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hello everyone and welcome to today's webinar designing an end-to-end sterility assurance program I'm Tim Wright editor of contract pharma magazine today's presentation is being sponsored by Nelson labs they're a provider of microbiological and analytical lab testing as well as consulting services for the pharma and med device industries our speaker today is going to be Martel Winters he's a director scientific competency at Nelson labs and he's going to talk about why sterility assurance for a farmer product is critical over the course of the next hour he's going to address the various aspects of sterility assurance and provide guidance on establishing a complete program we will be accepting questions throughout the presentation you can send those in using the box at the lower left of your screen questions will be answered after the presentation and a brief Q&A and this presentation will be archived on our website contract pharma comm for one year if you're experiencing any type of technical difficulties you can type those into the box as well and someone from the broadcast vendor will help you out so at this point I'll turn it over to Martel okay thank you appreciate that introduction so I'm excited to be able to to be with you today and to go through some thoughts that that I've put together regarding and end-to-end fully assurance program and likely most of these things are are not brand new to everybody that a lot of the things are fairly common sense but there are some specific things that I that I I'm going to be covering that I hope will will be of benefit so when I talk about civility assurance in the industry I think in the past for for many years the font was often that a that ability assurance was largely the sterilization process and we're trying to I think the industry as a whole is going towards a more holistic approach to to what stability assurance means and how to make it happen for their products so there's a relatively new standard from 2017 from ISO its ISO 199 3-0 and in that document the definition for sterility assurance is a qualitative concept comprising all activities that provide confidence that product is sterile so note that in that there's no reference to any number no no particular stability assurance level or sterilization processes mentioned so the idea of a qualitative concept is really important in that there really are many aspects in stability assurance and it's not just what happens at the end once the product is packaged and then ready for for delivery and it really really assurance at a whole a complete ability assurance program is very much an issue of just good project management where you are incorporating the right people at the right time and considering the right topics at the right time the collaboration is really important and having a complete ability assurance program so the the whole idea of silos where you do your step all do my step is very counterproductive to to a full program it's really important that that the this collaboration is occurring very early in the process so really even an RD stage it is it is useful and important to have that that collaboration beginning so a other document so Amy the Association for the Advancement of medical instrumentation is working on a document for the u.s. it's going to be st 100 standard 100 on end to end facility assurance with some concepts there that would apply to all to all forms of health care products and of course FDA 21 CFR part 2 11 talks about product safety identity trained quality and purity and in eight 20 talks about safety and effectiveness so but we all know that there is no specific guidance and in the CFR regarding how to achieve quality and safety I just talked about the importance of obtaining that and sterility assurance of course is a critical part especially of quality and safety so in summary just on the big picture of stability assurance that really truly assurance is not a sterilization cycle amount of bi test results or product stability tests resolve these are of course components of stability assurance but what it is is a much bigger picture it is it is there are things that are addressed in product design manufacturing packaging and sterilization and we're going to go now into into more details of some of these specific steps so still the assurance when we use the term end-to-end truly assurance we're really referring to the the whole the cradle to grave mindset so and in each of these stages we're going to talk about this so that Rd design of product sourcing of product components raw materials manufacturing shipping and in the customer each of these has a have a critical role in stability assurance when it's done properly [Music] the one one thing to keep in mind one important part here is is who needs to be involved versus actually just being aware of some steps and the importance of not having silos of collaboration being critical but clearly some people are going to be more critical at some parts of the of the overall product process as opposed to others so identifying and this again this is going to vary from company to company but identifying in your company what the list looks like as far as at each stage of the process who needs to be actually actively involved versus just being aware and for for very large drug manufacturers there often is fairly extensive internal expertise and so if that's the case and that's great where that internal expertise might be lacking then bringing in experts from the outside is really important and you know I often even if you do have great internal expertise the I often mention that that contract location to their manufacturing laboratories etc in a year's time the the people the the project managers the the laboratory managers at contract facilities they see a much greater variety of product types than you would normally see when working for an actual menu for a drug manufacturer or device manufacturer and seeing that that great that greater breadth of product type really really helps you to get good information on how you might tackle different different problems in different ways so even if there is a fair amount of internal expertise it never hurts to to bring in a couple of people from contract facilities that you trust just to get some additional perspective from them now stability assurance is all about improving patient outcomes and safety and so of course it what that means where it's related to improving improving company processes I'm sorry I mean if possible even though that the primary part is related to patient outcomes and safety if we can also as companies if we can also improve our own processes and profits and that's a win-win that's what we're all shooting for and one thing that we all know that that really hasn't has a problem or causes problems with company profits and processes are recalls I did a quick look through recalls on the FDA website and in 2018 for device there were 32 device recalls and 2019 so far there have been 29 and mostly the for device they've been related to product functionality issues and for that on the drug side so farther than 54 recalls in 2019 about 15 of those are still 'ti related issues and as you know that they don't provide a lot of details on there but but they are clearly facility related issues and then about about 29 of those are detection of impurities and particulates and so the question of obviously recalls are not inevitable ratar-o recalls are avoidable and it really when it there there are many factors involved in what can cause a recall from a still attea surance standpoint it really comes down to this the proper function of end-to-end facility assurance rather than just having the final step be either an aseptic process the stability test or a terminal sterilization process but some examples of poor and and stability assurance these are things that that we've seen here at Nelson and so you have a situation with a product that needs to be a drug product that needs to be filtered as part of it as part of its process of part of sterilization it's very viscous and so in order to to perform the filtration validation then what is commonly done is the the drug product is heated up so that it becomes less viscous and that works great for the filtration validation but of course that means that that generally you'll need to be doing that same thing in manufacturing and if that something has not been addressed ahead of time then that it can be difficult to implement that type of a process when when the process has already been fairly well established and so that can cause some issues questions or comments like well it can't be sterilized or radiation won't work oftentimes those types of comments are implied they're not necessarily empirically derived with data or if they are sometimes it's a very they're very simple attempts at determining a sterilization will function and so again with radiation for example the good when it when a when a simple attempt is made they might try dosing it at that forty or fifty kilo great of a worst-case high dose type of thing and say well it damages the product or maybe it's irradiated at room temperature and there there are many things that can be attempted both the you know in all forms of sterilization to to to mitigate some those potential issues so and again with heat you know it doesn't always have to be 1.1 C or 132 C for for for steam sterilization so so these types of things often if they're addressed properly at the very beginning stages then then everything is going to be be much better off want to talk a little bit about a couple of topics here first is terminal sterilization versus aseptic processing and I think everyone would would recognize that generally terminal sterilization is preferred and personally I am seeing a slow trend regarding a stricter review of where the terminal sterilization was was was actually attempted and was it attempted at Eddie with a decent amount of effort or was it or was it a feeble effort to attempt terminal sterilization I'm not seeing a huge shift towards requiring lots of data but I but I am seeing I am have had companies so over the last few years that have said that they're seeing more scrutiny regarding how much work they did to determine if terminal sedation is is possible with their products so in considering feasibility of sterilization what we should be looking at generally is more optimized sterilization cycles for example radiation it is it's quite easy to determine a radiation dose down to about 15 kilo graves and in the coming year or two it's going to be just as easy to determine a dose of as low as about about 11 kilo grace minimum and it's not as easy but there are current validation approaches where you can get salvation doses down to around around 8 or 9 kilogram in um um and that would be for a 10 to minus 6 ability assurance level 4 EO u does not require you can obtain good sterilization without having the fairly normal higher temperature RH and and higher higher gas concentrations so you know still vation processes can be validated for EO at lower lower temperatures like 3 degrees Celsius and low and lower relative humidity like about 30 percent RH and even lower gas concentration so I think in the end when we talk about optimized sterilization cycles and what we're really saying is don't just default to overkill cycles or worst-case cycles - in an effort to try and show whether sterilization is feasible for a for drug product or not so that one more option just to make sure that that there is an awareness around this is there is an ISO document worldwide and an ANSI ami document for the US regarding disability assurance levels and the options of of considering 10 to minus 3 to the minus 4 or 10 to minus 5 rather than 10 to the minus 6 which is the typical level of obscurity assurance that that is that is common so there are rationales in both of those documents to help understand how you might rationalize for example 10 to minus 4 as a terminal sterilization process which which still provides I think I think arguably provides more safety than an aseptic process because there is an active sterilization component at the end of of the manufacturing and packaging process so anyway just today and to make sure is an awareness around those options FDA and the the ASG 67 is an FDA consensus standard and so they they understand the benefits of that approach and and are open to to that if if they if necessary for product and it is a final comment that really thermal sterilization does simplify many aspects of facility assurance because there are there are fewer questions that can be asked at the end of the process and so there is there is a benefit there whenever it's possible I want to talk also just a little bit I've been using the term stability assurance level and I know and the and in the drug world there's also some frequent use of a probability of a non sterile unit pnsu so I know it's interesting how the device industry and the farm industry seem to have evolved somewhat separately regarding use of these two terms even though at the end you'll see that they really both mean the same thing usually but I want to talk to you a little bit about this this concept so there are some in the industries that say that SI l is for terminal sterilization and that pnsu is for aseptic processing and so let's talk about this for just a minute so it clearly SI l is is a proper term for terminal sterilization it is the term used in the iso sterilization standards but is pnsu really different so in the last couple of years over time i've done a pretty thorough review of use of the term pnsu and of what i what i don't see in any standards or guidance documents is is a discussion of calculation of numerical value as an output of anesthetic process simulation and i think everyone realizes that for a septic processing you do not take the output you don't you do not take the process simulation results and throw those into a calculation to derive any particular value you the process simulation is really a pass/fail test and it is something that you you establish the appropriateness of the sample size based off of a number of number of a number of inputs and the output result is that the that they septic process is validated or not so if if the term pnsu in this situation if it is use only the concept meaning you know that conceptually we just want to keep our probability of non sterility as low as possible then certainly that that term can be used it can be applied to a septic processing now conceptually with with aseptic processing the that if we're using pnsu and the scope of antiseptic process this would be a point where a product is non sterile whether it's due to one viable microorganism or a clump or a large number of viable microorganisms really doesn't matter the issue is it's it's supposed to be sterile is now non sterile what is due to one CSU or our sorry one viable cell or many but even though conceptually that is the case there still is no numerical value that is assigned to an aseptic process now most uses of pnsu in my review of literature they do refer that there is a corresponding numerical value and we're going to talk about that a little more here so when there is a numerical value assigned to pnsu it usually carries a negative exponent so usually for example 10 to the minus 6 which is an identical usage to SI l so but whenever there is a value that means that a calculation has been performed which means that it was it is only associated with terminal sterilization when there is a value assigned a pnsu USP 1229 a relatively new document from USP still evasions compendium articles does say that articles intended to be sterile must attain a less than or equal to 10 to minus 6 probability of a non sterile unit ie less than or equal to 1 chance in a million and 1 million that viable bioburden microorganisms are present and then in that in 1229 does have this note it says note this is also called the utility assurance level the term probability of a non sterile unit pnsu is used throughout this chapter because it is descriptive and substantially easier to understand so ing to this to this paragraph here and USP SI l equals pnsu that they are equivalent in in definition and usage and really it's more an issue of personal preference whether pnsu is used over SI l now one difference is that SI l does the SI l definition does say in it a single viable microorganism as opposed to in 1229 it says viable bioburden microorganisms are present whether it be one or many but VIN it so even though conceptually there could be that distinction between Si LP and su we have to recognize that whenever a calculation is performed for PN su that that calculation is performing that calculation is determining the first opportunity for non Cyrilla T which is one viable microorganism so even though conceptually we're saying that pnsu might be one or many when you calculate a pnsu value you are always calculating for a single viable microorganism just like you are with si el so really the two are in function the two are identical alright so let's talk about some of these different stages of stoolie assurance of an end-to-end really assurance program so R and D so in an early Rd I know that the typical question is can we do it can this work and once there's been proven some level of feasibility then Rd should be should become beyond can we do it and this is that this is really the proper place to involve the right people and to get everyone at least everyone initially oriented on this product candidate and this is where I I see company to do this quite well and I see companies do this quite poorly and it's it's this is the right stage will to bring in people from and I have the list they're engineering manufacturing packaging sterilization are a qa/qc and again if you lack the internal expertise bring in experts or even if you just want other people a bounce ideas off of them bring in these external external experts but this and and there might be more people that might that you might add in your situation but these are some good examples of how to start off so based on the product and I mentioned this previously where we're that you have two types of people that are involved in these and these truly insurance programs where you have those who are actively involved meaning routine participation versus those who are aware at different stages of the process people who are aware will merely receive summaries or maybe step in the occasional meeting just to keep updated but really the recurring meetings to discuss these to just hit the the primary topics of what's happening and to get input from the right people at the right times is is really beneficial real reason for bringing in people beside just the Rd group just to find find out can we you know can we make this work is there are a lot of potential setbacks or issues that can that can potentially be it could be avoided if the right people are brought in earlier on so experts for example in sterilization processes can help identify potential issues really early even in Rd stages we with a knowledge of the the types of materials the types of products etc this is a good time to perform an initial microbiological assessment just to understand what the potential microbiology issues might be with with and with a basic knowledge of the manufacturing process or the assembly process and then the people who really know what they're doing can derive quite a bit of good information at these early stages and then provide some good guidance so along with that microbiological assessment you're you're determining potential risks and as a result of those risks you're determining potential monitoring detection and prevention of those risks and if the risk is greater than of course the mitigation should also be greater and it might seem like doing too much this early on I'm not saying that you get into lots of detail regarding these things but in a good awareness of what the potential issues might be is really beneficial at this stage those specific things additional specific things to address going Rd are in the material selection are the raw materials suitable or sterilizable in some form are they suitable for sterilization and this is a good stage where different materials can be attempted where you might find that different additives or materials you might have as an option between a few a few different types and this is the right time to say you know if we use this want to be easier for processing or for sterilization rather than later on in the process and you might find that actually if you that the same the variety of products or ingredients that you're selecting turns out they all can be sterilized the same still vation modality then then that means that thermal sterilization will be relatively simple for for this product so Rd example so these are some some things from from a laboratory perspective so this first example this is what we've usually kind of discussions we love to see so this is a large drug manufacturer who is very aware of the manufacturing side and the R&D side of their drug products but when it comes to terminal sterilization although they have a lot of knowledge they did not consider themselves experts and so they brought us in we we talked about different modality options as far as sterilization types and we talked about sterilization optimization we talked about some of the process microbiology so many potential product bioburden issues because at that stage they had a fairly good idea what the assembly or what the what the manufacturing process would look like and so with though with that that basic information we were able to provide pretty good guidance as is anyone who really uh people who are experts in in the field of stability assurance alternatively we've also had had a fairly small drug manufacturer so they tried several process simulations or media fills and and they had failed them and they read a loss as to why they were failing these process simulations and these types of things at this stage so the Hardys pretty much done there they've already sourced the materials now they're actually into some form of manufacturing for for small batches for some R&D and in very early very early clinical trials and so at this stage of course an on-site visit is more appropriate to understand what's going on and in that visit we're able to identify some some clear improvements to the actual aseptic process they determined through the environment of that aseptic process as well as equipment that they were using and things that are obvious to to me for example as a sterilization microbiologist or the industrial microbiologists are not always as clear due to someone whose focus largely is on drug R&D so another plug so they're bringing the right people the right time to to overcome these issues as soon as possible the next step that you might call it the design step so this is where again based on your product and your situation you know determine who should be involved versus aware and again recurring meetings just to keep just to keep things keep the knowledge distributed but this is where you then begin to address items that that have been brought up in the Rd discussions so in are any discussions you've already have already talked about about determining potential microbiological risks and so at this stage this is where it becomes more critical to put some some solid processes around monitoring and detection and prevention of those risks and specifically here's where where you're establishing controls and monitors both what those controls and monitors are as well as when they are when they are taken and during what stage of the manufacturing process they're taken now I'm going to talk more specifically about target values for controls and monitors later but really this is not the time to establish those those target values usually at this stage you want to determine what you what you want to be doing and you might have desired values but to establish them in a procedure which I've seen done at this stage normally would be counterproductive so in the design phase often this is where you're also selecting your partners so you're gathering you're determining who your material suppliers are who the manufacturers are using any contract manufacturers you're establishing sterilization laboratory facilities whether internal or external you're you're getting putting some parameters around supply chain transportation and this is once you've got a decent idea of who those partners are going to be then this is a great time to get to get advice or feedback from those partners especially those that are external which which have not been incorporated previously so if some specs of these partners are already established then as I mentioned they can be really beneficial in the end in the R&D stage rather than in the design stage but one thing that that I've been seeing as a as a potential issue more and more recently as as you're selecting these these potential partners or for a product or a process to prepare them for their supplier qualification process so just make them aware of the types of things that you are going to need from them as a supplier or as a partner so that there are no surprises later on and I'll give an example of that a little bit later this is also a good time to ask questions about about customers so can the customer the doctor or nurse patient wherever the customer is can they use the product without impacting truly assurance and this is a good time to be asking those questions of where might we improve truly assurance base off of use of the other customer then also understand the potential negative impact of product on the customer and of course this is this is always I think at the forefront of your mind making sure that the customer is not impacted by potential facility Assurance issues and in implementing mitigations for those potential issues ample that I meant I referred this just recently just in the last slide so avoiding material supplier partners that don't allow a good review their process so just just see weeks ago I was working with a customer and they were trying to perform some degree of grouping of product types together for their sterilization process and those of you that are familiar with start with family groups for sterilization processes know that the that you will need to understand that the manufacturing process to be able to group things together appropriately and one of their big suppliers said well we're not going to tell you bout our process because we considered IP so we're not going to tell you about what types of cleaning steps we do on our raw materials or our components that we send to you if you want to come and audit personally we can talk about those a little bit but but largely its IP and so it make that does make it difficult for you to fully understand your stability assurance program when a supplier does not especially a critical supplier is not willing to share information on on what they do another the other point there is that microbiological risks that are identified early on those should be used to develop the proposed manufacturing process so that there will be adjustments made in manufacturing process based off of the risk identified whether the whether the process is enhanced to in an effort to mitigate microbiological risks or whether the manufacturing process is altered to allow to allow easy retrieval of samples for testing for for controls or for monitoring so now the the next age we'll talk about here is is the sourcing stage so this is where the the you're performing very thorough supplier qualification and but this is something unfortunately I see even very large companies that they I realize it's a complex thing to do but to categorize your suppliers based off of critical among critical suppliers and if they are truly our critical supplier than an on-site audit for especially for addressing microbiological issues is really critical quality issues of course are always something that should be addressed but I think oftentimes the quality audits they they often do not address potential microbiological issues and then when microbiological problems come up that's something that is addressed separately and and it's always better to address those early on as part of this big picture stability assurance program so and on-site audit for critical suppliers of course you're focusing on topics like endotoxin about compatibility aspects and and just overall product and manufacturing bioburden so change control assessment and notification I think I think it's safe to say that for most of those the the recalls that I referred to and I did not dig into every single one of those but for most of those it seems like manufacturing you know everything was fine for a period of time and then the the issue that that I wrote that that arose was because of a change that occurred somewhere in a process that was not properly addressed so change control it is critical to two good products truly assurance raw material component receipt process so I know it is common for or manufacturers to to have some sort of receipt process where if it's a if is a if it's a physical product a hard product or performing maybe dimensional analysis or inspection if they're powders or liquids sometimes they're doing other types of quality assessments of those as part of the incoming process and those are good but but this is a good time to make sure that those are performed in a way that they do not impact the finished product and I think I'll give an example about that in a minute so and then reviewing dative material and component cleaning processes so cleaning processes I've seen I'll talk about this a little bit more again a little bit but I've seen too many cleaning processes that really are not beneficial there's someone at some point thought it would be cool to add a cleaning process just to be safe and those processes ended up not being beneficial so again examples so I've really touched on these so you have a critical supplier with a I've seen companies that have critical suppliers where there is no established expectation regarding bioburden endotoxin for example and there is change control in place so they notify when a change occurs but there was no thorough microbiological assessment performed early on in the process and because of that there's no understanding of the baseline so when you don't understand the microbiological baseline of a supplier then to to do to add or earlier to address changes it's good but not best regarding inspection dimensional analysis I've seen situations there where raw materials or components as part of incoming process like I just mentioned after those are inspected they're placed back into inventory and and the level of control that well sometimes there's no level of control regarding those sample that undergo those types of inspections so addressing those ahead of time make sure that making sure is not happening would be really important material component cleaning processes again I've seen too many cleaning processes with no data behind them so they do it because they think there's a benefit but really unnecessary processes or processes without data behind them are terribly counterproductive to still the assurance and so if fills can be addressed at this stage and either added because there is benefit or remove because there's no benefit but then then that's the time to do it on the manufacturing side so I've been a manufacturer the manufacturing stage so this is where you've implemented some types of controls and monitors and this is a good time to be trending those and re-evaluating those as needed so establishing alert national levels and I have level bolded and underlined there too often I see the term limit being applied to action to alert in action values and generally those should not be considered a limit they are levels they are there are aspects of quality control there are inputs to the overall process but they are not a limit meaning that if they achieve that value that the product is no longer is no longer good so establishing and those levels and and reviewing those is really beneficial to sylheti assurance raw materials components finished product packaging so all those things guards to controls and monitors if you've got valid controls and monitors and all those stages it really enhances the process microbiology so in the world of microbiology one CSU and three CSU really are the same number so USP 1116 is a great resource for this concept and it has statements such as microbiologically is a microbial microbiology is a logarithmic science and it says normal variability is plus minus 0.5 log an actual quote variability of as high as 10 fold as possible numerical values that vary as much as five to ten fold may not be statistically significant and then it also uses the example that fifteen and twenty five Cs you are likely not different so just when you are establishing alert and action levels when you're comparing numbers to each other be aware of the normal variability that occurs in the world of microbiology is very different than what you'd expect to see in chemistry and physics and when along these lines as well when you're seeing lots of zeros it is common to establish these values based off of things like standard deviations etc sometimes keeping log transformations of those values and sometimes that's beneficial sometimes that is not but with lots of zeros and this concept is also raised and you ESPE consider perhaps using the frequency of occurrence of any microorganisms as opposed to what the actual numerical value is because again whether the value is one three or five those are all the same number so the nice thing in manufacturing a few again on the sterilization side if you've been mitigating potential microbiology issues early on then likely you're obtaining low bio burden which means you can have greatly optimized sterilization parameters so this is where the sterilization ends up not being a hope you have designed sterilization into the process and you've designed optimized sterilization cycles in the process which is always going to be better so cleaning and disinfection procedures so this is the right time to make sure those are have been validated and that you are doing some type of routine control of those procedures water system controls and processes again those are those are being regularly reviewed with the controls and monitors and it's very common to say well we don't have any water in our process so it's not an issue but I think it's safe to say that if you look back at suppliers raw material suppliers and gradient suppliers component suppliers there is likely some water in those processes earlier on and there there needs to be really strict procedures regarding standing water especially in in processes for for solid stability assurance to occur another thing is there really should be very strict processes for adjusting packaging parameters I've heard say and seeing some beta suggests that many of the recalls and stability issues are related to packaging which is a fairly simple thing we would think but packaging parameters can be often changed over time as as the packaging engineers you're trying to get the perfect seal today versus tomorrow and sometimes changes are made that have other impacts that are not understood and so the more solid approach to understanding - to adjusting what happens before adjusting packaging parameters temperature pressure etcetera would be would be wise so examples of these I've mentioned the one city versus three CFU I don't know how many times I've seen alert limits established one CFU inaction limits establish at 3:00 or 5:00 and again those are the same numbers so there you are you're missing the point behind alert in action if the resulting values are the same so in thermal starvation I've seen situations where you hit an alert level and they cease manufacturing and that's really more than what should be done or so for many types of controls or monitors that are being performed so the I've also seen situations where you have the same established leveled alert and action levels across multiple products or multiple materials or components and although that does simplify matters that does make it complex and it is not beneficial to the process when you when you have a single value applied single values apply it across the board I've seen waters water in clean rooms that are changed when needed and that's because the suppliers or there were the manufacturers themselves we're not paying attention to the potential impact of water and then clean components that are cleaned and water processes and left overnight to dry again that is in microbiology we call that incubation rather than cleaning so the last couple of quick topics here so shipping so the change control of packaging processes I've talked about that and a shipping configuration are really important to still the assurance to Maine to ensure that package integrity is maintained and I'm going to touch more lightly on these last couple of topics here shipping generally is not an issue once it is once it is properly established but maintaining change control a good change control over those processes is critical and then as far as the customer goes so of course the customers is the primary purpose of still the assurance and we've talked about these questions and the customer use a product correctly and the Dow's address are in design stage and what impact can can sub standards for the assurance have on the customer also addressed or in design by keeping the customer in mind during all stages I think many companies are very good at doing that and just maintain that mindset is critical acquisitions acquisitions or situations where I often see that ability assurance is not considered as part of the due diligence process and that in those earlier stages and even as the acquisition is coming to a close oftentimes sterilization or stability Assurance issues end up being a surprise after the fact and as many of these processes that are many of these these questions that can be asked or addressed early in the acquisition stage really helps to mitigate issues that come up after the fact a last last main topic here is the last main slide so it's really testing a sterilised product so sylheti testing of a tourmaline sterilized product should not really should never be a component of a student's program so as we've talked about so the assurance sa LPNs you usually 10-6 that's a 1 and 1 million probability of a viable microorganism so some Sun I hear companies think well that's really testing is useful it's just an extra control measure or it's kind of warm and fuzzy data point or customers expected really this should not be done this is this is one of the biggest risks that you can implement in a built-in surance program it really is much greater of a risk than it is a benefit in performing facility testing of a of a fully sterilized product so really do not do it it's difficult if not impossible to prove a false positive that really should not have been positive it was because the laboratory or shipping or something else there are no valid data that you can derive from testing 20-30-40 products in a process that is supposed to demonstrate a one-in-a-million probability and if the customers expected then let's educate the customers rather than giving in let's educate the customers as to what the proper way to verify truly assurance which is with everything that we've been talking about not with not with performing something like this like it like a utility test because fda document addresses is very nicely and guidance for industry i have that there it's a container enclosure integrity testing and lieu of school d testing as it can adjust and this is specifically as a component for the stability protocol so the focus of this is for stability but the same concept applies to any situation where you're performing ability testing of a term in sterilized product both that is the end of what I have for the presentation all right great thank you very much Martel it was a great talk I we have a few minutes here for a couple questions so just jump right into it the first question asks we have a product that is currently manufactured using aseptic processing but we do not have any record of trying different forms of sterilization prior to going with accept 'ok do you think we should go back and try some sterilization methods at that point okay this is a question that we actually get quite often when and this addresses the same question hits other topics as well where when companies go back and look at their history that they're documented history that often there can be very little found as far as some of the earlier stages what was tried as far as sterilization goes or other things and normally if if the product is a if it's a if if it's been approved has been out ministry and if it's working well normally I would say to not go back and to try to add sterilization as a as a process unless there is a particular need that arises or as part of a bigger picture change it's that's occurring normally I'd say if it's if it's not if it appears not be broken don't fix it that everyone knows that adage and I think that same situation applies here okay great thank you moving to the next question asks can you go into more detail regarding optimized sterilization cycles and how to approach those yes so the I can use maybe I'll use radiation as an example I think it's it's quite commonly used for drug components and and one of the more common if not the more common method used when terminal so relation is part of the process there I mentioned already about the very low sterilization doses that can be validated there's a method called method to that where you can establish a very low salvation dose down to about eight or nine kilo grades as a minimum dose value but in addition to that I mentioned an alternative si L so instead of hitting ten minus six putting together a a justification as the scribes in those two standards I mentioned for for example ten to minus four and when you implement ten to minus four as as the SI L or pnsu then the sterilization doses get quite a bit lower you can even get those you're looking at like four or five kilo gray or a sterilization process and then if you're implementing things for example in an ox and an toxic condition so you're removing oxygen from the process so if you're processing a product at very low temperatures for example dry temperatures that does often mitigate radiation damage to the product so those are a couple of things a couple of common things that are done on the radiation side another forms of sterilization that they're normally overkill cycles like ethylene oxide and steam instead of using an overkill approach if you use a bioburden based approach or a bioburden bi based approach those cycles can get extremely short and and really do a good job towards mitigating product damage due to the sterilization process okay great next one we have suppliers that have cleaning processes for components but we don't think they provide any benefit should we ask them to stop performing those steps yeah that's a oftentimes so I think the simple answer is unless there's a reason to know again if it's if it doesn't appear to be broken and the perhaps don't fix it but usually when customers I work with when they find out there is a cleaning process in place it's usually because of a problem that is occurring and and there have been a couple times where that problem that that bioburden problem that was occurring was directly tied to the this supposed cleaning process so so I think if it's discovered as part of an issue then I'd say definitely yes it's not something that you still want to do without gathering some data but but I I would recommend addressing those very carefully as part of investigations you know microbiology investigations because they're they can be the cause of a problem rather than something else that might jump out of an issue you have to look very carefully at the cleaning processes if there are no data behind them and determine if it should be removed or not okay thank you let's say think we have time for one more here do you recommend benchmarking bioburden during R&D on an early-stage product made at lab scale with little-to-no bioburden controls in place or wait until the clinical scale production system is in place to assess bioburden yeah that's a good question obviously you do not want to get into too much detail regarding product bioburden where there are a few controls in place however the I do see a benefit and gathering data gathering some amount of data because the you're starting to understand the bio burden that is coming in on the on the material from the supplier and as you start to understand what that looks like early on that can help you mitigate problems later on I think that one of the points behind the question you know how much data do you gather on the actual manufacturing process regarding bioburden I agree that there's not a lot of benefit to doing thorough evaluations of process bioburden at that stage but you definitely want to gather some data because you know the product bioburden can influence the results of the clintons clinical trials and so gathering some day is appropriate but not a lot of that stage I think that makes a lot of sense ok great thank you so yep that's about all the time that we have for today if you had a question and we didn't get a chance to answer it a Martell and the folks over at Nelson will follow up with you directly I just like to give another thanks to Marteau for his presentation and to our sponsors Nelson labs and as I mentioned earlier this session is going to be archived on a contract Pharma comm for one year thank you very much everyone for joining us and have a great rest of your day