The US FDA pre-approval and routine CGMP inspections – Complex Generics and Biosimilars



hello again in this talk I wanted to share some thoughts on the US FDA pre-approval and routine cgmp inspections in the context of complex generics and biosimilars as we discussed previously biosimilars and generics fall under two different statutes or laws in the US and traditionally they have had a very different approach to GMP inspection be LA's by definition require a license for with facility whereas generics did not biosimilars have traditionally have a team-based inspection generics complex general expert ocularly are moving in that direction so building on my previous talk expect the unexpected I wanted to focus on the point the reference product manufacturing process is claimed to be Six Sigma and what are the ramifications what are the consequences potential consequences of that happening on the market penetration market acceptance and assurance associated with biosimilar which may not be deemed interchangeable or s or declared interchangeable by FDA real the topic I wanted to discuss to place this discussion in a proper context I wanted to share with you the interactions and interrelationships between complete response letters CRLs that FDA is issuing for the development of after the CMC review process and the form 483 observations and warning letters these three things come together interact in ways that essentially give you a signal that FDA does not have the confidence or assurance in your development process validation continued process verification and overall in your quality system now we also discussed previously that in the experience economy with social media being so prominent furthermore the political polarization anxiety fear fear of imported drugs is so high assurance of quality also has an impact on adherence rate of patients and as well as I think prescribing practices of physicians so this becomes a very significant and complex topic and challenge to manage assurance not making mistakes not having warning letters not having complete response letters and not having a negative media car and social media coverage has become very important who makes the medicine I take is a very critical question that patients have started asking and they are seeking out corporations manufacturers that they have confidence in and are actually asking for I'd rather have if I have a generic or a biosimilar I rather have one from this company or that company so that is their very fundamental and important consideration so for example a recent warning letter to a biosimilar manufacturer says you formed failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed failure investigation out of specification investigation invalidation of out of specification investigations has become a very important consideration and FDA to express its no confidence also has increased the number of letters where FDA states cGMP consultant recommended when when FDA recommends cGMP consultant that is a very very serious consideration because cg mps our basic foundation and FDA just told this company they don't know they that company doesn't know what it's doing and I think this is something we have to work to avoid as we shared previously competencies for effective pharmaceutical quality management system requires appreciation for system psychology of change on on the soft skill sides but at the same time it requires theory of knowledge and knowledge of variation and inability to get to root cause investigation is an illustration of all four aspects so I think we are system of good practices exist says we expect an ordered and complicated system for ordered and complicated system good practices work and we have to know when we cross the ledges between order and disorder crossing though the ledges between order and disorder is very easy in our system so we need to maintain caring propensities and disposition necessary to be aware and respond to emergencies quickly and appropriately we need to understand to appreciate a system we need to understand the types of system the types of systems are simple complicated complex and chaotic chaotic is not disorder chaotic is a system that is prone to initial conditions very sensitive to initial conditions and therefore it is unpredictable because of that sensitivity and and and a chaotic system can be a simple complicated or complex system which is which happens to be very sensitive to starting conditions what are the starting conditions starting conditions are your raw materials starting conditions are your education training in experience of people another aspects so when you are not able to get to the root cause that means cause and effect relationships are not known when cause and effect relationships are not known you're already in a complex or chaotic system and and that means the development was incomplete and and incomplete in its ability to reduce complexity and uncertainty to a level of a complicated system inability to reduce uncertainty is at the heart of biosimilar step-by-step biosimilar development program you go from analytical characterization to to do clinical assessment in order to reduce uncertainty and then that is the very serious consequence so I think as we saw before I think the generic drug sector is in chaos currently and an adherence rates have been impacted by even change in color which is which we never considered very important and and and FD had to issue a guideline on shape and size matters they could not mention color in that because color often is a trademark although and then FDA still trying to increase generic competition while FDA is promoting continuous manufacturing and and has declared continuous manufacturing has in high impact on the quality that's a signal that we are moving into a system where continuous manufacturing would have a high assurance of quality because that's one way of getting to Six Sigma but there are other ways to get to Six Sigma or low rate of errors yet many companies have breaches in assurance of data integrity or bad eye warning letters and and and the hospitals in the US and the public in general are fed up with drug companies and in this particular case in New York Times January 2018 there was a news item that many hospitals have starting their own manufacturing system so we are at a very difficult situation at a precipice again and the journey for many come is to go from 666 which is an evil designation to 2 Sigma to Six Sigma and as we noted before FDA reorganized its office of quality and created a new office of quality to seek one voice between reviewers inspectors all along and then there are many reason for that one of the dimensions I want to emphasize now is integration of FD a facility evaluation and inspection for human drugs a concept of operation a pre-approval facility evaluation led by cedar and ORF participation pre-approval inspection led by RA with cedar participation so you see that the team approach to biological inspection is now coming for small molecule complex generics also and I think this is a clear indication that future letters future observations will focus heavily on out of specification investigation consumer complaints and other aspects so alongside the real-world evidence manufacturing state of control suitability and capability of your manufacturing system is fundamental suitability and capability of your manufacturing system depends on suitability and capability of your starting conditions your raw materials the people education training inexperience has become a very significant aspect and with the apprehension with the concern of about imported drug FDA ACP seeking one voice and if you look at the FDA goals starting that were announced on February 2018 the message is very clear from what domestic manufacturing advanced new domestic drug industry bringing med tech manufacturing home create a new medical data Enterprise advanced real world evidence modernized generic drug development and review to enable increased competition but in the context of I think domestic manufacturing increased manufacturing scrutiny and then in that regard I think the roadmap for suitability and capability of manufacturing processes have been laid out for many years now I think I see h q8 q 9q 10 q 11 now the draft q q q 12 FDA's process validation with continued process verification all have existed for many years yet many companies are unable to connect the dots integrate and interrelate between these guidelines this knowledge that has existed and also to do the same thing they they still work in silos of R&D regulatory tech transfer operations and quality unit and I think this gap has to be filled and this gap can be filled only by appreciation of a system and understanding psychology of change so people measurement system manufacturing process their lifecycle approach which I CH q10 has outlined for for several years now so to give assurance in the real world to ensure adherence by patients in the real world to ensure availability of medicines in the real world to assure affordability you have to put in assurance adherence availability and affordability on the pre market and pre-approval segments and that really is the way to progress now one of the case examples that I had an opportunity to evaluate was amgen's journey to Six Sigma without the burden of any warning letters such as breaches in assurance of data integrity took Amgen about ten years to achieve this this this goal and and in in us freedom of information as well as freedom of speech come together Amgen can advertise that they are Six Sigma and I think that Six Sigma aspect can have a important consideration for example we have been discussed previously therapeutic equivalence is made up of four parts pharmaceutical equivalence bioequivalence labeling GMP for biosimilars pharmaceutical equals is a big challenge labeling is different and now GMP comparability we have not never talked about comparability of GMP but I think we are moving in that direction of is your GMP comparable and we will achieve we will sort of move in that direction through quality metrics and through considerations of warning letters recalls patient complaints and all of this sort of comes together in real world and interchangeability considerations I believe we'll have to account for all these aspect so interchangeability a biosimilar will depend on that why did it take Anton such a long time to achieve the lower error rate of 3.4 defects per million opportunity of Six Sigma I think it goes to psychology of change much of the industry does not want was not willing to change why victims of our own success products have strong patent protections we are isolated from economic cycles regulatory system promoted and encouraged to inspect and test quality in the 21st century initiative that I had the opportunity to lead at FDA who started to change that paradigm to Quality by Design and and quality by design is now becoming a reality after after almost 18 years so new prescriptions for drug makers update the plans why is pharmaceutical manufacturing lagging behind those operatorship in laundry detergent was a front-page article in in Wall Street Journal on 3 September 2003 so 15 years later I think we are now at a tipping point for for moving over to Six Sigma and Six Sigma a level of errors really is going to be a hallmark and benchmark and and will I think I believe will have an impact on market penetration because it it will be related to adherence and confidence patients and providers have particularly in the context of social media and media coverage of the negative amount amgen's journey required a change in mindset psychology of change change in mindset and it focused directly on effective root cause investigations of out of specification and it took a long time to institute risk-based classification system – – to focus on processes that are not stable are capable improving trending and non-conformance improving management review developed Network metric control plan standardized root cause analysis there were technical writing course for investigators in wall quality science in investigations asking why why why why for root cause investigation is critical Quality by Design takes the ýÿ ýÿ upfront to define the QT PP and to identify the CQ ace to identify the CPP's and to do risk assessment to us to establish processes that are say stable and control and and – and to transfer that knowledge and know-how to operations to maintain stability and capability through continued process verification so that really is at heart of this issue ICS q10 product lifecycle approach also sort of focused on this management responsibility is the key leaders must commit to monitoring manufacturing process and product attributes using familiar roadmap to process capabilities leaders focused on poorly performing manufacturing process and – to identify and and improve processes that need improvement such as processes at P P P K a performance index of lower than one and effective root cause investigation was the key I think that is the key challenge to too many companies at the moment leaders focused on prevention of errors significant emphasis placed on qualification and certification of investigators that's a starting point education training and experience and professional development becomes a key attribute of a successful company and I think we are moving in that direction right now so in summary I think if I don't look there is no problem to problem solving to prevention of error those are the stages of development of individuals and corporations when you succeed the power of error reduction is shown by the data from engine where I think it took many years but the out end result is very satisfying not only terms of professional satisfaction but also in terms of money saving money so previously I had introduced the concept of immunity to change in the in the category of psychology of change now development is equal to overcoming immunity to change to be able to address complexity and uncertainty of the type of biosimilars and complex generics you have to adopt a mindset of you know what you're doing and you engage with the regulator's through their meetings to to have a collaboration and not take the position tell me FDA what to do or file first to figure it out later that is a recipe for disaster so if I look at the journey of Amgen they went from if I don't look there is no problem to problem solving to prevention of error in terms of adult human development those line up very nicely with the constructive development here of adult human development of professor Keegan and to progress in that you have to overcome your immunity to change so the immunity to change is made up of three parts change prevention feeling system and knowing system we have to attend pay attention to the feeling system within the corporation and that is something we don't do very well because we think we are professionals we focus on being objective and then analytical that is necessary but not sufficient you have to build your appreciation for system and you have to recognize the psychology of change or immunity to change you have to overcome the emotional aspects of management of professional working of collaboration and without collaboration you don't get recruit allottee of evidence in a way so if you want to think about immunity to change think about a very simple model you have a Russian nested doll model as an example and and for the intrapersonal for to judging where your development is yourself think about our own development you want to look good we want to be good we want to do good and we want to be seen good so each of those development stages is achieved through our education and training but the more at one stages of development only occur through our experiential learning and experiential development and experience is more than just practical contact with an event experience also means feeling and how do we feel inside internal validation is the key so feeling system fear of looking bad if I don't look there is no problem and the illusionary power of Procrustes one-size-fits-all and you don't accept anything else that's not the way we can manage complexity and uncertainty of a complex generic or a biosimilars the change prevention system corporate management waring file first and taking fda-approved and validated as gospel and a reason to set expectations of right first time on staff that makes them prone to beaches and data integrity the regulatory regular system struggled quite a bit but now is moving in the direction of quality by design and how we set specification has been a challenge in many parts of the regulatory system and and i think this is where the engagement and meetings with the regulators in a step by step development process is a wonderful opportunity to do that humans develop in stages our development goes from impulse control to imperialist to socialized mind to to self authored mine which is not shown there at the fourth order and then to self transforming mind systems thinking appreciation for system really begins at after the food that the fourth order of consciousness when we have internally validated our own knowledge we are self authored in what we do and and and how we know and what we know and and clearly i think we need to be self transforming to develop further knowing system knowledge management is not information management what we know is important how we know what we know is equally important so pay attention to how you know what we know question the information you accept and and you need to know the authenticity accuracy and precision of information that you use we must be self authored in every job and every level of a corporation or a regulatory agency both analysis and synthesis are essential and and and this is the key how good is your quality overall summary of your development report and nothing becomes a key test to do this and in case of biosimilars particularly with the step by step development approach with multiple meetings of FDA this becomes an opportunity you cannot really failed to use appropriately knowing is necessary but not sufficient wisdom is action care knowledge and action how we feel think and act must be aligned to overcome immunity to change your inertia and anybody who registers for a medical intuition is a patient so in that sense we all are patients so the doing system the knowing system the feeling system and the change prevention system have to be considered so if you look at MJ's journey damages journey progressed focusing on analytical characterization of raw material the starting condition starting point this and and and agreements with their suppliers was the key management involvement in every step continual monitoring and understanding the sources of variations particularly your for your analytical method benchmarking your analytical method so that you know you can keep decreasing there's a variability training qualification and certification and above all a focus on supply chain controls so this is these are the critical elements that you need to think about so we are a system we work in a system and we have to improve the system we work in so to understand how you need to know the types of systems simple complicated complex and chaotic chaotic systems are extremely sensitive to starting conditions complex systems are systems where cause and effect relationships are known after the fact are not known very well so if you are unable to get to the root cause your investigation of all of specification is not getting you to the root cause you are repeating the errors you are either in a complex world complex system or you are you in a chaotic system so you have to think differently there good practices SOPs project management work very effectively only in the complicated and simple system in simple system you can even go to best practices because cause and effect is very self evident in a complicated system cause and effect require certain expert knowledge and expert judge manat as evident so so remember which type of system you are in so if you're in a complex system emerging practices when cause and effect is only evident in hindsight or after the fact so the whole idea of research and development is to reduce complexity to the level of complicated so that good practices would work the entire system of evidence collection for biosimilar is based on reducing complexity in uncertainty and if you have residual uncertainty you may get an approval for biosimilar but you may not get an approval for interchangeable and interchangeability it's going to be a key aspect so just to remind us pharmaceutical quality system is a hybrid system and I think how we operate and how we function requires that knowledge and I won't go through this list of all the aspect but the key signal of your system what type of system you're in is your ability to do effective root-cause investigation so that you make the corrections in time and you don't repeat the same mistakes or errors from occurring again corrective action preventive action when successful suggests you are in a complicated system you're good practices are working and therefore that is where FDA inspectors would be satisfied if not they would ask you to hire external consultant and that is extremely extremely serious and bad situation so best practices without considering complications and complexities post risk one size doesn't fit all compendium standards and the defaults that we tend to use in the small molecule generic world like soo packed annex fortunately have not been as popularly used in biotech but biotech is also prone to similar default situations and and legacy challenges so I think that that's an important message pharmaceutical quality system is a complex adaptive system at least at the management level at the level of the operators it has to be complicated so that the SOP if they follow should yield predictable effect and if SOPs when followed correctly do not produce predictable effects then the S this system has become complex not appreciating complexity leads to emergency and chaos many contemporary practices are best practices applied erroneously without consideration for complexity please remember that so making sense of pharmacal quality here are some ways of thinking about how do we make sense of pharmaceutical quality fer to twenty-first century if we are only relying on opinions of others such as fda waiting for fda to give a guidance our sense making is checking the box if our checking the box approach we are not able to address complexity and uncertainty in our responsiveness is to warning letters to patient complaints consumer complaints is not adequate as read to be systematic we have to be fourth order we have to be self fought that quality is above and beyond USP NFPA here we start building brand identity and and we start building confidence in quality to be really mature you have to appreciate systems of systems maturity to shape standards where we can deal with creating competitive advantage for complex and novel product categories and I think the larger companies are able to do that but in the 21st century even the smaller companies will have to play a significant role or a leadership role to shape that and for that they will have to create a culture of quality within the corporation to be able to achieve this goal so there are many gaps between what we know and what we can implement my fundamental concentration is the professional development is the key education training and experience is is is essential an experiential learning is a path to professional development we must invest in development to be self authored at every level so I think the training we do for SOP even for operators operators need to be self authored in the job they're doing not not depend on external GMP consultants to write this o P they should be writing there so P themselves even if they don't know English that's perfectly fine then you can translate that in English as necessary I think it is an important consideration the pharmaceutical quality for the 21st century is occurring in a highly polarized socio-political environment that's making it difficult to achieve and maintain a higher order of consciousness we must work collaboratively we all are regulators I think is the key marriage here and the the advantage for companies that are self authored have supported professional development is humongous but the challenge to companies that are not supporting professional development that do not have their higher order of K critical mass of higher-order consciousness is a significant challenge unfortunately much of the industrial sector has been socialized to check the box and that in within that some makeup hidden checklist to get the I've done with violets of GMP and bad I remember this is this is not just a farmer problem this is not just a biopharma problem this is a human problem because we have a tendency to so to focus on economic growth and economic growth Trump's economic development our supply is a global supply chain we have variable education training and experience and assurance patients need has been increasing assurance is a cause and the effect is real-world therapeutic out so real world assurance and adherence with outcome based reimbursement pay for performance and value-based pricing adherence to good practices and adherence to prescription I think comes into play in a very interesting way and I think we have to reduce errors and we have to improve adherence so that patients will adhere to the prescriptions expect the unexpected I think so I think I want to end here with the question have you considered the consequence for your approved or in development by a singular product when the reference product manufacturing process is is claimed to be Six Sigma what will happen to the level of assurance you provide what will happen to the likelihood of you getting into changeable designation for your bio silver thank you for listening if you have any questions please email me my email address is down on every slide I will be glad to answer any question thank you for listening

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