Simulated moving bed (SMB) chromatography technology is a continuous mode of adsorption with enhanced separation efficiency and productivity. The countercurrent effect of this technology also results in improved purity, reduced resin, and buffer requirement. Currently, as a part of the EU subsidized Horizon 2020 project PRODIAS, Xendo gained extensive knowledge of applications and innovation of SMB technology in both packed bed and expanded bed adsorption (EBA) modes
As a technology developer, we share the vision to not only address new challenges but also to create a platform to share knowledge that can trigger both the industrial and academic world towards practical, efficient and sustainable process solutions. Through this symposium, we would like to bring together experts from different sectors to communicate state of the art knowledge on adsorption based technologies like EBA and SMB. After the talks, we aim to conclude the symposium with a priority list of opportunities to drive future implementations and innovations.
The talks are driven by following key attributes while focused on EBA and/or SMB technologies:
Approved delegates will be provided with registration details for the symposium and enjoy a complimentary networking dinner and full accommodation.
27th June 2018, Castle Oud Poelgeest, Oegstgeest (close to Leiden), The Netherlands
As the deadline for the implementation of the safety features stipulated by the Falsified Medicines Directive (Directive 2011/62/EU) approaches, marketing authorisation holders (MAHs) should have long started preparing for the introduction of the unique identifier (UI), a two-dimensional barcode, and anti-tampering device (ATD) on the outer packaging of their medicinal products. So let’s have a look at the regulatory implications.
By 9 February 2019, all prescription-only medicines, except for those listed in Annex I of Commission Delegated Regulation (EU) 2016/161, and the non-prescription medicines as per Annex II of the same Regulation must bear the safety features for the purpose of authentication, identification, and verification that the packaging has not been tampered with.
The European Medicines Agency (EMA) and Heads of Medicines Agencies (CMDh) have already provided guidance on how to introduce the safety features and the impact thereof on the marketing
This blog post summarises the regulatory requirements for the implementation of the UI and ATD and offers several points regarding the planning of submission that you want to consider.
REGULATORY REQUIREMENTS FOR THE UNIQUE IDENTIFIER
In order to facilitate the introduction of the unique identifier (UI), the Quality Review of Documents (QRD) template has been revised to include standard statements in sections 17 and 18 of the
For existing marketing
REGULATORY REQUIREMENTS FOR THE ANTI-TAMPERING DEVICE
As the anti-tampering device (ATD) is to be placed on the outer packaging, it is expected that its implementation will not have any impact on the product information. Should there be no outer packaging, the ATD has to be placed on the immediate packaging. In this case, if it affects the container closure system, the dossier has to be updated and a variation submitted. However, if the placing of the ATD on the immediate packaging does not have any impact on the container closure system, no regulatory action will be necessary. It should be noted that an Article 61(3) notification should be submitted if the ATD interferes with the readability of the information on the immediate packaging.
POINTS TO CONSIDER WHEN PLANNING REGULATORY SUBMISSIONS
This list is not exhaustive but can form a general basis for your planning. Since the requirement to implement the safety features can affect the entire portfolio of a company, strategic decisions need to be taken for the efficient and timely handling of the regulatory submissions to ensure compliance with the provisions of the Falsified Medicines Directive and the Delegated Regulation.
Blog by: Tin Choi Lam
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
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).
This blog described six important challenges you may face with the
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,
It is clear that the digital clinical trial evolution has not yet come to an end.
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.
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.
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.
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:
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:
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.
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.
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.
Next up, we had brainstorm sessions for each of the steps we determined, e.g. for drug substance preparation:
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”
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:
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).
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
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)
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:
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
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:
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.
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
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:
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.
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
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.
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.
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.
For most potential pitfalls, there are simple solutions.
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
Like always, we will also be
Every day we will be
Monday - Brexit Ahead
Learn about the impact of Brexit on the life sciences industry!
Including some perspective on areas like Quality Assurance, Clinical Trials, Pharmacovigilance, Regulatory Affairs. Most importantly, we will be providing some guidelines on how to prepare for upcoming Brexit challenges.
Tuesday - Gene therapy
This presentation focuses on the rocky regulatory road to market
Wednesday - Biosimilar development
Ard Tijsterman from Biosana will present on biosimilar development and how to set up an efficient developmental program.
More info: https://ebdgroup.knect365.com/bioeurope-spring/
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
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/
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.
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.
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.
In addition, terminology might change as nomenclature for Adverse Events and Patient Harm will be (re)defined.
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
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.
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.
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
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
|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
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
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
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
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:
All Member States have implemented these two Directives in their national GMO legislation and whether a clinical gene therapy trial is seen as
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
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
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
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
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.
The basic set-up is the following:
The scheme below gives a broad overview of how the system is designed.
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
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:
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.
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
Feel free to contact us to find out how or any other questions you might have.
Blog by: Nick Veringmeier
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
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.
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.
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.
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
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
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(
The kaizen is all about direct observation: M(
To keep the process on track is one thing, to keep people on track is a completely different ball game:
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
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
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.
Blog by: Marc Stegeman - Certified Black Belt at Xendo
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