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thank you very much thank you very much for the kind of introduction thank you the organizers and the management for giving me the opportunity to talk to you in this forum i hope you are all doing well you just heard the talk by dr hasman patel about the post-approval changes and the guidances and regulations related to post-approval changes once a drug is approved it becomes post approval and all changes that are made during the during the process after approval is post approval now i am going to use the word life cycle in the place of post approval and i'm telling you i'm going to tell you why i call it a life cycle now defining a life cycle so as long as the drug is being developed during the process you go through discovery pre-clinical the pre-clinical phase one phase two and phase three trials the drug is still in the process of being made and even though the clinical trials happen in patients is all still experimental stages that is it is like a baby still in the mother's tummy once the drug is approved by a regulatory agency that is when you are legally allowed to market the drug to the public anything that is approved becomes post approval and all changes related to the approved product will be post approval changes when the drug goes through a life of within the post-approval stages over several years when the patent expires patent expires and exclusively expires then it gives rise to many generic drug products it's like having its own child then uh the generics become mature and post-approval for changes happen even generate drugs now what determines the life cycle there are a lot of things that factors that go into life cycle of a product only after approval the real activity of a drug can be observed it's indication how well it happened works the efficacy in patients safety long term safety in patients then in the quality perspective you have manufacturability when the case of new drugs when they are being developed the drugs are made in pilot scales or reasonably less smaller sizes compared to the larger sizes that fit into the market after approval so the scale up and manufacturability of these kinds of drugs and its stability its quality maintaining the quality and how much of continuous improvement they can make to make economic prospects you know they give brings ultimately for a company it is extremely important to make the business point of view that's economics and how they can make sure that these drugs are produced in economical fashion and make more money out of it that's one of the things that is important the safety efficacy quality the quality determines the safety and efficacy and ultimately for a business it is economics as well matters i'll give you some examples here in this slide about some of the life cycle of the life of some of the products how it turned out to be these are interesting examples just for the sake of knowing telephone nadine and flexophenetic this is telephonedating is a drug which has developed for allergies a new molecular entity now what they did is this drug was was marketed for almost 12 years in the 80s and early 90s this drug was marketed as seldene the prop they found that it had a lot of side effects especially arithmetic and serious adverse events when they found that out they during the drug was when it was being marketed they found the actual reason for its efficacy for allergies but because of this carboxylic acid group which is one of the metabolites of this particular drug so this metabolite was later synthesized and did a parallel clinical trial when brazil in the market so they saw that they saw this efficacy was far greater so they pulled this drug out of the market and they this is the one of the blockbuster drug for allergies the toxicity was much lower compared to this one now there's another drug which had a short lifetime of five years this is one of the blockbuster drug could have been a blockbuster drug but it had unfortunately it had a serious adverse events you all can see all these things these are all publicly available in the database of wikipedia you can go to wikipedia and see that then uh there's another drug tessagara this was for colitis and um this didn't last too long either it did a lot of serious adverse events and patients and so they had to put it out of the market now i gave you three different examples of three different indications first one is uh for allergies the second one for for i think arthritic pain the third inflammation and the third one was for colitis it all each one has a different indication but still you know nevertheless that if it becomes a a problem for the patient safety for the patient then it goes away this lifetime is very short what happens in the life cycle see the real pain the reality of a drug is really seen only after it is approved in by the regulatory agency right the real efficacy long-term safety and then the stability issues that are related to the formulation that has developed during the clinical trial all these things come into play after approval and there are a lot of things the changes that happen even during development but there can be unintended consequences in the long term which could not be seen when the drug was being developed so we can see all those things in the life cycle in the life of a product and potentially alternate dosage forms if it's a tablet it can become an injection it can become a syrup oral syrup it can become many different forms that can take place uh in the life cycle and challenges in maintaining high standards is very important during a life cycle now during the life cycle when a drug is approved may become a blockbuster a lot of things can happen and become a blockbuster so the company makes a lot of money so when it becomes a blockbuster they can't keep up with the market right so they have to make a scale up so we have to make make sure that the quality is up to the mark and they may have to come up with different strengths um so sometimes it may have unintended adverse events not seen during the clinical trials so they have to address those things and uh in the labeling and maybe withdrawn during serious addressing we saw three examples before and may prove to be a more effective indica for for something else than this indication for example i'll give you minoxidil minoxidil is one of those is a genetic name minoxidil is was really developed for hypertension but it became a very good hair growth product because people who took the medication had less impact on the hypertension over growth of the hair so it became a very cosmetic product sold over the counter now now managing the approved drugs is very important after approval is a very crucial step for the companies to manage them and extend its lifetime so you have to maintain to make sure they have to monitor the drug so the entire thing in the post approval is a phase four it's almost like that's being in the market but they still they have to observe all the data and collect them and that helps the company too managing their approved products is the balance of risk management so understanding the past experiences evaluating what is happening in the market the present situation and planning for a better future with all the lessons learned during this process and changes are necessary to avoid pitfalls there's a lot of changes that happen so post marketing changes are inevitable no matter what for multi-various reasons now why postdoc this is i've pre-empted this slide in my previous talk the previous slide so the optimization this happens during the post marketing production scale up fine-tuning the controls making sure the company then during the development of the drug you know a lot less attention is paid because they're not sure if it's going to be approved so once it's approved the confidence of the company grows and more money is put in are pumped into this product so that they can make more money out of it the changes are global nowadays everything becomes a global or globalized economy so different parts of the drug come from different parts of the world and so the changes that are made for should have to maintain the quality so at different levels right so it's the global changes may impact the product quality so we have to watch out those those changes have uh an impact on the quality so that's why we have to follow certain guidances now quality changes are tied to the economics of the company that's why they're going around for finding the cheapest product uh cheapest material from different parts of the world and multiple changes at multiple levels for multiple reasons are the life cycle changes what are the different kinds of changes that you're going to see right one one of the important things this prior approval changes these prior poll changes have higher risk changes okay that means it will surely impact the quality of the product so you the this means that means that the company cannot implement the product with without approval of the agency now the review clock is four months there's a shorter time and if it is the change with respect to the labeling or for another indication efficacy then it's a ten month clock or a six month block depending upon what the change is how the priority of the changes then changes being effective 30 days is a moderate risk change high moderate risk change so moderately higher risks but it's a moderate risk so this review clock is six months so 30 days means 30 days gives the agency time to assess this application if the agency is satisfied okay you can go ahead and implement you may go ahead and implement it after the 30 days if you didn't hear from the agency and if if you got an acknowledgement letter saying yes it's filed as a cbe30 supplement you can go ahead and implement the change and the review clock is six months then there is another change which changes being effective zero days that means you can submit the application to the agency and implement it simultaneously that's the legal definition of it now the review process again six months this is also we consider as a moderate risk but lower moderate risk and this moderate risk changes are necessary for documenting and making sure that we review them sometimes we are not happy if we are not happy with the cpptv zero changes we think it's it has to be raised to a higher risk we will call the company and let them know that it is a higher risk and it will be changed to pas or cbe30 now there's another change it's unable to portable changes which are lower risk changes or no risk changes for example editorial changes or no risk changes no actually editorial changes do not have a risk on the quality of the product directly that's where they call no risk or low risk and there are other the stability extension of expiry is one other example i will give you examples for all these changes okay now triangular changes the example some of the examples new formulation change including changes into excipients labeling changes additional strengths primary container closure system changes compatibility protocols you learned about comparative protocols in dr patel's talk before and manufacturing facility changes to sites with no with no gmp histories available now you will hear from rose who is following my talk will talk about the facilities and what are the risks associated with the facilities and what kind of changes uh are you can implement or not implement then the stability protocol changes these are all high-risk changes considered as high risk and they need to be supplement they would submit it as prior approved supplements now cbe 30 changes cbe 30 changes are some of the manufacturing facility changes again and i told you that zeros will cover these you know there's a little bit of overlap here but this she will cover in detail uh the manufacturing facility changes which has a gmp history already available and if we are confident you can go ahead and make the change within 30 days after the 30 days then the cp 0 you can do within 30 days but cb 30 after the 30 days change in testing facilities with where gmp history is available then manufacturing process changes analytical method changes those are all moderate risk changes now cb0 changes that examples are additional specification controls but if you have an additional specification so you need we need to wire document it so you can submit it as a cbe zero change method modifications editorial changes corrections missing data software commitments and depending upon the risk changes that do not impact uh the step of quality safety and efficacy in any way can be zero you see be zero submissions annual reportable changes are some of the changes that you need to for you could submit uh in an annual report for every drug that's approved on its after the first anniversary within a month you need to submit an annual report and that annual report should contain a certain amount of information which you can look up the guidance on annual reportable changes what kind of report you need to submit in that you can even extend the expiry dating period with an agreement with the agency during the nda approval process and long-term stability data is required to extend the expiry dating in such cases you can do that that's one of the highest changes that you are allowed to do that but some of the high-risk products we don't let them do extend the date unless you submit the supplement to the cpas or cbe 30. now asmook also talked about ich q12 the guidance for uh for life cycle management of uh of uh drug products now this is like the company has a blueprint of an approved product what they are going to do over the period of its life and uh they're not necessarily the life the life may be uh over a period of next five years and they can come out with a plan and they can come with to the agency and ask for what they what the expectations of the agency are for the specific changes they have they're planning to make and those are established conditions and all established conditions those have a risk-based approach to the changes now this gives a regulatory flexibility to the company so that they know what to expect from the com from the agency and they company is also our plan also aware of what kind of planning we have to make for those kinds of changes and this is always dealt by a case-by-case basis now the objectives of this uh ich q12 is to really give a regulatory frame framework for the during the life of the product and the companies um knows what the to what the agency expects and the agency knows what the company is expected to do is expected to do and what kind of supplements are going to come in for the submission for the particular product if there is a problem market alert they can tell the company to make changes ingly innovation and continuous improvement is one of the reasons for this uh is the encourages innovation and competence improvement for uh for a particular technology application or even optimization of the process etc now common changes in uh after approval during life cycle are many and some of them examples here are formulation dosage forms introduction of a new strength and changes in testing facilities changes in manufacturing facilities changes in manufacturing process all these kinds of common changes happen these are not not just limited to this but there are a lot more happening but i'm not going to spell out every different change every little change that comes to us we're just giving you an example here now what i decided to do is to give you some study case studies now these case studies are embedded questions in it and the ques this is this will also serve as a ce question and answer session kind of thing okay just to make you think just to make you think uh based on what you learned very little you learned here and what what you can what kind of influence you can divide derive and what kind of decisions you can make based on these case studies okay now let's read the first case study i have read it out to you an immediate release tablet um direct product was approved five years ago all right now the manufacturing process was the batch process now the applicant wants to change the process to an efficient continuous manufacturing process what should they do i'll give you a few seconds to think a little bit what kind of a submission they have to file or what kind of a process they have to do let's go to the answer now case study one this is a novel technology so continuous manufacturing continuous manufacturing has been used in the food processing world for decades it has been loaded the food food area for decades but implementation in pharmaceuticals has always been uh i think was shied away because there was always a problem that you know this may may not reach to the standards of the expectations from a regulatory agency's perspective now the technologies have improved so much with the onset of higher capacity of detectability of various analytical techniques we are able to use these techniques in the pharmaceutical world so the best thing to do that this is considered as an emerging technology now the best thing to do to implement this is to come up with a package request a meeting with the agency send the package with relevant questions to ask so that you know what the expectations from the agency are and usually these emerging team technologies team will get involved and we also encourage a pre-operational visit to the company to see so that when the review when the submission is submitted when the supplement is submitted to the agency the reviewer will have an idea of what to expect in case study too this question okay is a usually the the first case it's always the prior approval supplement okay in the case of this particular case a liquid sterile product in the polymeric primary container graduate system the applicant wants to change the resin due to discontinuation of the currently used polymeric resin what should the applicant do in terms of implementing the change okay you have a polymeric resin container no longer available for them to package in the product in the particular container closure system so the new resin polymer is now being sought after and what should the applicant do to implement the change let's look at the answer so this will be what kind of filing the change will involve a higher risk so it's a prior approval supplement filing okay then the stability data of the product in the proposed resin is important because there's no history on that we don't know what this resonance what resin will do what kind of products it'll leach out so or what kind of reactions this particular product is going to have on this new resin so the best thing is to make sure that you have the extractable data and leachable data for this particular product the extractables are done in different kinds of solvents highly polar to highly non-polar solvents both organic and aqueous high ph to low ph and aqueous and make sure what the leachable data what kind of exactables you can collect and based on those except for exactables you need to find out what kind of elements that leach into the drug product when it's stored and under stability conditions up to the expiry dating period now based on the exact on the leachables the pharmacology toxicology needs to be evaluated and the this is very important because this may impact the safety of the patients so these leachables should be below the reporting threshold okay study three after approval of an extended release oral drug product the applicant wants to change the analytical method without changing the specification what kind of submission is required analytical method so i've been i never told you what analytical method okay so you have a leeway to answer it the answer would be it depends that's a good answer okay now it can be a pas or a cbe 30. invariably it's a pas or a cbe i'll tell you why but if it's an extended release product and if it's an extended release order dosage form then the dissolution can have a serious impact when the method is changed so that will be a prior approved supplement however if it is say lc to if you're changing from hplc to a uplc that can be submitted as a cbe 30 supplement or if you are changing the solvents in the hplc for a better resolution you can separate as a cbe30 supplement solvent or a buffer or you know conditions of chromatography everything can be in under though those kinds of changes can be cbe case study for an applicant submits a supplement for a change in the supplier of an active pharmaceutical ingredient now reference is a brand new dmf drug master file if you don't know what drug master file is i can explain i'll give you a very short definition of it direct master files are independent uh owners of suppliers of components of the tech product so direct master files can be for drug substance or or a drug product now any company can go and buy the drug substance directly and these are the drug master files will be allowed to be reviewed only on the authorization of the drug master file owner and the agency requires that that to be required to be reviewed and that dmf should be adequate the direct master files uh if you don't know i i'm sure somewhere along the line somebody must have uh defined it to you uh either in the post approval or pre-approval supplier you know discussions so the manufacturing facility has been previously inspected for this the owner of the reg master file where the drug product is approved now it has an acceptable gmp compliance however no changes in the process or impurities were reported the specification is exactly as it was approved in the original mda what would be the filing category remember one one caveat here this is a brand new dmf it's never been approved never been reviewed so and under such circumstances it would be a priority supplement and you guessed it right okay this um it's a brand new dmf it needs to be reviewed after it's missing so so if the facility is in good standing prior pro inspection may not be required but it may be required if that profile class was never that profound class was never reviewed okay or never uh reviewed and or inspected you will learn more about it in rose's talk and let's go to case study five in case study five a prior approval supplement references dmfa for a new drug substance manufacturer the mfa references dmfp dmfb references tmfc during the review it was reviewed determined that the facility used in the manufacture of the type of substance was recommended for approval and data provided dmfa and dmfb were adequate and however dmfc when reviewed this found was found deficient what would be the outcome of the review what would the agency say it is obviously it's a priority supplement i gave you the answer what would be our outcome of the review tmf a everything looks good dmfc all the data looks good the mfp all the data looks good but tmfc is adequate but remember dmfc is referenced by tmfp so the case 35 since the dmfc is referenced by dmxp all dmf's a b and c will be inadequate okay hence the entire application will receive a complete response letter you know if it's the chain reaction so because well whatever your reference should be adequate for that one to be adequate that's why i'm going to give you a little bit of an example of one example on combination tech products uh give you an example of pulmonary devices the pulmonary devices are very complicated because if you have many moving parts and how you inhale uh is very important what is inhaled and how much of drug goes into the lungs is very very important for the efficacy and the safety of the patient because many of these drugs are emergency medication because you get your small asthma attack they want to have the inhalation done immediately especially for albuterol kind of things so you want to have it in hand and everything should work properly at that time so the devices have to work good along with the drug delivery that's very important now in the case of parliamentary i want to show you what are the issues that are very very important the dose delivered is important the when the dose what is delivered one of the other important aspects of it is the aerodynamic particle size distribution it should be between two and five microns two and five microns if it's lower than two microns it just comes out it doesn't go to the length if it's higher than five microns it goes and stays in the throat so the 215 micron is optimal for the lungs to be absorbed and the plume geometry i will show you an example a small change can vary the probe geometry when the of the aerosol spray and extractable leachable information is very important you don't want something that's uh which which is a thing that's leaching that's going into the lungs because lungs are extremely sensitive organs and the human factors how the device is used how intuitive the device is is very important now they're giving you an example of a meter meter dose inhaler well this is a liquid aerosol is the the particles of the drug a active parasitic ingredient is distributed or doesn't do in the form of a suspension into the aerosol and when you press the device the plume comes out the the drug is dispersed into the mouth to go into the lungs so if you see the number of parts so many parts there are almost 20 parts into this product okay this device and the product has two parts that is the aerosol and the the active ingredient with an example when they change the aerosol from cfc that's the chlorofluorocarbons treon to hfa which is another kind of aerosol which has alcohol in it so what happens the plume geometry varies so this appears to go deep right this seems to produce better plume geometry compared to this so there is a large a lot of lot of difference of obviously due to material protocol cfc is no longer available but i want to show you the difference uh what's very small changes can impact uh the the the draws delivered the drug that is delivered to the patient in a large uh in the larger way in conclusion to my talk life of a drug product starts only after its approval by the agency changes to drug product after approval are essential for multivariation i told you why they have to change what what are the kind of different kinds of changes and why these changes are important than the risk-based analysis of these changes and how we review them so you have to evaluate the risk on your own and if the company sometimes may feel the risk is so low but we in the experience of what we do everything is the case by case basis and the risk may we may think in a different way and the risk may be higher maintaining the high quality throughout the life cycle of the product is very very important and the focus on the patient should be the ultimate goal so whatever changes you make would you make sure that it is of high quality and make sure it is safe and efficacious in all the patients that are going to use it now last but not the least as i showed you the patient the big elephant is the quality so you can look at different parts of a drug and different aspects of the diet and however when you make the small changes on one end it can have an impact on the other end so you have to consider the elephant as a whole drug as a whole for impacting and establishing the quality throughout this life cycle and thank you for your attention you