many international companies have regarded the UK as a bridging point to the rest of the EU thanks to their facilitating role and infrastructure, but also due to the fact that they were indeed a part of the EU.

A relevant example is the upcoming new ‘Clinical Trials Regulation 536/2014 adopted June 2014’ which is expected to come into force by October 2018. This particular regulation will allow for a single application for clinical trials across the EU with single portal and EU-wide database. The UK will be bound by it in the near future but only until its departure from EU after which companies would probably need separate submissions for the UK. And then there is also the question whether or not EU approved products will be considered an unauthorised product in UK Clinical Trials.

 

Pharmacovigilance

QPPV function and the location of the PSMF

Currently, the majority of the QPPV functions (N= 1,300; 60%) is located in the UK and,   many of them will have to decide to either relocate abroad or find new employment. As stipulated by the European Commission  (Article 8 of Directive 2001/83/EC & Article 74 of Directive 2001/82/EC PSMF) that:

“the QPPV must reside and carry out his/her tasks in the Member State of the Union (EEA)”

Companies will need to take a strategic decision to decide how to move forward with the QPPV function and investigate the different options; such as relocation or appoint new QPPV and/or deputy who resides within one of the remaining member states.  As a consequence, the location of the Pharmacovigilance System Master File, must be brought in line with the Brexit situation and in compliance with the Commission Implementing Regulation (EU) No 520/2012. Again, this will be accompanied by an administrative burden and costly fees because QPPV and PSMF details need to be updated through Article 57. 

How to prepare?

From what we’ve seen many companies are adopting a ‘wait-and-see’ approach. This is very understandable due to the high degree of what is actually still unknown/uncertain. However, to support the preparation process and to ensure business contingency, a good prepared and more proactive approach is advised.

 

If there is any helpful advice to be given to biotech and pharmaceutical companies at this moment it might not be to prepare for the worst. Regarding the specific nature of these upcoming issues, which are bound to be different for all companies, it might be wise to investigate all business cases individually to prevent unnecessary costs.

Every company should at least follow these steps to ensure that they are properly prepared:

  • Know what activities are currently being carried out in the UK
  • Consider the impact of all possible scenarios
  • Analyse risks (but don’t forget to see opportunities either)
  • Determine risk minimising strategies
  • Map employees having to leave UK to return to EU (or vice versa send employees to the UK with unknown prerequisites)
  • Prepare for questions by investors, what is impact on existing financing and timelines

For any further questions, please contact us.

 Blog by: Nick Veringmeier - Xendo