Discover the Perfect Dr Receipt Format for Product Quality

Dr receipt format for Product quality

good afternoon and welcome to this uh second in our 2021 webinar series uh delivered to us um to you by dr tim sandal these monthly webinars will be covering different aspects of annex one and hopefully they'll help you prepare when it goes live today's uh webinar will cover quality risk management aspects of annex one but before we get into it i'd like to do a little bit of housekeeping if you have any technical issues if you can send a short message in the questions box on the right hand side of your screen our team will try to respond and try to resolve your issue please be aware that we are working remotely so sometimes there might be a slight delay um and there's only so much we can help you with from our side of things during the webinar rss i would like to invite you to ask as many questions as possible using the questions box again on the right hand side and at the end of the webinar time permitting will try to answer as many of these questions as possible any we don't get around to today we will answer offline and we'll share them with you all along with a copy of the slides from today and a link to view the webinar again in case you have any issues with your connections so for those of you who didn't attend our webinar series of last year or the first webinar of this year series my name's annette russell and i'm the sterile manufacturing lead at rssl i work in the commercial team at rssl working primarily with our pharmaceutical microbiology team to help support our clients both in sterile and non-sterile manufacture if you're interested in any of the services that rssl can offer to help support you please do get in contact with me via the details on the webinar on the slide in front of you before i start the webinar properly i thought um i'd start with a little poll for you all so um as we are starting to see covid restrictions lesson across the um countries i went wondering which of these you would most likely be doing as the first thing when the restrictions are lifted in your particular area so i'm going to give you a few minutes to answer the poll and let's see how many people are going to hug their family or go to the pub are quite happy how it is or are going to come and attend more rssl webinars so about three quarters have voted give you a couple more seconds excellent so um share with you the results so it looks like most popular thing and it's not really a surprise is that people want to go meet their family for hugs and i really appreciate this having a young grandson myself that i haven't been able to hug for a quite a long time i i see where you're coming from with that um 37 of of you would like to go to the pub or restaurant with friends and again another great thing to be doing nine percent of you are quite happy with how it is and i love the eight percent of you that are going to be attending our rssl webinars so thank you for that so i'd give you a little bit of overview of what we do here at rssl um we have been providing analytical support to our clients for over 30 years during which time we've grown and adapted as the industry requirements have changed in 2019 we were lucky enough to have been shortlisted for business of the year an employee of the earth the thames valley awards and we actually won the best cro and enlightened employee in that year we are based not far from reading um with good links to heathrow and of course we're mhra fda approved and we have a dedicated life science commercial team to help guide you to the correct technical support that you may need we cover a broad range of different areas as you as you know i'm the sterile manufacturing glued so my area is specifically around all those offerings um within that area the sterility and microplasmid being two of the key ones but we also have a biopharma division that can look after any of your biopharma analytical requirements we have an impurities division that specializes in eking out those impurities and at the moment the nitrosamines is a big thing there we have a medical devices division that can help with extractable unleachables or with physical testing of those materials and then our bread and butter is our our core work so this is the pharmaceutical analysis of raw materials across the board in the pharmaceutical industry and as well as finished product batch release testing but how can rssl um help you with annex one support as i said i work with the microbiology team uh they're based at our new working and facility which is about six miles from our main site and those of you who have attended previous webinars will have seen some of the teams in some of my slides so we can help with all aspects involved in annex ones such as the environmental monitoring and risk assessment which we might be going into a little bit more detail today and this can include identification of organisms we have a new multi-top which can identify those organisms that you might have found on your em plates or in your bio burden cultures we can help with cleaning validation this could be with a full clean validation assessment with consultants visits or just doing the analysis side of things for you we can also help with your disinfection validation again um we can help both um from a consultative point of view or we can actually do the the analytical work for you annex one talks a lot about single-use plastics and a move towards these in the industry so you may need to know the extractable unleachable profile of your plastics as i mentioned previously we have a team that's dedicated to this and our raw uh core business that test all the raw materials again are there to test um any of raw materials that going into your manufacturing across the whole industry especially this is especially true in the biopharma sector where pharmacopoeia methods generally aren't available and we might need to develop or tweak a method for you and of course the microbiology team i work with can do all the the bio burdens the endotoxin the microplasma testing of those raw materials we can also look at your vials and stoppers if in your aseptic field finish sites and we can help with container integrity testing as well particulate control is a key area and we have a large microscopy team that can help identify particulates that you might find in your manufacturing process um of course we do the sterility as i've mentioned previously we've had our sterility facility up and running every year now and finally we can help train your team we have a training group that are dedicated um to both running virtual courses they used to do in-house courses with companies um and they've also got some online training that they can help with any of these if you're interested please just contact me i'd now like to introduce you to dr tim sandal who i'm sure many of you have heard of and subscribe to his many different publications tim has over 25 years of experience in microbiological research and biopharmaceutical processing tim is the member of several editorial boards and he has written over 600 book chapters peer review paper and technical articles relating to microbiology tim works for a pharmaceutical manufacturer in the uk and also finds time to be a visiting tutor at both the university of manchester and ucl so i'll now hand you over to tim hey thank you very much so just switch slides okay hopefully everyone can see the slides okay and so it's a great pleasure to be back um with you and on that poll i think i would also be um hugging family and friends and uh visiting a pub and restaurant but of course i might be listening to a webinar while i'm in the pub of the restaurant um so welcome to this um presentation again the reason for picking this theme as a net alluded to was again linked to the forthcoming changes to annex one and it's very clear in reading the revision of annex one that the term quality risk assessment or quality risk management appears on many occasions and we know that regulators have expressed concerns about the quality of risk assessments and the way that risk assessments are being used and that includes not using um risk assessments um proactively and there's too much too many cases of risk assessments being used um retrospectively so there's a number of things that need to be um strengthened here and so risk assessment can be expressed as a formal process and it does contain a number of key steps which are on the slide so this involves establishing the context and environment that could present a risk identifying the hazards and considering the risks these hazards present to a product and ultimately to the patient an analysis of the risks including an assessment of the various contributing factors evaluating and prioritizing the risks in terms of the actions required and identifying the range of options that are available to us in order to tackle these risks and also to decide how to implement robust risk mitigation strategies so to perform this kind of exercise there are a range of risk methodologies available probably far too many and some quite obscure so part of what we're looking at is some of the more common and useful risk assessment methodologies and some are going to be more applicable to a given situation than others and it's always important to bear in mind that risk assessment doesn't need to be and really shouldn't be a complicated process and it should be appropriate to the type of sector that we're working in this particular product or the particular scenario that's presenting itself so what i'm going to do is run through risk assessment in general some risk assessment tools and then in order for it not to be too dry and abstract is to kind of round up with some examples of applying risk assessment in real life and i've picked environmental monitoring for that purpose um so to begin with um what is risk and often the term risk is any outcome of the risk assessment is confused with the word um hazard and what risk is is an expression of a hazard and a hazard is the potential source of harm and the hazard either exists or it doesn't exist and what the risk assessment does is it assesses the hazard in terms of its likelihood to occur and the severity should it occur some hazards are of more concern than others and just because hazards exist or multiple hazards might exist in one situation doesn't necessarily mean they are a problematic risk and in fact many hazards are dormant only having the potential to cause harm should a particular set of circumstances cause them to um be something that's bad and so the hazard concept can only really be understood with the probability or likelihood of the cause of the hazard causing harm and then when it occurs the degree of severity and we can divide hazards up in the healthcare and pharmaceutical context as something that could be physical chemical biological even psychological or ergonomic so risk is a consequence of hazard occurring and it's then also clearer to consider risk as a probabilistic concept and something that's inseparable from the factors of probability and on uncertainty so it's just a different way of conceptualizing what we mean by risk so in terms of types of hazard as i said we have physical hazards that something could cause direct harm to a person or to damage a piece of equipment chemical hazards could cause harm to a person or they could cause product adulteration so something connected to cleaning validation for example biological hazards are biological agents that could cause harm to the human body or they could adulterate the product and obviously a clear-cut example here are microorganisms and microbial toxin by-products psychological factors can play a role in pharmaceuticals and healthcare particularly with operator fatigue and we know that fatigue operators can present contamination issues particularly within aseptic processing as can ergonomic hazards if we can't adequately reach things and we have to then engage in non-aseptic practices so the hazards that can present risks to pharmaceuticals and healthcare operations are going to be varied and we need to apply this kind of thing into things like materials and ingredients the physical characteristics and composition of the product the processing procedures that we're following the microbial controls and microbial limits clean room design equipment design process flows the cleaning and disinfection regime the activities of people and steps to minimize the potential for human error and control of utilities and so on and in terms of expressing risk and we often talk about this probabilistic risk that i mentioned earlier this refers to risk assessment approaches that draw on a often numerical or at least qualified expression between severity and probability and in terms of a numerical expression when we come to look at failure modes and effect analysis this is a prime example so under these circumstances risk is characterized by two quantities the magnitude or severity of the possible adverse consequences and the likelihood probability of the occurrence of each consequence i'm going to keep going back to these these terms so the outcome or consequence can be expressed numerically in order to express how severe something can be and their likelihoods of occurrence can also be expressed as probabilities or frequencies how likely something to happen and the total risk is the expected threat the relationship between this severity and this probability and we can if we want to use a numerical score express that by multiplication so we can multiply a severity score by a probability score now we also need to consider risk reduction and risk mitigation and sometimes this can be driven by improvements to training strong procedures or the adoption of new technologies so for example if we consider aseptic processing if we look at open wraps on the left hand side of the screen that presents a theoretically greater risk of microbial and particular contamination than does the image on the right hand side of the screen which is a fully closed barrier isolator so the same risks are there the same potential severity let's say microorganisms getting into an aseptic product so the severity is equal for both of those pieces of equipment but the likelihood that the risk might occur is more likely on the left-hand side and less likely on the right-hand side so we can reduce risk through technological improvements now one of the conundrums or quandaries of any risk assessment is to what level should or can a risk assessment process aim to lower risks and what is an acceptable level of risk reduction and sometimes people talk of this a lara concept or as low as reasonably achievable and this can be useful to a degree but we still have to be sure that we're not going to harm a patient and this approach was first used in the earlier days of risk management when it was more common in the health and safety field before becoming adopted by other industries like pharmaceuticals and some advantages of like thinking in this concept is that the at least the residual risk is known and the basis of acceptance of the residual risk is clearly defined and agreed by all parties and also we can establish a baseline of what can be achieved versus the effect and we can consider available resources technical capability investment requirements and the level of technology so at least when we're talking about reducing risks we can verbalize what we mean by by that whether that's acceptable to everybody is a different thing but at least there's an approach within that then to deliver risk and we've spoken about risk tools if you start searching across the internet you will start to find a myriad of different risk assessment tools some are the same just dressed up in different languages and repackaged by one organization over another and some are fundamentally different some require complex computer programs and equations such as monte carlo modeling others can be approached on a more simple basis and they're the ones that i'm going to be concerned with because again in most cases we have a an issue we want to address either something before we've done something or after it and we want to deliver a robust risk assessment but we want to deliver it relatively quickly so we have things like fishbone diagrams which are a simple and effective tool to help group discussion and they can help shape cause and effect and we can draw a lot from flowcharts and process mapping but perhaps the two most um common tools that we will experience within the pharmaceutical and healthcare context are failure modes and effect analysis and this is an approach that evaluates every potential failure and then takes the users through a process of risk reduction so it not only rates the risk enables prioritization of the risks and this works fairly well on items of equipment and then we have the building up of the flowchart process mapping approach which is through hazard analysis critical control points or hassob and this approach then enables us to show the flow through the process and then to pinpoint critical control points and establish limits for those control points when we've attempted to reduce the risks i'm gonna have a look at those in a little bit more detail now so beginning with failure modes and effect analysis this is a step-by-step approach for identifying all possible failures in a design a manufacturing or assembly a process or product or a surface so for example it could be a ultra filtration unit it could be an isolator unit it could be a new design a vessel these are the kind of examples where fmea can prove useful so we're looking at these things called failure modes and this is the means or there are this means the ways or the modes in which something might fail so failures are errors or defects and then we have the effects analysis part which is looking at the consequences of those failures should they occur so you see we're looping back again to that same expression of risk and failures are prioritized to show how serious the consequences are how frequently they occur and also the fmea builds in how easily they can be detected so it's about guiding us to take actions to eliminate or reduce failures and we can start with the higher risk ones through a risk ranking process then with hasab so hasab originated in the food industry in the in the early 1960s but because that's all geared around hygiene improvements the same philosophy applies to a pharmaceutical process so hassab is a management system in which safety is addressed through the analysis of biological chemical and physical hazards and it can begin with anything like raw material production through to final formulation and distribution of a product and it uses a flow chart approach to look for contamination risks points of risk mitigation and monitoring points and we loop back to hasa when we look at some of the case studies shortly it's also important to benchmark benchmark risks and have an understanding of those so benchmarking is a measure of performance that's using specific indicator and it results in a metric that then we can compare one risk with another risk or one risk assessment to another risk assessment or between projects or even between organizations um so the idea of benchmarking is quite useful and this also features in the necessity to re-review risk assessment so risk assessment should not be things that should sit on the shelf gathering dust they should be pulled out every change control that's applicable or reviewed on a regular basis as well so we can make regular comparisons with best practices it can help to identify gaps we can explore new ways of improving how things are done we can then ideally introduce improved processes and we have a way of monitoring and measuring progress as we work through different systems or re-review risks we also need to consider whether doing a risk assessment is a productive use of time so it might seem a little strange that we're running this webinar about risk assessments to raise the question of um are risk assessments beneficial or to phrase it more accurately are all risk assessments beneficial but understands that sometimes risk assessments are either not necessary or at least they're unnecessarily complex and sometimes having risk assessments that are too complex can lead them to going wrong not seeing the wood for the trees to use a cliche or it may not justify the time spent on them when the actual thing we're dealing with is relatively obvious and we have to bear in mind that risk assessments can be expensive processes to run especially in terms of time and resources and so we may need to want to do a you know a risk benefit analysis and we can simply we can simplify the process for example just by running two lists and cross comparing them so there are sometimes more simple tools that can be used for more simple issues and i'm not diminishing the need for risk for serious contamination events but there are other times where we can use more simple risk approaches and risk assessments are also fundamental in terms of annex one and annex one guides us to embed risk assessment into the pharmaceutical quality system so the pharmaceutical quality system as defined by annex one is a strategy to develop and to use effective monitoring and control systems for process improvement and product quality so it's all about a mechanism to provide assurance of the suitability and capability of our processes and that also links with the aims and expectations of ich q10 so the risk assessment the risk management approach is useful for identifying and monitoring those control systems and it's also a good way to capture organizational knowledge and to use that knowledge appropriately and we can also connect up the risk and the pharmaceutical quality system with the contamination control strategy which is going to be the subject of the next webinar in this series so there's a quite a good interconnection with all of that and it's also notable that annex one says that for anyone tasked in the batch release process so qualified person and others have to be fully conversant with all of the risks that the pharmaceutical healthcare organization is facing at any particular time and what any gaps are and what any risk mitigation strategies are and whether existing risks are at an acceptable level so you see everything bounds together in that process now a lot of what annex one is talking about in terms of risk assessment comes down from ich q 9 which sets out a wide ranging set of objectives around quality risk management so for example just just pulling some of those things from that you know it's obviously the manufacturer must be producing products that are fit for their intended use and not placing patients at risk so we need to understand what we mean by the the patient risk um there's also built into that that senior management must have a system in place for conducting risk assessments that are geared around product quality and safety and that resources are there to enable those risk assessments to take place and that the risk management system must be bound up with the quality assurance system and be a fundamental part of good manufacturing practice that risk should be fully documented and their effectiveness continuing to be monitored as part of the life cycle approach and those undertaking risk assessments must be the appropriate subject matter experts and understanding what they are addressing so in terms of the kind of the two fundamentals that come out from the ich q9 expectations as i see them is that we need to use a scientific approach to risk assessment on the understanding that we know what we are um talking about so for example i'm a microbiologist so if we were undertaking a risk assessment that might say extend a product hold time then if that didn't involve a microbiologist that would be a concern because extended hold times provide the opportunity for increased microbial growth so you need to have that knowledge going into the process and also risk assessment can help us to build the with new products a targeted product profile and we can help us to identify critical quality attributes that we want to take forward and that kind of fits in with the detection and monitoring process now quality risk management is frequently the subject to gmp and spectra deficiencies this is either due to not doing them or not doing them correctly or using them inappropriately so some examples have just pulled out from searching gnp deficiencies or failure to embed a risk assessment within gm within recall procedures um not using risk assessment for change controls risk assessments being inadequate by not assessing all of the hazards in relation to cross-contamination or risk assessments being inappropriate like including low risk and one of the dangers to get across and one of the challenges with um inspections is not to sort of get in a room and say right how do we come up how do we make this a low risk because that can be perfectly obvious and one thing that inspectors are very critical of the so-called sat nav risk assessments where you're deliberately trying to guide to a particular outcome the risk assessment should be unbiased and the outcome is the outcome and then you attempt to mitigate those risks and then specifically with the revisions to annex one there is an expectation that quality risk management is used to review existing products and processes it's used to help the development of new products and processes to fit in with quality by design and also to address problems and procedures that arise in terms of helping to shape deviation management so although regulatory authorities are encouraging risk assessment this is with the expectation that the majority of risk assessments are proactive so you're looking at things in advance you know that we're about to buy a new piece of equipment or about to make a change to the process what do we need to think about and one of the criticisms is is that there are too many reactive risk assessments which could be interpreted as attempts to risk assess your way out of trouble which is not really an appropriate use of risk assessment now those kind of things are sometimes going to occur but the more proactive risk assessments have been done then the fewer reactive risk assessments that should arise plus there is this concern about pre-judging outcomes which i've mentioned and there are some areas as well where those three aspects of risk assessment don't necessarily always work so severity is important and likelihood is important but we do need to be careful with detection so if we're going to take something like environmental monitoring where we're taking small sample sizes using methods that at best can only give us 50 recovery and that 50 recovery is only of culturable microorganisms and bear in mind that a number of non-culturable to approach anything and just say oh well we've got a few plates out everything's okay is often going to be less acceptable given the limitations of environmental monitoring as a full proof detection tool and other points to draw out is again looping back to ich q9 is that there's mention there of risk management being a systematic process and it includes in that not only the assessment but the building of the necessary controls but also things like communication so there's no value in doing a risk assessment say within quality assurance and producing a nice document and and putting it into the filing system if those who will be impacted by that are unaware of the outcome and then again we have the issues of regular review and embedding those requirements into the change control process so i said before a good risk assessment is one that uses sound science as part of the decision making and it should be systematic and have a structured process perhaps not too rigid a structure that this could lead to key concepts being overlooked but there needs to be an approach that can be followed with a degree of logic the risk assessment should also be transparent so it should be easy to look back and understand what was looked at and what was covered so even things that might be excluded it's good to list those as we haven't looked at these elements because they are not deemed to be significant but at least it's up front they also need to be inclusive so again going back to that example if we're doing a risk assessment into a production process if it was to be quality assurance and r d meeting to do the risk assessment and not involving production that would not be inclusive regularly reviewed and fitting into changes and any continuous improvement ideas and risk assessment is part of risk management and risk management is a broader umbrella term and that describes the identification the need to do a risk assessment as well as the assessment and as well as the prioritization of risk so if we as an organization have 40 risks that we've identified in border order are we going to approach those and it would be again generally logical to deal with the high risks first and also risk management needs to assess whether time and resources are available and also the process of mitigating a risk versus the degree of inaction that might stem from not immediately mitigating that risk so the risk management should ensure there are is a clear purpose and a meaningful outcome to the risk assessment process and it's probably a good idea to have a board in place to evaluate that and so risk management is this process of identifying risk assessing risk and taking steps to reduce risk to an acceptable level and risk management also needs to define the processes which techniques and tools are we going to be using what are going to be the team roles and responsibilities and how will they change for different projects so a risk management plan would describe how the risk management process is structured and then how the risk assessments are executed so again it's ideal there's somebody with that responsibility and there's a cross-functional group who are going to be regularly reviewing that so they can identify risks check on the assessments of the risks evaluate significance look at how responses are going to be handled we have a reporting structure we're ensuring that we're communicating and then driving any changes to procedures or setting corrective and preventative actions and then even to allow for an independent oversight and some may flag the concern of whether you know we actually know where the risks are so how do we identify risks and how do we know whether any new risks have appeared so there are some things that might constitute good practice that we need to draw on so we can observe staff behaviors we can trend deviations we can trend cappers we can ensure the degree that we have a quality culture we can have management walk in the floor on a regular basis we can draw data from internal audits or local ownerships we can ensure we have experts reviewing data and trends and we have kpis that are not just there about say maximizing profit on a product but are also there to assess the quality of the product so we can do things like develop risk registers as shown on the screen there it's just an example of risk ranking a series of different risks and it allows us to work through that process and then we have issues of um developing appropriate plans and then also about aligning things to appropriate budget and resources and also setting realistic timelines so here's another example of risk prioritization this is quite a simple four-way matrix but it's a way of saying you know we've got 40 or 50 risks in the organization so we can group some of them as into high severity high likelihood and some into low severity low likelihood in other places and at least this shows to an auditorium inspector or to our internal management that we are dealing with our risks in an appropriate order and we have some kind of game plan in place okay so that's lots of theory a bit of philosophy a bit of practice a bit on the tools and that's all very good but how do we actually use risk assessments in practice so i'm going to focus on environmental monitoring and just in the final part of the webinar just have a look at some examples of that um so with environmental monitoring we need to consider what the hazards are and a lot of that is going to be what we might class as intrinsic extrinsic hazards so these are entities that are not integral characteristic of the product or the process so for uh the the intrinsic issues we'd have issues with buy burden control within the intermediate manufacturing but for this perspective what we're looking at here we're looking at extrinsic contamination so this could be the microorganisms present on people or say microsomes in the general cleanroom environment or in relation to any water any cleaning processes and this considering these hazards looks at the risk of ingress the risk of accessing the risk of actually contaminating and the risk of actually being retained into the product and we can work through that as prime resources to secondary sources and ending up in the product and this can help us to structure the risk assessment um so we could like apply this in say in the context of aseptic filling for example and generally we have these these kind of two main concerns about direct surface to surface transfer such as a personnel directly touching a product component or with airborne transfer say with poor airflow as an example and so that's one area we can begin to think about another area would be to look at the environmental monitoring program and to use risk assessment to assess how often we might be monitoring for and so if we've got a large facility we've got a cnc area we've got grade d grade c how often should these be done the guidance is strong in annex one about aseptic processing in grade b continuous in grade a but other areas we may want to weigh up a number of factors so we might look at these factors and weight them differently so we might want to give a higher waiting if there's a more dirty activity being performed in an adjacent room we'd want to assess during that activity there's no transfer to the cleaner area we might want to focus on routes of transfer incoming goods areas of component preparation want to factor in duration of activity we might want to give higher frequencies to ambient areas as opposed to cold rooms we may want to give more weighting to areas where we're using water sources compared to areas without water sources or where we have product opening or we may want to follow the process cascade and increase our weighting as we move downstream through purification to final formulation so there's no right or wrong approach but we can introduce a degree of risks thinking to environmental monitoring now i mentioned hassep earlier so remember that's the hazard analysis critical control points and this can be very useful particularly for helping to pinpoint environmental monitoring locations so it helps us to identify hazards which are the contamination risks including their various sources so air services people for example and then the routes that they might track through the process and this can help us pinpoint things like we might be concerned at areas adjacent to clean rooms we might be concerned about interfaces between clean rooms of different grades so this leads to airlocks for example we might be concerned where we have less than ideal airflow within a room we may have certain surfaces that present themselves as hard to clean that are close to where product is handled we may want to focus about where more people congregate within the room we might be concerned about particulate generation when a cip unit is run so there are various factors and often we're focusing quite a lot on human activity entry and exit routes and also the way that materials are transferred into clean rooms of different grades so like pass through boxes and proximity to the product but again these are just generalized examples of how we need to introduce risk based thinking into sample selection and to do this we need to have a thorough understanding of the process we can't do this in isolation and micro microbiologists can't do this by themselves because they would need to work with those who have knowledge of the manufacturing process and the methods of producing and formulating product of what the different manufacturing stages mean and what um microbial reduction steps there are in that process i'll be using for example affinity chrome photography where we might have a different charge effect to remove microorganisms or where are we using steroid materials where we use a single use technology and so on um so there are a whole range of factors that we need to consider and the hassip risk model guides us in this process because it enables us to assess risk it enables us to determine the monitoring points which we can call critical control points in the in the hassop lexicon to help us establish critical limits to establish a system to monitor and control these critical points it can help us guide to appropriate corrective actions when we find that something is not under control it allows us to establish procedures to confirm and verify that things are working we can build in documentation of reporting and we also have a tool to help train and educate staff and we'll end up with data to collect and there are various um asset flow charts and decision trees available and there's just one example on there but you can find those quite readily so we have a formalized structure that isn't too deterministic and we end up with this appropriate tool that we can train people against and a series of questions can help guide our thinking so we can sort of ask ourselves as we go through this flow what areas what would be a environmental monitoring location that is close proximity to the processing activity what sites or equipment are contacted by personnel where do people interact which sites might represent the most difficult areas to clean and disinfect where is the greatest amount of activity what are the roots of flow what are the roots of entry points and then we can superlay that with the different vectors of contamination that could occur relating to air supply room air surfaces people machines and equipment and we can assess the importance of each one of those as part of a decision basis to weigh up whether they are genuine hazards and whether they need to be controlled or not and also assess the likely level of contamination and as well as its potential transfer as well as the ease of dispersal and often that requires an understanding of proximity of that as well and also what methods we have in into control and what methods can we add so we need to look at the quality of hepa filters we need to look at segregation of equipment we need to look at which areas might be considered to be dirty such as equipment cleaning relative to where we are processing um to the types and design of surfaces the surface materials the gowning of people and how well they are trained so a whole myriad of factors we can come in and then we can also then decide what is the most valid sample to take is it a swab is it a contact plate is it a saddle plate is it an active air sample is it a sample of personnel or even introducing a rapid microbiological method and what kind of alert levels do we want to be responding to and a general rule is the greater the hazard the less control and assurance we have around that then the greater the level of monitoring we're likely to do or if we see issues with trending then we may want to feed that back in as well and with any establishment of this kind of hazard it's important to periodically verify that to ensure that the control system is working effectively so this involves reviewing key targets like rejection rates sample results control methods and so on so a robust way of reviewing data is also important and when we for those of you who are here for the environmental monitoring session last year we put a great deal of emphasis upon trending and that the environment monitoring without trending is is very weak okay so bringing the presentations to an end in the time that we have um we have set out to provide an overview of hazards and then the risk assessment process and also what is involved in a good risk management system and we looked at some of the general requirements pitfalls and challenges and some of the things that regulators are keen on and examples of good and bad practices and we looked at examples of environmental monitoring to show that and you know the key message is that risk assessment needs to be needs to have a purpose it needs to have a multidisciplinary team it needs to follow some kind of logical process and it needs to be communicated reviewed and any gaps acted upon so thank you very much and we can move over to the uh q a and hand back to an end thank you tim that was really useful i'm sure many people will have some questions we've had one or two come through while you've been talking um so people have asked what do regulators think of risk assessments generally that's a tricky one um risk assessment should be i mean the the ich guidelines came out many years ago and i think then regulators have said that they're good for some things but they're not necessarily um being done um as well or correctly as they should be so um a good risk assessment is a good risk assessment but i think the the guidance is that most should be proactive most should be open-minded most should have at least two versions so you do it first you come up with um a number of risks you go away set tasks to mitigate those risks and then you come back and do your next version to show those have gone and that the reactive risk assessment should only be for really free emergencies not trying to risk a way out of out of trouble so i think it's good in theory but regulators have picked up a lot of examples of poor risk assessments okay um i've got a question from ezra um she says for highest severity high detectability low probability the risk will be low are there any special considerations to be taken in this case as it's still a high severity um i think it depends on the context i mean if you're saying like aseptic filling when there's no um final sterilization step a microsome getting in is always going to be something of high severity because it could cause patient harm but if you've got good controls in place you've got adequate cleaning and disinfection sanitization barrier systems well-trained staff and obviously that likelihood drops off and then you're boosting that with um a wealth or our environmental monitoring program that would be an example so there's probably no more you can do but if it was something like you might be storing gas cylinders near the works canteen that would be high severity if they blew up but you might have loads of controls in place and you may have good detection alarm systems if you get a leakage but why not just move those away from the canteen anyway so just trying to do different examples so it's always a yes or no answer all right excellent um adams asked in order to be proactive in risk assessment is the ccs key to this um i think so certainly from the um specific microbial chemical in particular contamination i think they go hand in hand because and i think the the contamination control strategy would be um essential in the risk identification because um that allows you to take a thorough look at everything look at areas where you might be weaker and then you can feed that into the risk assessment process carry out the risk assessments reduce those risks down and then go back to the contamination control strategy and then you can uh complete a gap within that so i think they're interconnected the same way that risks are also interconnected to the pharmaceutical quality system okay thank you uh sadly we've run out of time um so thank you for answering the questions tim um we'll put a few more to you to get answers back as i said we'll send out the questions and the answers along with the slides and a link to the recording for people who attended um thank you all for listening i hope you found it useful if um please remember that we've got a webinar running every month um this year and our next webinar is on the 26th of may and that's going to be covering as as tim alluded to the elements of contamination control strategy so on behalf of rssl and the sterile manufacturing team here i'd like to thank tim for continuing to deliver such informative webinars for us and for everybody out there for listening please do not hesitate to contact me if you have any questions or if you would like to know more about any services that we can support you with um and we look forward to seeing you in may thank you thank you you