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In 2015, Brinker Pharma has merged with Xendo. Together we offer a broader palette of services and are able to take on larger projects in the Life Sciences industry.
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).
Experiences from speaking at the DIA USA in June 2017; read about the challenges of a global pharmacovigilance system and strategies to manage it.
During the DIA USA in June 2017, I was one of the three speakers in the session: The Brave New World; The Ongoing
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.
"Plans are nothing; planning is everything." Dwight D. Eisenhower
During my presentation I shared some pitfalls for each strategy from my personal experiences:
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
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
UK converts current EU law into British law (‘business as usual’)
UK participates as
UK develops sectorial agreements with EU (join Switzerland in European Free Trade Association)
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
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.
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).
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
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.
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.
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.
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
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
In the case of the
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
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
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.
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:
For any further questions, please contact us.
Next blog: Picking a new Reference Member State
Blog by: Nick Veringmeier - Xendo
"Does a Design & Build contract suit the realisation of my new facility?"
A question many contractors have been asking themselves in recent years.
The building process is increasingly complex, especially for complex Life Sciences buildings such as laboratories, cleanrooms, and production facilities. This causes many clients to choose a design & build (like) construction according to the UAV-GC (Integrated Contracts). This way the responsibility for both (a part of) the design and the implementation is carried by one party. Traditionally, responsibility lies with several parties, all of whom are directed by the client.
The main part of this blog is written in Dutch but available in English upon request. If so, please send us a short message to receive it.
“Past een Design & Build contract bij de realisatie van mijn nieuwe faciliteit? “
Dat is een vraag die veel opdrachtgevers zich de laatste jaren stellen.
Het bouwproces wordt steeds complexer, zeker bij complexe gebouwen als laboratoria, cleanrooms en productiefaciliteiten. Dat brengt veel opdrachtgevers ertoe om voor een design & build (achtige) constructie te kiezen volgens de UAV-GC (Geïntegreerde contracten). Hierbij wordt de verantwoordelijkheid voor zowel (een deel van) het ontwerp als voor de uitvoering integraal bij één partij ondergebracht. Traditioneel lag deze verantwoordelijkheid bij verschillende partijen die allemaal door de opdrachtgever aangestuurd werden.
De voordelen voor de opdrachtgevers van een geïntegreerd contract zijn er dan ook zeker:
Toch lopen nog niet alle design & build contracten naar tevredenheid, vooral bij deze complexe gebouwen ervaren we dat de resultaten niet altijd helemaal binnen de verwachtingen vallen of dat er tijdens het proces nog veel sturing nodig is om het gewenste resultaat te bereiken.
Voor een succesvol design & build traject voor een complex gebouw zijn 4 succesfactoren belangrijk:
Allereerst valt of staat een goed design & build traject met een goed programma van eisen en een goede vraagspecificatie. Wanneer de uitgangspunten niet volledig genoeg zijn of niet de lading van de wensen dekt, kan een aannemer nooit een goed product leveren en zal het project voor alle partijen onbevredigend uitpakken. Je krijgt immers wat je vraagt. Bijvoorbeeld als je alleen specificeert dat je een cleanroom wilt die voldoet aan ISO 5, zonder daar aan toe te voegen dat dat geldt voor deeltjes van 5 µm en 0,5 µm “in operation”, bestaat de kans dat je eindigt met een cleanroom die niet aan alle benodigde eisen voldoet voor het beoogde proces. Zorg dus voor een goed en uitgebreid programma van eisen dat de kritische aspecten voor het proces helder omschrijft. Helaas ontstaan nog te veel meningsverschillen door het niet helemaal eenduidig vastleggen van de eisen of het niet tijdig in overleg treden over de intentie van bepaalde artikelen in de vraagspecificatie. Bekende discussiepunten zijn bijvoorbeeld interpretaties van kwaliteit, flexibiliteit, modulariteit en duurzaamheid.
De UAV GC biedt voldoende mogelijkheden om bij de selectie van de D&B partner het procesverloop vooraf goed te definiëren. In de UAV GC kunnen we volgens Annex III en Annex IV een acceptatieplan en een toetsingsplan vastleggen. Hierbij wordt aangegeven op welke momenten of op welke stukken je een controle wilt uitvoeren (zonder harde consequenties voor de D&B partner) en bij welke momenten of op welke stukken eerst formeel goedkeuring kan worden gegeven alvorens het proces verder kan gaan. Het niet goed vastleggen van deze toets en acceptatie criteria, zeker in combinatie met verschillende interpretaties van het PvE, monden vaak uit in een discussie over geld en tijd. Een goed begin met juiste en volledige uitgangspunten voor eisen en proces zijn dus cruciaal voor een goed design & build traject.
Zorg voor een goede (functionele) vraagspecificatie waarin ook het procesverloop en de controle momenten goed zijn omschreven. Door de eisen en ook het proces goed te definiëren krijgt de design & build partner ook de kans een goed gebouw uit te werken.
Een productie- of laboratoriumfaciliteit zou altijd vanuit het gebruikersproces moeten worden ontworpen. De faciliteit moet ten dienste staan aan het proces dat er plaats gaat vinden. Daar zit gelijk een risico voor dit type projecten. Een adviseur die gewend is om te gaan met de eindgebruikers kan hierbij de juiste procesvragen stellen die vervolgens worden vertaald in een solide technisch ontwerp. Juist in de beginfase is het belangrijk dat de opstellers van de specificatiedocumenten het gebruikersproces goed leren kennen. Echter, zodra het proces helemaal inzichtelijk is bij de ontwerpende partij dragen we bij een design & build traject het ontwerp over aan een nieuwe partij. Deze partij heeft doorgaans minder kennis van de bewuste processen en kent het specifieke gebruikersproces nog helemaal niet. Dit kan leiden tot interpretatieverschillen die aan beide zijden als heel logisch gezien worden en te wijten zijn aan een verschil aan kennis van het gebruikersproces. Denk bijvoorbeeld aan filters die regelmatig vervangen moeten worden oorspronkelijk buiten de werkruimten bedacht zijn, maar in het D&B ontwerp toch in het plafond boven de productieruimten geplaatst worden. Hierdoor zou het proces stilgelegd moeten worden om de filters te vervangen. Technisch een gunstigere oplossing maar desastreus voor het werkproces.
Ook leert de ervaring dat er veel verschil kan zitten in ontwerpkennis bij de aannemers. Een vraagspecificatie is geen uitgewerkt bestek (detail ontwerp), hier is nog een belangrijk deel van het ontwerpproces (van het functioneel ontwerp naar het uitvoeringsgereed ontwerp) voor nodig. Begrippen als functionaliteit flexibiliteit, modulariteit en duurzaamheid blijven bijvoorbeeld nog weleens achter, evenals een goede total cost of ownership (TCO) benadering voor de ontwerpkeuzen. Het komt het resultaat van een design & build traject ten goede als de proceskennis geborgd blijft bij de overdracht van de vraagspecificatie naar de ontwerpende aannemers. Dit kan bijvoorbeeld door de adviseur die de vraagspecificatie heeft opgesteld een actieve rol te geven in de uitwerking van het technische ontwerp en de uitvoering. Eventueel kan een expert gebruiker met technische achtergrond deze rol ook vervullen. Een adviseur kan zowel aan de opdrachtgeverszijde of aan de opdrachtnemerszijde (D&B partner) acteren bij de uitvoering van het design & build project. Hiernaast is het een belangrijke taak van de design & build aannemers zelf om ook kritisch te kijken naar de vraag (achter de vraag) van de klant en oplossingsrichtingen te spiegelen met de klant en de adviseur. Met deze maatregelen wordt de intentie van de vraagspecificatie gecontroleerd, geborgd, en wordt er veel dubbel werk, extra kosten en frustratie voorkomen.
De voordelen van een design & build traject zijn zeker aanwezig, met één contractpartner voor de uitvoering zijn de communicatielijnen kort en de verantwoordelijkheden helder. Doordat vroegtijdig een aannemer wordt ingeschakeld kan hij of zij eigen specifieke kennis van de uitvoering en inkoopvoordelen inbrengen. Ook levert het tijdwinst op doordat de besteksfase en de uitwerking tot werktekeningen in een keer wordt gedaan. En niet te vergeten is er eerder zekerheid over de prijs en de planning.
Met goede startdocumenten, geborgde proceskennis, en een goede aannemer met voldoende technische ontwerpcapaciteit en -kunde kan een dergelijk proces erg goed lopen en zal het zeker voordelen met zich meebrengen. Enkele zeer succesvolle projecten zijn op een dergelijke manier verlopen. Bij een van mijn eigen projecten in een dergelijke constructie is bijvoorbeeld de ruwbouw sneller gelopen dan gepland en zijn er bouwkostenbesparingen gerealiseerd (tot wel 10%) zonder functieverlies voor het proces door gebruik te maken van ervaringen en inkoopvoordelen van de aannemers.
Het is erg belangrijk te starten met een degelijk Programma van Eisen en een gedetailleerde vraagspecificatie met definitie van het gewenste procesverloop. De tijd en het geld dat in dit eerste deel wordt geïnvesteerd betaalt zich dubbel en dwars terug in de rest van het traject.
Een design & build traject voor een complexe gebouwde omgeving kent een aantal risico’s. Met name de kennis van het gebruikersproces en de gewenste functionaliteit is belangrijk om te blijven borgen tijdens het hele proces. Ook is het selecteren van een kundige aannemer cruciaal voor een goed verloop. De proceskennis en de juiste uitwerking van het technische ontwerp kan geborgd worden door een expert van de opdrachtgever of een adviseur een sturende rol te geven bij het uitwerken van het technische ontwerp door de aannemers.
Concluderend biedt een design & build constructie ook bij complexe gebouwen belangrijke voordelen, mits de proceskennis en het ontwerp- en bouwproces goed worden geborgd.
Blog by: ir. Bert Wielders - Xendo
Today an article with an interview with André van de Sande was released with the Dutch Financial Times in a special edition about the Biotechnology sector in the Netherlands. In the interview, André explains how Xendo has developed into a company that's capable of delivering a complete spectrum of services to the Life Sciences industry and how it remains able to distinguish itself.
Adverse Event Reaction
Adverse Drug Reactions (ADRs) are a major contributing factor to morbidity and mortality resulting in 6.5-10.9% of hospital admissions and mortality rates of 0.15-2.9%. A considerable number of ADRs are preventable particularly those caused by drug-drug interactions and overdoses. Preventive measures such as adhering to Risk Management Plans (RMPs), ongoing Pharmacovigilance (PV) awareness training for healthcare professionals and patients could help reduce the prevalence rates of ADRs.
Adverse drug reactions are an acknowledged factor contributing to morbidity and mortality universally and have caused the withdrawal of 28 drugs from the US market between 1976 and 2007. The World Health Organization defined an ADR as any noxious, unintended or undesired effect of a drug that occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy. ADRs are classified into two major groups:
Other minor categories include:
This paper discusses ADR rates of morbidity and mortality and ADR prevalence factors with a particular interest in Drug-Drug Interactions (and overdoses. Preventability of the ADRs is also discussed.
ADRs remain a significant contributing factor to morbidity and mortality worldwide despite increased awareness, past mistakes or experiences, and stricter regulations. The figures are likely to increase if preventive measures are not exercised. Most reported ADRs are Type A (predictable and dose dependent) and as such could be prevented. Drug-drug interactions and overdose contribute to a significant portion of preventable ADRs. The most promising prevention approach by far is
This publication was written by:
We have updated our Medical Device and In Vitro Diagnostic classification chart due to the huge success of the previous version. Have a look at the chart and feel free to ask us if you have additional questions.
Various drafts of the Medical Device Regulation and the In Vitro Diagnostics Regulation have been published back in 2016, already giving indications into which direction the regulations would evolve, upgrade the requirements compared to the respective directive and their effect on the technical documentation and thus the medical device manufacturers.
Recently, on May 5, 2017, the final text of the European Medical Device Regulation 2017/745 (MDR) and the In Vitro Diagnostic Regulation 2017/746 (IVDR) have been published in the Official Journal of the European Union. Consequently, both regulations come into force on May 26, 2017. Three years later, the application for the MDR will take place on the date of May 26,
The MDR will combine the Active Implantable Medical Devices Directive (90/385/EEC -- AIMD) and the Medical Devices Directive (93/42/EEC -- MDD) into one regulation. The IVDR will replace the In-Vitro Diagnostic Medical Devices Directive (89/79/EC -- IVDD).
The update of the tech documentation will start with the verification of the classification of your medical device or in-vitro diagnostic. Compared to draft publications of the regulations, the classification rules have been further upgraded with respect to numbering.
To assist you in your efforts to classify your IVD or Medical Device we have put together the criteria according to these novel regulations in an updated flowchart.
Contact: Marc Klinkhamer - Principal Consultant
Submissions in NeeS (Non-
Currently, electronic submissions of dossiers for human medicinal products in the EU are acceptable in two formats: NeeS (Non-
eCTD was first established in 2002 and became mandatory for all centralized electronic submissions to EMA by 2010. The National Agencies, however, allowed a longer transition period to transfer national, decentralized procedure (DCP) and Mutual Recognition Procedure (MRP) dossiers from NeeS to eCTD. For new marketing authorization applications submitted via the DCP and MRP,
Source: eSubmission Roadmap
From 1 January 2018 onwards, eCTD will be mandatory for all CP, DCP and MRP submissions. The eSubmission Roadmap has been extended for national procedures, but European national submissions for new applications will be required in eCTD format from 1 July 2018 as well and the NeeS roadmap will definitely end on 1 January 2019 with eCTD being required for all submissions, including those for nationally registered products. This implementation date set should be strived for by all National authorities (see Annex 2 to the HMA eSubmission Roadmap).
Although this is not a strict requirement, authorities will request transferring the existing dossier to eCTD format prior to submission of a new variation or update. The creation of an eCTD is done via a baseline submission, usually only covering the Quality part (Module 3) of the dossier. A baseline submission is a compiled submission of the current status of the dossier, i.e. resubmission of currently valid documents that have already been provided to an agency but in another format (TIGes Harmonised Guidance for eCTD Submissions in the EU Version 2.0 August 2011). The advantage to the company of creating a baseline eCTD first is that this will provide a well-structured overview of the information already contained in the dossier. As a
To prepare for the upcoming deadlines, companies are advised to assess their current situation by following these steps:
For products registered through MRP/DCP:
For products registered through National Procedures:
Or if you have any questions don't hesitate to contact us.
Authors: Patricia Baede, Liesbeth Hoff & Almut Holz
We can support you with ファーマコビジランス, 規制関連業務, 品質管理 & リーンシックス・シグマ?
Or as you might know it in English: Pharmacovigilance, Regulatory Affairs, Quality Management & Lean Six Sigma.
Since 2001, Xendo has built up extensive experience in Japan and has provided
Thanks to our success in this region, the new Xendo website couldn't be left without Japanese content. So, to be able to better cater to the needs of our Japanese relations, our website now offers Japanese translations for several of our services. We would like to invite you to have a look!
|Pharmacovigilance||Regulatory Affairs||Quality Management & Lean Six Sigma|
|ファーマコビジランス||規制関連業務||品質管理 & リーンシックス・シグマ|
“Using the current directives while preparing for the new medical device regulation and IVD regulation”
Modern medicine strongly depends on the use of medical devices for purposes of both care and cure. Medical devices have become a vital part of modern healthcare and practically no diagnosis or treatment is possible without them. Types of medical devices range from large capital hospital fixed equipment, through high-technology implants, surgical and monitoring equipment, to more familiar products such as wheelchairs, sticking plasters, syringes, incontinence aids, and spectacles.
In the medical device industry, the success of a novel medical device launch can often determine the positioning of the company for the coming years. Having a great product is essential and a good starting point, but is not enough to ensure it succeeds in the market. One of the most important determinants is obtaining a so-called CE mark before the device can circulate on the single European market. According to the European directives, a CE-mark (‘Conformité Européenne’, i.e. European Conformity) is mandatory for medical devices placed on the European Union single market. The CE-mark indicates product’s compliance with EU legislation and thus, implicates that these devices meet EU safety, health, and environmental protection requirements. By bearing a CE-mark, the medical device is considered as a product with sufficiently proven performance and safety for application in clinical practice and enables free marketability in the European Economic Area. Thereby the manufacturer declares, on his sole responsibility, conformity with all of the legal requirements to achieve CE-marking.
Throughout this article the manufacturer will appear and the definition is as follows: ‘manufacturer’ means the natural or legal person with responsibility for the design, manufacture, packaging
The requirements to obtain a CE-mark vary among the different types of medical devices and may result in a significant expense with respect to certification (resulting in costs of thousands up to million Euros) and long process (varying between a couple of months and several years). Preparation in an early development process is, therefore, essential to deal efficiently with this burden and warrant making the right legal choices; this last point will prevent costly changes in the design of the device in the latest stage of the development process (to minimise the risk of non-compliance with the requirements of Notified Bodies (NB) and thus to minimise costs and time).
Currently, medical device and in vitro diagnostic developers need to demonstrate that their medical device meets the requirements of respectively Directive 93/42/EEC and Directive 98/79/EC (in this article the active implantable medical devices are out of scope
Figure 1. Transition period new MDR and IVDR.
This article will not deal with the changes that will take place but will explain the ins and outs of the current legislation. The reason for this is that during the transition period (Figure 1), which is between the publication date of the MDR and IVDR and May 2020 (MDR) and May 2022 (IVDR), it is still possible to CE-mark devices according to the current legislation, i.e. the Medical Device (93/42/EEC) and In Vitro Diagnostic Directives (98/79/EC). Especially for start-ups it could be strategically beneficial to CE-mark their products according to the current legislation and make the switch to the future legislation at a later stage. In this way, the increased regulatory burden that is imposed by the MDR will be spread over several years and also time to market could be shortened. Also, manufacturers that have products on the market and want to expand their product portfolio could take advantage of this approach; for example, the In Vitro Diagnostic industry will be faced with major changes and it could be advantageous to continue using the IVDD and wait until the dust has settled. Because the CE-marking process is often regarded as a confusing, costly and complex procedure which takes up a lot of a company’s precious time, this article will discuss the most important steps and will provide more clarity and an overview in the complex matter of CE-marking.
Figure 2 represents the steps in chronological order on how to develop and CE-mark your product. These steps include (1) identifying the directive(s) applicable to the device by identifying the type of your device, as there are different directives for each different type of device; (2) verifying the device-specific requirements and (harmonised) standards, as each type of medical device is further specified within classes or lists; (3) identifying if an independent conformity assessment from a notified body is required, as for some medical devices the involvement of a notified body is required (see 1.3); (4), further designing and developing the medical device and checking its conformity since each design of a device has to be carefully verified and validated according to the EU directives; (5) drawing up and keeping required technical documentation available, which has to be presented on request to the appropriate national authorities or sent to a notified body for review; (6) affixing of the CE-mark to the device and generating a declaration of conformity, as the CE-mark must be affixed accordingly, visibly, legibly and indelibly to the product or its data plate and the identification number of the notified body must be displayed if involved.
Figure 2. Steps to undertake in order to obtain a CE-mark.
First, the appropriate directives, standards, and requirements must be identified since the requirements to obtain a CE-mark vary amongst the different types of medical devices. To determine the appropriate directives, one must first determine the appropriate type of medical device. Medical devices are divided into three categories; medical devices (MD), in vitro diagnostic devices (IVDs) and active implantable medical devices (AIMDs) each with their own EU directive (93/42/EC, 98/79/EC and 90/385/EC respectively).
Medical devices; 93/42/EC. According to 93/42/EC, a ‘medical device’ means any instrument, apparatus, appliance, software, material or another article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:
and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.
IVD; 98/79/EC. According to 98/79/EC, an ‘in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:
Specimen receptacles are considered to be in vitro diagnostic medical devices. ‘Specimen receptacles’ are those devices, whether vacuum-type or not, specifically intended by their manufacturers for the primary containment and preservation of specimens derived from the human body for the purpose of in vitro diagnostic examination. Products for general laboratory use are not in vitro diagnostic medical devices unless such products, in view of their characteristics, are specifically intended by their manufacturer to be used for in vitro diagnostic examination.
AIMD; 90/385/EC. This category of devices fall outside the scope of this article and will not be further dealt with. However, it is important to determine if the device can be defined as an AIMD or not.
After the right category of device has been selected, the appropriate device-specific requirements have to be determined. The medical device categories are further subdivided into classes or lists for each medical device directive. The applicable class or list for both MDs and IVDs has to be determined in order to verify which tests are required to obtain a CE-mark.
The MDs are classified in either Class I (including Is &
how long the device is intended to be in continuous use,
whether or not the device is invasive or surgically invasive,
whether the device is implantable or active,
whether or not the device contains a substance, which in its own right is considered to be a medicinal substance and has action ancillary to that of the device.
The IVDs are categorised in either self-testing, list A, List B or other/general devices. To verify the category of the medical device, the flowchart presented in Figure 3 can be used.
Figure 3. Flowchart for verifying the classification of IVDs.
In order to generate evidence for conformity of the medical device to the applicable directive and specific requirements for each class of devices, multiple verifications, and validation studies must be executed and documented. Although the directives do not prescribe a specific methodology on how to perform these studies and leave the choice to the manufacturer, it is best to follow widely accepted methodologies described in standards (that can, for example, be obtained via the European Commission). For example, if a medical device is a sterile product, then the sterilisation process must be validated and for different sterilisation processes specific standards do exist; they are most often published by the well-known ISO organisation. In case a standard has been adopted by either CEN or Cenelec (Commission of the European Union) they are considered to be harmonised. The advantage of such a harmonised standard is that when a medical device (i.e. its design and the required manufacturing and packaging processes) is in conformity with a harmonised standard, the compliance with the essential requirement is presumed.
After identification of the type of device and its class or list, the manufacturer should determine the involvement of a notified body (NB) as a third step in the procedure. For low-risk medical devices the involvement of a NB is not required, as explained in the next paragraph.
A notified body is an organisation which is accredited by a competent body to verify whether a medical device meets the essential requirement of the applicable directive and eventually provides a CE-certificate. Each member state of the European Union specifies its own competent body (-
To obtain a CE-certificate that allows the manufacturer to CE-mark the device, the manufacturer must apply at
Part of the activities of the NB is to assess the quality management system of the manufacturer by performing an audit. Besides NBs, also so-called registrars can perform this activity and even issue a certificate of compliance to the applicable standard, i.e. the ISO13485 standard. Although it is allowed to use a registrar for this, the disadvantage is that the registrar cannot issue a CE-certificate that is required for CE-marking. Also, the registrar charges additional prices and, therefore, it is recommended to use a registrar for assessment of the quality management system.
Table 1. Conformity routes of medical devices and in vitro diagnostic devices.
The selection of a NB should be a performed with utmost attention. Quality and costs amongst different
For the conformity assessment, different routes can be chosen from. In most of the cases, the Annex II route is chosen because this allows the manufacturer a greater freedom to operate. The differences between the routes are mostly determined by the level at which the NB is involved in the assessment of the device’s design and the way it is secured that produced devices are appropriately controlled.
For certain medical devices (MDs class I and low-risk IVDs) the CE-certification by a notified body is not mandatory. The manufacturer can continue the following steps independently, ending in a self-certification that will be described later on in this article.
The design and development process of a medical device is one of the most important steps, because it will render to documented evidence by which the safety and performance of the device is guaranteed. Especially for devices where the involvement of a NB is required and that are at higher risk, it advisable to start with a regulatory strategy before finalising the design and development of your device. The requirements for CE-certification by a notified body and an overview of these steps to meet the requirements can be preliminarily reviewed by the notified body. After agreeing on this strategy by both partners, the manufacturer and the notified body, agree on this strategy, including the category and classification of the medical device, the manufacturer can finalise the design and development of its device. Discussing this strategy before finalising the design and development of the device will notably shorten the duration of the official CE procedure since it will prevent non-compliance with the NB requirements.
In addition, compliance with quality management system requirements described in the ISO13485 standard ensures the manufacturer’s ability to meet customer and regulatory requirements. This will not only facilitate the CE-certification process but also provide added value for the reputation of your company.
Besides a structured and standardised approach for the design and development process, including proper design inputs and application of risk management, also the verification testing to be performed is essential. Because of the variety of medical devices, including in vitro diagnostics, is enormous, it is impossible to go into detail into this topic here. In general, ample attention should be given to topics such as sterility, biocompatibility, electrical safety, electromagnetic compatibility and usability (of course only if they are relevant to the medical device in development). Each and every verification test must be documented, meaning that pre-approved protocols and reviewed and approved reports should be generated. Verification testing is also sometimes referred to as bench testing and can be done in the facilities of the manufacturer or outsourced to third parties. In the latter situation, the manufacturer should keep in mind in the case of outsourcing the final responsibility remains with the manufacturer.
The testing of the medical device (or the in vitro diagnostic) by the user in the actual situation where the device will be used is named design validation or clinical validation. It is required to obtain clinical evidence based on actual data to demonstrate compliance with the essential requirements described in the applicable directive. Guidance on how to obtain clinical evidence can be found in the guidance documents Meddev 2.7/4 and Meddev 2.7.1. The collection of clinical data can be completed by execution of a clinical investigation unless it is duly justified to rely on existing data. Naturally, such justification will have to be based on a proper clinical evaluation. In general, the higher the risk class of a medical device, the higher the chance is that clinical investigations with the device should be executed. By comparison with suitable comparators, additional clinical investigations may be feasible to support the existing clinical evidence. The provided clinical data, for all types and/or classes of medical devices, must consist of:
Safety and performance can often be demonstrated by other means. However, for IVDs in list 2 and MDs class III, in particular, data must be generated to:
Thus, a clinical investigation on a non-CE-marked device must be designed to prove that the performance claimed by the manufacturer can be demonstrated and that the device is judged to be safe to use on patients. A clinical investigation on a non-CE-marked device must at least be considered when:
Alternatively (in particular for line extensions to products or for products already on the market outside the EU), clinical data may include a complaints analysis in combination with a literature compilation with an expert summary, post-market surveillance data, and so on and this might be sufficient. Clinical evaluation is based on the assessment of the risks and the benefits, associated with the use of the device, through either:
After these steps, the technical file can be created which includes general aspects of the device, device description, essential principles and evidence of conformity, risk management,
Depending on the strategy chosen, the technical file can contain more or less of the original verification and validation documents. If the original document is not included, then providing a summary and making reference is acceptable. A reason to keep the technical file lean and mean is that will be easier to maintain throughout the lifecycle of the medical device. On the other hand, reviewers could always ask for the original documentation, which could result in a slower review process.
The technical file is handed over to the NB for review In addition to this review, the NB will also audit the manufacturer on site in order to assess the quality management system and the processes for manufacturing and packaging. Also, on-site audits for critical subcontractors are often part of the review.
After completion of technical file, the manufacturer should generate a Declaration of Conformity (DoC). In case the medical device classification required the involvement of a notified body, there is the logical prerequisite that the review and approval process by the NB should have been successful and a CE-certificate issued. With the DoC generated, the manufacturer then affixes the CE-mark. As mentioned in the beginning of this article, the CE-mark must be affixed visibly, legibly and indelibly to the product or its data plate and the identification number of the notified body must be displayed if involved.
Once the device is correctly CE-marked it does not need the additional approval to be marketed in the EU, EEA or Switzerland as the CE-marks represents free movements in these states. However, these states can request the manufacturer to register the device and can require device information in the respective language. Thus, in case if the device will be marketed in a state other than registered the national authorities should be contacted.
One final note should be made for those medical devices for which there is no NB involvement; these devices need to be registered at Eudamed, the European databank for medical devices. Eudamed is a secure web-based portal acting as a central repository for information exchange between national Competent Authorities and the Commission in accordance with the Medical Devices Directives. The information in it is not publically available. It also contains data on devices where a NB was involved and the information is entered by the NB self.
Within this article, the complex CE-marking process is simplified by providing a comprehensive 6-steps route towards obtaining a CE-mark. Even though the current legislation will be replaced, it could be a strategic choice to continue to comply with the Directives during the transition period and switch over to the Regulations at a later stage. Essential steps, such as verifying the applicable directives by defining the appropriate class/list of your device, should be addressed before finalizing the design and development of your device. It should be noted that discussions with a notified body (if relevant) is of utmost importance before undertaking this finalization step. Neglecting advice from
|Contact Xendo if you need assistance with the regulatory approval procedure. This includes defining the appropriate strategy and planning for your device and setting up the required quality management system.|
|Michelle van Wijk - Consultant||Marc Klinkhamer - Principal Consultant|