Process Validation Guide
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Six focus areas to drive a succesful process V&V. Presentation from the MedTech UK 2014 Conference.
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Process Validation Guide
- 1. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Process Validation and Verification Rina Nir Rina.Nir@RadBee.com www.RadbeeQMS.com 105/2014
- 2. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com 205/2014
- 3. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Process Validation and Verification From Prototype To Product Six Focus Areas 305/2014
- 4. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Consistent Output 405/2014
- 5. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Controlled Process 505/2014
- 6. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com 05/2014 Erez Adiv, MedicSense Neomi Katz, Pharma Quality Europe Chris Monchinski, Automated Control Sun Kim, QbD Works Markus Roemer, Comes Compliance Services Kirsi Rosenqvist, Medtentia Line Szlamka, 4Echo, member of MEPY BENELUX One anonymous (off-record) Interviewees: (In alphabetic order)
- 7. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com GET YOUR CEO COMMITTED #1
- 8. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Management Commitment? Quality We stand for quality. We live our quality system according to ISO 9001:2008 and ISO 13485:2012. www.<NAME>.com/quality 805/2014
- 9. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Management Commitment! Using photo: http://upload.wikimedia.org/wikipedia/commons/1/1d/ Auguste_Rodin-The_Thinker-Legion_of_Honor-Lincoln_Park-San_Francisco.jpg by Yair Haklai . Using: Entypo Font 905/2014
- 10. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com http://www.imdrf.org/documents/doc-ghtf-sg3.asp 1005/2014
- 11. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com http://www.imdrf.org/documents/doc-ghtf-sg3.asp 1. Body - 11 pages 2. Intro to statistics – 10 pages 3. Example – 12 pages 1105/2014
- 12. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Culture Change 1205/2014
- 13. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Culture Change 1305/2014
- 14. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com What Could Go Wrong? 1405/2014
- 15. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com 1505/2014
- 16. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Affected pumps were manufactured in 1998. Recall issued in 2014! 1605/2014
- 17. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com ESTABLISH AN INTERDISCIPLINARY TEAM # 2
- 18. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Where Magic Happens 1805/2014
- 19. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com What variability do we allow? 1905/2014
- 20. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com What Risk Exists If Parameters Are Out Of Range? Diameter Composition Curvature Soaking liquid Etc. 2005/2014 Are They All Equally Important?
- 21. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Consistently Producing A Stunning Product 2105/2014 The Free4 Concept Wheelchair. Designer: Mr. Markus Ofner, FH JOANNEUM GesmbH
- 22. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Requires Multidisciplinary Expertise 2205/2014 The Free4 Concept Wheelchair. Designer: Mr. Markus Ofner, FH JOANNEUM GesmbH
- 23. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com START EARLY # 3
- 24. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com 2405/2014
- 25. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com 2505/2014
- 26. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Wishful Thinking 2605/2014
- 27. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com A More Practical Approach 2705/2014
- 28. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com V Model Planning 05/2014
- 29. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com KNOW YOUR SUPPLIERS AND SUBCONTRACTORS #4
- 30. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Not Equal Partners 3005/2014
- 31. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Contractor Selection • According to level of risk (criticality). • Expertise. • ISO-13485 for this particular type of process. • Certification by a reputed body. • Serves big companies. • Pre-contract audit. • Quality agreement. 3105/2014
- 32. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Quality Decision 3205/2014
- 33. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Quality Decision 3305/2014
- 34. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Quality Agreement • Quality decision details. • Certification Of Compliance and other forms. • Quality process commitments (V&V). • Forbid non-authorized modifications. • Record retention (with Escrow agreement). • Audit right. 3405/2014
- 35. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Where Magic Happens 3505/2014
- 36. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com MAP YOU PROCESS #5
- 37. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Know Your Process “If you ask people to describe their process, very often different people will describe it differently…. There is no consensus about how the process is. They have many work instructions but not a single schema which describes the process.” Markus Roemer 3705/2014
- 38. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Process Map 3805/2014
- 39. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com “Obtaining a process that consistently conforms to requirements requires a balanced approach using both mistake proofing and variation reduction tools” GHTF Guideline 3905/2014
- 40. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Poka-Yoke No way to get it wrong 4005/2014
- 41. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com MANAGE THE MANUFACTURING RECORDS #6
- 42. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Data Flow Complements Your Process Map 4205/2014
- 43. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com One FDA Investigation Report http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/UCM382514.pdf 4305/2014
- 44. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com A Thorough Investigation http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/UCM382514.pdf 4405/2014
- 45. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Controlling Computerized Systems http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/UCM382514.pdf 4505/2014
- 46. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Paper-Forms and Back-Dating http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/UCM382514.pdf 4605/2014
- 47. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Do Not Use Sticky Notes! http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/UCM382514.pdf 4705/2014
- 48. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com Using Excel In Manufacturing 4805/2014
- 49. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com When Subcontracting • Include records related commitments in the Quality Agreement: – Access – Retention – Escrow • Include records investigation in your audits. 4905/2014
- 50. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com CONCLUSION
- 51. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com 1. Gain CEO commitment. 2. Establish a multidisciplinary team. 3. Start Early. 4. Know your suppliers and sub-contractors. 5. Map your process. 6. Manage the manufacturing records. 5105/2014
- 52. This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Photos are copyrighted as per their respective license. Rina.Nir@RadBee.com 05/2014 Erez Adiv, MedicSense Neomi Katz, Pharma Quality Europe Chris Monchinski, Automated Control Sun Kim, QbD Works Markus Roemer, Comes Compliance Services Kirsi Rosenqvist, Medtentia Line Szlamka, 4Echo, member of MEPY BENELUX One anonymous (off record) Interviewees: (In alphabetic order) Rina.Nir@RadBee.com www.RadbeeQMS.com
Editor's Notes
- Before moving to production, a MedTech company can be resembled to your home kitchen. Some home cooks can come up with very impressive, and even inventive food.
- When the home-cook wants to become a restaurant chef she needs to scale-up her cooking. In this process she will have to consider what are the key elements that are required to keep its taste and uniqueness, and how she can consistently avoid mishaps. Process Validation and Verification is needed to guarantee that when a MedTech company scales-up, not only the essence of the product is kept but that the chances for risky faults are practically nil.
- We need to build a process which consistently produces exactly the output we expect.
- And we need to define how we will know that we got what we expected.
- As this presentation is only 20 minutes long I wanted to use this just as an opportunity to provide you with few ideas on what to focus on when planning your V&V. On top of my own experience in operations in Medical Devices, I wanted to be sure I cover a bigger spectrum of opinions and ideas. Thus, in preparing this presentation I have interviewed 8 subject matter experts from various countries: 3 people who have leading roles in MedTech companies, and 5 who are expert consultants. In the process of distillation of all the information six focus areas emerged as the key drivers to successful Process V&V. I am very happy to share these with you today.
- The very first focus should be the Executive commitment to the process.
- Sure, many companies have commitment statements appearing on their web-sites or in their mission statement.
- The commitment we are talking about involves three very specific elements: the first is a budgetary commitment: sure, V&V will eventually save you costs in more then one way, but the upfront investment is not small. The second area is personal engagement and involvement with the issue, and the third relates to how much do Quality issues occupy the communication bandwidth between executives and their staff. In other words- how much of the meetings hours, email communication, etc, relate to quality.
- For executives who want to engage with V&V, I highly recommend reading the “Gold standard text book”- the GHTF Guidance Document.
- It is a rather short read- only 11 pages- and is written in very clear language. Any Executive can better understand what V&V entails after reading this.
- What we are looking to achieve within a company is a cultural shift. Many entrepreneurs and fast moving businesses are adopting an excited optimistic view point which emphasizes potential up-sides.
- Process V&V, is really about diligently working to find the potential down-sides and solving them. A successful V&V means that we have high level of certainty that problems will not happen, and to achieve that we have to search for the potential root-causes even before the problem did actually happen. Therefor, a successful V&V can happen only in an organization who searches for problems- not in one that assumes that they will never hurt us.
- We are required to anticipate today problems that may occur very far into the future. This is an infusion pump. Recently few customer complaints about a malfunctioning door have been received- when the door does not close properly pump does not function correctly.
- A Class 1 recall, which is the most urgent type, was issued by the manufacturer.
- This recall happened 14 years after the manufacturing problem first occurred! The cost of this recall today, not to mention the potential for harm, is much more significant then a fix that could have prevented this problem to happen in the first place. As an executive, you have to lead the way in giving permission and supporting your people in asking the difficult questions and looking for the problems.
- 2nd focus area emphasizes the need for multidisciplinary expertise.
- Even if you are a small, or perhaps even a virtual company- make sure that you get all the required disciplines involved. Those experts should cover the whole life cycle of the product- from design to manufacturing, distribution, and usage, and they need to communicate intensively with each other.
- The reason is that when we ask the right questions- the answers typically require input from several domains. This contact lens, has a design specification- the manufacturing line will not produce it precisely with the same measures.
- There is always variability and we have to ask questions abouestion this variability. The answers to these questions are critical to the way we will build our manufacturing process and are closely tight to the V&V process. So, when approaching V&V do not try to just tick the list of regulatory requirements- use the process to your advantage and to gain deeper understanding of what you really need. Apply risk assessment and decide which parameters are really critical. At the same time- you will identify parameters which are less critical and where you may apply a less stringent approach. This level of understanding can emerge only when you have all the right people around the table.
- This is the case even if your device is not a high level risk device.
- Having a good understanding of your product and production requirements will drive a much more effective V&V process.
- Third focus point is about starting process V&V at a very early stage.
- Sure, we are all familiar with this recommendation in many aspects of life,
- So we do our project planning and time planning etc,
- And in those plans, many times this is how the project looks like. If only life were so simple. Unfortunately, good V&V people are “trouble makers” and they will ask questions and raise issues. Building the process and only then starting V&V is exactly like building the house and only then asking if it has the right number of rooms.
- Process V&V planning should actually start at the same time as the Process planning, and they both should start really close to the product design and requirements collection. As explained before the manufacturing is highly influenced by the product requirements, but also vice-versa. With such a timeline, you are more likely to limit the amount of re-work you need to do.
- The V model is another way to show how Validation, Process build and V&V are closely interconnected and should feed each other- from a very early stage.
- The vast majority of devices are produced with the involvement of one or several subcontractors. This brings us to our fourth focus area.
- Just to be clear- you have much more skin in the game then your sub-contractor. Not only you have the absolute liability in the eyes of the law, a recall or a serious incident in the field, may be the kiss of death for a small or medium size entity. To protect yourself you have to be very vigilant when selecting your subcontractors.
- I have put here a short checklist. True, very often we do not have a big selection of sub contractors to choose from- either because the type of process is very specialized or because we are looking to manufacture small quantities. Be aware that when an item in the checklist is missing, this will mean higher burden on your side to guarantee that quality is still there. Two points which should never be omitted are the pre-contract audit and the Quality Agreement. Those should really be conditions to any sub-contracting in case of a critical supplier.
- A key component in the Quality agreement is the Quality Decision. How does the sub-contractor judge the production batch to be eligible for shipment?
- The quality decision has to be driven by the Risk Assessment and design constraints which we have defined for the product, and establishes the permitted output ranges.
- Besides the quality decision details, the quality agreement should include the information about the Certification Of Compliance and other quality influencing commitments. The role of it is to assure a controlled production line and compliance with your legal obligations.
- A good quality agreement is the foundation for a successful long term collaboration with your sub-contractor.
- The 5th focus area relates to the need to have a process map.
- A process map is a schematic view of the process, broken down into the various stations and steps. We see often that people will have work instructions for each step, but will not have one plan which shows the entire process. Not only is this map useful to you when planning your V&V, it is also very useful in cases of audits and inspections, very often the first question you will be asked is to explain how your process is. A process map will help you answer reliably and swiftly to the question.
- This is an example of a process map- for a very short process. For each step it shows the inputs and the expected output (blue). The color coding for the input (green, yellow, red) helps us designate which parameters are controlled and which are subject to uncontrolled or unknown variability. One of the key roles of the process V&V stage is to better understand how much variability in the output is introduced by the variability in the input and whether this is within the acceptable range. Knowing what are the acceptable ranges is key and has to be clear before we enter the V&V tests.
- Successful process planning involves putting a lot of controls and tol-gates in place, but, as the GHTF Guideline reminds us, control is not enough. We need to take specific measures, especially when the consequences are severe, that output variability is reduced and mistakes will not happen.
- Few error prevention approaches exist. One well known approach is Poka Yoke and I have brought here an example which we all encounter- the press-handle on the side of the modem connector has no role in the functioning of the modem- it’s only there to prevent the error of inserting the cable in the opposite way. If you have a parameter or a factor which is very critical and could be produced in a wrong way- take care of applying error preventing methods and do not settle only for control points.
- The sixth and last focus area are the manufacturing records, or in the FDA language- the objective evidence that manufacturing was done according to standards.
- Data flow schematic shows the records that are created during the manufacturing. They need to be available to the person who performs the Quality Decision. Very often those records are created by a variety of electronic systems with additional paper records. The challenge is to assure that the quality decision has all the required input available. Sometimes, the quality decision requires a real “data hunt”- this is something that harms efficiency, costs money, and may compromise the quality decision.
- Records are also a very important element of any FDA inspection. This is a real life recent example of an FDA 483 form and the next slides show extracts from the very same form. Note that FDA staff are not called auditors, but rather- investigators. And investigate they do.
- … Very thoroughly. As written here- they will open the drawers of your cabinets and look for papers which are misplaced.
- They will not only check the validation reports of your electronic systems, but will want to know who has access to them and could potentially unduely change the records.
- They will review the paper forms and will look for any sign of back-dating
- And if they find any sticky note on a partially filled and signed form- this will be really unfortunate.
- Many people still use Excel in manufacturing. This is not a recommended practice because very often may lead to errors- as formulas and data may be easily modified unintentionally. If you do use excel- take the necessary precautions to control and backup properly.
- When subcontracting- make sure that these records are dealt with in the agreement and are part of any audit you perform.
- By this we have covered our six focus areas.
- If you: Gain CEO Commitment Establish a Multidisciplinary team Start Early Know you sub-contractors Map your process And Manage the manufacturing records You will not only have a successful V&V process, but will be more certain that your product is both useful and safe.
- Thank you for making the time to attend this presentation, and I hope you enjoyed it. Any questions are welcome.