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?
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!
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!
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!
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
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)
Although it is too early to speak of a game
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.
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
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
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.
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.
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.
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
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.
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.
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!
Oracle Argus is regarded as the ‘golden standard’ pharmacovigilance safety database. By applying a multi-tenant approach and by using the Argus workflow manager
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
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.
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
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
Our dedicated Adverse Event Management team is optimally integrated with other
As Argus is very adaptive, all process steps can be managed by
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.
Please use the contact form to request a demonstration of Argus or receive additional information on how this solution might benefit your company.
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
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:
Industrial Bioprocesses can be
Reducing downstream process steps can reduce capital investment and operational costs and reduce the overall energy consumption of an industrial process.
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
A typical process flow diagram is shown in the figure below.
Conventional bioprocesses can be
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
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
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:
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
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
In general, a process development study can be approached from different angles and started or
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
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.
Here we can enter two different scales for piloting.A
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
Simulated Moving Bed has distinct benefits over classical single column systems with significantly higher
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
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.
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,
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
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
Lack of sponsorship is the most likely reason for failure, so just a few more words on promoting taking responsibilities, the right
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.
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.
Introduce a system where everybody in the
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
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
A place in the Top 250 is awarded to companies who were economically active on January
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.
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.
Maud Breitbarth - Consultant at Xendo
If you have any questions don't hesitate to contact us, we can be your pair of ‘fresh eyes’!
André van de Sande, CEO,
Linda Thunell, CEO, Sofus added: “This was a natural step for us in the further development of our business. As part of the
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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
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
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