Contact

Xendo - Office

Who we are

Xendo is a leading consultancy and project management organisation in the fields of (bio)pharmaceutical products, medical devices, and healthcare. Thanks to our multi-disciplinary, knowledge-driven approach, Xendo can deliver a broad palette of services to the life sciences industry, applying the right colour to projects we participate in. For over 25 years we have successfully completed thousands of national and international assignments for start-ups as well as for the largest, established multinational companies and organisations. Over 230 experienced and highly educated professionals offer their expertise ranging from strategic advice and project management to auditing, operational support, and training; providing a full-colour spectrum.

Our clients

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

19-04-2018
Read more

#6 Quick tips to ensure data integrity in a digital clinical trial

While clinical trials used to be predominantly paper-based, technology is taking over the management of clinical trial data. Nowadays we often make use of electronic patient diaries, Case Report Forms and Trial Master Files. Investigational sites have started to maintain their medical records electronically. Even the electronic Patient Informed Consent Form is on the rise.
Digitalisation has certainly introduced more efficiency and better insight into clinical trial data, but it has also brought new challenges. How do we ensure that trial data and results are and remain reliable? How do we deal with a mixture of paper and electronic records, and/or a combination of different systems? This blog gives insight in some of those challenges with references to the recently adopted ICH E6 (R2) guideline for Good Clinical Practice (GCP).

  1. Make sure you define the location of essential documents including source records
    With the use of many different paper and electronic systems, it can be difficult to keep track on the location of study-related data. Data could be recorded and retained by different departments.

    A documented overview of the location of all essential documents, including source records, can be very useful. This can be done in a list and in a visual overview of connected systems and data storage created during a data mapping assessment. The maintenance of a record of trial document location(s) is now required for Sponsors and investigational sites per revised ICH E6 (R2) (section 8.1).

  2. Source records should be reliable and available
    A growing number of investigational sites are using electronic medical records (EMRs). There are many different systems and they are not always meeting the expectations as laid down in the GCP guideline. While ICH E6 (R2) details requirements for study and source records, it is not always easy to translate those into requirements for EMRs.

    A checklist helps the monitor / investigational site to assess any site- or hospital-specific electronic systems that are used for clinical trials against GCP. This can certainly avoid issues later on. Since this evaluation is also IT-specific, a standard questionnaire could be prepared for completion by the investigator and the site’s IT department. Different health authorities, such as the European Medicines Agency (EMA) and the UK Medicines & Healthcare products Regulatory Agency (MHRA), have provided useful guidance on risks of and expectations for EMRs, which can be used as a reference.

  3. Investigators should have control of and access to data generated by the investigational site
    Paper (copies of) completed CRFs, patient diaries and questionnaires used to be retained at the investigational site. Nowadays, most Sponsors make use of electronic versions, which are completed and retained online. In the opinion of Health Authorities, this often has resulted in Sponsors taking over control of data generated and/or reported by investigational sites or study patients.

    ICH E6 (R2) (section 8.1) now includes an explicit requirement that investigators should have control of and continuous access to records generated or reported by their investigational site. This means that in the selection and set-up of clinical trial solutions, such as eCRFs and ePRO/eCOA, Sponsors should consider options to allow investigators to control their own data, e.g. by building in options to retain a local copy of the data they have submitted to the Sponsor.

  4. Clinical trial solutions are provided by (many) different vendors
    There is a wealth of new and innovative clinical trial solutions on the market. They can build efficiency in the conduct and analysis of studies and save costs. It might be tempting to select these systems just on price and convenience. However, systems may have hidden costs. Inadequate system set-up and validation can lead to data integrity issues and unavailable systems and data.

    ICH E6 (R2) 5.5.3 provides now further detailed expectations for proper handling of electronic study data and systems, which includes, system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. These processes are time- and cost-consuming and require IT specialists with GCP-specific knowledge. What is the support the vendor can provide in system validation? Which efforts should the Sponsor take before a system can be used? This should all be considered during selection of clinical trial solutions.

  5. All data (and metadata) should be retained, archived and available for inspection
    Study record retention requirements as defined in ICH E6 (R2) 5.5.11, but also as required by EU and country-specific legislation, obviously do not only apply to paper, but also to electronic records, including metadata (e.g. audit trail or applied signatures). While storage, archiving and accessibility of data is relatively straightforward for paper records, secured storage of electronic records requires more efforts.
    How (in which format?) and where are records stored? Are data stored in the cloud? Where are the data centres? What about system security? Is data (in the original format, i.e. including metadata) still accessible after a system is retired? Considerations for electronic record archiving should start at vendor selection and could finally be a reason for not selecting a particular vendor.

  6. Transfer of data through different systems may pose the integrity of the clinical study at risk
    So far, we have considered systems as separate entities. However, this is not how it works in most clinical trials. All systems used for one clinical trial are integrated into one (trial-specific) electronic platform, in which data may be processed and transferred from one system to another. At the end of the day, all clinical trial data should end up in one clinical database. By that time these data should still be complete and fully reliable for biostatistical analysis and development of the clinical study report.

    To ensure a continuously proper working electronic platform and a reliable exchange of data between the different systems, potential risks should be identified before the start of the trial. Data mapping will help you to visualise how trial data are being exchanged between systems and where potential risks or gaps exist.

    Before a trial-specific platform can be used, all interfaces with the data generating and processing systems have to be tested. This should be part of the validation of the platform and the systems included. Such validation should ensure that the integrity of the data continues to be ensured, even though they have undergone processing and transfer.

This blog described six important challenges you may face with the digitalisation of clinical trials. This is not an exhaustive list of issues you may encounter in a digital clinical trial. Think of, for example, the challenges you can face with the introduction of an electronic Trial Master File or the collection (and retention) of patient data in electronic patient diaries and questionnaires (ePRO/eCOA). Though we haven’t described all of them here, we can share additional information on them upon request.

This blog made clear that the use of more and different electronic systems results in a need for additional efforts to ensure the integrity of a trial. However, digitalisation of clinical trials also introduces many opportunities. It does not only allow you to run a trial more efficiently, it also allows you to gain better insight in the data collected in a trial and as such may even increase the quality of the trial conduct, with fewer resources.
It is clear that the digital clinical trial evolution has not yet come to an end. Next to the expansion and improvement of existing electronic systems, the application of other solutions to make the execution of clinical trials more effective and efficient, such as mobile apps and wearable devices, are expected to become more present in clinical research.

Blog by: Henrieke de Bie



If you would like to learn more about this subject, have a look at a blog that focuses on data integrity and Quality Management System compliance:
Data integrity: 5 ways to be GxP compliant.

23-03-2018
Read more

#Lean Six Sigma Value Stream Mapping (Theory + Case)

You may wonder what all the flows and diagrams are about. It’s a value stream map! In Lean Six Sigma, we really love putting these down on flipcharts and post-its. For a good reason though; it promotes cherry picking.


The theory

Value stream mapping is one of the most-used Lean Six Sigma tools. It’s the process where a representative supply chain from supplier to customer is mapped. This is done in close cooperation with stakeholders such as Production, QA, Logistics, and Planning. Data on the process, like process steps, lead time, waiting time, inventory, # of operators, is collected and presented in visually.

Based on this map, you select projects that you think will offer the highest added value. Basically, it assists you and your company in selecting the best improvement projects. In addition, it results in a concrete understanding of all key stakeholders how everyone’s tasks and responsibilities interrelate with those of others. Value stream mapping has two main elements: preparation and data collection.

Preparation is everything.

Having a sponsor in place and with whom you agree upon the scope of the value stream mapping and who should participate in it.

Tip: Don’t step head over heels into a complex issue.

Start with a small process first, a simple and stable, preferably one product, and later on you may extend to other products and customers. It’ll probably be an eye-opener how many opportunities for improvement you can identify. Might even turn out that the process isn’t as stable as you thought it to be. Some examples of good starters for pharmaceutical companies are:

  • Bulk tableting (or filling vials), packing and shipping to customers
  • Receipt of goods, storage, order picking and shipment
  • Ready-to-use preparation of medication at hospital pharmacies

Next step: collecting data.

This may be a cumbersome task. If you collect too much, your team may be pretty critical. And if you collect too little you’ll probably encounter the same problem. So, what kind of data are we looking for? Remember that the objective of a value stream mapping is identifying waste and determining where in the process an improvement is most effective. It is after all, not for the sake of collecting data and making impressive charts (and putting them on flip-charts). It’s usually best to go out and actually observe together with your team what’s going on in your processes. Some examples to get you started:

  • Cycle time –time needed to do something in a process, e.g. vial filling and packing
  • Lead time –total time needed for a process, including waiting time as well (which is waste in lean)
  • Metrics like the number of people involved, shifts, transportation distance, and type of equipment, etc

The case

VALUE MAPPING IN PRACTICE

One of our customers requested us to do a mapping of one of their production processes. They chose a process which they considered to be pretty much stable. The team consisted of more than 10 people from production (media preparation, drug substance, drug product and packing), logistics, warehousing QC and QA.

MAPPING

First of all, all process steps were mapped, from the receiving of materials until their shipment to customers. Based on this map, we decided what data to collect.

VALIDATING

After the data collection, the first job was to “validate” the data. A critical step, to make sure that your decisions are data-driven rather than subjective thought like: “I really think that…”, “I believe that...”, “I strongly feel that…” etc. Decisions based on the latter aren’t usually the most constructive kind.

BRAINSTORMING

Next up, we had brainstorm sessions for each of the steps we determined, e.g. for drug substance preparation:

  • What/who are: supplier, input, process, output, customer (in lean: a SIPOC)?
  • Which step is rate limiting?
  • Where is the waste in the process (in lean: TIMWOOD – transport-inventory-motion-waiting-overprocessing-overproduction-defects)
  • What are the top 3 improvements we can identify?

Tip: Organise a kaizen for validating the data with the team and determine where to improve.

Together, we collected our top 3 improvements and voted for a final list of priorities and actions to be improved upon.  And you may expect this from a lean fanatic, like me. But what did the team say?

“Very positive:  can only become better”

“Brings a lot”

“Nicely shows the interactions”

“Excellent overview of the specific supply chain”

 “Working together”

PRESENTING YOUR RESULTS

Finally, we presented the whole workshop planning, process, and outcome to senior management, by showing them around in the meeting room filled with flip charts.

So, what did it show? A lot! You may have noticed the triangles on the map. They represent waiting time/storage and, therefore, waste. The actual process time is less than 20 days while the whole process, or the lead time, takes over 200 days. Just imagine the value of all that (intermediate) stored product; or, as you could put it, money not paid by the customer. Some of the more recognizable findings were:

  • a third of the waiting was caused by waiting on documentation, somewhere, before QA release
  • the testing and release of some starting materials took as much as two months
  • the QC/QA release process is the #1 priority

And yes, of course, there were many other opportunities for improvement: the process planning; transportation to and from the warehouse; decreasing waiting time of the drug substance, and change over time at packing (the list goes on).

CONSIDERATIONS

The only step left is to actually start improving on all your new improvement projects! If you’re getting the feel of lean you might want to read about the DMAIC-methodology (define-measure-analyse-improve-control). This methodology will help you and your team to be data-driven, focused on bottlenecks and result-driven.

Blog by: Marc Stegeman - Principal Consultant & Certified Black Belt at Xendo

Click to enlarge example value stream map.

 

 

 

20-03-2018
Read more

#Data integrity: 5 ways to be GxP compliant

Are you always ready to be inspected for your (GxP) activities in your facility? Is compliance and data integrity implemented firmly in your QMS? Are the systems in your (GxP) area constantly in a validated state? Are all your colleagues trained according to the required standards? And how about the Data Integrity (DI)?

It’s evident that you should always be ready for a(n) (un)planned internal/external inspection. Preparations for these external audits can be done by planning internal ones to ensure that both compliance and performance are controlled and corrective actions can be taken at an early stage. This way you and your colleagues are all prepared to face to the inspectorate as they make their way through your facility and documentation.

Although there are various types of audits and inspections, there is a trend that shows the inspectorate is focusing increasingly on data governance and data integrity.

So, what do we mean when we mention data integrity? Most usually it refers to the ALCOA+ principles, a commonly used acronym for:

Attributable

Legible

Contemporaneous

Original

Accurate

It puts an additional emphasis on the attributes of being complete, consistent, enduring and available (implicit basic ALCOA principles).

Data integrity standards are met if the degree to which a collection of data is complete, consistent, traceable and accurate. The data is considered to be integer assuring that the accuracy and consistency of data over its entire life-cycle are always guaranteed.

If your data falls short of these standards (after an inspection or gap assessment), you have encountered a data integrity issue; an action or event that could cause, or is evidence of false, misleading, inaccurate, or incomplete data and/or documentation.

You really don’t want this to happen and should always try to be avoided regardless of the costs. These issues have serious consequences for your facility, compromising your company’s legal status/leaving you vulnerable to lawsuits. Government agencies actively conduct audits on this topic and enact fines.

Data integrity and compliance are entangled to such an extent that good data integrity management has become an important component of the pharmaceutical industry’s responsibility. It’s being integrated in the legal framework to ensure patient safety and also the efficacy and quality of medicines. Because of this, it should be firmly embedded in your QMS and all people involved should be trained accordingly.

Setting up a basic QMS is a vital first step and the basis of a company’s assurance that it delivers what it promises. The main challenge here is to keep it up to date at all times. As a fundamental part of the QMS, data integrity needs to be documented properly in it and follow the ALCOA+ principles.

CLASSIFY YOUR DATA

Data can be classified by its level of sensitivity, value, and criticality regarding your facility. This classification of your data will help you to determine baseline security controls for the protection of your data. For example, confidential data is a generalized term that typically represents data classified as restricted to authorized persons only. This term is often used interchangeably with sensitive data. The way that your company classifies data should be documented in the QMS.

KEEP TRACK OF DATA FLOW

Keep in mind that all your activities regarding data handling in a controlled data lifecycle environment must cover the following aspects:

  • Creation or recording of GxP information
  • Collecting, processing and transferring data
  • Data use, reporting, replicating, and distribution
  • Data retention (including archiving), backup, restoration, obsoleting, and retirement

This list above for data management and GxP records is applicable to all personnel involved in e.g. research, design and development, sourcing, production, testing, retention, shipping, distribution, installation, service, marketing, and post-market surveillance of any pharmaceutical product.

All activities performed within above-mentioned aspects need to traceable. You always need to be able to reconstruct a complete roadmap of a drug or medical device’s history and you’re accountable to be able to resolve who has contributed what to which activity where and when.

IMPLEMENT ACCESS CONTROL

Working with a computerized system in a controlled environment forces you to have access controls for systems and audit trails in systems (technical measures) in place. This is to ensure that only authorized people can log in with their credentials using only the role(s) there have been assigned. This role is assigned based on personal training and a level of activities to be performed in the system. To ensure access can be granted correctly, appropriate policies, procedures, and controls need to be in place (in the QMS) to remain compliant with the applicable legal requirements.

Once logged into the system, the software should have an up to date audit trail which is basically a chronological record of activities performed in the system. It’s considered sufficient when you’re able to reconstruct, review, and examine the sequence of activities surrounding or leading to each event from inception to the final output.

On a regular basis, an audit trail review needs to be performed. So, what does that mean for your facility? You need to arrange for a periodic assessment that should include a sample of relevant audit trails, raw data, and metadata as part of self-inspection to ensure on-going compliance with relevant policies and procedures. The way of performing the assessment should be written down in a work instruction which is maintained in the QMS.

CREATE AWARENESS

In the pharmaceutical industry, training of all personnel is key, so an understanding of data integrity principles and issues should be included. If your personnel is trained adequately, they’ll be able to identify possible data integrity issues while performing their own assigned tasks and duties; use this to your advantage. Like everything else, these training sessions are recorded in a training record and consequently stored correctly and can be presented to the inspectorate if necessary.

PREPARE FOR INSPECTIONS

Ideally, you should have a stable situation in your facility where a complete QMS, containing work procedures, describes and guides all your processes. By having this QMS in place, trained personnel create various integer deliverables according to predefined processes. And the inspection should only be a confirmation of this.

Obviously, nobody’s perfect and probably no QMS is either. With this in mind, it’s encouraged to demonstrate that you have remedied possible data integrity issues by hiring a third-party auditor to determine the scope of the problem and by implementing a corrective action plan. This yields extra confidence that you are proactively closing gaps in processes related to your facility, equipment, personnel or procedures.

Consider this take away message for your daily agendas:

Look at inspections and inspection results. Frequently, deficiencies relating to data integrity are the ones leading to GxP Non-Compliance. Subsequently, data integrity is not only an IT topic; it includes all handling of information in GxP environments. Every change to data has to be initialed and dated by an authorized person, the reason for change need to be crisp. The original data has to stay legible despite all changes performed, this for paper documentation and electronic records.

Feel free to contact us to with any other questions on data integrity or have a look at one of our other blogs on the topic.

Blog by: Ton de Ridder

09-03-2018
Read more

#6 Ways to avoid pitfalls in hygienic design

In Life Sciences, GMP aspects of product contact, process functionality and capacity often determine the design of equipment, utilities, facilities and cleanrooms. Hygienic Design of the exterior aspects of equipment is often neglected. 

Cleanrooms and utilities are cleaned and sanitised or disinfected relatively easy with a wide range of standard solutions available. Equipment exterior, however, that is a different story. Its cleanability is often left to the manufacturer to consider and, usually, both the end-user and the manufacturer focus primarily on functionality and process cleanliness.

What is often forgotten, is that the equipment is stationed in a classified cleanroom and that the physical design and materialisation choices of parts like control cabinets, printers, motors, and insulation have a big impact on the air cleanliness and bioburden of the cleanroom.

Validation issues at the final stages of facility acceptance could be the result of the improper hygienic implementation of equipment in cleanroom environments. In many cases, the Hygienic Design of the equipment exterior is insufficiently addressed in the equipment’s specification. When issues regarding cleaning and disinfection are identified later during the installation and qualification phases the remediation will result in delays and rework and thus substantial additional costs. Addressing it at an earlier stage can prevent this from happening.

Hygienic Design issues related to equipment exterior can be minimized keeping the following possible root causes in mind when you are writing a specification for new equipment:

Equipment supplier has limited or no experience with production scale equipment

Particularly in Research and Development situations, new production developments or production upscaling situations where new types of equipment are used and technologies for large-scale production are not readily available and must be developed specifically.

Scaling of equipment (standard piping/ fully custom)

Another reason that hygienic design of equipment exterior could be impacted negatively are the design decisions made by the supplier during scale-up of the equipment. For example, different solutions for process piping, connections, parts, and electrical cabling might be needed during the scale-up process. In the development phase, disposable tubing with couplings could be used while a production scale might require a different approach. E.g. the limited experience by the supplier can lead to the selection of standard piping with couplings where fixed piping with full welding documentation would minimize the use of couplings and ability to clean the inside and outside of the equipment. Another solution could be to keep the full process path fully disposable

Limited experience with installation in a cleanroom environment

A Research and Development environment usually has different requirements than a production department when it comes to cleaning of the outside of the equipment and particle generation. A supplier that is not used to deliver equipment for use in a GMP cleanroom environment might select solutions that are well accepted in the development phase but not in a regulated manufacturing environment.

Additional, special requirements (e.g. ATEX)

Implementation of additional requirements, special non-standard requirements can impose a risk on the hygienic design of your equipment. Examples of these additional special requirements are ATEX requirements. It is important that the introduction of non-standard solutions are submitted to a proper assessment of possible alternatives and impact on the ability to clean the equipment.

Changes in the design requirements

Some may say that a project without changes isn’t a real project. True, but changes after the specification phase impose a risk, especially when changes aren’t assessed integrally, resulting in solutions that are only assessed on functionality. When changes are required, they should be assessed against the initial starting points and this assessment should be performed by the original design team. In addition, a proper change procedure can help to address this problem.

Solutions for these pitfalls:

For most potential pitfalls, there are simple solutions.

  1. The simplest and most effective solution is ‘being aware’ of these pitfalls and the fact that external hygienic design of your equipment definitely impacts your cleanroom.
  2. Ask for reference projects and assess solutions before placing the order.
  3. During the construction phase, request not just drawings, but also pictures or even better visit the manufacturing site.
  4. Assess non-standard solutions before prior to implementation.
  5. Look for options to avoid the installation of difficult to clean equipment in your cleanroom. E.g. locate the difficult-to-clean equipment outside the cleanroom and only have your process connection in the classified area.
  6. Finally, start as soon as possible. If the hygienic design is impacted, a solution should be found to mitigate the impact. The best moment to do this is during the design phase instead of doing this after installation and qualification.

It might sound simple, but is it really? Not always.

Sometimes things become difficult and complex because you get tangled up during the process and your vision gets blurred. So it’s wise to take some time to reflect on the matter and clear your head.

As Steve Jobs once said: “Simple can be harder than complex: You have to work hard to get your thinking clean to make it simple.”

Blog by: Gerco van Veen

15-02-2018
Read more

#MDR/IVDR: Highly-anticipated guidance documents you should not be waiting for

The transition time for the two Medical Device Regulations is rapidly ticking away: economic operators shall be fully compliant with the MDR by May 2020, and with the IVDR by May 2022. Are you an economic operator – in other words are you a Manufacturer, Authorized Representative, Importer, Distributor, System/Procedure Pack Assembler or Sterilization Service Provider? Then you might be eagerly waiting for further guidance (in the broadest sense of the word) from Europe. Here’s what guidance you can expect – and why you should not wait for it.

Roadmap for implementation

In November 2017, the Competent Authorities for Medical Devices (CAMD) issued a roadmap for implementation of the MDR/IVDR. CAMD identified seven technical areas/work streams and one over-arching/cross-cutting area/work stream. For each technical area/work stream, a list of actions items and priorities for various working groups was defined. This list outlines the roadmap for these working groups, according to which they can develop the guidance that you need for effectively implementing the MDR and the IVDR. Here’s what you can expect.

1. Clinical evaluation and clinical investigation (for Medical Devices); Performance evaluation and performance studies (for In Vitro Diagnostic Devices)

Expect guidance documents and/or Implementing Acts on the topics of equivalence, well-established technologies, clinical evidence and performance evaluation.  Several templates will be developed, such as templates for Summary of Safety and Clinical Performance, Clinical Investigation Application Form, SAE/device deficiency reports and timelines, PMCF Plan, and PMCF Report (and their IVD equivalents). For IVDs, new Common Specifications will be developed to replace the current Common Technical Specifications. Guidance regarding companion diagnostics is also to be expected.

2. Scope and classification

With the revised classification rules for MDs and IVDs, guidance will be developed around classification rules and scope.  Common Specifications are to be expected regarding Annex XVI products (products without an intended medical purpose). Implementing acts will be developed on the topic of reprocessing single-use devices.  Also, expect guidance on the appropriate level of interacting with relevant authorities regarding combination products and companion diagnostics.

3. Notified bodies and conformity assessment

These are specific for Notified Bodies and not for Economic Operators, however for Economic Operators it will be interesting to see the development of these guidance documents as they will give insight in, for example, the different routes for conformity assessment, the definition of ‘significant change’, or the differences between IVD Class B and C conformity assessment procedures.

4. Post-market surveillance and vigilance

New guidance will be developed on requirements for vigilance reporting. Also, various templates are going to be developed, such as a new Manufacturer Incident Report (MIR) Form, Field Safety Notice (FSN) and Periodic Safety Update Report (PSUR).
In addition, terminology might change as nomenclature for Adverse Events and Patient Harm will be (re)defined.

5. Eudamed and Unique Device Identification

According to the CAMD roadmap, expect clear and early instruction to stakeholders on how to interact with the system.  Guidelines will be developed on the topics of UDI assignment, UDI carriers, UDI marking and registration.

6. Market surveillance

CAMD is going to develop guidance or infographics for Economic Operators clarifying expectations around economic operator obligations, responsible person, liability, interaction with Eudamed and registration requirements.

7. IVD-specific issues

Specifically for IVDs, you can expect guidance on how to assess Class D IVDs in the absence of Common Specifications.
As already covered in previous work streams, also expect template documentation for performance studies, as well as guidance for assessment of companion diagnostics, classification, the appropriate level of interaction on combination products with relevant authorities, the nomenclature for Adverse Events and Patient Harm, and vigilance reporting.

8. Over-arching and cross-cutting priorities

Expect further definition of the responsibilities for conformity assessment of parallel importers and reprocessing of single-use devices. Also, guidance will be developed on the clarification of the role of the Medical Device Coordination Group (MDCG) in the governance of the regulations. Action items are defined to ensure that Eudamed will go live as planned (March 2020). As covered in the Eudamed work stream, instructions will be released to stakeholders on how to interact with the system. Current status is that functional specifications for Eudamed are to be released in May 2018, which implies that the progress towards the go-live date is still on track.

In January of this year, transitional provisions have been released by the CAMD Transition Sub Group, in the form of FAQs for both the MDR and the IVDR, covering initial questions on the topics of Eudamed, placing on the market of MDR/IVDR-compliant devices until date of application, placing on the market of MDD/AIMDD/IVDD-compliant devices after date of application, and the “sell off” provision in the MDR/IVDR. Keep an eye on these FAQs, as they are intended to evolve and expand over time.

Don’t wait, act now

Are you an economic operator waiting for guidance from Europe? Then there is little doubt that the expected guidance documents will be instrumental to you in implementing the requirements of the MDR/IVDR. These guidance documents may come in various sizes and shapes:

Delegated Act        Common Specification
Although not mentioned in the CAMD roadmap, Delegated Acts may be prepared and adopted by the European Commission. These non-legislative acts are based on, for example, specific objectives, content, scope, and duration that have been set out in the original legislative act (like the MDR or IVDR), and are considered to supplement or amend the original legislation. In other words, a Delegated Act tells us more about what actually is considered the law. The use of harmonized standards is good practice in order to presume to be in conformity with the General Safety and Performance Requirements. But in case relevant harmonized standards are considered not sufficient, or perhaps even not existing, the Commission may adopt Common Specifications which will have the same use as the harmonized standards. Specifically, regarding IVDs, current Common Technical Specifications may be replaced by such Common Specifications.
MEDDEV-like guidance documents
Designed as non-legally binding guidelines, MEDDEVs were intended to promote a common approach to be followed with regards to the three Medical Device Directives (MDD, AIMDD, and IVDD). As these Directives have been replaced by the MDR and IVDR, new MEDDEV-like guidance documents will be prepared to provide guidance with regards to the MDR/IVDR requirements. These may simply be updates of existing MEDDEVs, or may be entirely new guidance documents.
Implementing Act Other guidance documents
A non-legislative act that is considered to be procedural: a practical implementation of the rules that already exist in the original legislation, and thus may result in practical things such as templates, procedures, deadlines etcetera. In other words, an implementing act tells us how to implement the original legislation. These include any kind of (non-legally binding) guidance not covered by the above, such as infographics or FAQs.

But even though these guidance documents are highly-anticipated, here is why you should not wait for them – or more appropriately: why you should stop doing nothing while waiting for them.

Three reasons why time is running out:

  1. Although the preparation of a number of guidance documents, for example in the technical area of Clinical Evaluation, has been set to the highest priority, timing is the problem: as the CAMD roadmap does not define specific timelines for the release of the various guidance documents, it is not clear as to when exactly these guidance documents will be released – so chances are that it might be too late if you still have to start implementing.
  2. Judging from the CAMD roadmap, the amount of work ahead for the involved working groups and other stakeholders is substantial. For a number of the discussed guidance documents, it may even be a matter of years rather than months before they will be released. In the meanwhile, the date of implementation of the MDR and the IVDR is coming closer and closer, leaving you with hardly any time to become fully compliant with the regulations should you decide to wait.
  3. An additional obstacle is Brexit. Tough divorce negotiations between Brussels and London and the time-consuming work for MedTech experts involved in this topic will surely not help swift implementation of the CAMD roadmap and could cause serious delay in release dates. To add to that, historically the UK’s MHRA has played an important role within the European Union in developing policy aimed to protect public health as well as to support innovation in medical technology. If the MHRA steps out due to Brexit, this may add even more delay to release dates or adversely impact policy development.

Get time back on your side

It’s clear that the time that is left for you to get all the work done should not be underestimated. And the road ahead may be full of questions. You may find yourself at a crossroads now: should you sit and wait for guidance to arrive with the risk of having insufficient time left to become compliant, or should you get up and start transitioning already based on current knowledge with the risk of having to adjust once new guidance arrives?

Your best option is to start now and anticipate as best as you can on what is to come instead of wait and react. Start building a transition program based on what you can use from current guidance documents. As soon as new guidance documents are released, use these to double check to which extent you already comply with the MDR/IVDR, and to which extent you will have to fill any remaining gaps. This will get you further and will save you more time than doing nothing at all.

As we pointed out in our previous blog on MDR, time is running out fast: the longer you wait with the implementation of the MDR/IVDR requirements, the higher the risk will be that you will lose money.

Blog by: Urville Djasim – Consultant at Xendo

05-02-2018
Read more

#Gene therapy trials: a harmonized procedure across EU?

After the first clinical trial with a gene therapy medicinal product (GTMP) in 1989 and years of development and improvements, more and more GTMPs are now entering late-stage clinical trials and the first therapies have received market approval. In view of these developments, it seems that the field of Gene Therapy is about to pay-off and regarding the tremendous potential of emerging technologies (e.g. CRISPR-Cas), even more promising developments in the field of GTMPs seem to be ahead of us.

With the installation of a new Clinical Trials Regulation, the European Commission (EC) aimed to harmonize and thereby ease the application of clinical trials within the EU. However, the environmental legislative divergence between the Member States seems to neutralize the benefits of this Regulation for the clinical development of GTMPs.

CURRENTLY: DIFFERENT REQUIREMENTS FOR GTMPS ACROSS EU MEMBER STATES

In contrast to an application for market authorization, an application for a clinical trial is currently not harmonized in the EU and requires a separate submission in each Member State in which the trial will be conducted. In addition to all regular requirements of Directive 2001/20/EC, a GTMP trial is also subject to specific environmental legislation because it contains or consists of genetically modified organisms. This legislation requires an assessment of the potential risks for man and the environment. In the EU, two different Directives can apply to a clinical trial with GTMPs:

  • Directive 2001/18/EC, in which the trial is considered as deliberate release of a GMO into the environment (the GMOs are expected to be introduced in the environment),
  • Directive 2009/41/EC, in which the trial is considered as contained use of a GMO (the GMOs are expected to remain in dedicated rooms in the hospital).

All Member States have implemented these two Directives in their national GMO legislation and whether a clinical gene therapy trial is seen as deliberate release or contained use, differs among the Member States. Several Member States have chosen one of the Directives to apply to all gene therapy trials, which are performed in their country. However, in other Member States a clinical gene therapy trial is in one situation considered as deliberate release, while in another situation as contained use. In these Member States, it depends on the characteristics of the trial and the classification of the GMO used, which of the Directives applies.

Apart from the fact that each Member State has its own national legislation, they also have their own procedures and timelines for filing and assessing a clinical GTMP trial application. It goes without saying that the requirement for an environmental risk assessment combined with differences in legislation, procedures and timelines doesn’t exactly ease the path for a multicenter GTMP trial across several EU Member States and requires regulatory expertise and know how to coordinate and apply for such a clinical trial.

OBJECTIVE: HARMONIZED CLINICAL TRIAL APPLICATIONS IN EU

In 2014, the European Parliament launched a new Regulation (No. 536/2014) on clinical trials with medicinal products for human use, replacing the Clinical Trials Directive 2001/20/EC. Its objective is to harmonize the electronic submission of and the assessment process for clinical trials conducted in multiple Member States. In short, medical-scientific and product quality assessments will be centralized, but national issues like informed consent and compensation arrangements will still be evaluated separately by each Member State. Although this Regulation came into force directly after its publication in the Official Journal of the European Union, it won’t be applicable until the necessary EU portal and database are fully functional, which isn’t to be expected before the end of 2018.

REALITY: ENVIRONMENTAL LEGISLATION FOR GTMPS IS NOT COVERED

The new Regulation applies to all clinical trials with medicinal products for human use, and therefore includes GTMPs. Unfortunately, it doesn’t cover the requirements for the extensive assessment of the potential environmental risks. This means that the approval of a GTMP trial, in terms of its environmental safety, still resides at the level of the Competent Authority of each Member State with all its differences in national legislation, procedures and timelines. Consequently, gene therapy trials still face complex and non-harmonized regulatory requirements and procedures in EU.

CONCLUSION: NO BENEFIT FOR MULTINATIONAL CLINICAL GENE THERAPY TRIAL

Obviously, it would be most desirable if EU Member States could agree on the harmonization of the environmental legislation for clinical trials with GTMPs. Unfortunately, the EU Member States are widely divided in their GMO policy. This makes it unlikely that a centralized procedure for clinical trials with GTMPs, which also covers the environmental risk assessment, will come into effect in the near future, if at all. Until that time, one should consider carefully if a multicenter gene therapy trial in different EU Member States is really worth the effort to apply for the required environmental approval in each one of them.

PLANNING A MULTICENTER GENE THERAPY TRIAL: POINTS TO CONSIDER

  1. Limit the multicenter trial to a minimum of Member States (preferably one).
  2. If more than one Member State is required, choose your primary Member State based on your contact and previous experience with potentially qualified clinical centres.
  3. List the Member States with similar legislation for gene therapy trials as your primary Member State of choice, i.e. Member States with national environmental legislation that is based on the same Directive,
  4. Identify and contact the different involved parties in each Member State of choice to get insight in:
    1. the requirements for environmental approval
    2. the procedure of assessment
    3. the timelines that apply
  5. Select the Member States that most closely resemble the requirements, procedure, and timelines of your primary Member State of choice and that contain the most qualified clinical centres to perform your trial in.

If you're looking for additional experience and/or know how on GMO legislation and environmental risk assessments for clinical trials with gene therapies feel free to contact us and one of our experts will get back to you! We are familiar with the differences in national requirements and could support your company to navigate in this complex and non-harmonized playing field in order to design your regulatory strategy and work on a successful submission process

Blog by: Erik Schagen - Sr. Consultant at Xendo

28-01-2018
Read more

#Serialisation: What's it gonna cost you?

Adapting packaging lines, implementing a new anti-tampering system, a 2D data matrix with a unique serial number, software adjustments, efficiency loss because of slowed production, and costs related to data exchange between European and national data banks. These terms probably sound dreadfully familiar to those involved in serialization.

Falsified medicines can easily be confused with their authentic counterparts but may contain ingredients of bad or toxic quality, or in the wrong dosage; posing a very real risk to patients.  This threat to global health is answered by a comprehensive strategy both at a European and international level in the form of serialization. The EU Directive: 2011/62/EU aka Falsified Medicines Directive (FMD) is intended to prevent the entry into the legal supply chain of falsified medicinal products; thus creating a safer environment for patients.

So how does it work?

The basic set-up is the following:

  • Manufacturers register packaging to the European system (EU-Hub)
  • EU-Hub Transfers data to the national systems (NMVS)
  • Pharmacy holders and wholesalers are connected to the national systems
  • Wholesalers perform risk-based sampling
  • Pharmacies scan the product to check the status of a serial number and sign them off
  • Competent authorities receive reports to enable research possible falsification

&

  • The patient is ‘assured’ a safer product

The scheme below gives a broad overview of how the system is designed.

Higher costs per packaging

Obviously, nothing is free and to no one’s surprise, the current hot topic is the price of medicines, which is bound to rise. The European Commission has already carried out an impact analysis in 2015 (Ecorys) to determine the effect of FMD on the price of drugs. They estimated a rise of up to 3 euro cents per packaging in general (so no differentiation between innovative drugs or generics etc.)

Other reports show significantly differing numbers like a report from CapGemini in which the additional costs of the FMD for the Dutch manufacturers of generic medicines are estimated at an average of € 0,17 per packaging.

Investments for manufacturing companies

As for the manufacturing companies that will be affected, the organization ‘Medicines for Europe’ has estimated that updating packaging and production lines will cost the average company 5 million with an additional 2 million annually for running and maintenance costs. According to their calculations serialization will cost the entire pharma industry 5 billion to update packaging and production lines and also 90 million the implement the EMVS accompanied with an equal amount annually to keep it up and running.

These additional costs that companies will be facing can vary to a great extent as they depend on factors like:

  • Adaptation of packaging processes with new packaging lines, set up and testing, artwork, and implementation of software and data-connections
  • Generation and management of serial numbers
  • Training
  • Registration dossiers
  • Higher stocks
  • Contribution to NMVS and EMVS
  • Project costs

Also, depending on total revenue, the number of products, and their presentations, FMD costs will vary per manufacturer. Especially for companies with relatively low volumes and/or low margins in a relatively small medicines market, costs will be ‘higher’ due to the vigorous investments (which have no guarantee of any possible payback). For instance, this will put a lot of pressure on generics and small scale companies, which may consequently choose to discontinue certain products or worse.

The intended result of increased patient safety will be paired with significant costs in any case and may even be too much to handle for some of the smaller companies. But how much exactly? Based on our experience we’ve come up with a calculation tool which should give you some insight into the ballpark figure to help you prepare.

RECEIVE OUR CALCULATION TOOL HERE.

Considerations

So, now you may have a ballpark figure, but what’s next? Preparing a business case, funding and actually getting started are the logical next steps. It might be helpful to consider using Lean Six Sigma as a methodology, this approach offers various tools that are well-suited for projects like these. And though compliance with the FMD is the primary objective you may very well be able to realise substantial savings in the process to compensate for these investments.

Feel free to contact us to find out how or any other questions you might have.

Blog by: Nick Veringmeier

10-01-2018
Read more

#How to organize a Kaizen (Lean Improvement Workshop)

Kaizen: The Japanese term commonly used for lean improvement workshops. Its meaning expresses what it’s all about: change for the better.

In life sciences, we tend to associate change with change control, which is usually justified because there are plenty common reasons why you need to be in control of every detail. But most of the time we don’t really change anything significantly at all because it’s ‘complicated’ and we go on like before.  In lean, change implies improving. Measuring and demonstrating success as you move on and leaving your current state behind for a new and improved one. The Kaizen specifically has proven itself in many different situations and in many businesses and has the very beneficial side-benefit that people feel heard, engaged and empowered.

For example, taking a number of people to one of their warehouses to "go see what’s actually going on there". They will probably experience that the people who actually work there are surprised when asked what could be improved. This is exactly the essence of Kaizen: not talking about but with your staff.  

What to improve

So to get started. The first step is identifying the area you want to improve on, or in lean terminology: define the problem. There’s plenty of formal tools to make the best choice like value stream mapping.  For instance, creating a complete map following a biopharmaceutical product including the receipt of materials, upstream and downstream processing, aseptic filling, release, and shipment to a customer. This map could show you that something like the water production is the actual bottleneck you’ve been looking for (and now you can improve it). Or it may be the time you need for batch record review or product release. Conclusions like these are usually the result of a Kaizen and are fully data-driven and, therefore, (most of the time) fully supported by the whole team. You can also brainstorm with a group of people and pick one improvement project. Most of the time people actually already know very well which areas can be improved on. Data-driven conclusions may be different from team-based intuition though, obviously.

Secure a sponsor

The next step is identifying your sponsor. If there is none who wants to support you, stop. Basically, there’s no way of organizing a proper Kaizen without sponsorship. Let’s say the event/deviation handling process in a packaging department needs to be improved and the involved Quality Officer doesn’t have time for the Kaizen.  As a result, he or she isn’t very likely to be engaged and in all probability not the most likely person to agree on the proposed improvements. Therefore, you need a sponsor to make sure that every stakeholder actively participates in the event and facilitate a unanimous agreement.

Prepare prepare prepare

After having made sure there is a sponsor it’s your role as facilitator to actually organize the Kaizen. Preparation is key, so agree with your sponsor on things like the definition of the problem, the scope of the Kaizen, would be considered a successful outcome, who’s on the team and the planning. Once these aspects are all settled, you can proceed with data collection.

Start with a plan and try to balance between the needed data and the effort to collect it. This depends mostly on what you want to improve, or in lean: what is problem? If you want to improve the workplace, like the warehouse, for example, observation is your best friend, in a QA release process data collection is more likely the preferred route and in other cases, you might want to focus on material movement. More generally, it may even be refreshing to actually observe what people are doing on their computer.

The Kaizen

At last, the day of your Kaizen has arrived. Make sure that all stakeholders show up and ask your sponsor for help to assure this. These sessions get cancelled occasionally simply because people don’t show up. At least you could tell yourself you’ve defined your first problem if that’s the case.

Your role as a facilitator is key during the Kaizen and you should try to focus on keeping the process going as planned. DMAIC is a very helpful tool here because you’ve already agreed with your sponsor upon the problem, scope, timelines, team, and Kaizen; thus, you already completed D(efine) and because you collected data, you also completed M(easure).



The kaizen is all about direct observation:  M(easure) and determine the root causes and complete the A(nalyses).  Flip-overs and post-its are most useful to support the analyze phase, e.g. to map the process and to prepare a fishbone, a cause and effect diagram which helps to identify root causes by visually displaying the many potential causes for a specific problem or effect.

To keep the process on track is one thing, to keep people on track is a completely different ball game:

  • People can become frustrated with each other in which case you’ll have to address this to some extent, otherwise people get disengaged.
  • Sometimes the subject matter experts seem to know everything about the topic at hand and tend to dominate team discussions. Unfortunately, there is a lot of “I think that”, “I believe that” or boldly “This is how it works” behavior in many companies. And because of this, you will need the data you previously collected to either confirm or reject statements.

Question, question, question and conclude. Make sure that everyone is heard and guide the entire group towards one eventual, consensual conclusion. Other “tools” you definitively need are enthusiasm, energy and humor.

In the traditional approach, all stages are done in five days but it depends very much on the company whether this is necessary or even realistic. You may also choose to end the Kaizen with root causes and solutions identified. In that case, implementation and control become part of business “as usual”.

Evaluation of the Kaizen

Make sure you get tangible and sustainable results. That’s critical. For sure, a properly executed Kaizen boosts team morale, but the hard work starts afterward. And this is all about project management and implementation. The reward, however, is an improved process with tangible results, e.g. errors decreased by 30%, lead time reduced with 40% and yield increased by 10%. And when the team experiences that their daily work has become easier, you can count on it that they won’t be able to wait for the next Kaizen to start.

Tip: If you’d like to experience Lean Six Sigma yourself have a look at our Lean Game of have a look at the Yellow and Green Belt training we provide with the Biotech Training Facility.

Blog by: Marc Stegeman - Certified Black Belt at Xendo