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6 Quick Tips About Excel Sheet Validation (GAMP)

#6 Quick Tips About Excel Sheet Validation (GAMP)

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

And what does an umbrella have to do with it?

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

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

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

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

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

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

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

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

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

Definition of ‘gamp’, found on:

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

Blog by: Nynke Noort - Consultant

Did you like this blog? You might also be interested in our sequel: 7 Quick tips about Excel sheet operation (GxP / GAMP)

NEW: We invite companies who are looking for an efficient way to validate their Excel sheets in an optimal way. You provide the necessary information and we'll provide you with a compliant sheet. Check it out!

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

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

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

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

EU Recommendation

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

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

What now?

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

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

Steps to take

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

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

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

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

Blog by: Marc Klinkhamer - Principal consultant

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5 zaken om op te letten bij een Richtlijn 7 meting

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

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

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

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

Een Richtlijn 7 meting leidt niet tot afkeur

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


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

Wat belangrijk is om te weten voor u als gebruiker

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

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

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

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

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

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

Auteur: Alex van den Berkt - Managing consultant 

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

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

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

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

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

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

The set-up

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


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

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


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

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

LBSP Singelloop 2017

#LBSP Singelloop 2017

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

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

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

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

Last year's runners!

Argus Safety Database

#Argus Safety Database

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


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


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

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

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

PV Query Tool

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

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


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


Dedicated Xendo AEM team

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


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


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


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

Demo & Additional information

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

Learn how SMB reduces downstream processing costs

#Learn how SMB reduces downstream processing costs

Simulated Moving Bed Adsorption significantly reduces downstream processing costs

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

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

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

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

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

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

Downstream processing: the basics

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

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

Conventional bioprocesses can be summarised by the following steps:

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

Simulated Moving Bed Chromatography

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

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

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

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

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

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

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

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

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

Development studies

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

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

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

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

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

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

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

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

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

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


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

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

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

6 essentials to introduce Lean Six Sigma in Life Sciences

#6 essentials to introduce Lean Six Sigma in Life Sciences

6 essentials to introduce Lean Six Sigma in Life Sciences

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

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

1. Engagement

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

2. Sponsorship

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

3. Stabilize first

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

4. Activate

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

5. Shift the paradigm

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

6. Continue improving

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

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

If you want to learn more about applying Lean Six Sigma principles in the Life Sciences, please contact Xendo or take a look at the courses we provide together with the Biotech Training Facility (Yellow Belt & Green Belt).

Blog by: Marc Stegeman - Principal Consultant & Black Belt 



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

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


Outdated facilities – bring back the ‘c’ in cGMP

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

Blog by:

Maud Breitbarth - Consultant at Xendo

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

Xendo BV acquires Sofus Regulatory Affairs AB

#Xendo BV acquires Sofus Regulatory Affairs AB

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

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

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

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

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

For further information, contact:

André van de Sande – CEO Xendo
T: + 31 (0) 71 524 4000



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

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

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

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

Feel free to contact us in case of additional questions!

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

Contact: Marc Klinkhamer - Principal Consultant at Xendo