Contact

Xendo - Office

Who we are

Xendo, a ProPharma Group company, 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, we 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. ProPharma Group combined with Xendo has more than 1,000 professionals worldwide providing an unmatched variety of compliance related services including medical information, pharmacovigilance, clinical safety, regulatory affairs, and a continuously expanding range of compliance, quality assurance, validation, and consulting services; 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. By creating an integrated solution, ProPharma Group is your single-source, global independent provider of compliance, regulatory affairs, pharmacovigilance, and medical information solutions providing the insights and services needed to maintain the highest level of value and patient safety.

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.

13-11-2018
Read more

#The new Medical Device Regulation 2017-745: Safety by design and by vigilance

As an essential aspect of compliance to the new Medical Device Regulation 2017-745, this blog intends to shed some light on safety and performance requirements for medical devices and the way to monitor this, or better: vigilance in general. Of course, the scope of this blog also encompasses the In Vitro Diagnostic Regulation 2017-746, because vigilance is applicable to both.

Naturally, vigilance as part post-production activities, as well as post-market surveillance (PMS) are deployed to guard the safety and improve the performance of medical devices. Procedures for vigilance and PMS should be set up carefully, planned for, elaborated and where needed optimized and adjusted. Even so, PMS plans should be recorded within the technical documentation prior to CE marking and should be executed subsequent to its availability to the market. Several aspects of these processes have been intensified in the new MDR as compared to the Medical Device Directive (MDD). For instance, safety & performance, the supply chain and the Quality Management System (QMS) are affected significantly and we’ll discuss those in this blog. Potential issues can be identified by performing an audit on vigilance and PMS plans, so that identified gaps can be addressed appropriately and result in an MDR-ready system.

So who should be reading this? Basically, every economic operator in the EU who’s involved in the medical device industry and especially the manufacturer.

Or as defined in the MDR:

‘economic operator’ means a manufacturer, an authorised representative, an importer, a distributor or the person referred to in Article 22(1) and 22(3)

Note: article 22(1) and 22(3) deal with the person who combines devices bearing a CE mark into a system or a procedure pack.


Product Safety & Performance

Implementation of the mandatory vigilance is to guard the two integral focuses of any economic operator involved with medical devices: safety and product performance. In the fourth pre-amble of the MDR, vigilance is stressed as a key element of the regulatory approach and chapter VII is devoted almost entirely to describing the requirements and obligations regarding PMS and vigilance.

Over the course of development, the manufacturer is supposed to map a medical device’s safety and performance and both require accurate monitoring and where applicable adjustment.

The identification and estimation of the significance of incidents in the commercial lifecycle of a medical device and (adverse) events in the developmental (clinical) phase require in-depth research, root cause analysis and Periodic Safety Update report (PSUR). Subsequent to the results of this analysis, recurrent patterns in complaints, (adverse) events and incidents have to be precluded. Accordingly, the establishment of the Corrective and Preventive Action (CAPA) pinpoints the necessary adjustments and mitigating handlings. Consequently, the results of the analysis determine the magnitude of required adjustments for the design of the medical device and the QMS if needed.


Quality management system

In order to comply with the MDR, economic operators should invest in an efficient roadmap leading to an MDR-proof QMS for their product(s), that much is clear.

According to the MDR, this means making sure that:

  1. Emphasis on clinical data/evidence, PMS and vigilance will play a much more extensive role in addition to the clinical evaluation process.
  2. The roles and responsibilities of the economic operators, the supply chain from manufacturer to distributor (to the patient) have been outlined also regarding the handling of feedback from users, patients, healthcare providers, and other stakeholders, e.g. vigilance).
  3. The chain must be controlled.

 


Supply chain

The supply chain is the path a medical device travels from the manufacturer to the final destination of use. The parties involved are defined by the MDR as economic operators, which include manufacturer, authorised representative, importer and/or distributor, depending on what is necessary.

Depending on the organisation and the location of the manufacturer one, or more economic operators are involved/required for the supply chain. E.g., manufacturers located outside the European Union must have an authorised representative residing in the European Union.

For the supply chain of the medical devices, agreements describing the roles and responsibilities must be in place. This becomes more important in case the manufacturer and the distributor do not belong to the same organisation. Quality agreements then become essential, not only for the distribution of the devices but also for the vigilance obligations.


Set up of the QMS

A manufacturer, whose situation is matching with abovementioned concerns, might by now be interested in taking actions to set-up or insure of an MDR compliant QMS system. Manufacturers and other economic operators must keep in mind that there is not much of time left since MDR will officially be applicable from May 2020. Taking into account Brexit and the limited number of Notified Bodies that will be approved for the MDR, this limited amount of time becomes a constraint for manufacturers to:

  • Set-up an ISO13485:2016 and MDR compliant Quality System in order to get the medical device CE marked
  • Upgrade the QMS and CE marking of devices that are already compliant to the MDD on the European Market
  • Ensure that specific elements are also MDR compliant, e.g. Clinical Evaluation, Risk Management and Unique Device Identification (UDI)

Since the manufacturer is responsible for vigilance, the QMS must cover the feedback activities as well as trending and vigilance, from manufacturer to user. In case the distributors/importer are different legal entities, a quality agreement must be in place to take care of the vigilance responsibilities.


Room for improvement: pharmaceutical companies

It is a trend that pharmaceutical companies are more and more directly involved with medical devices, not only as a simple means to administer medicinal products. For example, they are involved in the development of novel combination products, where a drug is combined into a single unit with a device; also software as a medical device, better known as apps, is a new field where they are active in. Pharmaceutical companies are already familiar with pharmacovigilance, where the adverse events of a drug can be recorded and investigated. Vigilance for medical devices is at first sight similar, but it is not the same as pharmacovigilance. Therefore, pharmaceutical companies also handling medical devices must bring their systems in line with the MDD and/or the MDR to ensure that the requirements are met; to help them meet this goal, several Medical Device Guidance Documents (MEDDEVs) are available.

Within the medical device industry, the vigilance system gives input to the manufacturer to improve the safety and performance of their medical device (-s). Also, other means can be used for this, e.g. post-production information, feedback, and complaints from users, patients, healthcare providers, and other stakeholders

From a business efficiency perspective, it’s interesting for companies to investigate how to integrate their Pharmacovigilance and (material- or medical device) vigilance systems. Instead of having two separate systems with their own upkeep, a well-combined system can be both compliant and cost-effective.


Checks and balances: auditing

So, how exactly do you make sure that all is well and you’ve got yourself covered? The answer is: as a manufacturer (or any economic operator), you should perform a system audit to verify that your supply chain does not only supply to your end users but also ensures that events are reported accordingly, vigilance and that proper feedback from the market is obtained, post-market surveillance.

It’s recommended to make use of an (external) medical device vigilance auditor who evaluates and reviews your QMS throughout the chain and assesses its compliance to the MDR requirements. Additionally, an MDVA assesses also any non-conformities. Hereby the manufacturer is insured of a compliant Quality System throughout the supply chain and is primed and prepared for the audits of authorities and/or Notified Bodies.

Manufacturers of certain categories of medical devices might benefit specifically from such an audit because they are so-called ‘out of the ordinary’. Such devices are:

  • Self-certified medical devices; the classification criteria of medical devices are stricter whereby numerous Class I (self-certified) devices would be classified as Class IIa/b according to the MDR
  • Drug-device combination products; are classified as Class III whereby the safety and compatibility of the device, medicinal product and the combination of these two must be substantiated
  • Software as a medical device; is classified as Class IIa/b contingent to its (remote) options, configurational abilities, and risks with respect to the critical parameters

Naturally, for you as a manufacturer of Class II and/or higher Classes of medical devices, an audit will contribute to ensuring that the setup and maintenance of vigilance and post-market surveillance plan/method are performed appropriately. Of note, besides the benefits of an audit for medical device manufacturers, the MDR obliges the manufacturers to audit their critical subcontractors and suppliers as well. This aims to warrant accurate monitoring of the medical device’s integrity until it reaches the user/patient.

If you’d like to do your own pre-audit, you might want to start out with a free checklist for Medical Device Vigilance: request here.


In conclusion

The new MDR has been around for some time now and one of its focal points is the safety and performance of medical devices. To achieve this a manufacturer of medical devices, and even all economic operators, are legally obliged to set-up, implement and maintain an effective system for both vigilance and post-market surveillance. To check if the system is working properly, it should be subject of an internal audit. In this way, any third-party inspection will have a fully compliant outcome and, most important, the safety and performance are warranted for the patients.

Often we encounter situations within the medical device supply chain that an economic operator, manufacturer or not, is assuming its vigilance and PMS system to be compliant. Nevetherless, by asking right questions the contrary is proven. Thus, how do YOU ensure that the vigilance and post-market surveillance of YOUR product are fully compliant?

Blog by: Nadia Vazirpanah

19-10-2018
Read more

#Infographic - ATMP Development

Thanks to the popular reactions we've had on our approach to ATMP development we'd like to share this infographic.


As the face of modern medicine is changing, so should the development strategies of new medicines, including advanced therapy medicinal products (ATMPs). In the infographic, we present essential steps in ATMP development; how to design a valuable project plan, set critical milestones, and the identification of development gaps that can be intercepted without compromising on safety and efficacy, all to smoothen and speed up the process from ATMP development to marketing authorization.

Academia and startups are usually more focused on getting the science right but are often less experienced regarding the development of a medicinal product. As a guide through the development maze, it is of utmost importance to create a development plan and identifying all the interdependencies between non-clinical, CMC, and clinical development, from an early stage on. Furthermore, a tailor-made regulatory strategy should be developed. This regulatory strategy should provide guidance and focus, especially in early development where engagement with regulatory agencies supports to align development milestones and assure regulatory compliance in the end.

Although each ATMP is unique and needs a tailored development and regulatory strategy, critical steps can mostly be identified and anticipated on beforehand.

Check it out here!

11-10-2018
Read more

#Proactive Pharmacovigilance And Its Importance: Benefits And Challenges

Feel free to download the slide deck of one of our recent talks on the proactive pharmacovigilance which was presented by Sonia Mangnoesing at the PhV Day on October 10th, 2018.


With the changes in Pharmacovigilance regulations over the last years, a shift has been seen in how we conduct Pharmacovigilance. Moving from a more reactive approach to a proactive approach. Maybe also moving from the ‘person’s approach’ to the ‘human factors’ approach. But why is this important, what are the benefits? That is a question many of us can answer in a fairly good way. Some may have had the opportunity to experience its benefits more than others, but since the changes in regulation, most will agree that this is the way forward.

Yet, when we look at how Pharmacovigilance is executed in practice, we too often see that different challenges cause a less than optimal Pharmacovigilance system. The challenges that we all can face in pharmacovigilance are not unique, but rather universal and their solutions hopefully applicable to different settings.

Download presentation here.

09-10-2018
Read more

#Brexit & QPPV: Time to Prepare

Time is progressing, towards the official transition date in the Brexit process 30 March 2019 (actually as this is a Saturday, the implementation should be effective as of 29 March), as per notice from EMA in May of last year:

When the United Kingdom will have become a ‘third country’ all regulatory and practical consequences will become applicable. Although deeply affecting all business sectors, EU regulatory authorities, and individual citizens, the prospect of this transition, is specifically important for the pharmaceutical industry.

The English Health Authority published at 6th of August 2018 that the UK and EU agreed upon the terms of an implementation period to the end of December 2020, once finalised as part of the Withdrawal Agreement. It states amongst other things that marketing authorisation holders and qualified persons for pharmacovigilance will continue to be able to be based in the UK and access EU markets during the transition period. The Withdrawal Agreement as a whole still has to be finalised, aimed for October 2018.

QPPV

One example of where the impact will be particularly highly felt is the role of the Qualified Person for Pharmacovigilance (QPPV) with European responsibility.

EU law stipulates that companies marketing medicinal products in the EU are not just authorized in the EU/EEA, but they even enforce specifically that some activities must be performed in the EU (or EEA). For example, the execution of the QPPV role and its pertaining activities such as oversight of the pharmacovigilance system and safety of the medicinal products marketed by the EU MAH. This aspect is also directly important for patient safety in the EU and even globally. Hence, the consequences of the UK becoming a third country are therefore significant and preparatory activities need to be started in a timely fashion.

QPPVs fulfill a complex and difficult role as central pivot of the MAHs pharmacovigilance system and are uniquely responsible for the PV QMS as well as its outcomes, such as the benefit-risk balance of all the MAH’s medicinal products in the EU Market. The QPPV role requires therefore highly qualified, trained and scientifically and medically aware persons. QPPV are scarce resources and especially with so many currently established in the UK there will be a resounding impact when these QPPV drop out of the EU system more or less at the same time. According to the Article 57 database, there are about 150 UK-based QPPVs. In fact, this will be challenging to cope with for all MAH with products in the EU, since simultaneously with a move of MAH’s from the UK, the need for QPPVs will increase in the remaining EU countries. This will lessen the average available QPPV resources thereby putting the MAH already residing in the EU under additional pressure to find suitable personnel to occupy the QPPV role.

GUIDANCE

To help clarify where and how changes may be required, an extensive and very practical Guidance Document has been published on 19 June 2018 (EMA/478309/2017 Rev. 2). This document complements the Questions and Answers (Rev 03 from 19 June 2018 ) prepared jointly by the European Commission and EMA related to the United Kingdom's withdrawal from the European Union and is drafted to provide procedural and practical guidance to marketing authorisation holders (see also Notice to Applicants, updated on 23 January 2018). These documents and many more are available on the EMA website to support the MAH in their transition and it is advisable to use them.

EVALUATE AND SET UP A STRATEGY

BREXIT consequences will also enforce MAHs with their EU headquarter in the UK  to consider relocation to a remaining EU country, change the EU QPPV location accordingly as well as the location of the Pharmacovigilance System Master File (PSMF). This pivotal pharmacovigilance document, likewise, needs to be located in an EU country. Each MAH that will need to transfer the QPPV/PSMF responsibility must be aware that continued compliance with the regulations surrounding the QPPV role needs to be guaranteed throughout the change process and change control should cover all processes. This is at the same time fully under the responsibility of the QPPV incumbent at that moment, making the controlled change processes extra challenging. And at the end, the QPPV and PSMF details need to be updated in the Article 57 database.

PREPARE

It may be prudent for all MAHs affected by Brexit to evaluate carefully where in the post-Brexit EU they want to establish the QPPV and PSMF. Aspects to use for this assessment may be qualification and numbers of potential QPPV resources and reflect this e.g. against (co)rapporteurs, language as well as footprints of their company and medicinal products market to ensure a more evenly spread distribution of QPPVs. As a spin-off effect, this may even cause a more even distribution of regulatory burden for Health Authorities. 

27-09-2018
Read more

#7 Things to Consider in Medicinal Cannabis Development

Mention the word cannabis and the confusion starts; legal or illegal, nutraceutical or medicinal product, psychoactive or non-psycho-active, clinically significant or not. At the same time, the cannabis industry is booming and attracting many investors. Currently mainly focused on the growing of the plant and exploiting the benefits of medicinal cannabis but more and more the focus shifts to the use of purified cannabinoids into medical products. In this blog, you will find out more about the regulations regarding medicinal cannabis and what to expect of it in the near future.


1. Cannabis

The first thing to set straight is the name cannabis. This is not a specific type of plant or product but more an all-encompassing term of a number of plants, materials, and products. The two common active substances (cannabinoids are called THC and CBD and are representative for the majority of endeavors in cannabinoid product development. THC and CBD are quite different from one another and in the table below you can see a comparison. Next to these two, there are over a hundred other known cannabinoids with slightly different chemical structures.

 

 

THC

CBD

Psychoactive

Yes

No

Legal status

Listed in narcotic laws, exemption needed1

Not listed in most countries (except US, UK, and some others)1

Origin

Weed plant

Hemp (grown for fiber)2,3

Growing location

Hot and humid climate/greenhouses

Moderate climate2

Products

Medicinal/recreational

Nutraceutical/medicinal

Appearance in pure form

Sticky oil/resin

Crystalline material

Stability

Unstable towards oxygen and light

Stable

Receptor activity

CB1/CB2 partial-agonist

CB1/CB2 antagonist

Proven clinical effects

Relieving chronic pain, muscle spasms, nausea

Epilepsy

Products

Marinol, Sativex (in combination with CBD)

Epidiolex (Lennox-Gastaut and Dravet Syndrome)

  1. please check the legal status if you embark on a cannabis project
  2. specially bred CBD-containing plants are grown in greenhouses. These are mainly intended for medicinal products
  3. if hemp is grown to isolate CBD, an exemption from the narcotics law is required in most countries

2. Regulations

So how is medicinal cannabis regulated? Currently, there are 27 countries, mainly in Europe and the Americas, where medicinal cannabis is permitted. It is usually prescribed by GPs and provided by pharmacies. Pharmacies obtain their packaged product from wholesalers and those from growers of cannabis plants. Both the growers and the distributors require licenses from local governments to be allowed to work with this plant material. To obtain such a license you’ll need to demonstrate aspects such as:

  • protective measures to prevent cannabis material from going missing
  • the exact handling of the material
  • growing,
  • importing,
  • re-packing,
  • storage,
  • distribution,
  • R&D-activities,

Currently more than 100 producers have been successful in obtaining the license, mainly in Canada. Having said that, it’s complicated to work in several countries at the same time because each country has its own set of regulations.


3. Quality Standards

When producing medicinal cannabis, Health Authorities may require a product to comply with the standards described in the Good Manufacturing Practice guidelines (GMP), e.g EU countries. This is managed by clearly defining specifications for possible quality risk factors like:

  • content
  • moisture
  • foreign matter
  • microbiology

Information on GMPs can be found in EU GMP “Eudralex 4” or the United States FDA 21CFR part 210 and 211

Interestingly, the GMP isn’t required for planting or seeding of cannabis plants. Instead, this typically requires Good Agricultural Practice (GAP which secures a constant quality of the plant material and is often done in a secured greenhouse).  GMP usually starts at harvest of plant buds.


4. Extract or purified substance?

Currently, the cannabis industry’s focus is still on plant material possibly because the terpenes exert a beneficial effect and dried buds are easy to get by and use. Besides this, the actual use of plant material ranges from tea made from the leaves to smoking it. It comes as no surprise that standardizing the use of cannabis to secure constant dosing for patients is key and it’s certainly worthwhile to investigate more advanced ways of delivering cannabinoids.  For instance, by presenting an extract or purified THC / CBD to patients you increase your control over the contents and dosing becomes more accurate, opening possibilities to investigate treatment efficacy in clinical trials. A number of companies are already using purified THC and CBD (essentially pure active substances) in clinical studies aimed at obtaining marketing authorization.

Example:  Sativex. By extracting the active materials from the plant and formulating it as a spray, GW Pharma obtained a marketing authorization in the EU and Australia. They did the same to register CBD in the US for treatment of rare epilepsy syndromes.

This is remarkable because the extracts used for Sativex still contain a large number of other cannabinoids as well as terpenes. Although we assume it’s because of the THC and CBD, it is not clear which components are actually responsible for the efficacy in pain reduction or reduction of seizures.


5. Formulation

Whether extracts or purified cannabinoids are used, there is a number of possibilities to administer these active substances to patients; each with their own pros and cons. Therefore, when embarking on a cannabis project (or any project in fact) it is useful to start with the patient in mind and define requirements that will treat a patient in the most comfortable way possible.

Some of the formulations:
 

 

Pros

Cons

Oral tablet

Easy to use

High first pass effect (extensive metabolism by the liver)

Cumbersome manufacturing

Inhalation

Demonstrated way of delivery (recreational use)

High plasma level leading to psycho-active effects

Patch

Easy to use

Only low doses can be given

Mouth spray

Immediate delivery

Only low doses can be given

Chewing gum/pastilles/lozenges

Easy to use

Cumbersome manufacturing


6. Stability

One aspect that needs to be considered when extracting and purifying THC is its stability, or rather its instability. Unlike CBD, THC is vulnerable to oxygen, light, and possibly moisture and it is readily decomposed by radical oxidation. This means standard formulation techniques aren’t sufficient to provide a stable drug product and instead requires encapsulation techniques. Methods have been developed to protect the THC by encapsulation into a polymeric or a liposome matrix. Surprisingly, the dissolution in aqueous ethanol mixture also exerts a stabilizing effect as demonstrated by the Sativex spray developed by GW Pharma.


7. Clinical studies

As previously stated, a number of treatments have been approved by Health Authorities. These are mainly in the area of pain reduction, emesis, nausea and symptom reduction in MS-patients. It is known that cannabinoids act on a multitude of different receptors in the body, either as agonists or antagonists, and could potentially interfere with disease mechanisms. Therefore, cannabinoids are thought to have the potential to treat or cure also diseases such as cancer (see e.g. the excellent review paper of Massi et al.)


Future

So, why haven’t we found more cures to date? Is it possible that the multi-compound containing plant material has hampered the progression of cannabinoids in approved treatments? As indicated before, these are ill-defined materials of a number of cannabinoids and terpenes and with a multitude of administration routes. So, claims using medicinal cannabis can’t be substantiated with clinical evidence. With THC and CBD now readily available as GMP-material, the scientific community is more suitably equipped to perform clinical studies. Hopefully resulting in approved drug products that treat patients safely and effectively.

Blog by: Jan Zorgdrager & Marc Stegeman

12-09-2018
Read more

#How to manage the risk of Elemental Impurities (ICHQ3D)

ICH Q3D

The mission of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is to ensure safe, effective and high-quality medicines through worldwide harmonisation. Harmonisation achievements in the Quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management. In addition, the guideline ICH Q3D for Elemental Impurities has been implemented at the beginning of this year. This guideline provides a platform to develop a risk-based strategy to control and limit elemental impurities. As a consequence, this can have a major impact on drug development and more specifically on the quality of your drug. This blog will bring you up to date on the implementation of the Guideline for Elemental Impurities.

In every step of the drug development process, impurities can arise. Impurities are substances that are added or formed during the development process and have a non-intentional (potentially toxic) effect on the drug. They can be organic molecules, residual solvents or inorganic compounds. Elemental impurities are commonly called heavy metals and most of them are toxic to humans. Therefore, the levels of Elemental Impurities must be managed within acceptable limits in order not to harm the patient.


Development of ICH Q3D guideline

While initially used to control metals like lead, copper and other heavy metals that constitute a health hazard, the assessment of Elemental Impurities (EIs) has gained considerable attention over the last years.

ICH Q3D arose out of a need to develop a globally harmonized guideline and is the culmination of several initiatives intended to modernize the control of EIs in pharmaceutical products. The U.S. Pharmacopeia (USP) had been discussing the modernization of its heavy metals monograph for several years prior to the initiation of the Q3D Expert Working Group. The European Medicines Agency, after many years of discussion, had implemented a safety and risk-based approach to control residual catalysts in pharmaceutical products approved to be marketed in the EU. The ICH Q3D now replaces these earlier initiatives.


ICH Q3D Guideline

The ICH Q3D Guideline represents a list of 24 elements, classified in 4 categories according to the toxicity and probability of occurrence.
It promotes a risk-based approach to assess the presence of EIs in drug products. Since the new guideline relates to the relevant route of administration of your drug product, a more specific assessment of actual toxicological risk to the patient can be given. A safety-based Permitted Daily Exposure (PDE) has been developed for the oral, inhalation, and parenteral routes of administration for 24 elements that are classified based on safety and relative abundance in nature.

Click here for enlarged image.

ICH Q3D presents major challenges to testing and risk assessments related to meeting current stringent limits for specific elements to assess patient risk. The likelihood that certain impurities in a medicinal product are present, should be determined through a valid risk assessment. An important detail is to ensure whether the controls built into the process are acceptable to limit the level of EIs in the medicinal product. The risk assessment should also clarify whether the proposed control strategies are sufficient or if additional control strategies are needed. When the risk assessment indicates that the level of an EI may exceed the control threshold, additional measures need to be implemented to ensure that the level does not exceed the PDE.

These additional measures can include, but are not limited to:

  • Reduction of EIs to levels that do not exceed the control threshold through purification steps or implementing in-process or upstream controls
  • Selection of components of improved quality
  • Establishment of specification limits for the drug substance, excipient or drug product
  • Selection of an appropriate container closure system

Based on the outcome of the risk assessment, a clear control strategy needs to be provided.

As EIs can be present in every step of the development of your drug product, the control of EIs should be considered across the entire product lifecycle. Whenever changes are implemented, the risk assessment on EIs should be reviewed and updated because every change possibly impacts the EI content of your drug product. For instance, changes in synthetic routes, excipient suppliers, materials, processes, equipment, container closure systems or facilities on the original risk assessment should all be evaluated. Also, the regulatory implications of modifications to the risk assessment and control strategy should be considered, and, when needed, appropriate variations need to be submitted.

EI data for some components may be limited during drug development, which could direct the applicant to a particular control strategy. For example, the applicant may choose to carry out end product testing as the initial strategy. As additional experience and knowledge are obtained with time, the applicant may determine that a change in the calculation option, risk assessment and/or control strategy may be warranted to ensure the levels of EIs.


Risk assessment on Elemental Impurities

Since the implementation of the ICH Q3D guideline on EIs, drug product manufacturers are obliged to carry out a thorough risk assessment to identify and control EIs. As EIs can occur in drug substance as well as in the final drug product, all potential sources should be considered in the risk assessment. The risk of any elemental impurity occurring in the product at a level > 30% of its PDE should result in a control strategy for that particular EI:

Elemental impurities (EI) level

Actions and/or control strategy

Elements that are not likely to be present in the risk assessment

Risk assessment (RA), validated test method(s) used during the RA and results should be available during inspection and review.

No further action required.


Elements < 30 % of PDE
(below control threshold)

No further action required, i.e. existing controls to be considered as adequate.

Potential consideration for periodic testing.


Elements from 30 % - 100 % of PDE

Define additional controls:

Specification on DP or components.

Define upstream control and impact on EI level.


Elements > PDE

Evaluate safety assessment and rational to support levels higher than the PDE for specific elements.

Define upstream control and impact on EI level.

Because of all the implemented changes, the ICH Steering Committee decided that the development of a comprehensive training program and supporting documentation was necessary. They have developed a training program to ensure the proper interpretation and effective utilization by industry and regulators. Ten training modules are provided to assist industry with the implementation and include examples, you can find them here.

Get your knowledge on EIs up to date now!

Blog by: Bertine Vorstenbosch

10-09-2018
Read more

#A day in the life of: Nadia Vazirpanah

FACTS

Age: 31

Studied: Cardiovascular and immune diseases; Ph.D.

Experience: Ph.D. and Xendo (since January 2018)

Goals: Growth and contribute beyond myself


PERSONAL DESCRIPTION

I’m Nadia Vazirpanah and I joined Xendo’s Young Talent program (Medical devices) in January 2018. I was born and partly raised in Iran but it is in the Netherlands that I completed my bachelor study at the Medical Laboratory Research in Groningen and my two Masters at the Vrije University in Amsterdam. During my Ph.D. position at the UMC Utrecht, I had the privilege to collaborate with multiple national and international experts. Simultaneously while working for Xendo, I am completing my dissertation to defend my thesis by November this year.


MORNING

How do you get ready to start your day?

I live in Utrecht and travel daily to Leiden and use this time to prime my mind and plan strategies on how to tackle daily challenges prior to getting started in the office. However, once I reach Xendo - I first grab a cup of coffee!

What is something you look forward to every day?

Since I plan my day ahead, I am quite prepared for the things that I aim to accomplish throughout the day, hence, what really excites me are opportunities and unplanned events that just happen spontaneously!

Can you name some typical activities?

Selecting and applying appropriate sections of the Medical Device Regulation and standards and customize it specifically for the Medical Device in question. Also, defining and describing a product as adequate as possible is one of the essential activities.


LUNCH

Tell about your colleagues a bit perhaps.

Within Xendo, there are a variety of consultants with diverse ethnical and education background and expertise. Whenever there is a specific question, there is always a colleague willing to communicate and convey his/her knowledge and experiences with a cup of coffee or during lunch.


AFTERNOON

What is something you do every day?

The most amazing part of being a consultant is the variety of projects and challenges that you face. The rules are always the same, but the game changes continuously! And one thing we implement in all projects is to think and act along with clients.

What is the most challenging part of your job or day?

You have to imagine and picture a device in your mind completely in order not to leave any part undescribed and unaddressed; so you need a vivid imagination.

What makes you happy during your day?

I feed the monkey of my mind by having debates and discussions with my senior colleagues. This way I try to be challenged to think differently and see opportunities from multiple angles and to try and translate them into tailored solutions for each project.


CAREER

Why did you pick this job?

After finishing my Ph.D., I realized that I enjoy change, different ways of thinking, and delineating a subject over a longer period. Besides this, the contact with a large network of colleagues and clients makes each day of working-life unique and extraordinary.

How does it fit into your career plan?

I learn something by being present in this environment where you’re involved in multiple projects every day. Like Benjamin Franklin said; “Tell me and I forget, Teach me and I remember, Involve me and I learn.” This is how Xendo structures the Young Talent Program.

How does this company define your success?

Parallel to ‘learning on the job’ the success is achieved as a result of preparation, hard work and learning from failure.

To whom would you recommend this line of work?

If you need variety, want to be challenged, think outside of the box, work in a team, and contribute by taking responsibility in projects then you should consider this line of work. Are you gifted with a healthy and bright imagination and do you enjoy divergent projects? Consider working in this line of work within the wonderful world of Medical Devices.


Send us a message if you'd like to find out what your day could look like!

02-08-2018
Read more

#Orphan Drugs: Product Similarity & Market Exclusivity

The effects of the EU orphan legislation are substantial: over 1,950 orphan designations have been issued by the European Commission since the year 2000, of which 142 have resulted in authorised medicinal products so far (EMA Annual report 2017). The EU orphan incentives stimulate the development of medicinal products to make sure patients suffering from rare diseases have access to the same quality of treatment as other patients. For many start-ups and small pharmaceutical companies, developing a drug without the benefits of the orphan incentives is unthinkable and the orphan drug designation (ODD) is an absolute condition for investments.  

However, with more and more drugs getting approved while maintaining the designated orphan status, developers of drugs within the same orphan drug condition see themselves faced with a higher raised bar. Questions like “what are the options for a product to enter the market in case of an already approved drug for the same therapeutic indication” are frequently asked? The situation is complex as two different set of criteria of the orphan drug regulation apply, each with its own conditions and consequences:

  1. Market exclusivity of the competitor
  2. Maintaining the orphan drug designation status by showing significant benefit.

The criteria and options for entering the market in case of another orphan drug approved for the same therapeutic indication with market exclusivity period are summarized in the scheme below:

MA: Marketing Authorisation; ODD: Orphan Drug Designation

*Similar being defined as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism (EC 847/2000 Art 3.3(c), amended by EC 2018/781).

**Clinical superiority being defined as a medicinal product is shown to provide a significant therapeutic or diagnostic advantage over and above that provided by an authorised orphan medicinal product (EC 847/2000, Art 3.3(d)).

***Significant benefit means a clinically relevant advantage or a major contribution to patient care (EC 847/2000, Art 3.2)

 


1. SIMILAR PRODUCTS: MARKET EXCLUSIVITY

The first criterium in getting your product registered relates to the presence of a 10-year market exclusivity for another designated orphan drug being granted a marketing authorisation. I.e. another similar medicinal product can in principle not be placed on the market in the EU for the same therapeutic indication (Art 8(1) EC 141/2000). In this concept, a similar medicinal product is defined as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism (for detailed explanation, refer to EC 847/2000 Art 3.3(c), C(2008)4077, and EC 2018/781). The market exclusivity period can be extended by two additional years when the results of studies in the paediatric population are presented in accordance with a Paediatric Investigation Plan. The market exclusivity incentive prevents other companies to easily place a generic product on the market, irrespective of the legal basis of the original application and of the patent situation.

Marketing authorisation for similar products

If the active substance is indeed similar, your product can only be placed on the market for the same therapeutic indication when

  1. consent of the original marketing authorisation holder is obtained,
  2. the original marketing authorisation holder is unable to supply sufficient quantities or
  3. the medicinal product is safer, more effective or otherwise clinically superior despite having a similar active substance (for a detailed explanation see: C(2008)4077).

In these cases, marketing authorisation will be granted and the product can be launched but without the orphan drug status and the rights of market exclusivity.

If the situation and clinical program of your similar product allow, the planned indication might be adjusted to target a patient group not protected by the market exclusivity. Alternative indications might already be explored during the development of your product in case of the expected competition of a similar product. The adapted indication can but might not necessarily have an orphan drug status.

Marketing authorisation for non-similar products

If your product contains a non-similar active substance while the intended indication is similar, marketing authorisation can be granted by the EMA or national authorities without further provisions or restrictions related to marketing exclusivity of the registered competitive product. The usual positive benefit/risk requirement for your product applies for a marketing authorisation without ODD status and without benefits from incentives related to ODD status. In case the marketing authorisation of your product is granted via a full or full-mixed application, i.e. based on own clinical studies, the usual data exclusivity (8 years) and market protection periods for this type of application apply, protecting you from generic products for the same indication entering the market. Also, the patent protection period applies as usual.


2. MAINTAINING ODD AFTER MA FOR NON-SIMILAR PRODUCTS: SIGNIFICANT BENEFIT

In case ODD status is wished additional to the marketing authorisation, for either the protection period of market exclusivity or to increase market value, the second criterium of significant benefit has to be complied with. To maintain ODD status after marketing authorisation of your product, clinically relevant advantage or major contribution to patient care, compared to all authorised orphan drug product and other products and treatments for that orphan condition needs to be demonstrated.

This concept of significant benefit can be based on improved efficacy, improved safety or a major contribution to patient care and there has to be a high probability for patients to actually experience this benefit when using your product. At the time of marketing authorisation application, the demonstration has to be based on clinical comparison data. Depending on the situation either a direct or an indirect comparison between your product and the competitive product(s) can be made. Likewise, comparison with other treatments which the patients diagnosed with the orphan disease may receive needs to be provided. If benefits to patients are expected to be similar or if the investments to gather comparison data via clinical studies will be too high or time-consuming, your product can still obtain a marketing authorisation without the ODD status as explained above in this blog.

The concept and requirements for the significant benefit are further explained in Recommendations from the Committee for Orphan Medicinal Products (EMA/COMP/15893/2009), Guideline on the format and content of applications for designation as orphan medicinal products (ENTR/6283/00) and Commission notice 2016/C 424/03.


3. WHAT STEPS CAN YOU TAKE?

The approval of a competitor orphan drug product with rights of market exclusivity in the target indication of your product will raise the bar, but options still remain to register and market your product. If not similar in active substance, market authorisation with and without maintaining ODD status is possible. If you have an EU orphan drug status for your product, this is what you can do:

  • Continuously follow-up on programs of competitor products, similar or non-similar, in the orphan drug condition not to be surprised by granting of approval of another orphan drug in your target indication.
  • Even though competitor products have not been granted marketing authorisation, evaluate similarity and significant benefit criteria explained in this blog and the pros and cons for each option.
  • Anticipate if you need to prepare for alternative routes in your development program.
  • In case extra investments in the clinical program are needed to maintain the ODD status at the time of marketing authorisation, assess whether the investments balance the expected profits on the market.

4. RECOMMENDED READING

 

Blog by: Patricia Baede, Liesbeth Hof