Contact

Subscribe to newsletter

12-12-2017

#Brexit Life Sciences Highlights

Below you'll find the highlights that we have selected for you regarding regulatory, pharmacovigilance and quality related matters in the Life Sciences industry in a chronological order


The Netherlands welcome EMA, 20-11-2017 - General

Rembrandt and van Gogh, tulips, clogs and windmills, a sample of what we’re famous for. We might be small, but we’re a great country. And it’s our pleasure to welcome the European Medicines Agency to The Netherlands.

The Netherlands will prove itself to be a true home to the internationally oriented EMA community and its staff thanks to its excellent accessibility, high-quality of living, and a population consisting of over 180 nationalities.

Read more.


SERIALISATION AND UDI: 4 REASONS TO START TODAY
05-12-2017

#SERIALISATION AND UDI: 4 REASONS TO START TODAY

In recent years, new European legislation on traceability of medicinal products and medical devices was introduced to guarantee patients’ safety and to avoid fraud. Depending on the industry in which you work, you might have heard more of either Serialisation or UDI (Unique Device Identification). Below we will mention the difference between them. Although the terminology is somewhat different for medicinal Products and for medical devices, in both cases, this is about traceability. And to be precise, it is about track (where the product is now) and trace (where the product came from).

In this blog, we will explain why we advise you - as a medical devices supplier, a medicines supplier or as a logistics service provider - not to wait much longer and start implementing unique identification to take advantage of traceability.

The benefits of traceability

Legislation is not the only reason to implement unique device identification. Traceability has a significant impact on the efficiency of your own and your customers’ operational processes. Traceability is actually nothing new. In many other industries, logistical efficiency is crucial and for years, organisations have been ‘tracking and tracing’ their products with unique identifiers.

For healthcare institutions and pharmaceutical wholesalers, working ‘lean’ is becoming the new standard. For example, if your products do not have machine-readable barcodes, institutions might not purchase your products, as being able to scan all products, benefits them in many respects. Think of: having all relevant data available as soon as a product arrives, having insight of your stock levels, constantly knowing where it is or getting an alert when the expiration date is within e.g. a year. With traceable products, you are better prepared for your customers’ requirements and, of course, for your own efficiency improvements.

4 reasons to start today

As the legislation applies as of February 2019 (for medicines) and May 2020 (for medical devices1), you might think you still have time. But consider to start yet for the following reasons:

  1. Efficiency. Just because of the fact that efficiency is of increasing importance to you and your customers, traceability is recommended.
  2. Implementing traceability might require some significant organisational adjustments, think of:
    • Redesign of packaging and labeling
    • Adjustments to packaging lines and automation systems
    • Documentation of adjusted packaging specifications and procedures including getting approval for them
    • Validation of new or modified packaging processes, equipment, and IT systems.
  3. It is better to avoid rushing into (flawed) decisions. In case you need advice or support to design a new or modified process, the farther the deadline, the more time you have to consider your options.
  4. Practice in the United States has shown, that even with a segmented implementation and with a wealth of experience with UDI, manufacturers have difficulty meeting the deadlines.

The difference between Serialisation and UDI

The European Medical Device Regulation (MDR) 2017/745 published in 2017 elaborates on prior traceability regulations and introduces UDI for medical devices, which you should apply as of May 5th, 2020. UDI stands for ‘Unique Device Identification’ and consists of a device identifier (for manufacturer and model) and a product identifier (for packaging unit, batch, production date or expiration date). So, as it is prescribed now, ‘unique’ does not imply traceability of the smallest saleable unit.2

When reviewing Serialisation regulations for medicines, you will find that the identifier prescribed should be unique for every saleable unit, enabling traceability throughout the entire sequence from manufacturer to the last part of the supply chain, in particular cases even up to the individual patient. The Delegated Regulation (EU) 2016/161 published in 2016 introduces two safety features - a unique identifier (two-dimensional barcode) and an anti-tampering device - to be placed on the packaging of medicinal products as of February 9th, 2019. Although this level of identification for medicines is not yet required for medical devices, it is expected that future ‘Implementing Acts’ for the new MDR will include traceability of the smallest saleable unit, up to the patient as well.

Getting started

So, what now? Start orientating and ask yourself questions like: What is your organisation’s situation at this moment? What is your knowledge of the legal requirements and of the efficiency opportunities? What should be your next step? What do you need for that? How much time will it take? 

It’s well-advised to raise your knowledge level, provide a clear overview of your situation, do a gap analysis and provide solutions, explore different options, share best practices with others in the field, and start drafting an action plan. If you are uncertain about some aspects, don’t hesitate to contact us, we will be happy to talk to you about it.

Blog by: Louis Habets - Sr. Consultant & Trainer at Xendo

 


Footnote 1

If the European Medical Device Database Eudamed not fully functional is on May 26 2020, numerous requirements listed in the MDR and relating to where any information needs to be stored in Eudamed, will apply six months from when the Commission has published a notice declaring that Eudamed has achieved full functionality. While waiting for Eudamed to become fully functional, the corresponding provision regarding the exchange of information in the MDD and AIMDD will continue to apply. This regards particularly Vigilance Reporting, Clinical Investigations, the Registration of Devices and Economic Operators, as well as Certificate Notifications.

Footnote 2

When will UDI carriers really need to be placed on the label of devices and all higher levels of packaging as described in Article 123,3f, depends on the Risk Level of the product:

  • May 26, 2021 for Implantable and Class III devices;
  • May 26, 2023 for Class IIa and IIb devices;
  • May 26, 2025 for Class I devices.
  • How soon the UDI carrier need to be placed on re-usable devices is determined in Article 123,3g as:
  • May 26, 2023 for re-use Implantable and Class III devices;
  • May 26, 2025 for Class IIa and IIb re-usable devices;
  • May 26, 2027 for Class I re-usable devices.

Slide Deck: Changes in the Medical Device Legislation; the day after.
24-11-2017

#Slide Deck: Changes in the Medical Device Legislation; the day after.

Feel free to download the slide deck of one of our recent talks on the new Medical Device Regulation which was presented by Jan Bart Hak at the autumn meeting of the Pharmacovigilance  Platform Netherlands on November 21st, 2017.


The European Medical Device Regulation 2017/745 (MDR) is published on May 5, 2017, in order to replace the current Medical Device Directive 93/42; it will apply 3 years after this date. Requirements related to the technical file and procedures will be significantly reinforced, without the possibility of grandfathering.

These new requirements will affect the entire medical device (MD) industry with products in the EU. This implies that companies with products on the market within the European Union will need to come up with a transition plan to comply with these new rules and they have until May 25th, 2020 to do so.

A short calculation tells us that the countdown is at two and a half years at this point. As an example, in case the clinical evidence needs to be updated, one must start now. Clinical evidence can be collected in a clinical investigation or via post-marketing surveillance, which includes vigilance and post-marketing clinical follow-up studies. If a medical device company does not start now, it can be too late risking the CE mark and so market access.

Click here for the PDf of the full slide deck.

MDR: Why you should start now or lose money!
21-11-2017

#MDR: Why you should start now or lose money!

Although the new Medical Device Regulation (MDR) is now officially effective (in co-existence with the Medical Device Directive, MDD) we’ve noticed that some companies are well on their way with the transition (mostly EU companies) but there seems to be only a small percentage of US companies that has actually started to transition from MDD to the MDR. Especially for Regulatory Affairs (RA) managers this might be frustrating because they are well aware that from short-term perspective sticking your head in the sand, in the long run, might cost you serious money. Here’s why.


MDD TO MDR


For those who haven’t yet had the time to investigate what (mandatory) changes the future holds in the Medical Device field, we can summarize it as follows: requirements regarding your product are increasing and becoming stricter. Examples are requirements regarding, risk classification, clinical evidence, Economic Operators, and Post-Marketing Surveillance. All currently certified Medical Devices (MDs) must be re-certified in accordance with these new requirements.
First of all, companies are well-advised to perform a GAP-analysis to see how they want to proceed with their product. Three likely outcomes could be:

  1. You find no go GAPs which means ‘no worries’.
  2. Major GAPs meaning there’s a lot of work and you should start rather sooner than later.
  3. So many GAPs that you might consider discontinuing your product and withdraw it.


This implies that companies with products on the market within the European Union who find themselves in the second category will need to come up with a transition plan to be compliant with these new rules and they have until May 25th, 2020 to do so. A short calculation tells us that the countdown is at two and a half years at this point.


To assist RA managers eager to start a possible transition we’ve lined up some situations that might motivate all their colleagues to set things in motion. We suggest exploring the three most likely options that could be considered.


1. WHAT IF I DON’T?


Definitely a bad idea. The new MDR does not allow for grandfathering meaning that products that are currently on the market will not automatically be approved to stay on the market. So, if you choose not to transition to the MDR your product will no longer be allowed on the European market and consequently, you will lose income in other countries where turnover is dependent on a valid CE-mark.


2. I’LL DO IT LATER


Tempting, but not a good idea either. To explain this, let’s have a look at the math. To be compliant with the new MDR there are activities that have certain throughput times.
For example, let us assume that your clinical evaluation gap analysis shows that you need to upgrade your clinical data with data from a Post-Marketing Clinical Follow-up study (PMCF). If we pivot these numbers against the time left until you lose your CE-mark, we come to the following:

Activities that would have to be performed against the time it would take and the time that is left in months.

All these activities alone leave you with ‘0‘ months left until your CE mark (read: market approval) expires if you aren’t compliant with the new requirements. So actually, we can say that every moment that companies are delaying the transition to the MDR they will be facing a loss of revenue from the marketed product.


3. START NOW


Yes, we agree. This does not mean that you will be overwhelmed by additional work that can’t be handled.
For instance, your strategy on extending clinical data can be considered via Post Marketing Surveillance while still under the MDD using a PMCF study to gather this data. Under the new MDR, this collection of clinical data without a CE-mark will be considered a clinical investigation, which is subject to far stricter requirements. In that case, you’ll have to set up, for instance, a new randomized controlled clinical study with a 100 patients, a 6-month patient follow-up, and at 10 different sites which is a very costly process with patient insurance, submittal to the Competent Authorities and longer timelines than a PMCF. And also for other issues, a pragmatic approach can often be chosen so that your product’s certification remains valid and continuity of sales is not hampered by regulatory issues.

ARGUMENTS & BUY-IN


We can assure you that securing buy-in from the decision makers and different stakeholders in your company is essential in situations like these. So to pave the way we’ve lined up some arguments to use in persuading that you need to start today.
Since it all usually comes down to commercial considerations, this is likely to be your strongest argument. Here are some examples to paraphrase the money issue:

  • Loss of revenue in all countries where turnover depends on a valid CE-mark
  • Correct expected projections beyond 2020
  • Losing business will eventually result in a loss of qualified staff
  • Increased investments will be required to make up to regain lost market share
  • Investors are very aware of the MDR and usually require a transition plan
  • The company’s reputation is at stake

TRANSITIONING


The implementation of the MDR or the transition, if you will, is most likely an extensive project. And this actual transition is something we’ll get back to in another blog. To put it shortly, all companies are strongly advised to come up with a comprehensive transition plan including:

  • Relevant differences
  • Risk Class Determination
  • Conformity Assessment Procedure
  • Top Management Awareness and Commitment
  • Implementation Plan
  • Assessment Partner
  • Product Documentation
  • Quality Management System
  • Post Market Activities and Reporting

In conclusion, although the deadline of May 2020 seems far away, it really is false security. To ensure continuous compliance of medical device products to the new legislation, i.e. the MDR, a swift start and a solid plan are necessary. This will bring peace of mind to any Medical Device company because business continuity is assured.


So instead of waiting around to see what the future holds, get started and find out where you’re at. And if you’d like some more specific information don’t hesitate to leave us a message.

Blog by: Nick Veringmeier - Xendo

EMA: Welcome to the Netherlands
20-11-2017

#EMA: Welcome to the Netherlands

Rembrandt and van Gogh, tulips, clogs and windmills, a sample of what we’re famous for. We might be small, but we’re a great country. And it’s our pleasure to welcome the European Medicines Agency to The Netherlands.

The Netherlands will prove itself to be a true home to the internationally oriented EMA community and its staff thanks to its excellent accessibility, high-quality of living, and a population consisting of over 180 nationalities.

As a fast-growing company, we are ready to support all life sciences companies during the transition of the EMA from London to Amsterdam. With over 240 efficiently cooperating consultants (including QPs, QPPVs, and Auditors) in different fields of expertise, we’re able to offer our customers a complete palette of services. Especially our familiarity with The Netherlands’ Health Authority, the MEB-CBG, will prove to be an asset for all companies that require expertise regarding their upcoming Regulatory Affairs changes that this transition will bring about.

Please contact us to find out more.

Xendo awarded for the third time in a row as FD Gazelle
14-11-2017

#Xendo awarded for the third time in a row as FD Gazelle

Xendo was named an FD Gazelle 2017 again, meaning we belong to the fastest growing companies in the Netherlands for the third time in a row. The Gazelle Awards, an initiative of the ‘Financieele Dagblad’ (Dutch Financial Times), are awarded annually to the fastest growing enterprises, where the main criterion is a turnover growth of at least 20% per year during a three-year period.

André van de Sande (CEO, Xendo) says:

Our clients increasingly know how to find us for our expertise and support in all phases of product development and we are very grateful for the trust they place in Xendo.

Based on this trust, we have been able to grow our organization from 60 to over 240 employees. We plan to further expand in the Netherlands as well as internationally and as such we are always open to getting into contact with new potential colleagues. Please visit our website to see an overview of our most recent vacancies.

COMPLETE PV SYSTEM: READY IN 1 MONTH
14-11-2017

#COMPLETE PV SYSTEM: READY IN 1 MONTH

Bringing new products to the market while managing all pharmacovigilance (PV) requirements within a reasonable timeframe can be challenging, especially now that the technical requirements of a PV system are becoming increasingly complex. Getting it right the first time will help you off to a good start.


A high-quality and cost-effective solution

This is exactly what we can provide you with regarding the necessary support. Our PV experts provide cost-effective solutions in compliance with all regulatory requirements while you focus on what matters to you: the quality and safety of your product.

To assist in achieving a fit-for-purpose PV system and to safeguard your responsibilities as a Marketing Authorisation Holder, we offer an end-to-end solution for small and medium-sized companies who are about to bring a product to the market in the EU and need a fully functional pharmacovigilance system. We can provide the planning, implementation, and maintenance of any or all of the essential parts of your PV system. The complete set-up of your global PV system can be realised in 1 month, which includes:


State-of-the-art Safety Database - Argus

Our dedicated case processing team makes use of the industry acclaimed standard Oracle Argus Safety Database for Adverse Event Management; including Safety Database Hosting & PV Query Tool. By applying a multi-tenant approach and lean processes with a focus on first-time-right we’re able to offer this software as part of a cost-effective solution.  And with this state-of-the-art database, line listings and reports for case processing can be generated independently of the size of a corporation.

Have a look at the schematic overview.


Other PV services

After setting up your basic PV system, we are also fully equipped to provide you with all other PV services like:


Xendo - A trusted advisor

So why Xendo? Taking your product to the market requires experience and solutions beyond pharmacovigilance. This is why we aim to offer a complete spectrum, including all the expertise you’ll need to be successful.

Introducing our palette of services that complements our pharmacovigilance department and sets us apart as a full-service provider:

With many, effectively cooperating consultants in different fields of expertise at your disposal, we’re able to offer you a complete package and peace of mind.

Please contact us to find out more!


Posters ESGCT 2017
10-11-2017

#Posters ESGCT 2017

At the ESGCT 2017 conference, we presented two posters on CMC development and comparability strategies.  Afterwards, we received several requests for the posters and additional info, so we have decided to put them online! Have a look and leave us a message if you'd like more info as well.

Comparability Exercise

CMC Development

BIO Europe Berlin
08-11-2017

#BIO Europe Berlin

Xendo CEO André van de Sande and Xenia Freifrau-von Maltzan brought one of our customized VANMOOF bikes to this years' BIO Europe in Berlin. Several hundred participants showed that the raffle we organised with Berlin Partner was a huge success and attracted a large crowd. We wish to congratulate this years' winner and we are very much looking forward to another successful BIO again next year!

Brexit: Picking a new Reference Member State. How?
31-10-2017

#Brexit: Picking a new Reference Member State. How?

In our previous Brexit blog we gave a broad overview of consequences that are on the horizon for the (bio)pharmaceutical industry. Especially professionals in Regulatory Affairs, Quality Assurance and Pharmacovigilance will be affected besides those working at EMA headquarters. Though nothing is certain yet we stipulated that, for the moment, the best advice may be to prepare for the worst: a hard Brexit. An important item on the list is to select a new Reference Member State (RMS).

Reference Member State

A reference member state is like a marriage; you stick with it for life; at least your product does. There are only two reasons to request a change of RMS. Usually, the Marketing Authorisation Holder (MAH) can request a change of RMS under exceptional circumstances, as described in the procedural advice by the CMDh. The other reason is (you probably saw this one coming) Brexit; or more specifically, the triggering of Article 50 by an RMS. To whom would this apply? All companies that have a marketed product for which the RMS for a Mutual Recognition Procedure (MRP) or Decentralised Procedure (DCP) is currently the UK. Seeing as how the UK is in second place (right after the Netherlands) for the total amount of new applications (MRP/DCP) and in third for finalized procedures (2017), a large number of companies will be affected.

Below you can see the new applications (started and finalised) from January 1st to June 30th this year as reported by the CMDh; click here for larger image.

So just a quick summary of an RMS’ role. They act as:

  • scientific assessor of a dossier
  • regulatory advisor to the applicant
  • moderator between applicant and CMS

The RMS provides regulatory and scientific advice as well as assessment reports, they decide on timetables, evaluate responses, organize and chair break-out sessions, refer to the CMDh, inform the EMA if there is no consensus after referral, inform applicant and Concerned Member State (CMS) after positive conclusion and prepare the final assessment report as well as the public assessment report.

It’s clear there’s ample motivation to do some research on the different Health Authorities (HA). What should you look for in a new RMS?? Some of the items to investigate prior to your selection could be.

Things to consider when picking a new RMS

Know your RMS

Previous experiences with an HA can be of major advantage. These connections often make sure procedures move along according to the set timetables without any unforeseen trouble because you understand their point of view, they speak the same language so to speak.  These professionals look out for and mitigate unforeseen delays due to their experience with that RMS; they are familiar with their workload, approach and the way they communicate.

Differences among Health Authorities

Although we’re all in the EU, every member state is responsible for their own day-to-day business. Though not limited to just Health Authorities, this is certainly the case here as well. Some might be better communicators, others more prone to act in a timely matter and others more inclined to be open to more pragmatic approaches. Companies are especially recommended to check the pass-through times and a backlog of a possible new RMS and are required to contact the Health Authority in advance to check their availability to take over as RMS for existing procedures. Besides there is also a difference in not every HA has extensive experience acting as an RMS at all.

It’s also worthwhile to see which of the current Member States are actively preparing for Brexit like the MEB in the Netherlands.

The Medicines Evaluation Board (MEB) is preparing for the partial takeover of extra work which arises due to Brexit. In this context continuity is paramount. For that reason, the Dutch government is investing € 2 million in extra capacity for the MEB in the coming years. Investments are also being made in reinforcing the European network by facilitating extra training opportunities.

 

Initiatives like these will most likely help assure a smooth transition to a new RMS.

RMS has experience in a therapeutic area

Some RMS have more experience than others in certain therapeutic areas. Are you a generic, you might want to check the originator’s RMS; which is often also the RMS for other generics. This is noticeable when an originator product goes off-patent because almost all generics manufacturers will tend to apply with this same RMS with which the original was registered. Or does a Health Authority have a special focus regarding specific therapeutic areas? Have they been involved in the development of certain guidelines? If the new RMS is going to be one of the current CMS, recall what the attitude towards the product was during a previous application. These are all questions worthwhile to investigate before making a final decision.

Location of the company

Though it might seem like an open door, avoiding language barriers and having the proper infrastructure in place is always a benefit to the daily business. As a matter of fact, the EMA itself is currently in the process of deciding on a new location for its headquarters (deadline 22nd November) and in a technical report by the agency they name several aspects that are deemed to be important factors weighing into the final decision.

It’s also strategic to choose your RMS according to your company’s EU affiliates; opening up the possibility of direct communication with the HA. Increased contact and the ease of face-to-face counsel can contribute positively. This is especially useful considering we’re working in a regulatory universe that seems to thrive mainly on communication through elaborate documents. Besides these advantages, it also allows affiliates to join the strategic conversation with HQ and to increase their visibility and experience.

Commercial reasons

Last but not least: financial gain. There are several commercial reasons to interact with a certain RMS; straight-forward aspects like fees charged by HAs, the market size of the RMS and are there key opinion leaders available?

Practicalities and recommendations

Some practicalities to keep in mind:

  • there can be no change of RMS during an ongoing procedure (of importance for timing/planning);
  • it is the obligation of the MAH to ensure that both the current RMS and the future RMS accept the change of RMS;
  • it is the responsibility of the MAH to supply to the new RMS if any dossier/ assessment reports or other relevant materials are missing or for any reason not already in possession of the new RMS.

And some summarizing recommendations:

  • an organisation should map their situation and set up reasonable timelines for the upcoming changes
  • budgets need to be adapted to higher (or lower) costs; HAs charge different fees for procedures
  • investigate possible RMS to your best ability or attract external advice
  • contact your HA of choice well in advance to prevent any unwelcome surprises

RMS overview

Finally, remember that these changes are imminent, possibly causing a rush on popular HA’s and thus proper planning is well-advised, to say the least.

Below you’ll find all possible member states that can be chosen as an RMS. There are, of course, differences in the amount and nature of applications these states have handled in the past and it would be far too elaborate to discuss all possible differences. So to this purpose, we’ve highlighted the ones that we’ve personally worked with up until today. Should you have any questions we invite you to contact us for some additional specific information.

And we always welcome any new topics regarding Brexit that you’d like to hear more about!

Blog by: Nick Veringmeier - Xendo

Austria

Belgium

Bulgaria

Croatia

Cyprus

Czech Republic

Germany

Denmark

Estonia

Spain

France

Greece

Hungary

Ireland

Italy

Latvia

Lithuania

Finland

Luxembourg

Malta

Netherlands, The

Poland

Portugal

Romania

Sweden

Slovakia

Slovenia

Iceland

Norway

25 years of Gene Therapy: Advances and Challenges
26-10-2017

#25 years of Gene Therapy: Advances and Challenges

Xendo was exhibiting at the yearly conference of the European Society for Gene and Cell Therapy (ESGCT) in Berlin, where the society was celebrating its 25th anniversary. This update shares the major advances and the challenges that currently being faced in the field.

THEN AND NOW

In the early days, gene therapy was mainly investigated in academic research centers. Currently, the number of marketed ATMPs (including gene therapies) is still limited, but as there are over 900 ongoing ATMP trials you can expect that gene and cell therapies are well on their way to become an important treatment modality with a high potential to deliver new and improved treatments to patients. Currently, most development is still seen in indications where there is an unmet medical need but its expected that ’the focus on common diseases will also increase.
Since the inception of the European Society for Gene and Cell Therapy 25 years ago, it took 20 years for the first gene therapy product to gain market approval. And during this time we’ve seen the field mature; following the common lifecycle development of any medicinal product. Does that mean it’s already fully developed? Probably not, we could say it’s now in its teenage phase. Still young and full of energy but definitely on its way to adulthood.


Besides academic institutions, biotech startups are now also contributing significantly to gene therapy development. The approval of Glybera (uniQure) in 2012 was a major milestone for the entire field and may have initiated major biopharmaceutical companies to increase their involvement in Gene Therapy. The approval of Strimvelis (GSK) in 2016 was an example of a collaboration between start-up and big pharma and surely there are more to come as we know some multinationals are partnering with pioneers in the field.

ADVANCES

At the conference, impressive progression was reported throughout the major fields within Gene Therapy:

  • Ocular and central nervous systems Gene Therapy;
  • Cancer Gene Therapy;
  • Muscle and pulmonary Gene Therapy;
  • Metabolic and lysosomal storage diseases;
  • Blood Disorders.

In these fields, scientists presented their progress and companies their pipelines, both addressing the technical and scientific advances in gene therapy. Significant effort is being put into research and early development to overcome the many challenges that still lie ahead.

To be able to apply different treatments, new strategies are under development. Though gene replacement is still prominent in the field, technical advances are made to allow for a switch towards gene repair; with CRISPR/Cas9 as a well-known example. Nevertheless, it will remain challenging to assure the absence of off-target effects using this technology. In addition, RNA inhibition strategies add another mechanistical approach to the gene therapy repertoire. An elegant strategy was presented during the conference, where a single vector was used including both a transgene but also inhibiting shRNAs which nicely demonstrates that combinations of different approaches are currently filling the pipeline. In cancer therapy development, combinations of immunological cancer vaccines with oncolytic vectors illustrate how different fields in molecular medicine can come together to boost future development.

CHALLENGES

For some the sky may be the limit, still, there are serious challenges that need to be resolved before any major breakthrough of Gene Therapy in medicinal practice can be achieved. In general, these challenges show a high similarity between different fields and vectors.

Therapeutic Dose

Firstly, one should be able to provide a sufficient therapeutic dose to the target tissue and cells. This may be solved by increasing the manufacturing capabilities, allowing the manufacture of highly concentrated vector doses. However, when doses become too high this may also impact the safety profile of the vector and its use. In general, improving manufacturing platforms may not be the easy solution for this challenge. A different challenge is to improve delivery of a vector to the appropriate tissues and cells. A great deal of research is currently going on to improve vector platforms but also work on new vector types was presented. However, if you’re able to efficiently target the right tissues and cells at an appropriate dose, the transgenes would need to be expressed at a suitable expression level, which means not too low but definitely not too high.

Long-term effects

Another technical challenge is how to achieve a long-term effect which is especially relevant in areas where the mechanism of action relies on gene replacement or repair strategies. As is the case when a mutated gene is the underlying cause of a disease and needs to be replaced by a functional gene, which would (of course) need to be present throughout a patients entire life. Though only a marginal subfield within the gene therapy community, long-term effects of epigenetic modifications could definitely put a new perspective on things and will surely raise the regulators’ attention given the potential impact of epigenetic inheritance.

Prevention or intervention

The question whether you need to intervene in the development of a disease was argued both ways. In some cases, disease progression may be too far along in order to be able to effectively cure patients with gene therapy and early screening of patients may become more relevant in order to intervene in early stages of disease development. An issue here might be to demonstrate the efficacy of a treatment because the onset of disease symptoms in a non-treated patient may also take a significant time. Following this strategy you would need extensive follow-up, prolonging development and approval timelines.

Developmental Roadmap

The transition from a relative small lab-table to the larger industrial environment is one of the most commonly underestimated pitfalls. During the transition phase, a product and its manufacturing processes should be defined and controlled after which internal and external requirements are integrated and guide further development. Ideally, these changes and lot-to-lot variations of a product shouldn’t hamper pre-clinical and clinical studies. Many iterations and a creative problem-solving attitude are therefore required to build in sufficient robustness. Since quality cannot be tested into the product but only verified, the quality should be built into the process from the start.

Considerations

Given the numerous technical challenges, it’s paramount to integrate a solid regulatory strategy into your technical and clinical development strategies. If gene therapy development is conducted by SMEs and academics, it is often seen that these parties struggle with the regulatory path also because of lacking resources and an undervalued importance of implementing regulatory strategies in product development.

At the conference, a recurring topic during our conversations was related to the application and need of a product development mindset, which differs significantly from the academic mindset that is still dominating. Product development requires a multidisciplinary approach to achieve the required synergy between research, product and process development, regulatory, quality, analytics, non-clinical and clinical experts. A rule of thumb is that successful product development would need a backward strategy. In other words, start with the end in mind, define your stage gates and milestones and develop a strategy that bridges science with development and manufacturing and make sure it’s included from the very start. Obviously, there’s the funding issue that many of the startups are facing, usually resulting in a strong drive to cut corners during development. But if doing so you should understand the impact and risks that are involved in order to weigh the possible consequences.


blog by: Harm Hermsen and Christian Maasch

XENDO CEO SPEAKER AT EMBASSY IN JAPAN
23-10-2017

#XENDO CEO SPEAKER AT EMBASSY IN JAPAN

Xendo CEO André van de Sande was the keynote speaker at a seminar in Japan about the possibilities that the Dutch Life Sciences industry offers. This event was organized by the Dutch embassy prior to the BIO Japan expo where Xendo participated to increase our exposure as a leading consultant for Japanese companies looking to enter the EU market.

 If you are interested then please check out our Japanese service pages:

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

10月10日、パシフィコ横浜で開催される Bio Japan 2017 を前に、大使館にてオランダ・ライフサイエンス・セミナーが開催されました。オランダはレンブラントの時代から医薬学でのイノベーションを担っています。

 

NLinJapan

NL Life Science Seminar was held prior to #biojapanexpo. NL has been the forerunner of life/medical technology since the times of Rembrandt.

 

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

#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; meaning that from 2020 onwards only MDR will apply and before that time both the MDR and MDD apply. 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 SLIDEDECKhttps://www.xendo.com/images//pdf/phvday.pdf

&

INFO: New pharmacovigilance system (Argus)

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

#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

NEW: XPure Systems website
25-09-2017

#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

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

#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 

Lean Deviation Management
04-09-2017

#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

 

 

 

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

#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).

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

#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

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

#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. 

Next blog: Picking a new Reference Member State

 Blog by: Nick Veringmeier - Xendo

Design & Build: 4 Tips for Realising a complex Life Sciences facility
06-07-2017

#Design & Build: 4 Tips for Realising a complex Life Sciences facility

"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:

  • 1 aanspreekpunt/verantwoordelijke voor alle disciplines van het bouwproject
  • Verminderen van faserings- en afstemmingsrisico's
  • Betere prijs/kwaliteitverhouding (gebruik maken van inkoopvoordeel van de bouwers)
  • Eerder prijszekerheid
  • Meer kansen voor innovatie

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.

Succesfactoren

Voor een succesvol design & build traject voor een complex gebouw zijn 4 succesfactoren belangrijk:

  1. Een goed begin is essentieel
  2. Borg het procesverloop
  3. Borg de kennis van het gebruikersproces
  4. De juiste partners juist inzetten

1. Een goed begin

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.

2. Borg het procesverloop

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.

3. Borg de kennis van het gebruikersproces

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.

4. De juiste partners juist inzetten

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.

Voordelen

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.

Samenvattend

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

Xendo in special Biotech edition distributed by the FD
27-06-2017

#Xendo in special Biotech edition distributed by the FD

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.

Read the full article 'The broad palette of services for Life Sciences' here.

Adverse Drug Reactions related to mortality and morbidity
15-06-2017

#Adverse Drug Reactions related to mortality and morbidity

Adverse Event Reaction related Mortality and Morbidity: Drug-Drug interactions and Overdoses

Abstract

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.

Introduction

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:

  • type A are predictable reactions from the known pharmacological action of the drug, and usually dose-dependent
  • type B (idiosyncratic) are unpredictable and independent of the dose e.g. allergic reactions.

Other minor categories include:

  • type C which are chronic and are dependent on dose and time
  • type D which are delayed reactions
  • type E which covers withdrawal
  • type F for unexpected failure of therapy (Hinson et al., 2010).

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.

Results

  • Hospital admissions due to ADRs vary in literature, with estimates of 3% in the Netherlands and Germany, 6.5-8.8% in the UK, 5.8% in Italy, and 12.8% in Greece.
  • Mortality rates due to ADRs are estimated from 0.1-2.9%. A retrospective eight-year (1999-2006) study conducted in the US of >2 million deaths revealed that 2341 deaths (0.1 per 100,000) were ADR-related deaths. In 2005, drugs were the leading cause of death estimated at 739, 936 per year.
  • The socio-economic healthcare costs associated with ADRs are very high, £466m/year in the UK annually, and A$946 200 in Australia are related to ADR hospital admissions.
  • A significant percentage of ADRs are considered preventable with varying estimates of 40-77% in literature. Overdoses contributed to average 30% of ADRs while drug-drug reactions 4-32%.
  • Factors contributing to ADR prevalence and/or susceptibility include: increase in the number marketed drugs, type of drug, increase in aging population, pregnancy, gender, disease state, genetics, ethnicity, polypharmacy, and urbanization.
  • Type A are commonly reported, as such are preventable by either dose adjustment or avoiding drug interactions.
  • Medications errors, off-label use, misuse and abuse are potential causes of ADRs that are usually excluded from ADR studies. However, Iatrogenic deaths in the US cause up to 7.8 million deaths per 10years, and medication errors were estimated at 14% fatality rate.


Conclusion

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 precision medicine which combines genetic analysis with factors such as behavioural, functional, environmental and lifestyle information.

Read the full article.

This publication was written by:

Angella Angiji - Associate Consultant 

Dutch Biotech Event
12-06-2017

#Dutch Biotech Event

Xendo CEO André van de Sande moderating a session about Strategies for growth for Life Sciences companies at the recent Dutch Biotech Event. Synthon and Merus shared their insights about their successful company strategies.

UPDATED: MD & IVD CLASSIFICATION CHART
29-05-2017

#UPDATED: MD & IVD CLASSIFICATION CHART

UPDATE

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, 2020 and the IVDR will follow two years later.

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

NeeS: The roadmap ends in 2018. Are you prepared?
16-05-2017

#NeeS: The roadmap ends in 2018. Are you prepared?

Submissions in NeeS (Non-ectd electronic Submission) format will soon be history with the possibility of submitting in this format ending definitely for all procedures in the EU member states end of 2018.

Currently, electronic submissions of dossiers for human medicinal products in the EU are acceptable in two formats: NeeS (Non-ectd electronic Submissions) and eCTD (electronic Common Technical Document). eCTD differs from NeeS in that an eCTD dossier contains two XML files (index.xml and EU-regional.xml) providing a backbone to the dossier, and a util folder, together allowing easy navigation through the dossier and replacement of documents, while navigation through a NeeS is based on an electronic Tables of Content, bookmarks, and hypertext links.

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, eCTD format has become mandatory since 2015 and 2017 respectively, while variations for older approved dossiers can still be submitted in NeeS. The European Medicines Regulatory Network eSubmission Roadmap, adopted in 2014 and modified in February 2017, describes the transition from NeeS to eCTD (v.3.2).

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 result preparing the individual future submissions will require less work and allow a more efficient planning.

To prepare for the upcoming deadlines, companies are advised to assess their current situation by following these steps:

For products registered through MRP/DCP:

  • Identify all your products with at least one registration by DCP or MRP.
  • Identify for these products by when variations, safety updates or renewals are to be expected.
  • Check the current format of Module 3 of the dossier i.e. already in eCTD, (partly) in NeeS, paper scans, and CTD format or previous NtA (Notice to Applicants) format.
  • For dossiers already completely available in NeeS, the transfer to eCTD is relatively easy and can be done within short time.
  • For dossiers available in the old NtA format, the dossier has to be converted to CTD using the NtA-CTD correlation table. The correlation table works well for simple situations e.g. one formulation, one strength. In more complex situations, a critical look needs to be taken at the way information is provided in the dossier and a decision to be made on how to arrange the CTD dossier; Restructuring information in an efficient way avoids unnecessary dossier changes and variations in the future.
  • If applicable, harmonization of different dossiers in different countries for the same product can be taken into consideration as well.
  • Performing a conversion creates the opportunity to simultaneously make an inventory of possible non-compliances with current standards or internal procedures in the Quality module of the dossier. Although within the baseline submission, no content change is allowed, having such an inventory supports decisions on future updates and applications in new countries.     
  • Make a priority list of products for which the dossier will need to be converted to eCTD.
  • Create a work plan and assess whether you have the tools and resources to conduct the conversions.

For products registered through National Procedures:

  • Follow-up on announcements from National Agencies on the implementation of the mandatory use of eCTD in National Procedures on a local level based on the eSubmission Roadmap.  
  • List all your products registered nationally and follow the steps above, taking into account that the period for transition is one year longer for these products. However, depending on the number of products and possible different dossiers in different EU member states, creating a work plan on time is still advisable.
  • Having a work plan, the necessary internal/external resources ready and the required it-tools helps you to implement the eCTD conversion strategy, facilitating a timely implementation and compliance with the regulations. Performing proper planning and processing the eCTD conversion correctly from the start is certainly worth the investment.

Please see http://esubmission.ema.europa.eu/ectd and www.xendo-de.com/en-656/e-submissions.htm for more information.

Of if you have any questions don't hesitate to contact us.

Authors: Patricia Baede, Liesbeth Hoff & Almut Holz

NEW: Japanese Translations
08-05-2017

#NEW: Japanese Translations

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 above solutions to over 30 large and medium-sized Japanese (bio) pharmaceutical companies. And besides our regular visits to Japan, we have also established an affiliate in Tokyo in 2010. For years, we have been a trusted partner for audits, inspections, training, and other global activities regarding Pharmacovigilance, Regulatory Affairs, Quality Management & Lean Six Sigma. And conducting these audits and giving inspection training in the EU style, has proven to be very effective.

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!

SERVICES

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

A comprehensive 6-step route towards a cost-effective CE-mark
05-05-2017

#A comprehensive 6-step route towards a cost-effective CE-mark

“Using the current directives while preparing for the new medical device regulation and IVD regulation

Medical devices in Europe

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 and labelling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party.


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) . These Directives describe the approaches that have to be followed in order to obtain CE marking. However, the regulatory landscape is about to change significantly. In 2020, Europe’s Medical Device Regulation (MDR) and in 2022 In Vitro Diagnostic Regulation (IVDR) will come fully into force, which will impact all medical device and in vitro medical device developers, respectively. Even though the final version has not been approved yet (expected May 2017), it is clear that Europe’s new MDR and IVDR will bring substantial changes to the way medical device manufacturers bring their devices to the European market, and how they maintain compliance throughout the product’s lifecycle. 

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. 

Legislation of medical devices in Europe


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.

1. Identifying directives applicable to the device

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:

  • diagnosis, prevention, monitoring, treatment or alleviation of disease;
  • diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;
  • investigation, replacement or modification of the anatomy or of a physiological process;
  • control of conception,

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:

  • concerning a physiological or pathological state, or
  • concerning a congenital abnormality, or
  • to determine the safety and compatibility with potential recipients, or
  • to monitor therapeutic measures.

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.

2. Verifying the device-specific requirements and harmonised standards

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.

2.1. Medical devices

The MDs are classified in either Class I (including Is & Im), Class II (IIa or IIb) or Class III that covers the highest risk devices. The classification rules are set out in Annex IX of the directive 93/42/EC. These rules include:
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.

2.2. In vitro diagnostic medical devices

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.

2.3 (Harmonised) standards

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.

3. Involvement and selection of a notified body

3.1. Notified body

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 (-ies) to enact the directive within its territory. Each competent body selects its own NBs in each state, where the competent body controls the NBs. These NBs are registered at the EU New Approach Notified and Designated Organisations (Nando) information system. Today, around sixty NBs are present in the European Union.

To obtain a CE-certificate that allows the manufacturer to CE-mark the device, the manufacturer must apply at a NB for many types of medical devices. As observed in Table 1, this is mandatory for MDs class IS, IM, IIa, IIb and III, IVD list A, B and self-tests, which are all part of the high-risk IVDs. The manufacturer can, however, apply to any NB in the EU that is capable of carrying out the desired procedure, regardless of which Member State that NB is established in.

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 NBs can differ and in addition, it should be taken into consideration that not all NBs can assess all categories of medical devices and in vitro diagnostics. The following aspects could enhance the proper NB selection:

  • Consider any future plans; not all NBs have a worldwide presence. If you might consider expanding to other markets in the future, it is recommended to choose a NB which is present in these markets.
  • Size of NB; in general, people have more attention for established brands. Large NBs have, in general, more experience and could be used as a promotional tool for your device. However, small NBs normally work faster and at lower prices compared to large NBs. 
  • Analysis of service; in terms of timing, service of a NB is very important, even in the future. The service of a NB must be analysed in order being sure of receiving proper service in the future.
  • Special administrative charges; NBs can charge special administrative and renewal fees. It is better being informed up front about these fees to avoid surprises.
  • Experience of NB; ask the NB if they are experienced with the type of device. If they are familiar with this type, the certification might go quicker.

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.

3.2 Self-certification

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.

4. Further design and development of the medical device (including required clinical data)

4.1 Regulatory strategy before finalising design and development of the device

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.

4.2 Verification testing

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.

4.3 Clinical evidence (clinical data)

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:

  • A critical evaluation of the relevant scientific literature which is related to the safety, performance, design characteristics and intended purpose of the device, where there is demonstration of equivalence to the device of which the data relates and the data adequately demonstrates compliance with the relevant essential requirements, or;
  • A critical evaluation of the results of all performed clinical investigations, or;
  • A critical evaluation of the combined data provided from the two points mentioned above.

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:

  • Verify that the performance characteristics of the device are those intended by the manufacturer under normal conditions, and
  • Determine any undesirable side effects under normal conditions of use. These side effects must be assessed whether these effects constitute risks when weighed against the intended performance of the device.

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:

  • The device is an implantable or Class III medical device.
  • The introduction of a completely new concept of a device into clinical practice where components, features and/or methods of action, are previously unknown.
  • Where an existing device is modified in such a way that it contains a novel feature particularly if such a feature has an important physiological effect; or where the modification might significantly affect the clinical performance and/or safety of the device.
  • A device incorporates materials previously untested in humans, coming into contact with the human body or where existing materials are applied to a new location in the human body or where the materials are to be used for a significantly longer time than previously, in which case compatibility and biological safety will need to be considered.
  • A device, either CE-marked or non-CE-marked, is proposed for a new purpose or function.
  • An in vitro and/or animal testing of the device cannot mimic the clinical situation.
  • There is a new manufacturer especially of a high-risk device.

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:

  1. a compilation of relevant scientific literature, that is currently available as well as, where appropriate, a written report containing a critical evaluation of this compilation (the “literature” route). For this, the manufacturer must demonstrate the equivalence of the device to which the data relates and the device(s) for which conformity is being assessed. Furthermore, the applicability of the literature data for the device being assessed have to be demonstrated; or
  2. the results of all clinical investigations relevant to the device in question (the “clinical investigation route”); or
  3. a combination of I. and II. mentioned above. Where the clinical evaluation is based on such a combination, it should include an overall assessment. This assessment should take account of market experience, if available. It is important that the manufacturer relates the data to the specific device, having regard to the hazards identified.

5. Technical documentation

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, summary of design verification/validation, manufacturer information for process and accessories, and labeling. The summary of design verification/validation includes the required evidence which differs for each type of medical device.
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.

6. Affixation CE-mark

6.1 Declaration of Conformity

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.

6.2 Eudamed

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.

Conclusion

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 NBs can result in unnecessary (high) costs and time. After finalizing the design and development, collecting clinical data regarding the safety and performance of your device is a crucial next step in convincing NBs. However, it should be noted that the CE-marking process is a rigorous complex procedure that should be implemented in an early development stage and often warrants additional advice from experienced consultants, such as provided by Xendo. In addition, the CE-marking process is expected to get more complicated with the new Regulations that will come into force in May 2020. A comprehensive overview of this process will be published mid-2017 by ttopstart and Xendo

Provided by

Contact ttopstart if you need assistance with financing crucial development steps, such as to cover the costs of the regulatory approval procedure, of your medical device (e.g. finding relevant subsidies and applying for them).

&

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.

Authors

Michelle van Wijk - Consultant

Marc Klinkhamer - Principal Consultant
ttopstart is a science and business consulting company that serves leading researchers and innovative companies in the fields of life sciences, medical technology and health. ttopstart is specialised in the markets life sciences, medical technology and healthcare. ttopstart empowers biomedical innovators by supporting them with convincing VCs, subsidy providers, strategic partners and other stakeholders around the world to invest in their product. We want to enable their success in tackling the challenges associated with disruptive healthcare innovations, for the benefit of patients.

6 Quick Tips About Excel Sheet Validation (GAMP)
25-04-2017

#6 Quick Tips About Excel Sheet Validation (GAMP)

Are you using Excel spreadsheets? And are these used for GxP activities? Are these Excel sheets used again and again, as a template? Ever thought about validating such templates? Is the person who built your spreadsheet a genius with Excel, but doesn’t know how to validate? Want to use spreadsheet templates but validation issues are holding you back?

And what does an umbrella have to do with it?

Caricature by George Cruikshank (1792-1878) entitled ‘The Umbrella’ and dating from 1820.

It is fairly common that a spreadsheet template is created to do calculations which otherwise should be done by hand or calculator. Spreadsheet examples for GxP related matters range from a simple template for calculations of impurity in a sample to a highly complex spreadsheet for statistical analysis of clinical studies including Visual Basic for Application macros. Such spreadsheets may contain critical data, such as laboratory information, and may be used for making critical decisions.

Many companies think a spreadsheet template is just a calculator and don’t realize that you should actually think of it as an application. In fact, records generated by the calculations are electronic records and must therefore comply with EU’s Annex 11 and FDA's 21 CFR Part 11.

Did you know that by creating a spreadsheet template you are now considered to be a software developer? Your in-house developed software might even be a GAMP software category 5 application. The GAMP software category defines the extend of activities required to validate your spreadsheet.

But enough to scare you off, no need to be afraid. A good road map and some tips and tricks can help you on your way through the rough landscape of spreadsheet validation. Here we go!

  1. First of all, relax, you don’t need to show all your calculations are accurate and validate Excel itself. What you do need to show, is that the calculations in the spreadsheet are the right calculations. Now, how do we do that? Well, you’re halfway if you already know about validation and the ‘V-model’. Also embrace the GAMP guide. That’s ISPE's guide for Validation of Computerized Systems in the Pharmaceutical industry; the Good Automated Manufacturing Practice (GAMP). The GAMP guides you through the process and even gives you practical instructions on how to write the validation documentation.
  2. With all your experience, regulations and guidelines in mind, develop the spreadsheet that includes all necessary requirements. Think of the following aspects:
    • Use of the spreadsheet must be restricted to the intended user. So place the template on a (server) location with access limited to selected users. And protect the spreadsheet with a password that allows users to open the spreadsheet (as read only).
    • You want to protect the spreadsheet against any undesired changes, so lock all cells within the spreadsheet (except the cells in which the user needs to give input). So the user cannot change cells with formulas, constants, labels etc.
    • And give the input cells a color to make the spreadsheet more clear and easier to understand for users.
    • Make use of drop down menus or data entry limits to prevent entry mistakes.
    • Is the calculated result presented in the right way? Does it have the correct number of decimal places; is the unit of measure displayed?
    • You can create an audit trail to log what has changed when using the spreadsheet to make it more compliant to the EU’s Annex 11 or FDA's 21 CFR Part 11.
    • Like any application, implement a version number to the spreadsheet, which also comes in handy for change control.
    • When a user fills the (validated) spreadsheet template with data, the resulting spreadsheet file with data is an electronic record. So, just like the template, make sure these files are stored on a (server) location with access limited to selected users.
  3. Prepare all validation documentation. Depending on the impact on Patient Safety, Product Quality and Data Integrity and the complexity of the spreadsheet the GAMP can help you to find out what you need to do. Here you get the so called ‘GAMP software category’.
  4. During validation, manually verify the reliability of the spreadsheet. Verify the spreadsheet calculations by entering expected values and extreme values and verifying the behavior of the spreadsheet, or comparing the data with already known data.
  5. Make sure all necessary supporting Standard Operating Procedures are present, such as procedures for Change and Configuration Management, Backup and Restore, and Archiving and Retrieval. Also provide Working Instructions how to use the spreadsheet template for each type of user.
  6. After successful validation celebrate your success and release the spreadsheet for use. Any changes should go via Change Control and the actions for revalidation can be determined based on a Risk Assessment.

So, please don’t be afraid of spreadsheet validation anymore. It is actually very much doable.

However, we do have to make a remark: an Excel spreadsheet template is built upon the spreadsheet application Microsoft Excel. Which is principally not designed for regulated environments. So if the spreadsheet software changes, the spreadsheet template might be subject to validation again and should therefore be accessed with each update. For example, Office 365 is a platform that is continuously improving and expanding and implements updates each month. Knowing this, also consider using dedicated software, such as laboratory data systems, for your calculations.

What did the umbrella have to do with it? Here's your answer!

Definition of ‘gamp’, found on: https://en.oxforddictionaries.com/definition/gamp

If you have any questions don't hesitate to contact us!

Blog by: Nynke Noort - Consultant



Bend or break: increased regulatory burden for medical device Own Brand Labelling
07-04-2017

#Bend or break: increased regulatory burden for medical device Own Brand Labelling

For medical device Own Brand Labelling (OBL) manufacturers, the regulatory requirements in Europe will change significantly with consequently major impact on the way of doing business. Right now the rules are changing and it will be a bend or break situation.
Private-label products or services are typically those manufactured or provided by one company and sold under another company's brand. This approach is used by a great variety of organizations and also within the medical device industry. In short, the OBL sells the device, while the design, manufacturing, and packaging of the medical device are executed under the full responsibility of the Original Equipment Manufacturer (OEM).

Until now, compliance to the European Medical Device Directive 93-42/EC (MDD) is secured by a CE Certificate of the product of the OEM, which is the objective evidence that the medical device complies with the requirements of the MDD. The OBL only has to generate an abbreviated Technical File (TF), based on which a Notified Body (NB) can grant a CE Certificate to the product of the OBL. The prerequisites for this approach, are that the OEM product is not modified by the OBL, the labelling is essentially identical between the OBL and OEM product and the intended use is also the same. Recently, however, a different view on conformity assessment of OBL medical devices has been developed.

EU Recommendation


It all started with the European Commission recommendation “on the audits and assessments performed by notified bodies in the field of medical devices” that was published four years ago in the Official Journal of the European Union (L253/27-35, September 25th, 2013, 2013/473/EU). Though the recommendation on unannounced inspections was thought to be non-mandatory, many manufacturers were surprised by these audits. Additionally, this recommendation zooms in on the OBL/OEM situation, as can be read in a separate paragraph with the title “General advice in case of outsourcing of the production via subcontractors or suppliers”. It is remarkable to read that the OBL’s approach described above is no longer valid according to the Commission, because “manufacturers do not fulfil their obligation to have at their disposal the full technical documentation and/or of a quality system by referring to the technical documentation of a subcontractor or supplier and/or to their quality system" (meaning, a simple statement that the OEM holds the documentation is not deemed sufficient).

Following this recommendation, the British Medicines and Healthcare Products Regulatory Agency (MHRA) published a draft guidance on this particular OBL/OEM topic last year (Own Brand Labelling, Version 1.0, April 22nd, 2016). In this guidance, the Commission’s recommendation was fully embraced by the MHRA. In the introduction, it is also stated that review of an abbreviated Technical File was not deemed feasible not only by the British authority but also by the other EU Member States. The MHRA is quite clear and detailed on the responsibilities of the OBL with respect to compliance to the current MDD, and any OBL manufacturer will recognize that this will increase the workload of its regulatory department. The MHRA ends the guidance with a cliffhanger:“MHRA recognizes that in some cases Notified Bodies will take different views regarding own brand label and original manufacturers.”. This draft guidance was replaced just last month by a final guidance. Although the title has changed to “Virtual Manufacturing replaces Own Brand Labelling for medical device manufacturers” (Version 1.0, March 2017),the goal of the guidance remains unchanged. So the main question right now is: What are the Notified Bodies doing about this??

What now?


Although it is too early to speak of a game change, it is apparent that (some) Notified Bodies are already following suit to the Commission’s recommendation and the MHRA guidance. This is understandable because both institutions are of high reputation. It is also understandable from another perspective; the current legislation for medical devices will soon be succeeded by the so-called Medical Device Regulation (MDR). The MDR is much more detailed and clearer on many issues than the MDD. One of these issues is that the text of the Medical Device Regulation (MDR) supplements the lack of clarity in the Medical Device Directive on the roles and responsibilities of an OBL. Article 10(4) of the Regulation does not leave much room for the OBL, as it reads “Manufacturers of devices other than custom-made devices shall draw up and keep up to date technical documentation for those devices.”; no exceptions are granted for the OBL. The Regulation will be published in May this year and it is not expected that there will be any changes in this part of the proposed text as known today. So it is understandable that Notified Bodies will already tune their conformity assessment approach to the successor of the MDD.

One of the reasons to generate the MDR is given in the preamble of this regulatory document: “At the same time, this Regulation sets high standards of quality and safety for medical devices to meet common safety concerns regarding these products”, which is easily understood when one recalls the fraud case in France regarding leaking breast implants and the turmoil it created throughout Europe. The MDR will fully replace the current medical device legislation, i.e. the MDD, within a three-year transition period. During this transition period, a medical device manufacturer has the choice to either comply with the MDD or with the new MDR, and the CE Certificate issued by the Notified Body will refer to the chosen legislation. But it can be expected that some Notified Bodies will already enforce the stricter OBL obligations defined in the MDR, the MHRA guidance, and the Commission’s recommendation, even if the OBL manufacturer chooses to comply with the MDD and likes to continue their business as usual.

Steps to take


As a result, the OBL manufacturer should be planning for additional regulatory work in the three years to come or even sooner. The regulatory effort should be spent to the following main topics:

  • the current abbreviated Technical File for the medical device product should undergo an overhaul, with more emphasis and details on amongst others risk management;
  • a detailed quality agreement with the OEM needs be made up (not only the general aspects regarding distribution and pricing need to be spelled out);
  • detailing the various roles and responsibilities of both the OBL and EOM;
  • the OBL should engage in performing activities for Post Market Surveillance (whereby not only a reactive approach is followed but also a pro-active).

Continuing business as usual will not seem to last much longer; CE Certificates for new products or renewals will most probably be taken care of by Notified Bodies in a way that differs substantially from the past.

Concluding, regulatory burden for medical devices put on the European market by an Own Brand Labeler will increase in the future and this future is near. The OBL could argue that this increased effort will not increase the safety of the products, but the Notified Bodies decide in the end, and their new direction has become clear recently. Because the activities involved will require a substantial lead time, it is time to act now in case of the medical device OBL manufacturer.

Author: Marc Klinkhamer - Principal consultant

5 zaken om op te letten bij een Richtlijn 7 meting
04-04-2017

#5 zaken om op te letten bij een Richtlijn 7 meting

Nog steeds heerst binnen ziekenhuizen veel onduidelijkheid over het toepassen van de Richtlijn 7. Diverse beroepsverenigingen hebben er een mening over. Het opheffen van de WIP in de huidige vorm heeft hier geen positief effect op en het toetsingskader luchtbeheersing operatieafdeling van de IGZ maakt u als OK-managers onzeker over het mogelijke resulterende beschermde gebied. Want wat als er een (te) klein beschermd gebied als meetresultaat tevoorschijn komt. Is opereren dan nog toegestaan? Verschillende meetbedrijven komen met uiteenlopende conclusies en ook bij her-metingen verandert het beschermd gebied van grootte. Wat is nu waar? En welk bedrijf heeft er nu goed gemeten?

Laten we één ding vooropstellen; het doel is het verkrijgen van het optimale beschermde gebied. Dit gebied is afhankelijk van een veelheid aan parameters. U als OK-manager samen met de technische dienst en de Deskundige Infectie Preventie zijn verantwoordelijk voor het goede beheer van deze parameters. Een meetbedrijf bepaalt de eisen niet, dat doet u zelf.

In het werkveld valt er nog veel te winnen op het gebied van validatie en RL 7 metingen, het is dan ook vaak het geval dat in ziekenhuizen de OK-managers geen andere keus hebben dan afgaan op wat meetbedrijven zeggen. Het is niet voor niets dat er veel symposia georganiseerd en druk bezocht worden over dit onderwerp.

Een Richtlijn 7 meting leidt niet tot afkeur


Met een richtlijn 7 meting wordt aangetoond wat het werkelijke beschermd gebied is waarin relatief veilig geopereerd kan worden. Wanneer er ook instrumententafels, apparatuur en mensen in het beschermd gebied aanwezig zijn waardoor de ruimte als te klein wordt bestempeld moeten er maatregelen worden genomen.
Dat kan op verschillende manieren, maar eerst terug naar de basis: een Richtlijn 7 meting zal niet tot afkeur leiden van een operatiekamer, maar zal ook niet altijd het verwachte beschermd gebied opleveren.

Ontwerpeisen


Een OK wordt ontworpen op basis van ontwerpspecificaties met als oorsprong gebruikerswensen, wettelijke eisen en omgevingsfactoren. Het is belangrijk om op de hoogte te zijn van de ontwerpspecificaties, want op basis van deze parameters zal een RL 7 meting worden uitgevoerd. Wanneer er in verloop van de tijd parameters, zoals temperatuur, vocht en drukinstellingen, zijn veranderd (en hopelijk gevalideerd), zullen deze als uitgangswaarden gebruikt worden bij de RL 7 metingen.

Wat belangrijk is om te weten voor u als gebruiker


Als gebruiker moet u weten tegen welke parameters wordt gemeten voordat de meting plaatsvindt. Hoe gaat er gemeten worden? En welke werkwijze past het meetbedrijf hierbij toe?

Sensoren (zoals temperatuur, vocht en druk) dienen gekalibreerd te zijn. Wat is kalibreren? Kalibreren is het vergelijken van een meetstandaard of instrument met onbekende nauwkeurigheid met een andere meetstandaard of ander instrument met bekende nauwkeurigheid met als doel alle afwijkingen in nauwkeurigheid van de meetstandaard of het instrument met onbekende nauwkeurigheid te ontdekken, aan elkaar te relateren, te rapporteren en zo nodig en mogelijk te elimineren door justering.
Kort gezegd: Het te bemeten instrument samen met een herleidbare referentiestandaard plaatsen in een bron waar je verschillende waarden mee kan creëren. Bijvoorbeeld een temperatuurkalibratie op 10-20-30°C creëren in met een bron, aflezen op het monitoringsysteem en referentiestandaard.

In de praktijk betekent dit dat de meetmethode, ranges met afwijking van de sensoren, ingestelde gevalideerde parameters moeten worden vast gelegd in het luchtbeheersplan van de OK en opdekruimte. Ook moet hierin dus worden vast gelegd hoe er omgegaan wordt met veranderingen (Change Control) en storingen.

5 zaken om op te letten dat u als verantwoordelijke met een gerust hart een Richtlijn 7 meting laat uitvoeren.

  1. Zorg dat u, het OK-complex leert kennen. Wat zijn de ontwerpeisen geweest of met welke ingestelde waarden wordt de meting uitgevoerd;
  2. Vraag de uitvoerder van de meting om uit te leggen wat hij/zij gaat doen. Bij voorkeur in een protocol omschreven. U moet het eens zijn met de methoden van werken;
  3. Een te klein beschermd gebied leid niet tot afkeur. Ga opzoek met specialisten naar een oplossing. Dit zit niet altijd in grote verbouwingen of andere kostenverhogende oplossingen;
  4. Zoek een partner met verstand van zaken die u verder kan helpen dan alleen het uitvoeren van de meting en die u kan adviseren op het moment dat het bepaalde beschermde gebied te klein is.
  5. Zie een Richtlijn 7 meting als uitgangspunt om verder te kunnen bouwen aan een patiënt- en werknemerveilige omgeving.

Een Richtlijn 7 meting uitvoeren om alleen de omvang van een beschermd gebied in de OK en/of opdekruimte te bepalen is het basisniveau. Een reproduceerbare Richtlijn 7 meting uitvoeren vraagt meer expertise. De echte toegevoegde waarde zit in het verkrijgen van het inzicht waarop verder gebouwd kan worden om het beschermd gebied zo groot mogelijk en werkbaar te maken voor de gebruiker. Om verder te komen dan alleen een meetresultaat is het van groot belang de juiste kennis en ervaring in huis te halen om een robuuste oplossing te ontwikkelen voor een optimaal veilig gebied.

Auteur: Alex van den Berkt - Managing consultant 

Why we love the Lean Game (and you should too)
23-03-2017

#Why we love the Lean Game (and you should too)

Tight schedules and high stakes are pretty common in the Life Sciences industry and due to this continuous pressure, we sometimes forget to ask ourselves the right questions and challenge processes which have been in place for so long. When is the last time you asked yourself this like: “It may be effective, but how efficient? And what does it mean in terms of costs? And does it even increase certainty?”


• We always get the drug product manufactured in time, no matter what it takes!
• We deliver the project results, but it takes a lot of hard work to get everybody aligned.
• We filed the regulatory dossier, but it was a very complicated and extensive process!
• As logistics department, we are the last one in the chain and therefore our timelines are always tight and mistakes are easily made.

If any of these quotes seem familiar you and your colleagues might benefit from a Lean Game. Experience these sorts of practical examples in a Lean Game customised for the Life Sciences Industry!

Most industries are applying Lean Six Sigma principles in their projects and processes in order to optimise results and to deliver robust and optimal solutions. Originally part of Toyota’s Just-in-time Manufacturing, this strategy is now also widely implemented in biotech, pharmaceutical, and medical device companies in which waste reduction, time-saving and process improvement can make a significant difference, not just to the manufacturing processes but also to product and process development, Quality Assurance and laboratories. To experience these situations, we have developed a Lean Game specifically for Life Sciences companies. The Lean Game is a practical example of all the challenges we face in our daily work life. The Lean Game is about applying five principles consistently and rigorously. In short: produce exactly what and when the customer needs, without any waste.


The set-up

Pretend we have a pharmaceutical company, Xendo Pharma, which produces Xendolor tablets of 1, 2, and 5 mg. We get orders from our customer, GB Pharma which brings Xendolor to the market in 3 different countries. Your staff is divided into groups of about 8 players and each player represents an employee with a different role within the company; and one customer.


Roles

• A demanding customer
• A manager with a lot on his mind
• A meticulous planner – who takes orders from the customer and ensures the production planning
• Primary Packaging operator “does what is told” – responsible for the first line of packaging
• Secondary Packaging operator – responsible for the second line of packaging
• Internal transport - carries all materials to the various locations
• Warehousing – stores all of the product
• Distribution - handles customer orders and delivers the products
• Qualified Person – takes his QA role very seriously
• Improvement Engineer – enjoys improving all the time


These roles all have fictive actions similar to real-life experiences like gathering different tablets and creating batches, adding product labels and expiry dates, and continuously keeping up with documentation. After a brief explanation, three rounds are to be completed, with the ultimate goal of delivering the right quality at the right time to our demanding customer. Between round, each team has its own improvement workshop “kaizen” to figure out how to remove unnecessary motion, improve flow and to come up with an improved process and demonstrate it in the next round.


Realistic


Another important aspect is the discussion between the different groups to come up with best practices. It’s all about speed and flexibility versus compliance and documentation. In fact, dilemmas we normally encounter in real life, also pop up during the game. Of course, all throughout the game, participants have every possibility to ask questions to the Black Belt who facilitates the Lean Game to learn as much about Lean Six Sigma and how it might apply to their daily activities.
The game is concluded with a break-out session on how we can apply the principles learned in our daily work; this way you can put your newly found knowledge to the test immediately. The average length of a Lean Game is approximately 3 hours after which your team is educated and motivated to start improving efficiently.The outcome of a Lean Game is an enthused team with higher team spirit, a general awareness of lean principles and the possibility to identify improvement opportunities in your daily work.

When you are interested in learning what Lean can do for your organisation, or when you are interested in a team building exercise with your department or company, use the contact form on the right and we will get back to you to discuss the possibilities. We invite you to challenge yourself, your colleagues, and your processes and try our Lean Game.

LBSP Singelloop 2017
20-03-2017

#LBSP Singelloop 2017

Xendo and Leiden Bio Science Park organize a charity run during the ‘Leiden Singelloop’ on 14th  of April. This year we will be raising funds for the Xenia Hospice in Leiden. Both companies and individuals can join.  Last year we had more than 50 participants and we hope to see more enthusiasts join us this year!

If you want to join please register by making use of our contact form on the right; including your personal info and whether or not you will be sponsored by your company.

We are looking forward to seeing you at the Singelloop in April.

More info here. Please feel free to forward this event to your colleagues!

Last year's runners!

Argus Safety Database
13-03-2017

#Argus Safety Database

Oracle Argus is regarded as the ‘golden standard’ pharmacovigilance safety database. By applying a multi-tenant approach and by using the Argus workflow manager Xendo has lean processes in place enabling us to offer this software as a cost-effective solution. With this state-of-the-art database, reports for case processing can be generated independent of the size of a corporation. With the Argus Safety Database, Xendo offers the wide scope of activities to biotech, pharmaceutical, and medical device companies of all sizes looking for a cost-effective Adverse Event Management solution.

CHANGING PV CLIMATE

The focus on risk management and early signal detection have significantly increased, extending across the entire life-cycle of a product. Together with diminishing R&D budgets and a highly specialized environment, it has become a challenge to match the regulatory requirements of an effective pharmacovigilance system, and to ensure the minimization of possible risk to patients.

ARGUS 

In the ARGUS database, safety data are stored and can be extracted for signal management and periodic reports. It also allows to process substantial data sets of clients in a secure and efficient way, support the automation of the reconciliation and compliance reporting, and support the invoicing process, as the database is able to provide such task-specific reports.

Companies with a dataset are strongly advised to have a safety database from early development onwards, as this allows them to manage their safety data in a structured way, which is in line with the expectations of regulatory authorities. With the ARGUS safety database, we offer clients access to a first-class database managed, maintained and validated by professionals (Foresight), ensuring business contingency and management of their safety data fully compliant with regulatory standards.

The expedited reporting of ICSR to the different authorities is a regulatory requirement for sponsors of studies (SUSAR reporting) and MAHs of human and/or veterinary medicinal products and medical devices. Depending on the company and involved products we offer tailor-made solutions.

PV Query Tool


Additionally, we also provide our customers with the possibility to query the Global Safety Database to enable analysis of the safety data captured. This is a specific functionality offered by using the PV Query Tool, enabling provision of optimized datalistings, that would normally only be available to the larger companies. Using the tool allows additional ad-hoc querying and reporting against the Argus Safety MT database.


The Query Tool allows the user to create, execute, save and load ad hoc and client specific queries, which result in a case series/hit list being created when executed. The data is presented in an easy-to use interface, where the querying fields that are selected (like Receipt Dates, Drugs, Event Terms, SMQs, Study Information, Submission Information) can be presented on one single screen and capability to add additional tailor-made listings. The fields to be included is variable, which offers a high flexibility on the data presented. These queries can be run according to the clients need for data output.

Advantages

  • Self-service for end users
  • Reduced external dependency
  • Fewer custom reports / improved query response time
  • Improved response to unplanned queries (audits/inspections)
  • Ensures data quality and consistency
  • Increased insight into your data
  • Ensures data availability (querying and reporting on almost all Safety case data fields)

BENEFITS OF OUR MULTI-TENANT SOLUTION

Dedicated Xendo AEM team

Our dedicated Adverse Event Management team is optimally integrated with other Xendo teams, like  Medical Safety Science, Auditing, QPPV and Regulatory Affairs, combining over 25 years of experience. Additionally, we are experienced with the various agencies (including PMDA, Japan), and can ensure global compliance in an ever-changing regulatory landscape.This places us in the unique position to support our clients with an end-to-end solution to pharmacovigilance. 

Flexibility

As Argus is very adaptive, all process steps can be managed by Xendo but clients can also choose to perform any of the steps internally (e.g. medical review, QC). Another possibility is that the client grants access to its own database, allowing our staff to process data on their behalf.

Implementation

Configuration, validation, and migration are often rather challenging due to a very specific need for expertise. Therefore, our services include planning and execution from your current database to the Argus Safety Database.

Activities

  • Single global safety database
  • Data migration
  • Case processing
  • Case reconciliation/sharing – partners
  • E2B and ICH-compliant
  • Support data extraction for periodic reporting
  • Advanced querying and reporting
  • Visibility of KPIs and case processing metrics
  • Datasource and support for signal detection on Argus AEs

Demo & Additional information

Please use the contact form to request a demonstration of Argus or receive additional information on how this solution might benefit your company. 

Learn how SMB reduces downstream processing costs
28-02-2017

#Learn how SMB reduces downstream processing costs

Simulated Moving Bed Adsorption significantly reduces downstream processing costs


This paper gives an overview of industrial SMB chromatography and focusses on the strategy how to develop a purification system either in the early development phase of a product or to assess whether a batch process can be optimised and scaled into a continuous process.

Biotechnological fermentation processes are widely used in industry to produce an abundant range of organic products which often need to be purified in order to meet high-quality standards.
Typical bioprocesses comprise:

  • upstream (USP, e.g. prior to, and including fermentation)
  • downstream (DSP following the fermentation-harvesting, e.g. purification and crystallisation)

Industrial Bioprocesses can be characterised by a few common rules of thumb:

  • Typical fermentation broth contains many compounds (product, sugars, proteins and biomass residuals)
  • Downstream processing is necessary for purification and accountable for the highest process costs

Reducing downstream process steps can reduce capital investment and operational costs and reduce the overall energy consumption of an industrial process.

Downstream processing: the basics


Conventional downstream processing involves biomass separation from the soluble fractions of the fermentation broth as a first step (e.g. filtration, centrifugation). Hereafter, other downstream process steps follow, depending on the required product purity and concentration. Decolorization is often necessary to remove the brownish colour of a fermentation broth, caused by degenerated sugar and proteins. Adsorption chromatography is widely used to bind the product of interest or the impurities to a specific resin (sorbens), packed in a column (packed bed). The bound product is then eluted and can be used in further processing like crystallisation. After elution, the resin/column is regenerated and cleaned (CIP-Cleaning In Place).

A typical process flow diagram is shown in the figure below.

Conventional bioprocesses can be summarised by the following steps:

  • Biomass removal (e.g. flocculation, filtration, centrifugation)
  • Decolorization
  • Adsorption Chromatography
  • Concentration and Crystallisation

Simulated Moving Bed Chromatography


In adsorption processes, the adsorbent is held in a (pressure) vessel, most often called a resin vessel. The stationary phase is referred to as a packed resin bed. As the process fluid flows through the vessel, the resin attains an equilibrium with the process fluid, resulting in a mass transfer zone that gradually moves through the bed. If the mass transfer zone has reached the exit of the resin bed, the bed is saturated and “breaks through”. The resin needs to be washed and regenerated before it can be loaded again. As a consequence, continuous processing of the liquid requires at least two fixed beds, but usually, three beds are installed.

In the previous century, the advantages of continuous countercurrent processing have been recognised for adsorption processes, as well as for other mass transfer processes.
In SMB technology, the chromatography material is kept inside columns or vessels. The transport of the chromatography material is obtained by periodically switching in- and outlet positions.
In the 1980’s, the SMB concept was originally developed for binary fractionation processes, where a stronger and weaker binding component are present in the feed solution and are separated into two product streams:

  1. Extract phase, which contains the stronger binding component.
  2. Raffinate phase, which contains the weaker binding component.

A state of the art example of such fractionating system is the production of High Fructose syrup fractions in the sugar industry. Here the Fructose is the monosaccharide with a stronger affinity towards the resin compared to Glucose.

At a somewhat later stage, the same concept has also been developed for bind and elute systems. Bind and elute systems typically comprise –at least- the following zones:

  1. Adsorption of the active ingredient or, in some case, impurities
  2. Adsorption wash, to replace the mother liquor (from fermentation broth) by water. This is to prevent contamination between elution and adsorption zone
  3. Elution, to desorb the active ingredient that has been adsorbed in zone I
  4. Elution rinse, to prevent contamination between product- and feed stream (zone I)

This zone distribution is not restricted to the four as mentioned, for instance, regeneration and cleaning in place have been frequently applied.
Bind and elute SMB systems are designed in carrousel configuration, featuring a central rotating fluid distribution valve, and a static vessel configuration featuring a valve block for each individual resin vessel. Each valve block is identical and comprises a number of valves accommodating all in- and outlet flows that have been defined for the chromatographic cycle.

The below figure represents a typical conceptual flow diagram for a bind and elute system.


Bind and elute IX chromatography systems based on the SMB principle has opened a huge field of applications where valuable products are recovered or purified on a continuous basis thereby saving substantial water consumption as well as elute and regenerant agent.
Xendo has the experience and capability to design and build custom-made SMB continuous Ion Exchange and Chromatography systems under the product name XPure™.

Development studies


In general, a process development study can be approached from different angles and started or initialised in different stages of the study.
When developing a production process first the target objectives should be defined; what is the required yield and purity of the target compound; what is the composition of the starting material (feed); which recovery or purification process is most beneficial in terms of energy (including clean water) and material consumption and gives the least waste production; what is the scale of continuous operation.
If industrial (IX) chromatography could be a (or one of) potential route, we then start surveying the literature on the presence of similar or equivalent applications for the particular compound or molecule under study.
If literature cannot elucidate the case, based on the molecular structural or other adsorption relevant characterisation, a resin screening study can be conducted. The outcome would be one or several resin functionalities that are preferably commercially available.
A lab scale column test on a representative feed sample – a so-called pulse-response test- repeated for a few different resin species will obtain a strong indication of the effectiveness of a specific adsorption system.
Depending on the specific adsorption capacity of the target molecule onto the resin, further column tests – so-called breakthrough tests- will produce data on the resin capacity and information on how to elute (buffer composition, treatment ratio) the target molecule.

In the case, that potential resin candidates can be identified for the purification job the column tests can be elaborated with further break-through or pulse-tests at variable process conditions that cover the window of operation in a full-scale industrial setting. Typically this is conducted on one or two best performing resin candidates from the previous stage.
Here a Design of Experiment approach combined with the rationale of experienced chromatography engineering practice is used to define how many column tests will be conducted and what parameters will be varied at different levels.

Based on the data from the extended tests a preliminary process design and CAPEX/OPEX estimate can be made. Here we have developed our design tool where all relevant parameters can be put in and the outcome shows a full-scale SMB configuration and equipment dimensions. Dimensional data refer to a number of individual resin cells, dimensions of resin cells, line and valve sizing and pressure drop per distinct zone.

The design tool is based on the 2-film mass transfer kinetics model which is the principle for which we have created an algorithm. The design tool further features the (universal) Kremser equation for counter-current contacting.
A set of physical and mass flow-related variables have been accounted for. The most important parameters are:
Resin porosity, particle size (specific area) and evidently the most important -- specific adsorption capacity; diffusivity in both liquid and stationary phase; void fraction of resin bed; bed velocity; fluid viscosity and temperature.

The design tool could also be deployed if the adsorption system is a state of the art process, or close to this. In that case lab scale column tests could be skipped, and the specific feed characteristics need to be combined with the (specific) resin type that could do the purification/recovery job.

The output of the design tool can be used to do preliminary cost and value engineering. The outcome is essential to evaluate the purification/recovery process.
In the case of a positive decision, i.e. a (IX) chromatography process is the most beneficial and cost-effective route, the process can be optimised on a (slightly) larger scale.
Here we can enter two different scales for piloting.A mini pilot or lab-SMB system featuring small resin cells up to 1-inch column diameter and on average 200-500 mm bed height that still can be operated on a lab scale.

1. A mini pilot or lab-SMB system featuring small resin cells up to 1-inch column diameter and on average 200-500 mm bed height that still can be operated on a lab scale.

2. A large pilot SMB system featuring a bit larger resin cells from 1-4 inch column diameter on average 400-1000 mm bed height.

The selection merely depends on the availability of adequate feed and buffer volumes, any uncertainties that may not adequately be identified on an industrial scale, for example, impurities presence and identification, the presence of suspended solids or temperature variations.
The large scale pilot system typically works on site, close to the operating plant or at a pilot facility.

The outcome of a pilot study will be a robust design of the industrial scale process also featuring chemical consumption figures, product yield and purity. From the design data, the basic engineering of auxiliary equipment –like pumps, inter-stage tanks, piping, instrumentation etc.- can commence. Ideally, a commercial design proposal is the final delivery of a pilot study. The client/end user can now make a final assessment of the chromatographic process, possibly comparing this –if any- with alternative purification processes (e.g. batch wise adsorption, crystallisation, evaporation, distillation et cetera)

Considerations

Simulated Moving Bed has distinct benefits over classical single column systems with significantly higher yields / productivity and lower consumption of chemicals, water, and energy.  Also, it lowers production cost due to the lowered column volume and diminished use of chromatographic separation medium (resin) and, of course, less labour.

This continuous production system is increasingly used on industry scale and also becoming more popular in the pharmaceutical, fine chemicals and food sectors due to its capability to be integrated into production plants, where it contributes by delivering high concentrations of product under the beneficial circumstances mentioned before. Because of these advantages, we see a bright future for this technology for separation, purification and recovery, turning simplistic batch separation operations into profitable continuous processes. Next to these advantages, SMB fits seamlessly into the developing trend of sustainable solutions and the realisation of a bio based economy.

If you’d like to investigate what SMB could mean for your production processes don’t hesitate to contact us or have a look at our currently available systems: XPure-C & XPure-S. We also have a wide variety of pilot studies available for those interested.

6 essentials to introduce Lean Six Sigma in Life Sciences
14-02-2017

#6 essentials to introduce Lean Six Sigma in Life Sciences

6 essentials to introduce Lean Six Sigma in Life Sciences

We have come a long way in lean manufacturing since its introduction by Toyota and we apply it in most industries today. We take into account many relevant factors, such as costs, efficiency, supply reliability, quality, and compliance, and we define, measure, analyse, improve and control them. Our field, the Life Sciences, is as diverse as it is well-regulated, meaning it is most certainly a challenge to comply with ever-changing regulations and guidelines (which may or may not contribute to patient safety, quality and/or efficacy). But though it may be challenging, there are most certainly gains to be made here.

To assist in the first steps of setting up lean manufacturing processes we have some best practices lines up for you to try out in your organisation:

1. Engagement


Make sure that everyone, from CEO to supervisor is engaged. It is like an upside down pyramid where the top enables improvement at the bottom. First of all, demonstrate your commitment. You know about biotech, pharma. Learn about Lean Six Sigma and combine these. It’s not only about the processes, metrics, and the production system, but most of all it’s about mindset and behaviour. We are all very much aware of GMP and compliance in life science. Combine with Lean 6 sigma and integrate. Try to implement it in your daily routines. Do regular walk-throughs in the areas where it all happens. The real improvement doesn’t happen in the manager’s office or a meeting room. Ask questions and listen. Be present at opening and close-outs of improvement workshops (kaizens) and be present at daily stand-up (tier) meetings. In other words, people in the work place have the most extensive knowledge about ongoing processes and experience with daily activities. Don’t come up with solutions by yourself, but make it work with them.


2. Sponsorship


Lack of sponsorship is the most likely reason for failure, so just a few more words on promoting taking responsibilities, the right mindset and behaviour. In the old hierarchical way of doing things the boss knows best and tells you what to do and how to do it. In the inclusive approach, you should ask questions such as ‘What is the problem? Where is the problem? Are you able to solve it? Do you need others? How much time do you need? How can I help you?’ The role of the sponsor is to ask these questions all the time and to make sure they get answered. If we’ve learned anything from programs on badly run restaurants, it’s that 9 out of 10 times the manager (sponsor) is the root cause of the problem. Again, ask integrative questions, e/g what does the change imply for GxP? Have we considered the regulatory impact?


3. Stabilize first


Deviations are symptoms of processes not running smoothly. However, in life sciences, we have made compliant procedures for handling deviations. Make sure to get rid of deviations by searching for and solving true root causes, not just fight the symptoms. A practical approach is a kaizen, a workshop of a couple of days to define the problem exactly, to look for true root causes and solve these. When done properly, they give a lot of positive energy and, of course, annihilate deviation recurrence. The concept is not new, however. Therefore, green and black belts should have the proper background to prepare and facilitate kaizens. In my view, those belts should also have an understanding of life science and the processes at hand. It is the way to connect with people and to gain support for improvement. Again, sponsorship is essential to make a team available and continued support for implementing and sustaining solutions.


4. Activate


Introduce visual management and short (15 min) daily stand-up meetings – and become actionable. In many meetings, we talk about things. You will be amazed that just standing in a meeting rather than sitting will make the mood more actionable. It also allows you to escalate any issues within a day to senior management. Applying visual management enables you to make problems more apparent and once visible you can start solving them. It usually starts with a shift transition at production (tier 1): Are we meeting our production schedule? Are we experiencing any issues with people, safety, quality, delivery, and/or costs? What do the facts and figures show us? Ok or not ok? Can we solve all issues or do we need to escalate? At the next level (tier 2), the supervisor discusses the more substantial problems with the production manager, QA, logistics and others who might be involved. Also, metrics at a higher level are shown. Finally, the production manager meets with the management team at tier 3 for escalation of major issues. And this is all done within one day. And once again, it is the integrated approach that works, not Lean Six Sigma for the sake of saving costs. Lean processes are also more GMP compliant, safer, and yield better quality at lower costs. On top of that, people working in these improved environments are generally experiencing less stress and more satisfaction in their work.


5. Shift the paradigm


Introduce a system where everybody in the organisation focuses on solving problems definitively, not just fire-fighting, tweaking, and fixing. Not just the green and black belts for solving the major issues, but for everybody, at yellow belt level, is continuous improvement part of the DNA and their daily job. Solving many small problems can also add up to a large sum. Again, it is the mindset. In one example, 30,000 A4 paper was saved every year, just by asking the question: Do we need to print all this? And not just: we need to do this to be GMP compliant. In lean companies, everybody is trained as a yellow belt. This the entry level of belt training. And it is also their daily work to improve small things. Link this improvement process with the stand-up meetings to ensure follow-up and to measure success.


6. Continue improving


Always, all the time, everywhere, everybody. And sponsor!

In the next blog, we will show examples of effective deviation reduction, while maintaining GMP.

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: Marc Stegeman - Principal Consultant & Black Belt 

XENDO IN TOP 250 GROWING COMPANIES
01-02-2017

#XENDO IN TOP 250 GROWING COMPANIES

We are pleased to announce that after being named an FD Gazelle two times in a row (Dutch Financial Times award), we are now also in the Top 250 Fastest Growing companies in the Netherlands; an initiative by the Erasmus Center for Entrepreneurship (ECE) and 'NL Groeit' (NL Grows).

A place in the Top 250 is awarded to companies who were economically active on January 1st 2012 and have realised a turnover and/or employee growth of over 20% a year.

Link

Outdated facilities – bring back the ‘c’ in cGMP
24-01-2017

#Outdated facilities – bring back the ‘c’ in cGMP

New rules, old facilities. How do these two meet? Is it a big black hole or is there light at the end of the tunnel?


When you work in an older facility, you are probably acquainted with one-liners like:

“We have been doing it for years, how can this be wrong”, “never change a winning concept”, “the Agencies approved this before, they cannot suddenly disapprove it”.

Maybe you already faced an inspection, resulting in observations due to aging facilities, processes or procedures. It is a known fact that legislation can change, new developments change the expected ‘state of the art’ solutions. This evolution takes place faster than your facilities do. You probably already experienced that the ‘c’ in the GMP status needs to be brought back into your facility, processes or procedures and it looks like a big hurdle to overcome.
Quality Risk Management
With every recent change in Legislation, the term “Quality Risk management” (QRM) was introduced. Therefore, every Inspector takes it into account during inspections, and they should, because they are looking for evidence that their trust in you is valid. A good understanding of your processes enables you to base your quality-related decisions on solid risk assessments, which is usually beneficial regarding the outcome of an inspection.

Should you also apply this approach in regard to (older) facilities? Should you bother assessing the risks of a facility that you know by heart? Yes, you probably should! Not just to please the inspection, but because it is a useful instrument to assess if your aging facility is in compliance with the current GMP.

Use QRM to answer the question “Is my facility still suitable to my current activities”. How do you start? How do you organize a process like this? The best idea is to take it step by step. Take the time to learn, take the time to assess. Use the knowledge available across your organisation, it is one of your biggest assets. Most likely many risks have already been assessed, but you just never realised, nor documented it. You will definitely face hurdles, but also realise they can be overcome.

Potential hurdles – don’t let them scare you
Bad archiving practices (in the past and present) of both paper-based and electronic information are major bottlenecks in this process. Staff changes mean that some knowledge gets lost and this is usually regarding process history and where to find available information. The archiving bottlenecks can become enormous in these cases, trying to find information in old archives. But that shouldn’t keep you from accomplishing your goals, every outdated facility is facing similar issues.

Identification of gaps and opportunities
First of all, you need to assess your current gaps against cGMP. Ask yourself “What is required for my current activity?”, “What control mechanisms do I have in my process?”. Use QRM to assess the gaps in your facility’s design and its cleanability. Bring in a pair of ‘fresh eyes’ during the assessment, take a step back and dare to re-assess why you do it the way you do. During this process, unnecessary practices may become known. It’s possible that time-consuming activities can be replaced by more efficient practices or can become obsolete altogether. Maybe you can shorten process times because you realise that you overdo your controls. You will certainly gain some opportunities from these assessments. You will lose some, but you will definitely learn things that went unnoticed before.

Define potential risks and wins
Translate gaps into risks. Quantify problems, issues and potential risks. Include, amongst others, the qualified status of equipment, process robustness, knowledge from e.g. deviations, maintenance records, periodic equipment and utility reviews, environmental monitoring program and results. But please also, document why certain gaps are no risk at all!

Translate opportunities into wins. In lean six sigma terms, define the waste!

Analysis of identified risks
Next, you use QRM and you can apply lean six sigma techniques to identify what you really need to do to run your current activities. Define what is causing the biggest problems and wins, rank potential risks and wins in order to focus on the right points. Dare to break with traditions.

Risk Mitigation
Third, come up with a plan to get back into compliance. Even though GMP changed over the years, the fundamental principles have not. Outdated facilities are mostly engineered and commissioned using common sense, but rationales have not always been properly documented. Based on the outcome of your assessments, you can define your risk mitigation actions and this forms the rationale of what to repair or redo.

Set a realistic horizon. Document your thoughts and doings. Make sure you do what is needed and don’t overdo. Also, don’t be afraid to discuss your findings and plan with your inspectorate. Showing progress and willingness to improve can increase the understanding of your current situation.

Considerations


Legislation changes, though not as fast as it sometimes seems, because it follows the industry. Best practices are gathered over time and form a new baseline. Quality Risk Management is not something new and fancy, but an instrument, applied for ages, just not always formally documented. Make the change and assess your facilities with risk management principles and start to focus on repairs. This is the moment to diminish waste, lower costs, enhance process robustness and stay compliant.
The above exemplifies the risks involved with an ageing facility. When assessed with the right knowledge of legislation, inspections, and manufacturing, these risks can be remediated with a lean six sigma focus, observations can be prevented, and the ‘c’ can be brought back into your GMP status.

Blog by:

Maud Breitbarth - Consultant at Xendo


If you have any questions don't hesitate to contact us, we can be your pair of ‘fresh eyes’!

I4H 2017
19-01-2017

#I4H 2017

XENDO BIKE RAFFLE

Like last year, we will also be organising a raffle for one of our customized Xendo VANMOOF bikes! We are looking forward to meeting you there and don't forget to hand in your ticket at our booth (no. 34)!

INNOVATION FOR HEALTH 2017

Innovation for Health is the premier event on healthcare innovations in the Netherlands. It provides a unique opportunity to meet leading innovators, to catch up on the latest trends, to present cutting-edge innovations and to engage leaders and decision makers in healthcare innovation. Innovation for Health features renowned speakers, displays high impact innovations, highlights best practices and demonstrates inspiring developments in healthcare. By bringing together key players and stakeholders across the healthcare & Life Sciences spectrum, and fostering dialogue between research, markets, and policy makers, the event aims to contribute to the future of sustainable healthcare.

Xendo BV acquires Sofus Regulatory Affairs AB
16-01-2017

#Xendo BV acquires Sofus Regulatory Affairs AB

Xendo, the Life Sciences consultancy company, is pleased to announce that it has acquired the Swedish consultancy company Sofus Regulatory Affairs AB. Sofus is based in Stockholm and provides regulatory affairs services for all phases of the pharma and biotech development, from early development projects to post-approval services including pricing and reimbursement issues, and has a strong position in the Nordic countries. This acquisition will strengthen the two companies to continue providing the highest levels of consultancy services within the Life Sciences industry. Through this collaboration, both companies will be able to offer new services to their customers in an expanded region.

Xendo was founded in 1990 and is now a leading, independent consultancy and project management organization in the (bio)pharmaceutical, medical devices, and healthcare fields. Xendo currently employs over 150 experienced and highly educated professionals. The areas of expertise include a.o. Regulatory Affairs, Pharmacovigilance, Compliance & Validation, and Engineering & Technical Support.

Sofus was founded in 2002 and is the leading Nordic regulatory consultancy, supplying comprehensive regulatory, quality and safety solutions, to both multinational corporations and small businesses in the Nordics and in Europe. Sofus currently employs around 55 people.

André van de Sande, CEO, Xendo comments: “I am delighted to be leading Xendo in this next phase of growth. The addition of Sofus to Xendo will strengthen our position as a trusted advisor in Life Sciences. We operate in an exciting market and this acquisition offers a real opportunity to further develop Xendo’s services and extend our geographic reach. I am looking forward to working with Linda Thunell and her team.”

Linda Thunell, CEO, Sofus added: “This was a natural step for us in the further development of our business. As part of the Xendo group we will be able to strengthen our presence on the international market and at the same time offer a broader range of services to our clients. Our companies are a good match and together we will be able to offer more of the very best services to our clients.”

For further information, contact:


André van de Sande – CEO Xendo
T: + 31 (0) 71 524 4000
E:
W: www.xendo.com
W: www.sofus.se

IVD & MD CLASSIFICATION
06-01-2017

#IVD & MD CLASSIFICATION

How to classify your Medical Device or In Vitro Diagnostic under the new regulation

Medical Devices have been classified under the Medical Device Directive as 1, 1m, 1s, 2a, 2b and 3. With the increase of the class, the inherent risk increases too. As a result, the regulatory requirements will increase too, not only in number but also in nature. Under the new Medical Device Regulation this approach remains.

For In Vitro Diagnostics the new IVD Regulation will also apply a risk-based approach, which could be regarded as a paradigm shift with respect to the IVD Directive. The classes for IVDs range from A to D, with D the highest risk class. Also for IVDs the new approach will result in stricter regulatory requirements for higher class IVDs.

To assist you in your efforts to classify your IVD or Medical Device we have put the criteria according to these novel regulations in a flowchart.

Feel free to contact us in case of additional questions!

View chart here. (Info: Chart has been updated according to the new MDR)

Contact: Marc Klinkhamer - Principal Consultant at Xendo

Xendo announces management buy-out supported by Sovereign Capital
13-12-2016

#Xendo announces management buy-out supported by Sovereign Capital

The investment will strengthen the company’s position as a leading consultant and it will have a positive effect on the continuity of business. Current customers will continue to seamlessly enjoy existing services, and Xendo will be able to seek to expand its services and geographical reach, both through organic growth and complementary acquisitions. With a strong track-record as a ‘Buy & Build’ specialist, Sovereign Capital will provide the financial support to grow, develop and expand Xendo.

Under the new ownership the business will continue to operate under its own name. We are also delighted to welcome CFO, Arjen Huijs (previously Jacobs Douwe Egberts) to the current management team.

Read more

Xendo makes the Dutch Financial Times (Financieel Dagblad)
13-12-2016

#Xendo makes the Dutch Financial Times (Financieel Dagblad)

BIO International Convention 2016

Xendo CEO, André van de Sande, brought one of our customized VANMOOF bikes to this years' BIO International Convention in San Francisco.

BIO International Convention 2016

Approximately 400 participants showed that the raffle was a huge succes and attracted a large crowd. We wish to congratulate this years' winner, Ruud Smits of NautaDutilh. We are very much looking forward to another succesful BIO again next year!

Biotechbedrijven dromen zich rijk na megadeal Acerta

Xendo makes the Dutch Financial Times (Financieel Dagblad) again!
13-12-2016

#Xendo makes the Dutch Financial Times (Financieel Dagblad) again!

Xendo's recent management buy-out by Sovereign Capital has grabbed the attention of the Dutch Financial Times, which placed an article about it today.

In response to questions by FD-journalist Thieu Vaassen,  André van de Sande (CEO) gives insight in Xendo's successful turnaround over the past 5 years.

To read the article (in Dutch) follow this link.

Xendo – Vigilex accepted as candidate for Deshima Business Award 2016
13-12-2016

#Xendo – Vigilex accepted as candidate for Deshima Business Award 2016

The Deshima Business Awards are granted to Dutch companies in recognition of successful business achievements in the Japanese market and are awarded by the Netherlands Chamber of Commerce in Japan.

Xendo-Vigilex has shown rapid development, having grown from 60 to over 150 employees over the past years. Next to realizing excellent growth of our European offices, this candidacy shows Xendo-Vigilex is also successful with our Japanese operation. Xendo-Vigilex offers a full scope of pharmacovigilance activities and is successfully supporting many Japanese (bio)pharmaceutical companies, who conduct clinical studies or market their product(s), or intend to, in the EU or US. Besides visiting our customers face-to-face several times a year and having local representation, Xendo-Vigilex also organizes a yearly seminar in Japan, which focuses on understanding EU PV related legislation and guidance on how to implement this in daily business.

Even though the market is competitive, we continuously see growth opportunities for our business and the nomination for the Deshima Business Award confirms this.

Xendo awarded for the second year in a row as FD Gazelle
13-12-2016

#Xendo awarded for the second year in a row as FD Gazelle

Xendo was named an FD Gazelle 2016, meaning we belong to the fastest growing companies in the Netherlands again. The Gazelle Awards, an initiative of the ‘Financieele Dagblad’ (Dutch Financial Times), are awarded annually to the fastest growing enterprises, where the main criterion is a turnover growth of at least 20% per year during a three-year period.

André van de Sande (CEO, Xendo) says:

We have realised excellent growth over the past years and we have grown from 60 to over 150 employees. This is the second year we have been awarded a Gazelle, meaning we are showing robust growth of our company. Although we are operating in a competitive market, our clients increasingly know how to find us and we would like to thank them for the trust they place in Xendo.

IDMP compliance: 7 channels to get informed
08-12-2016

#IDMP compliance: 7 channels to get informed

Starting from mid-2018, all pharmaceutical companies having medicinal products registered on the EU market will have to have submitted IDMP-compliant data for these products. IDMP stands for identification of medicinal products and refers to five ISO standards defining terms and structures to uniquely identify medicines. While big pharmaceutical companies usually have projects started to ensure IDMP-compliant submission and maintenance of the data, SME companies are mostly still in a phase of orientation.

SME companies are currently analysing the requirements to create their own company approach towards compliance and to estimate the cost of it. Most SME companies plan to start projects in 2017 when detailed guidelines for IDMP requirements are to be published by the EMA.

SME companies usually face the following challenges on their way towards IDMP compliance:

Internal Resources

  • Usually no dedicated function for master data management/ regulatory data management
  • Limited resources available to train employees on IDMP requirements and to keep up to date with changing information

Cost

  • Limited financial resources for additional software
  • Limited resources (FTE/external costs) for data collection/ submission/ maintenance

Lack of Benefit

  • No internal business case for IDMP compliance: IDMP compliance is cost only

Limited Official Information

  • Final timelines not published by EMA yet
  • Final requirements not published by EMA yet
  • EMA database not published yet

However, IDMP compliance is not a mystical quest that cannot be solved by common sense. This post will describe 7 different channels of how to stay informed about IDMP requirements and implementation plans of the EMA and will compare their efficiency for SME.

Information Channels for SME Companies

One major challenge for SME companies is to stay informed about authority plans and requirements for IDMP compliance. While requirements are being defined and implementation plans are being changed by the EMA, direct information from EMA has been very scarce over the last years.

The following sources to stay updated about IDMP should be considered:

1. EMA website

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000645.jsp

EMA publishes official information regarding IDMP implementation on its website. The website also includes a webinar given by the EMA in August 2016 as well as meeting notes from the IDMP task force.

2. ISO standards and implementation guides

The ISO standards and ISO implementation guides can be bought online. They are currently under revision and new versions are expected in 2017 (for standard 11615 and 11616 in the second quarter, for standard 11238 in the fourth quarter, for implementation guide for ISO 11238 in the first quarter, for implementation guide for ISO 11615 in the second quarter of 2017).

The ISO standards ISO implementation guides will serve as a basis for the EU implementation guides. The EU implementation guides will define the actual requirements for the EEA and are currently created by the IDMP task force.

As long as EU implementation guides are not available, ISO standards and implementation guides give the most detailed information on which requirements for IDMP compliance can be expected. Special attention should be paid to the standards of the medicinal product and substances as well as the technical implementation guides.

3. Direct via IDMP task force

The EU IDMP task force consists of representatives of EU institutions like the EMA and NCAs, representatives of the pharmaceuticals industries and other interest groups like vendors. The task force is developing and implementing IDMP requirements in the EU. For big pharmaceutical companies and vendors in the area of RA data organisation, participating in the IDMP task force also serves as a direct channel to the implementation of IDMP. However, even within the task force, a lag of information delivery from EMA to industry/vendor representatives prevailed.

Participating in the IDMP task force does not only require sufficient time but also specific knowledge in the field. Therefore, it seems natural that this is not the information channel of choice for SME companies. However, information from recent task force activities can be found on the EMA websites in the task force meeting minutes and are also exchanged via the IRISS forum as described in point 2.1.6.

4. Conferences, external training

Since 2014, the number of conferences and professional training focusing on IDMP has steadily risen. Speakers from industry, vendors, and authorities can give valuable insights to their IDMP implementation projects. However, again mostly big pharma companies are attending, as conferences and training are costly and SMEs lack functions dedicated to the subject. Bigger companies already involved in internal IDMP projects are often updated by vendors and consultancies part of the project team.

SME companies not starting IDMP projects yet might consider using an in-house training held by experienced consultancies to inform all involved functions about IDMP instead. 

5. Informal networking

As official information from the EMA has been scarce, direct information from task force members has proven a helpful source of information. Informal exchange based on personal contacts also is highly helpful when implementing IDMP within the own organisation. Related functions in other companies usually face similar problems and solutions and experiences can be exchanged. Again, big pharma companies with functions dedicated to the subject have been in advantage here while RA departments often feel responsible for IDMP in SME companies. Nevertheless, exchanging experiences regarding IDMP implementation with related functions in other companies can be a highly useful, cost- and time-efficient source of information for SME companies as well.

6. IRISS forum

https://www.iriss-forum.org/

The IRISS forum refers to itself as “A Non-Profit Dedicated to Implementation of Regulatory Submission Standards Around the World”. Related subjects are discussed within topic groups and webinars, members come mostly from industry and vendor organisations. The IDMP topic group meets in a monthly t-con. The agenda usually focuses on recent activities of the EU IDMP task force and of the ISO technical committee currently updating the ISO standards. Speakers usually are members of both organisations. IRISS members can add questions, issues regarding xEVMPD activities are discussed as well. Records, as well as notes of the meetings, are published afterward. The forum also conducts surveys and collects feedback for the EU IDMP task force from its members.

As membership is comparatively inexpensive, SME companies should consider it as a cost- and time-efficient source of up to date information.

7. EMA efforts to cascade information

In its August webinar, EMA described its approach to set up a change network to cascade information regarding IDMP more efficiently. EMA will appoint industry change liaisons. Industry change liaisons will come from the IDMP task force. They are meant to cascade information and best practices directly and interactively to industry as well as to give feedback to EMA change network if additional communication is needed. They are meant to work together with key contact points at industry organisations to identify suitable communication channels like conferences or forums where they can present and communicate about IDMP. The industry is asked to get in touch with industry change liaisons if opportunities are identified that they can communicate with a wider range of industry stakeholders.

EMA promised to publish contact information of industry change liaisons soon. It needs to be evaluated how effectively they will improve communication. SME companies might want to contact their industry organizations regarding any related activities planned.

According to EMA, the SME office is also responsible for cascading information to SME and registered SME companies can submit questions there as well.

Considerations

In August 2016, the IRISS forum conducted a survey of its members about their IDMP compliance activities. The results are publicly available: https://www.iriss-forum.org/news/iriss-publishes-the-results-readiness-surveys-for-idmp

One of the questions asked was how companies stay informed about IDMP compliance.  Most of the 29 industry members answering the survey reported that they received information about IDMP implementation either directly from the task force, via the IRISS forum or from vendors and consultancies. When asked about their preferred source of information, however, almost all companies reported that they wish to receive information directly from the authorities.

While it is unclear whether more information directly from the EMA will be available in the future, companies currently are still asked to use various other information channels.

For SME companies the following approach can be helpful.

  1. Start with an in-house workshop to bring all involved functions to the recent level of IDMP information. The workshop should also answer all open questions regarding the contents of the ISO standards and ISO implementation guides. Xendo offers workshops as part of its IDMP consultation services. Please contact us for more information.
  2. Stay informed about new information using the following channels:
    The EMA website should be checked regularly for any updates
    Appoint a function to follow the discussions on the IRISS forum

Network with peers to get informed about experiences from organisations similar to your own.

Feel free to get in touch for some additional information!
Blog by: Almut Holz - Managing Consultant at Xendo 
Contact:

Using Scrum to Validate Software during Agile Development
27-10-2016

#Using Scrum to Validate Software during Agile Development

Scrum is an increasingly popular way to develop software, a methodology to implement Agile Software Development.  Though Scrum has been coming up for a few years now, it’s not always clear how to validate software that is being developed this way. Specifically for pharmaceutical and biotech companies it’s valuable to show deliverables of incremental sprints in Scrum can be combined with the deliverables expected by the GAMP 5 guide.

Scrum

There are several accepted definitions of SCRUM, but for now, let’s go with the following:

“Scrum is a development framework in which cross-functional teams develop products or projects in an iterative, incremental manner. It structures development in cycles of work called sprints.”

Sprints

Sprints are blocks in which Scrum-teams deliver their product. They are iterations of no more than four weeks each (the most common one being two weeks), and take place one after another without pause. These sprints are time boxed, meaning they end on a specific date whether the work has been completed or not, and they are never extended.

Usually, Scrum teams choose one sprint length and use it for all sprints. Though, if they improve they might decide to use a shorter cycle.  At the beginning of each sprint, a cross-functional team selects items (customer requirements) from a prioritized list.  Subsequently, the team agrees on a collective target of what they believe can be delivered at the end of that sprint. The benefit being that the work scope is small and there is a commitment from all participating team members.

During the sprint, no new items are added; changes are put on the product backlog and prioritized for execution in future sprints. At the beginning of every day, the team gathers briefly to inspect its progress and adjust the next steps needed to complete the remaining work in time.

At the end of the sprint, the team reviews the sprint’s results together with the stakeholders and demonstrates what has been built. In the case of software, this would mean a system that’s integrated, fully tested, end-user documented, and potentially shippable. The obtained feedback can lead to changes or additional requirements that are added to the product backlog.

GAMP

Good Automated Manufacturing Practice (GAMP) is a set of guidelines for manufacturers and users of automated systems in the pharmaceutical industry.

More specifically, the ISPE guide for Validation of Automated Systems in Pharmaceutical Manufacture describes a set of principles and procedures that help ensure that computerized systems, including software, are fit for purpose.

One of the core principles of GAMP is that quality cannot be tested into the computerized system, but must be built into the computerized system during each stage of its development. As a result, one of the key features of GAMP is computer system validation.

Computer System Validation

Computer System Validation (CSV) establishes documented evidence providing a high degree of assurance that a specific computerized process or operation will consistently produce a quality result, matching its predetermined specifications. In other words, CSV is demonstrating that the computerized system is consistently doing what it should be doing and that the data it produces is reliable.

V-Model

Normally the “V-model” is used to execute this kind of validation. In GAMP this model demonstrates the relationships between each phase of the development life cycle and its associated phase of testing.  The left axis represents the stages of a specification and the right represents the stages of verification or testing. Steps in the V-model are sequential, following the arrows, and every next step should only be started when the previous one is completed. During software validation, the deliverables of each step are checked

Validation starts by combining all requirements in a User Requirements Specification (URS). When this URS is approved, the Functional- and Configuration Specifications (FS and CS) are drawn up and the software can be developed afterward. After development, it can be validated together with its accompanying procedures. Only when everything is according to the URS and applicable procedures the software should be released.

Combining both methods

On first sight, combining Scrum and GAMP doesn’t seem possible, because Scrum is an incremental process, i.e. software is delivered in working parts, and validation according to GAMP is sequential i.e. the software is delivered in a whole working package.

However, when confronted with this problem, you can decide to treat each Scrum sprint as a separate “GAMP V-model”. This way, you can perform validation while the software is being developed and this is in line with both ways of working. To have a potentially shippable product it needs to be validated and to validate this product the specifications, functionalities, and documentation all need to be checked.

To establish this, the validation documentation is aligned with the scrum documentation according to the table below:

Considerations

By combining GAMP and Scrum like described, it’s possible that a cross-functional (development, testing, and validation) team is able to deliver functioning and validated software in a timely matter while meeting all predefined top priorities. Since time is usually fixed, lower priorities might not always make it in the first production release, but this is actually one of the strengths of Scrum; focusing on what must be implemented.

Most software developing companies do not work according to the V-Model anymore and have embraced Scrum. Pharma companies, however, often state that GAMP or the V-Model needs be followed. It is worthwhile to seek some flexibility on both sides to make it possible to start implementing Scrum while maintaining benefits of the V-model. Our experience is that Scrum can definitely help to successfully execute projects on time with the required functionality and quality.

Please feel free to contact us if you have any questions!
Blog by: Anton van Rosmalen - Consultant at Xendo
Contact: Joost Havers - Managing Consultant at Xendo
Email:

COGEM advice on MI classification when using Single Use Bioreactors
28-09-2016

#COGEM advice on MI classification when using Single Use Bioreactors

Earlier this year the Commission on Genetic Modification (COGEM) commissioned Xendo to investigate the current vendor and user experiences concerning the containment risks when using Single-Use Bioreactors (SUBs) in combination with Genetically Modified Organisms (GMOs)

Based on this Xendo report COGEM has written a letter of advice to the state secretary of Infrastructure and Environment (I&M), concerning use of SUBs in large scale industry. In this letter, it is stated that production in SUBs by the current standard is performed under classification MI-III.

Following these events, we received questions regarding the report and the letter, so we’d like to summarize the outcome of the Xendo research report and present COGEM’s advice to the state secretary and how this should be interpreted. Also, we’ll show what Dutch regulations concerning genetically modified organisms state about MI classifications (Micro-organisms Industrial scale) with respect to the interpretation of the COGEM advice.

Summary Xendo Report: “Updated GMO Containment Risk Evaluation Of Single-Use Bioreactors”

SUB technology has developed significantly since the first assessment in 2010, with increased experience at both the user and vendor side, many improvements have been made that reduce risk for loss of containment (e.g. operator handling errors or SUB control system errors).

Since 2010 interaction between SUB vendors and end-users has resulted in increased knowledge concerning SUB bag integrity. One example is a visual anomaly database in which anomalies are classified according to their impact on bag integrity. SUB bag production processes are qualified and validated. Shipping and transport also occur according to validated methods. Training is provided extensively to users of SUB systems at purchase and when significant design changes have been made. SUB production has improved, yet between vendors, there still is a different approach to SUB bag integrity assurance.

Users often rely on the expertise and quality assurance of the vendor for bag integrity. Most users do not employ dedicated integrity tests (e.g. pressure decay), but instead use a media-fill-test as their pre-inoculation bag test. Users also recognize that maintaining a high level of operator skill, through (vendor) training and use of appropriate equipment, is critical to successful and safe use of SUB technology without containment events like spillage or leakage.

It is anticipated that small defects located in the headspace of SUB bags (pinholes) pose a (theoretical) risk for containment, especially when producing viruses which are transmissible through aerosols. Pinholes in the headspace are not easily found using a media fill test. A pressure decay test may not be able to indicate these holes as they have a minimum detectable defect size based on bag volume.

It is concluded that the use of SUB technology in combination with GMOs generally does not pose an increased containment risk compared to stainless steel vessels. This is based on the following:

  • Any bag defect that could constitute a containment risk is typically spotted during the pre-inoculum phase. (Except the mentioned pinhole defects in the headspace)
  • Operators are properly trained and use the appropriate and validated equipment.
  • Vendors have good control over their production process and raw material supply.
  • Vendors and users freely and openly communicate experience and information and engage in continuous improvement of this technology.
  • Between different types of SUB bag configurations, no significant differences have been observed.

COGEM advice letter

COGEM presented the report to the state secretary of I&M and in the offer letter, COGEM explains the outcome of the Xendo research that has been done concerning the use of single-use bioreactors (SUBs) for large scale production. Throughout the letter, the increased safety and experience of users and vendors is explained and the residual risks related to pinhole defects in the SUB headspace were addressed.

In the letter, COGEM indicates that accidental escape of GMOs through pinholes cannot be excluded and that operators should be made aware of the risks of pinhole defects. Nevertheless, COGEM indicates that, following the current classification regulations, large scale culture of GMOs in reactors and SUBs should be performed in an MI-III environment.

MI-III implies that besides the SUB itself there is a second level of physical containment. In MI-III classification the likelihood of GMOs being released into the environment is considered to be minimal, even when GMOs would escape from the SUB through accidental pinholes.

It should be noted that this classification advice has not changed with respect to the current classification of similar activities, indicating the Xendo report has confirmed the suitability of current classification guidelines.

Regulations concerning large scale production using GMOs

In the applicable Dutch regulations concerning genetically modified organisms (Besluit & Regeling genetisch gemodificeerde organismen, wet milieubeheer 2013) the following 4 classifications are listed for process installations for large scale industry:

  • MI-I areas are for dealing with ML-I organisms that comply to certain criteria (very low risk). Inactivation of the biomass before disposal is not required.
  • MI-II areas are meant for dealing with ML-I organisms that do not comply to the IAB criteria. Inactivation before disposal is required.
  • MI-III areas are for ML-II organisms, and
  • MI-IV areas are for ML-III organisms

Noticeably, when used at laboratory scale, all ML-I and ML-II organisms are classified at MI-III in industry. This is contradictory to classifications concerning PKM (Plants) and DM (Animal), where levels I to IV correspond to ML-I to –IV depending on the ML classification of the organism in laboratory scale work.

Appendix 5 chapter 5.7.1 states that:

  • A. Dealing with organisms that are classified as ML-I in laboratory scale are classified as MI-III in industry.
  • B. Dealing with organisms that are classified as ML-II in laboratory scale are classified as MI-III in industry.
  • C. Dealing with organisms that are classified as ML-III in laboratory scale are classified as MI-IV in industry.

In general, the containment measures of MI classifications in the workspace entail the following:

  • MI-I: Use of physical containment (Bioreactor).
  • MI-II: Use of physical containment (Bioreactor) that limits the spread of GMOs. Filters in off-gas are mandatory.
  • MI-III: Use of physical containment (Bioreactor) that strongly limits the spread of GMOs. Hydrophobic absolute filters in off-gas and means to collect and inactivate the total content of the system are mandatory.
  • MI-IV: Use of physical containment (Bioreactor) that prevents the spread of GMOs. Further use of containment measures in the process area like a HEPA Filtered ventilation system, entrance through an anteroom containing a shower and gowning areas, a negative pressure regime, leak free or ventilated seals, hydrophobic absolute filters in off-gas and vacuum systems, and means to collect and inactivate the total content of the system are mandatory.

Also, procedural demands increase when the MI classification is higher. For further details see appendix 9 of the regulations concerning GMOs.

Procedures:

When applying for a license using ML-I or ML-II organisms at lab scale, always an MI-III classification is applied for in the industry. However, when dealing with low-risk organisms, following appendix 6 of the Dutch GMO regulations, a downgrading to MI-II or MI-II can be requested at the GMO office after the first MI-III permit is granted. Each application will be evaluated on a case by case basis often involving COGEM to advise on the related risks for the environment. The COGEM advice letter does not alter this procedure.

The GMO office and COGEM have confirmed that their advice does not change the current classification rules and regulations. Downgrading is still possible when safety is assured.

Downgrade examples when using SUBs

Numerous applications for downscaling have been evaluated in the past. A number of positive COGEM advices, on the acceptability of downscaling handling of GMOs on an industrial scale when using SUBs, are published on the COGEM website.

Considerations

The outcome of the Xendo report is that use of SUBs overall does not pose a higher containment risk in comparison to stainless steel bioreactors. However, pinhole defects in the headspace of the bag are difficult to identify and therefore pose a (theoretical) risk of loss of containment, especially when using viruses that can be spread through aerosols.

COGEM has reported the outcome of the Xendo report to the state secretary of Infrastructure and Environment (I&M) indicating the risk of pin hole defects. However, COGEM states that under the standard MI-III classification risk is adequately managed because of the 2nd layer of containment besides the reactor itself.

The Dutch regulations concerning GMOs follow a standard classification of MI-III for industrial scale applications for organisms that on a laboratory scale are classified at ML-I or ML-II. It also states that a downgrade to MI-II or MI-I can be applied for at the GMO office.

The GMO office and COGEM have confirmed that, although the risk of pinhole defects in SUBs is acknowledged, there is no change in the classification of industrial application of SUBs. Furthermore, applications for downgrading to lower containment levels can still be submitted and will be evaluated on a case-by-case basis following current standards.

Feel free to contact us if you have any questions.
Blog: Bert Wielders - Consultant at Xendo
Email:

The new Medical Device Regulations, are you ready?
06-10-2016

#The new Medical Device Regulations, are you ready?

Are you ready for the new Medical Device Regulations? While writing this, it is almost impossible to respond to this question 100% positive. But all manufacturers will need to review their product portfolios in order to determine if their products are covered by these new legislations and comply, or still comply, with all their requirements.

Discussions between the European Parliament, Council and Commission have taken a long time and resulted in two vast documents, no less than 400 pages each, i.e. the Medical Device Regulation (MDR) and the In Vitro Diagnostic Medical Device Regulation (IVDR). The official sign-off and publication of these two Regulations is expected to be Q1 or Q2 2017. And even then, further details in the form of Common Specifications and implementing Directives will need to appear in the coming years.

The combined info of the Proposals of the European Commission for the two Regulations (September 2012), publicized information, and discussions in- and outside Brussels and Strasbourg, show a clear picture of the most critical aspects. Important to know is that the new Regulations have taken a fivefold from the size of the Directives for Medical Devices and IVD-Medical Devices which they are to replace. So, it might be wise to develop a certain tactic if you plan on reading them and you have a specific product in mind. Beneath you find a pragmatic approach on how to assess the status of a product under the new Medical Device Regulation:

  1. Check the scope of the legislation (Article 1, Annex XV);
  2. Compare the manufacturer’s description of the product with the definition of Medical Device (Article 2) and with Annex XV;
  3. Determine the particular roles and responsibilities of the Economic Operators, with some newly defined entities such as the importer and the distributor (with Article 2);
  4. Re-determine the risk classification of the product taking its Mode of Action into account (Article 41, Annex VII);
  5. Select the preferred Conformity Assessment Procedure (Article 42);
  6. Identify the applicable “Essential Requirements” (Article 4, Annex I);
  7. Generate or supplement the Technical Documentation (Annex II);
  8. Apply the applicable Conformity Assessment Procedure (Annex VIII, IX, X or XI);
  9. Complete the Declaration of Conformity (Article 17, Annex III);
  10. Affix the CE Mark (Article 18, Annex IV), now showing compliance to the Regulation.

A “warm welcome” to manufacturers of products without a Medical Purpose

Manufacturers of non-Medical Devices will also have to become familiar with the new legislations because a series of products without a Medical Purpose has been brought into its scope. Although not complying to the general definition of a Medical Device, the application of these products carry many, if not all, aspects of the use of a real Medical Device. Examples of such products are colored contact lenses or other articles intended to be introduced onto or into the eye; substances intended to be used for dermal or mucous membrane filling by injection; equipment for liposuction, all kinds of light emitting laser equipment intended for skin treatment, or cosmetic implants (under Annex XV).

It is expected that their safety will be assessed as if they were classified in line with the best matching classification. Their manufacturers will need to start developing Technical Documentation. Notified Bodies will need to focus on risk separately, as opposed to a risk-benefit ratio where they usually compare residual risks to proven clinical benefits. For presenting compliance to the requirements, Common Specifications will be provided.

Other eye-catching issues

Discussions around these new legislations predominantly focused on improving the organisation of the system, i.e. on stronger supervision and intensified oversight of Notified Bodies by national authority personnel with proven qualifications; more thorough testing and regular checks on manufacturers, including commonly applied Un-announced Factory Inspections; the mandatory implementation of a rotation scheme for Notified Body assessment staff and permanent proven "in house" expertise in the Notified Bodies’ organisation, especially in the field of clinical experience.

Between the many critical elements in the new Regulations, improved device traceability throughout the Supply Chain using UDI systems and the extended registration requirements in the EUDAMED database need to be mentioned. The database focuses on the certificates issued, suspended, withdrawn, refused and restricted by Notified Bodies, on Clinical Investigations, on vigilance data, such as Field Safety Corrective Actions and Field Safety Notices as well as on market surveillance measures taken by Member States. Manufacturer registration and UDI will probably be moved into a separate system.

Significant are the stricter requirements for Clinical Evidence. Clinical evaluation reports are mandatory for all classes of Medical Devices. What changed particularly, are the terms of Clinical Evidence for high-risk devices. The evidence should predominantly be based on data sets with a focus on Clinical Performance Studies covered by detailed described GCP-principles. Class III devices manufacturers will also need to enhance their active and systematic analysis of data on quality, performance and safety using Post-Market Surveillance and Post-Market Clinical Follow Up. They need to report on with Periodic Safety Update Reports, continuously monitoring the Risk/Benefit-Ratio.

Classification and Technical Documentation content of existing products to be re-assessed

Manufacturers should be aware that their current products have to be re-assessed in order to confirm that they still conform to the requirements. Or to determine the gap to be resolved before being allowed to continue marketing their products in Europe. Fortunately, they have three years, or five for IVDs, to perform this re-assessment.

Although they will be able to perform this assessment themselves or with specialized support, a Notified Body is needed for the official confirmation of conformance.

Please note, all Notified Bodies will need to be accredited for these new Regulations before being entitled to assign CE-certificates. To this purpose, the capacity of the joint audit teams of the authority Accreditation Bodies that oversee Notified Bodies has been enlarged. One of the implementing acts prescribes how this should be managed. Probably, Notified Bodies who audit high-risk devices will be able to start relatively early, given the requirements that are being introduced for such products. Having these certifying organisations accredited on time will, most likely, be a challenge for the Accreditation Bodies of the Member States.

In conclusion

Even though the new regulation has not been published yet, and three years for implementation seems far away, it is strongly advised to start your assessment against the new regulations as soon as possible. There are many topics to address and the more time you have available, the easier it is to ensure conformance of your products within the set timeframe. Therefore, do not hesitate and take the ten step approach above, and you will have a quick insight to where you stand with your products.

If you have any questions, feel free to contact us!
Blog by: Louis Habets - Senior Consultant, Xendo
Contact:

Emerging genetic engineering in medical biotechnology
18-07-2016

#Emerging genetic engineering in medical biotechnology

Emerging genetic engineering in medical biotechnology

After the DNA helix was uncovered in 1953 and in 1968 Rogers and Pfuderer demonstrated a proof-of-concept for virus-mediated gene transfer, about two decades ago the first gene therapy trials were performed. In 2003 the sequencing of the human genome was completed, which provided new opportunities for further development of molecular medicine. In 2003 Gendicine was the first gene therapy product approved for clinical use in humans in China. In July 2012, the European Medicines Agency recommended Glybera for approval, which was the first recommendation for a gene therapy in either Europe or the United States. With the increased understanding of molecular medicine, the field is now developing even more specific and efficient therapeutics that repair gene function, which is now producing clinical results.

Commissioned by the Ministry of Infrastructure and Environment (Ministry of I&M) and the GMO office (Part of the Netherlands Institute for Public Health and the Environment, RIVM) Xendo executed a scientific literature evaluation on novel and trending molecular genetic techniques applied in medical biotechnology.The GMO Office is responsible for the processing of license applications with respect to GMO handling on behalf of the Ministry of I&M and it is intended to develop new policies for medicine based on new molecular biotechnologies. 

Trending themes within molecular medicine such as genomics-based medicine, epigenetics, nanomedicine, personalized medicine and synthetic biology are all impacted by the development of techniques that facilitate and improve genetic engineering. Four technology areas were identified: genome editing, epigenome editing, gene expression regulation and gene delivery. Within these technology areas, the following technologies were identified: ZNF (Engineered nuclease), TALENs (Engineered nuclease), CRISPR/Cas9 (Engineered nuclease system), siRNA and miRNA and Modified Antisense Oligonucleotides.  The table below presents the technology areas and the underlying techniques as well as possible applications.

Endonucleases

Genome editing by engineered nucleases (ZFN, TALENs and CRISPR/Cas9) is of great value in research to understand functions of individual genes but also as medicine for genetic disease treatment. Currently, genome editing strategies are developed as therapeutic agents. A critical breakthrough for gene targeting approaches was the discovery that by creating a site-specific DNA double-stranded break (DSB) at the targeted locus it is possible to strongly stimulate genome editing by homologous recombination. Engineered nucleases are not only used to introduce permanent deletions or insertions in the host genome but can be re-designed to control epigenome modification and gene expression. Engineered DNA binding domains of artificial endonucleases can be fused to functional domains of chromatin-modifying enzymes or a transcription activator/repressor. This type chimeric protein is able to control chromatin modification status, or regulate gene expression at the transcriptional level.

Small noncoding RNAs

Micro RNAs (miRNA) and Small Interfering RNAs (siRNA) have been discovered two decades ago and added a new dimension to our understanding of complex RNA-mediated gene regulatory networks.  These RNA molecules can exert regulation of gene expression. As such, molecular medicine base on these small RNA molecules can be applied at an additional level, for example, to regulate developmental and physiological processes or to treat a wide range of disorders including cancers and infections.

Antisense oligonucleotides

Therapeutic oligonucleotides (including small noncoding RNAs) that intend to have an effect on gene expression in general need to be able to enter the targeted cells and stay biologically active to be able to reach their DNA or RNA target sequence. As nucleotides composing RNA and DNA are linked to each other by phosphodiester linkages that are easily cleaved by endo- and exonucleases such molecules often are not suitable for the intended medical use. Many types of modifications have been described, and besides backbone modification; sugar modification (Locked Nucleic Acids, Bridged Nucleic Acids), nucleobase modification (Base Analogues), and terminal modification (coupled sugar, lipid, and peptide) have been applied to improve oligonucleotides properties.

Delivery systems

In most cases, the described technologies and their future development depend on efficient delivery systems. About 70% of gene therapy clinical trials carried out so far have used modified viruses to deliver genes. Although they have substantially advanced the field of gene therapy, several limitations are associated with viral vectors, including patient safety issues and difficulty of virus production. The development of non-viral vectors is attractive because of advantages such as fewer safety issues and fairly simple manufacturing processes. Many non-viral systems have been developed for delivery of genetic material, including the injection of naked DNA alone or in combination with physical methods such as gene gun, electroporation, hydrodynamic delivery, sonoporation, and magnetofection. These techniques are generally less applicable to systemic gene delivery in humans than in small animals such as mice. Therefore, a range of synthetic delivery vectors has also been developed, including lipids and liposomes, polymers (linear and branched polymers, dendrimers and polysaccharides), polymersomes and inorganic nanoparticles.

Paradigm shift

The most attractive aspect of the novel therapeutics based on the technologies described is their ability to target virtually any gene(s), which may not be possible with classical small molecules or protein-based drugs. While the efficacy of these novel therapeutics has been successfully demonstrated in vivo, several technical barriers still need to be overcome in order for many clinical applications. The novel therapeutics allow for direct and sustained interference with disease related gene expression and gene regulation, in most cases without the necessity to change the endogenous sequences of the genome itself. The ethical and safety concerns of changing genome sequences are herewith in most cases circumvented and a clear paradigm shift from gene repair and replacement to gene regulation can be observed. Nevertheless, some concern remains related to the transgenerational effects of medical treatments in general and specifically for treatments that strongly affect gene expression. New insights into epigenetic mechanisms revealed a new high-speed evolution system independent of random DNA changes: epigenetic evolution by chromatin modifications, such as acetylation and methylation, in response to environmental changes including medical treatments and even psychological experiences, which are transmitted between generations.

With the recent surge in intensive research investigating new therapeutic mechanisms and combinations of new tools, it can be expected that significant advance will be made for their future role in therapeutics.

To read the full report follow this link.

Feel free to contact us if you have any questions.

Blog & report by:
Harm Hermsen - Managing Consultant
Paul Joosten - Sr. Consultant 
Xiaoxi Zhu - Associate Consultant

Email:
Website: www.xendo.com

A Secure way to maintain Data Integrity while using Shared User Accounts
14-06-2016

#A Secure way to maintain Data Integrity while using Shared User Accounts

Data Integrity

According to the US Food and Drug Administration (FDA), “ensuring data integrity is an important component of industry’s responsibility to ensure the safety, efficacy and quality of drugs” *1 and in recent years the FDA has found increasingly more violations involving data integrity. Because data integrity is a too broad of a topic to deal with in a single blog we will focus on one specific aspect of it: data integrity for systems that use shared user accounts. Furthermore, we will focus on addressing the requirement that data must be retained as “original records”, “true copies” or “other accurate reproductions of the original records” (“reliable and accurate data”).*1

The FDA defines data integrity as:

”The completeness, consistency and accuracy of data. Complete, consistent and accurate data should be attributable, legible, contemporaneously, recorded, original or a true copy and accurate (ALCOA)”. *1

During development or production of pharmaceutical products it is important that all used data is correct, available, accessible by authorized user only, and therefore can be relied on in decision-making. To achieve this, data integrity must be ensured.

If data integrity cannot be ensured, than the possibility exists that the produced /developed products do not meet the quality requirements and/or do not work as intended. Or worse, the pharmaceutical product may have properties that have a negative effect on patients’ health. This is why regulatory authorities are currently focusing on data integrity.

Thus, the importance of reducing your data integrity risks, and ensuring controls are correctly implemented and appropriately managed throughout the entire record life cycle is very clear.

Shared User Accounts

Data integrity while using shared user accounts is a difficult one. Shared user accounts could be an Operating System (OS) - or application user account that are not specific for one user, but are used by more instead. 

Some computerized systems are used with shared user OS accounts e.g. because the application software must be running 24/7, other software is only working when it is run with an administrator account (this is a user account with all possible user rights) or an account with elevated rights (more user rights than a normal locked down user). This results in increased data integrity (and security) risks.  Using such a computerized system gives the users the possibility to (accidentally or deliberately) alter or delete data stored on local hard drives.

Furthermore, if someone is logged in with a shared user account it is not registered which specific user it is. If a user is editing data, it is only logged that that shared user account did the editing, and not which actual user. So it cannot be checked who was the one responsible. Therefore, measures must be taken to avoid this.

Security software

One of the measures to  implement is to install security software that is designed to limit the rights of the users on the computerized system, while the rights of the application software stay the same.

Note:

  • User rights: A set of rules defining what a user can or cannot  do and for what folders of a computerized system  these rules apply, such as read, write and delete.
  • Software rights: A set of rules defining what an application can or cannot do and for what folders of a computerized system these rules apply, such as read, write and delete.
  • Both sets of rules can be set independently.

The security software acts as a ”point-police man” between the operating system (Windows) and the application software regulating the users and the application software, so to speak. With this security software, it is possible to:

Set the rights of the application software:

  • Define which folders the application software can access and with which rights;
  • Define which Windows dialog screens the application software is allowed to use (e.g. “Save As” window).

Set the user rights

  • Define which applications can be used;
  • Define which folders the user can access;
  • Define if executable files can be started or not;
  • Define network access (network folders, intranet and internet).

How the security software enforces the rules to meet compliance can be configured too:

  • Define if the application software is started automatically or a menu with several applications is presented.
  • Define if besides the applications software other software or the explorer may be used.
  • Define which phericals (USB sticks, DVD, Mobile Devices, etc. may be connected to the system.

To illustrate this theory pretend you’re using application software (DataPro900) that is run under a shared OS user account with elevated user rights. The steps taken to configure the security software would be:

  • Configuring the security software in such a way that its interface is started on booting of the system. Users can only start DataPro900 or File Manager which is a secure replacement for Windows Explorer;
  • Selecting which folders the users can access using File manager, in this case the directory with the data files of DataPro900. File Manager is configured in such a way that these files can only be read; no files can be edited or deleted. No executable files (e.g. .exe, .com, .bat files) can be executed.
  • Blocking system critical key combinations
    Blocking system critical key combinations
  • Blocking internet access, but allow intranet access.
  • The users cannot get on internet and accidently download a virus or download software that could compromise the integrity of the computer and therefore also data integrity;
  • Locking CD/DVD drives and blocking USB drives.
  • The users cannot accidently introduce malware or a virus from a CD/DVD, Phone, USB drive or use those media to install software that could compromise the integrity of the computerized system and therefore the data integrity;

When the system is rebooted after this configuration, the following start-up screen is presented:

As you can see the system is completely locked down, only the DataPro900 application software and File Manager can be started.

The security software has an interface that makes configuration rather straightforward, you just have to tick or untick the options you want to set for the software. The interface has several screens where you can set the different options you want to use for your software.  This security software stores its configuration in HTML language. The main advantage of the use of the interface is that no prior knowledge of HTML is required to configure the software. 

Ofcourse, knowledge of the application software and the system it is run on is needed because this knowledge is needed to guarantee the best possible protection when using this security software.

For an example of one of the interface screens, see the picture below.

Considerations

In the case described above it is possible to make computerized systems with shared user accounts more secure, reliable and compliant with GxP regulations, when using security software. 

Data integrity is maintained because users have “reliable and accurate” *1 data to work with, which cannot be altered from outside the software application or the File Explorer.

Shared user accounts need to be assessed on a per system basis. E.g. The above procedure will not completely fix the problem when the application software uses shared accounts, like accounts based on roles (e.g. Analyst, Study Director, Lab Administrator). Then the application software itself is not compliant and that cannot be fixed by installing the security software. The advice then is to investigate new application software and make sure it has all functionality before taking it into use. At Xendo we developed and use standard lists to check if systems comply with 21 CFR Part 11 and Annex 11 for this purpose. Ideally, when starting from a  green field, infrastructure and application should both be assessed before deciding upon a computerized system to use.

*1 FDA Data Integrity and Compliance With CGMP Guidance for Industry DRAFT GUIDANCE

Blog by:  Anton van Rosmalen - Consultant at Xendo
Contact: Joost Havers - Managing Consultant at Xendo
Email:

Quality by Design in the development of biopharmaceuticals – how Regulatory Affairs can mitigate bottlenecks
06-06-2016

#Quality by Design in the development of biopharmaceuticals – how Regulatory Affairs can mitigate bottlenecks

If you are involved in (early) development of biopharmaceuticals, have you ever experienced serious delays because of problems arising from tech transfer? Or because of the first pilot scale batches not meeting important criteria of the specification that was adopted early in the program? Or because of a serious comparability issue between non-clinical, clinical and commercial scale batches? Or because the Agency does not agree with the proposed strategy, when your company finally decided to obtain Scientific Advice? A big chance you experienced not just one, but several of these “bottlenecks”.

Biopharmaceutical development necessarily requires a multidisciplinary approach, that is sometimes at odds with the realities of corporate structures and experience available in (smaller) companies. It is a challenging task to understand inter-dependencies between different pharmaceutical-technical aspects of a development program, together with the organizational aspects of a multidisciplinary approach. Once a development issue is noted by an individual, it can be difficult to translate this into action by the organization. Regulatory Affairs is arguably the single function where it all comes together; from technical CMC issues to nonclinical and clinical safety and efficacy studies, their interrelationships, and how to translate such issues in an efficient regulatory strategy.

When making an analysis of the many challenges in biopharmaceutical development four main bottlenecks can be identified: specific aspects of drug development that represent common root-causes for either delayed, over-budget or failed development programs. This blog will focus on these bottlenecks and how regulatory affairs specialists, working closely together with all relevant disciplines in the company, can offer advice and hands-on support to recognize and navigate through these successfully.

Manufacturing Process Development: tech transfer, scale-up and modifications

CMC development of a biopharmaceutical involves highly-experienced specialists that are very competent at their main task which is, necessarily, only a small piece of a complex puzzle. The first bottleneck regards the integration of the different pieces of the puzzle which typically requires involvement of regulatory specialists into the process.

Early involvement of regulatory people and thinking is essential to ensure that all aspects of the CMC development are integrated, aligned with nonclinical and clinical development and carried out according to an efficient regulatory strategy. For instance, regulatory specialists can enable a company to better manage tech transfer and scale up activities (which typically involves contract manufacturers and labs) by providing advice on the differing requirements from health authorities around the world for such activities, or to implement Quality by Design (QbD) concepts more efficiently by ensuring that the development is aligned with the regulatory strategy and QbD principles.

From QTPP to CQAs to Specification

The ICH Q8 Guideline describes the process by which pharmaceutical development progresses from concept to control strategy. According to the Guideline, a company first identifies a Quality Target Product Profile (QTPP) for the product to be developed and then identifies specific attributes that are critical to the quality of the product in accordance with the QTPP (critical quality attributes or CQAs). The essence of QbD (or the enhanced approach) described by ICH Q8 is the stepwise and iterative process needed to translate the QTTP to a product specification. According to this approach, first a risk assessment is expected to be carried out to systematically analyse all CQAs. Since the manufacturing process of biopharmaceuticals is complex, this necessarily involves many technical disciplines and can be a quite lengthy process. The risk assessment is followed by development studies to verify criticality and interrelationships of the many materials and process variables, normally using design of experiment studies. Based on the results of these DoE studies, the list of CQAs and the risk assessment is updated (reflecting the iterative aspect of the approach). As part of the DoE, a design space may be constructed, though the latter is not an essential part of the enhanced approach.

ICH Q8 covers a complex, multidisciplinary area that was identified as a common bottleneck due to the fact that many companies struggle to carry out their development projects in a focused and consistent way over the many years such a project takes. Instead they tend to operate more empirically and ad hoc. The concepts introduced in ICH Q8 (either the traditional or enhanced approach) are now seen as regulatory requirements in many cases. For instance, EMA biosimilars guidance states that “The QTPP should form the basis for the development of the biosimilar product and its manufacturing process.” Regulatory specialists can typically guide and drive these complex projects because they know what agencies expect and because they can communicate with all disciplines involved at a sufficient knowledge level. They can help establishing the (interrelated) development, control and regulatory strategies that adhere to global regulatory guidance.

Comparability

Ensuring that your product remains comparable after manufacturing process changes during the complete product life cycle may be one of the most important challenges of drug development , and is the cornerstone of all CMC development and maintenance. (According to ICH Q8, development concerns the complete product life cycle, including the time that the product is on the market.) Comparability is a typical development bottleneck due to the fact that issues with it are a major source of Agency major objections to Marketing Authorisation, Extension and Variation Applications.

It is critical to prospectively determine acceptance criteria and design robust studies capable of detecting differences between pre- and post-change product. (Such a prospective approach would “automatically” follow from a QbD approach as described above.) Additionally, care should be taken to identify CMC changes that could impact product safety and/or efficacy, as it is well-documented that relatively minor changes can have serious effects. Regulatory specialists are well-placed to advise on the types of changes that alert the Regulatory Authorities.

Scientific Advice

When companies underestimate the importance of early Scientific Advice meetings with Agencies, this can often create a bottleneck in development if the outcome of such meetings means that a company needs to adapt a strategy/program that has already been initiated. This could have been avoided, had the meeting been sought earlier in development. In larger organisations there usually is sufficient experience in this field and it is common practice to prepare intensively and conduct rehearsals for these meetings. In contrast, this type of preparation slips by the wayside in smaller companies, to their potential detriment, as these meetings are a great opportunity to get valuable information about the viability of your development program, and thorough preparation enables a company to maximize the benefit they receive from the meeting.

Regulatory specialists are used to communicating with Agencies and, as a consequence, have the expertise to determine what questions are likely to elicit useful information from the agency, write the briefing book to the standards expected by the agency, to consult on meeting formalities, and to design rehearsals. 

The above examples illustrate four typical bottle necks that can seriously slow down development programs of biopharmaceuticals. But these examples also illustrate how strong involvement of Regulatory Affairs specialists early on in the project can make a big difference toward solving or preventing them.

Blog by:  Frank Hermens - Sr. Consultant at Xendo
If you have any questions don't hesitate to contact us!
Email:

How Risk Management is integrated in the revised ISO 13485:2016
30-05-2016

#How Risk Management is integrated in the revised ISO 13485:2016

The word “risk” is mentioned over 15 times in the revised ISO 13485:2016; which is considerably more compared to the previous version, where it is mentioned twice. In the ISO 13485:2003, risk management was applicable for activities related to product realization, including the design and development of medical devices.  The revised ISO expands risk management to more processes; e.g., purchasing and training. This means quality management systems need to be updated.

In the new ISO 13485:2016 clause 4.2.1 it is mentioned: The organization shall apply a risk based approach to the control of the appropriate processes needed for the quality management system. Anything that affects the quality system needs to be viewed from that risk perspective. This is nothing new, but what are appropriate processes? In general the revised ISO requests companies to make risk-based decisions related to purchasing and product realization activities and other aspects of the quality management system, like training.

The term risk, used in the standard, pertains to safety or performance requirements of the medical device, or meeting applicable regulatory requirements. Failure Mode Effect Analyses (FMEA) are typically used to assess design or production controls, but can also be used to incorporate other aspects of the quality system. Below, several chapters of the ISO 13485:2016 are highlighted, the italic phrasings are literally from the standard, and it is explained how risk management can be implemented pragmatically. Clauses regarding risk management that were already addressed in the previous version of the standard, are not dealt with as they are already known for many years. But first, to define the right mind-set, the definition of risk and risk management, according to the revised standard, is the following:

Clause 3 Terms and definitions

Definition: risk

"combination of the probability of occurrence of harm and the severity of that harm" - [SOURCE: ISO 14971:2007, 2.16]

Definition: risk management

"systematic application of management policies, procedures and practices to the tasks of analysing, evaluating, controlling and monitoring risk" - [SOURCE: ISO 14971:2007, 2.22]

Clause 4 Quality management system

4.1 General requirements

4.1.5

When the organization chooses to outsource any process that affects product conformity to requirements, it shall monitor and ensure control over such processes. The organization shall retain responsibility of conformity to this International Standard and to customer and applicable regulatory requirements for outsourced processes. The controls shall be proportionate to the risk involved and the ability of the external party to meet the requirements in accordance with 7.4. The controls shall include written quality agreements.

When processes are outsourced, the standard requires that the controls that are going to be put in place for suppliers should be considered from a risk perspective. It starts with the selection of the supplier. Consider that the purchased item is a critical component for the device, what will be the risk if the supplier does not have a Quality Management System, including aspects like a complaint handling process? And when the supplier is selected, what happens if the supplier doesn't meet the specifications of the purchased components? How will that affect the final device? The standard determines that organizations should consider such risks and that they should have risk controls in place to mitigate possible hazards.

4.1.6

The specific approach and activities associated with software validation and revalidation shall be proportionate to the risk associated with the use of the software.

For some cases where software is used, the approach is straightforward. If electronic batch records are used, the risks of the software should be considered, which is normally routine. Also for implementing ERP-software systems, a risk-based approach is appropriate in the organization. But what if data of equipment is sent to a server and used in an Excel-spreadsheet to determine the process capability of the equipment, should that be validated? Software validation can be very complex and organizations often do not know what exactly, or how to validate the software. Therefore, a risk based approach to determine the criticality of the software is strongly recommended, it provides justification that any possible hazard of the software has been anticipated.

Clause 6 Resource management

6.2  Human Resources

The methodology used to check effectiveness of a training is proportionate to the risk associated with the work for which the training or other action is being provided.

The risks should be considered if the given training is not fully understood. Consideration should specifically be given to what could be the consequences, if employees interpret the essence of a certain training incorrectly and what the subsequent impact could be on a product’s quality.

The aspect ‘proportionate’ is clarified further by the following comparison:  Training on the job in the field of final inspection of a medical device should be properly checked for effectiveness, as the risk of an improperly performed inspection is fairly obvious. However, if an employee wishes to improve his or her level of the English grammar, then the check of the English course that was followed is of less importance. However, if it is a desire to have all procedures in English and the employees are not native English speakers, the risk can be considered to be higher. An ineffective training could have consequences for the safety of the device and the hazard involved. Therefore, the organization should have risk controls in place to avoid mistakes and should have preventive procedures in place also for training.

Clause 7 Product realization

7.4 Purchasing

7.4.1 Purchasing process

The organization shall document procedures to ensure that purchased product conforms to specified purchasing information. The organization shall establish criteria for the evaluation and selection of suppliers. The criteria shall be proportionate to the risk associated with the medical device. And non-fulfilment of purchasing requirements shall be addressed with the supplier proportionate to the risk associated with the purchased product and compliance with applicable regulatory requirements.

The extent of verification activities shall be based on the supplier evaluation results and proportionate to the risks associated with the purchased product. When formulating a risk-based approach to evaluate new or existing suppliers, it is important to first identify the critical control points for the purchased component. These are the points in the process, where failure could result in significant harm to patients and to the business. FMEA can also be used to identify areas of significant risk at suppliers that demand special attention, and to ensure that the risk stays as low as possible.

Clause 8 Measurement, analysis and improvement

8.2 Monitoring and measurement

8.2.1 Feedback

The organization shall document procedures for the feedback process. This feedback process shall include provisions to gather data from production as well as post-production activities. The information gathered in the feedback process shall serve as potential input into risk management for monitoring and maintaining the product requirements as well as the product realization or improvement processes.

With feedback obtained from users, patients and other stakeholders, an organization could consider to change the design of a medical device or certain processes, e.g. production, shipping, etc. In the case where a device should be stored and distributed in a temperature range of 15 - 25 °C, which is assumed “room temperature”, consider what would be the harm to the safety and performance of the device when it is shipped by plane under “normal” conditions. Is the impact negligible when shipped at higher or lower temperature? So the question is whether the actual situation is aligned with the required temperature range? And if not, would this result in negative feedback from the user? Feedback needs to be evaluated and could be an input to risk management, bearing in mind the safety of the patient and performance of the device.

8.3 Control of non-conforming product

8.3.4 Rework

The organization shall perform rework in accordance with documented procedures that takes into account the potential adverse effect of the rework on the product.

The heading of this sub-clause is new in the standard, however the clause itself remains the same. The word “risk” is not mentioned in this clause, but “adverse effect” can be understood as a risk. Certainly something to focus on; if rework of the device can occur before or after delivery, it should be considered which risks are introduced into the device. For example the device is packaged and during inspection there is an irregularity in the seal, could the device be re-packaged? And how many times is re-packaging allowed? And what is the effect of the device during re-packaging? Is extra heat treatment safe for the device and will the device still function according to the requirements? Are the features of the whole batch of devices completely equal with the included reworked devices and what is the hazard of having differences of these features in one batch?

Also, if the device has been delivered and is returned due to a non-conformity (e.g. equipment for analyzing purposes), the potential risks should be considered, before being returned back into the field.

Conclusion

From the above explanation of several clauses of the revised ISO 13485:2016 standard, it is clear that the new standard puts more emphasis on risk management; there are more but also different sorts of activities, in comparison to the previous standard. Selected software for supporting the product realization processes should be challenged with risk management. Focus should also be kept on training. Could this training affect the safety or performance of the device, and what are the risks and hazards if the training is misunderstood or wrongly interpreted. And further, what will be the impact on the device when selecting a new supplier or when the device is reworked? With a pragmatic approach and the examples given above, each organization should be able to update its quality management system appropriately. The result will not only be compliance to the risk management requirements of the new standard, but also better allocation of the organization’s resources, i.e. the activities that would benefit most, will be appropriately addressed.

For consideration:

Although the standard mentions nothing about risk management regarding management reviews, these meetings are a huge opportunity for achieving improvements. When conducting management review meetings, it should be specifically addressed how risk management is incorporated into the areas under review. As mentioned before; all Quality Management System processes can be approached risk based.

Blog by: Claar van Berge Henegouwen , Consultant at Xendo

04-05-2016

#Hoe geef je vorm aan de GDS norm?

Batchdefinitie, training van personeel, validaties en kwaliteitssystemen zijn speerpunten tijdens GDS inspecties door de IGZ. Bent u er klaar voor? Lees er meer over in deze blog.

Om de patiënt te ondersteunen bij de therapietrouw wordt er al langere tijd gebruik gemaakt van geautomatiseerde geneesmiddeldistributiesystemen (GDS).  Geneesmiddelen worden daartoe in een apotheek verpakt in doseringseenheden die het de patiënt eenvoudiger maken om op tijd de juiste medicatie te gebruiken.

In 2015 en 2016 heeft de Inspectie voor de Gezondheidszorg (IGZ) de inspectie van apotheken met GDS activiteiten hoog op de agenda staan. De kans is reëel dat de Inspectie langskomt of al langs geweest is in uw apotheek om te toetsen of uw apotheek voldoet aan de GDS norm. Bent u hierop voldoende voorbereid?

Historie

In 2002 bracht de IGZ een rapport uit naar aanleiding van inspecties bij 11 GDS apotheken. Eén van de aanbevelingen van dit rapport was het opstellen van een veldnorm, met het advies GMP (Goede Manieren van Produceren) voor bepaalde onderdelen te hanteren.

In 2007 heeft het KNMP bestuur de eerste versie van de GDS norm vastgesteld, gevolgd door een herziening in 2011. Volgend jaar viert de norm haar tienjarig bestaan. In de praktijk blijken er verschillen in verwachting te bestaan tussen de IGZ en de GDS apotheken, over de interpretatie van de GDS norm. De IGZ bevindingen tonen aan dat bijna 10 jaar na het vaststellen van de GDS norm veel GDS apotheken nog niet op het afgesproken niveau zijn.

Xendo heeft meer dan 25 jaar ervaring in de interpretatie en implementatie van GMP en aanverwante kwaliteitssystemen.

Vanuit onze ervaring willen we onze gedachten over de volgende actuele onderwerpen delen:

  1. Kwaliteitsysteem
  2. Training (van personeel)
  3. Batchdefinitie en batchgewijs werken
  4. Validaties

Kwaliteitssysteem

Een belangrijk doel van een goed functionerend kwaliteitssysteem is het vastleggen van wat er is gedaan, wanneer en door wie.  De bekende en uiterst belangrijke  hoofdregel van GMP is “als het niet is opgeschreven, is  het niet gedaan”.  De andere even bekende en belangrijke hoofdregel sluit daar naadloos op aan:  “Doe wat je zegt en zeg wat je doet”.  Indien beide regels goed zijn ingevoerd is er volledige traceerbaarheid van inkomend materiaal naar het eindproduct en weer terug (of vice versa). Deze transparantie is noodzakelijk volgens GMP, maar ook volgens de GDS norm. Het betekent dat het GDS proces is vastgelegd in eigen procedures en werkinstructies (GDS 3.1.1).  Hier aan toegevoegd zijn invulformulieren, logboeken en elektronische systemen.  Wijzigingen en gesignaleerde fouten worden eenduidig vastgelegd zodat de zorgvuldigheid waarmee men altijd al heeft gewerkt ook aantoonbaar is voor de Inspectie (GDS 5.4.1 en 5.4.2). Om alle documenten op elkaar te laten aansluiten is het belangrijk dat het kwaliteitssysteem daarover helderheid en overzicht verschaft. In het geval waar documentatiesystemen ‘organisch gegroeid’ zijn kunnen eventuele extra eisen of aanpassingen niet gemakkelijk in de documentatiesystemen doorgevoerd worden.  Dat kan de oorzaak zijn dat integrale aanpassingen aan  documentatiesystemen lang zijn uitgesteld  of helemaal niet uitgevoerd. De onvermijdelijke extra documenten worden dan los toegevoegd en de gewenste overzichtelijke documentatie piramide valt op enig moment uiteen in een hoopje los zand.

Training (van personeel)

Om een variatie op een bekend gezegde te gebruiken:  ‘Een kwaliteitssysteem is zo goed als de zwakste schakel’. 

Het is belangrijk dat iedere medewerker aantoonbaar geschikt is voor het werk dat hij of zij doet. Training binnen een GDS organisatie is dan ook uitermate belangrijk (zie GDS 1.2). Dit betreft training over de opzet en structuur van het documentatiesysteem en in het bijzonder training van alle van toepassing zijnde procedures en werkinstructies. De vastlegging van de trainingen is van belang voor de aantoonbaarheid. Dit lijkt logisch, echter is in de praktijk niet altijd vanzelfsprekend. Gelukkig is dit goed op te pakken. Onze ervaring is dat iedereen graag wil weten hoe het moet en wil meewerken om het proces te verbeteren, zeker als medewerkers zelf mogen meedenken en bijdragen.

Batchdefinitie en batchgewijs werken

De GDS norm (3.2.3) vereist een definitie van een batch en laat tegelijkertijd  ruimte om deze zelf te definiëren, dit kan dan ook per GDS apotheek verschillen. Bij de definitie wordt gekeken naar een optimum tussen de grootte van de batch, samenhang binnen de batch en de inrichting van het productieproces. Op deze manier wordt het productieproces inzichtelijk en controleerbaar gemaakt. Batchgewijs vrijgeven geeft een groot vertrouwen dat producten op een juiste en consistente manier zijn geproduceerd en geschikt zijn voor de patiënt.

Validaties

In de GDS apotheek geldt dat zowel de apparatuur als de processen gevalideerd moeten zijn (GDS 2.6.2).

Valideren betekent het verkrijgen van (gedocumenteerd) bewijs dat een specifiek proces of apparaat consequent resultaten produceert die voldoen aan vooraf vastgestelde specificaties en/of eisen. Het validatieproces bevat verschillende stappen beginnend bij een zogenaamde User Requirement Specifications (URS), gevolgd door een aantal kwalificatiestappen (IQ, OQ en PQ). Denk bijvoorbeeld aan validatie van het (GDS) apparaat (en eventuele fotocontrole), de aansturingssoftware en toegangsrechten van gebruikers(groepen). Ook de validatie van de schoonmaak van de GDS machine is belangrijk. Het uitvoeren van een validatie vereist de nodige tijd en kan best een uitdaging zijn wanneer u voor het eerst een validatie uitvoert, echter de winst zit in het feit dat objectief aangetoond wordt dat een apparaat of proces een voldoende mate van zekerheid biedt voor het beoogde doel. Daarnaast wordt tijdens het validatietraject kennis vergroot van de systemen en processen.

Tot slot

De kwaliteit van de GDS apotheek wordt sterk bepaald door de aanpak van de vier genoemde onderwerpen. Hiernaast zijn er diverse andere relevante onderwerpen die mede van belang zijn voor het aantonen van optimale productkwaliteit en borgen van patiëntveiligheid.

Patiënt en IGZ mogen verwachten dat hun producten van hoge, aantoonbare kwaliteit zijn en tijdig geleverd worden; dit is tegelijkertijd de grote uitdaging waar de GDS apotheken voor staan. Hierbij geldt een bekend citaat: “Het leveren van kwaliteit kost geld, het niet leveren van kwaliteit kost kapitalen”.

Wilt u reageren neem dan contact of bent op zoek naar advies op maat? Neem dan gerust contact op of bezoek ook eens onze website.

Blog door: Mathijs Addink MSc PharmD - Xendo
Contact:  Hanny Nelis - Managing consultant, Xendo
Email:

The revised Annex 16 on QP  Certification and Batch  Release, are you prepared?
18-04-2016

#The revised Annex 16 on QP Certification and Batch Release, are you prepared?

As far as changes in GMP legislation effect our daily work, the revised Annex 16 might prove to be quite a transformation. To account for rapid changes in the pharmaceutical landscape, the revision has been adapted substantially to include just about every development in the last fourteen years as well as new legislation coming into force. Especially the Qualified Persons (QP) will most likely see their workload increase to be able to ensure that batches are certified in a GMP compliant manner prior to their release. Because schedules are tight as it is, we have summarized some significant changes to the revised Annex 16 to get you up to speed.

History

After considerable time, on 15 April 2016 the revised version of Annex 16 will replace the one that has been in effect since January 2002. The revision process started back in October 2011 with an EMA Concept Paper on Revising Annex 16  followed by a Public Consultation from 5 July to 5 November 2013 for which no less than 30 reactions have been received. Finally resulting in a document which should probably last for quite some time.

Structure of the document

One of the changes that is difficult to miss, is the restructuring of the document. Sections containing different scenarios related to the origin of manufacture and possible existence of a mutual recognition agreement (MRA) have been omitted and the order has been changed to reflect the process of certification of a batch followed by GMP assessment by third parties, handling of unexpected deviations and finally the release of a batch.

Complexity of the supply chain and falsified medicines

Supply chains can be increasingly complex as more and more countries are involved, even in the EU. Each manufacturing site in the EU is obliged to have at least one QP (1.4) and Appendix I is added to prescribe the contents of the confirmation statement on the partial manufacturing (transfer of QP responsibilities between sites). The contents of a batch certificate needed for the certification are described in Appendix II.

The entire supply chain has to be documented, in a diagram for example (1.7.2).  Risks should be determined through risk assessments and safeguards should be built in to reduce the risks of falsified medicines finding their way into the supply chain ( 1.5.7). All arrangements between sites and parties should be in the form of written agreements.

For companies operating outside of the EU Annex 16 has another effort at hand. For medicinal products manufactured outside the EU and destined for release in the EU or for export, the complexity of the supply chain and locations of manufacturing sites is even higher. So basically the same process of certification is applicable, however with additional requirements (1.5). Mentioned specifically, are the storage and transport of a batch and any samples taken at the manufacturing site, for instance. This is allowed as long as these samples are fully representative for the batch. Formal quality risk management is required to support this assumption and the procedure should also be justified and documented (1.5.6).

New legislation for active pharmaceutical ingredients and excipients

In 2013, the import of active pharmaceutical ingredients (APIs) from outside the EU has been subjected to additional measures according to the ‘falsified medicines directive’ (2011/62/EU).  APIs can only be imported if they are accompanied by a written confirmation from the competent authority of the exporting third country stating compliance of the manufacturing process and the manufacturing site with EU GMP.  

Also in 2013 the revised GDP guidelines (2013/C 343/01) came into force,  containing requirements for GDP to cutback the number of falsified drug substances and drug products and requiring additional tasks for the supply chain that should be covered in quality agreements. Recently, legislation for excipients has been issued (Guidelines 2015/C 95/ 02). It is now required to carry out formalised risk assessment for ascertaining the appropriate GMP for excipients of medicinal products for human use.

The QP has to assure compliance with all legal requirements mentioned above.

Investigational medicinal products

The revised version specifically mentions inclusion of investigational medicinal products (IMPs) whereas the previous Annex 16 may be applied for IMPs.

Responsibilities of the QP

The revision specifies the responsibilities in much more detail. According to section 1.6, the QP must now personally ensure that several operational responsibilities are fulfilled prior to certification of a batch. These comprise of:

  • permission for certification under the terms of the manufacturing and importation authorisation (MIA)
  • compliance with national legislation
  • use of a register to record the certification.

In addition, the QP has the responsibility for ensuring that 21 points  are secured. In comparison to section 8 of Annex 16 of July 2001, at least 10 additional items have been added:

  • supplier management of starting materials and excipients (1.7.6)
  • GMP and GDP compliance of APIs (1.7.7) 
  • importation of APIs (1.7.8)
  • manufacturing of excipients (1.7.9)
  • TSE status (1.7.10)
  • finished product quality control (1.7.13)
  • regulatory post-marketing commitments (1.7.14)
  • technical agreements (1.7.18)
  • self-inspection programmes (1.7.19)
  • arrangements for distribution and shipment (1.7.20)
  • safety features of the packaging (1.7.21)

It is evident that all these duties may be delegated to other (trained) personnel or third parties. As a result of this the QP should have on-going assurance that reliance on the pharmaceutical quality system is well founded. In case third parties are involved this assurance should be done in accordance with Chapter 7 of Volume 4. Special attention is given to audits and the use of risk assessments to determine the critical aspects to be audited and the frequency of repeated audits (2).

Continuous training

More emphasis is placed on the requirement for the QP to have detailed knowledge of the product(s) and the processes as well as technical developments and GMP and should be able to prove continuous training regarding these aspects (1.2).

Handling of unexpected deviations

New to Annex 16 is the inclusion of the EMA 2009 reflection paper on dealing with unexpected deviations and the effect on batch certification. The QP may consider certification of the batch only when all specifications present in the MA are met, the impact has been assessed via a quality risk management process, a thorough investigation has been carried out and the root cause has been corrected. In other words: the manoeuvring space for the QP is limited, but clear.

What has not changed?

The principles of Annex 16 have not changed regarding the role of the QP in certification and subsequent batch release of medicinal products for human or veterinary use holding a MA or made for export. As always, the QP is still responsible for ensuring that each individual batch has been manufactured and checked in compliance with national laws of the Member State where certification takes place, in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP). Emphasised in the revised version of Annex 16 is that the marketing authorisation holder (MAH) has the ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, as also laid down in Chapter 1 of Volume 4 

In conclusion

Several new aspects have been added to the revised edition of Annex 16, next to the restructuring of the entire Annex. As a consequence there is an increase of the  responsibilities of the QP within the EU to ensure compliance of the pharmaceutical quality system  with the requirements laid down in the MA, GMP and national legislation. To be able to do that is a challenge for pharmaceutical companies. So again, are you prepared?

Read the full text here: http://ec.europa.eu/health/files/eudralex/vol-4/v4_an16_201510_en.pdf.