Dr. Reddy's Active Pharmaceutical Ingredients’ Post

Transcript

Hi everyone. My name is Ramani Susarla. I am a chemical engineer by training. I hold a pH. D and postdoc degree from the New Jersey Institute of Technology. I have been associated with Doctor Reddy's for over a decade now and currently I lead the new technology flow chemistry and the continuous manufacturing platform. Today I'm here to talk to you about the continuous manufacturing. It's implications and implementation at Doctor Reddy's. So the continuous manufacturing or the flow chemistry has got huge traction, especially over a decade with the ETP and the FDA also heavily backing it up. So the main advantages of the flow chemistry or the continuous manufacturing over the traditional batch processes is that it provides enhanced safety and due to the enhanced heat and mass transfer you are able to explore chemistries. Which may be very challenging to explore in batch, you can have flexibility in manufacturing. For example, you could utilize the facility to manufacture product A for half the year and product B. And due to process intensification the cycle times the manpower required is hugely reduced. And due to the inherent advantage of automation, the inline analysis and the outline data integration really allows for. Overall time cycle reduction. So these are some of the benefits that we can immediately think of when we talk about continuous manufacturing. So Doctor Reddy's has been in the game of continuous manufacturing and flow chemistry for more than a decade now and the huge motivation behind it was mainly going into greener chemistries, sustainability and you know exploring chemistries which are very difficult and challenging to explore in batch. So with that in mind as of today, we are happy to say we have. Explored multiple chemistries in flow, with some of them successfully executed even at the plant scale. So we have explored the Grignard chemistries, the butyl lithium chemistries which are quite hazardous at batch batch level when cyanation reactions are exothermic runaway reactions. So these are a few that can be named. Apart from this, it's very interesting that flow has also helped the batch process in the sense the kinetics. And the use of experimentation or flow has helped in picking up the knowledge and implementing in batch processes which have enhanced or rather reduced the cycle times for the product development. So as I mentioned previously, the biggest advantages are safety, flexibility in manufacturing, data integration, consistency in quality and reduction in overall into manual. Intervention. So I think I will. There are multiple products that we have worked on. I'll give 2 examples, first being the butyl lithium chemistries. So in the butyl lithium chemistries, if you consider a traditional batch process, you have huge hold up volumes of butyllithium which is a hazardous compound, it's pyrophoric. So there's always this scope of something going wrong when you come into the continuous manufacturing platform, the advantages at any point in time because the reactor. Volumes are small and the process is continuous. Your volumes that you're dealing with come down drastically. So there is there can be an intervention even if anything is going wrong which is also very, very rare in case of a continuous manufacturing because everything is enclosed, it's under pressure, there is no scope for moisture to get in, get out or any gas to get in or get out. So with this we have really explored the Grignards, Friedel Crafts and Brutalities in flow and really the physically seen the advantages that. Can bring in on a different platform. We have been able to adopt continuous for atorvastatin calcium starting right from the reaction all the way through the downstream of crystallization, filtration and drying. Here we saw the huge advantage that the cycle times in each step were drastically reduced while you're getting the same quality as you know consistent quality and the same quality that you would get from batch in much shorter times. So this is a tricky question but to answer it. Yes, it can be flexible depending on what would be the end outcome desired from the continuous manufacturing. For example, if you want to do a customer seating all through the year, you can run the setup all through the year for the same product and see that for the customer need. Or if you want to run multiple products, again based on the throughput that is desired and the chemistry that fits into your rig that we call it, you can run multiple products all through the year. So that's the great flexibility. That the continuous manufacturing offers. So what I can think of if you really have a product that is continuously running and suddenly you realize there is a molecule where the demand is huge and you do not have a site that is ready. I think continuous manufacturing is a platform where the process development intensification can be very fast. So the product development cycle itself can be fast and then you can implement into the existing rig or the setup. So I think that is the example that I can think of. So I think uh coming to regulatory, I'm very happy to inform that the ETP, the emerging cell technology and FDA like I mentioned is backing up flow technology, continuous manufacturing and all the regulators are also coming together in understanding what are the needs and how are they different from a typical batch processing. So at Rudy's I can proudly say that our regulatory team is working very closely with us in understanding the constant evolution of the ICH Q13 guidelines and. What are the key areas that we need to implement? Yeah, with respect to the R&D and scale, absolutely. I think when it was at a niche or evolving phase, there was a lot of confusion of how you would define a badge, how you would validate a product. But I think now with all the information that's also put out in the ICH Q13 and also the regulators really putting their minds and you know, interest into it, we are able to now come up with hard definitions, the requirements. Which are will be required for filing. So I think it's becoming easier and very encouraging for the pharmaceutical scientists to adopt continuous. So I think it's it goes without saying that continuous manufacturing and technology go hand in hand. I think it has been an evolution together. I'll give you examples. We all know about the process analytical tools, but I think the continuous manufacturing platform has exploited and exploded to the maximum. We actually have inline tools where the data is fed in continuously. And it goes through a feedback. So it's actually used to control your process or monitor your process. And coming to the modeling tools, you have something called the funnel plots and the mechanistic modeling integration of DOE. So all these simulation platforms are coming together to actually predict what can go wrong and have mechanisms in place to avoid those dangers in the continuous manufacturing platform. I think all the technologies coming together is what has really benefited continuous manufacturing like I said. You have these niche reactors, your microreactors, your dynamic reactors. You have varied pumps which are precision pumps, so the mesh that comes to the machinery part. Then you have this process, analytical tools which are doing inline analysis, the UPLC inline waters patrol HPCS. Then you have the modeling and simulation tools which are actually fed in for a control. It could be even for downstream particle size control or even your reaction monitoring. So yes, all of them together is defining the continuous momentum. So excellent question. I think without collaboration the continuous manufacturing platform would go nowhere. The reason being it needs a chemical engineer, it needs a chemist, it needs an analytical chemist, it needs an instrumentation personnel as a minimum to make the setup and run successful. At Doctor Reddys, we are happy that the cross collaboration between the chemistry groups which are called clusters and the center of excellence which were the continuous manufacturing platform belongs to has worked very closely and that's what has helped us. And evaluating over 30 molecules and you know successfully demonstrating over 20 molecules which can be taken up in flow. So there's a great cross functional collaboration. And I would also like to add that the BQA which is very important for the documentation and because the whole landscape of documentation is different for continuous and the regulatory also have come in and the safety personnel because the requirements are different. So I think over the last six years. So we have put mechanisms in place where we have our own sops to train the scientists, the new joinees, which gives them some basic training of all the equipment, the data and analytics, the dos and don'ts. So this has really made it easy for us to quickly train whoever is coming on board and explore their talents to the maximum. And this, I think this is what has led to exploring so many chemistries in such a short period of time. So I can talk about the cost savings with respect to the chemistry roots, like I mentioned there were some. Challenging chemistry routes which could not be adopted in batch because they led to runaway reactions which we were very efficiently demonstrated that the flow could handle or the continuous manufacturer could handle. And we developed a hybrid flow plus batch process where the runaway reaction was taken care of by the continuous manufacturing sector and then the reaction and the downstream was taken care by the batch processing. So I think this is one example that I can talk about I think with with with regards to continuous. Uh, it it's all it's going into the it's it occupies a huge space in the green chemistry arena where you're reducing your solvent volumes, you're recycling more. So all of this is definitely in the agenda of Doctor Reddy's. So I think in that area, I would say continuous manufacturing alliance. I think I'm happy to inform the Doctor Reddys quite ahead in the continuous manufacturing arena going forward. I see more and more scientists adopting it, more close collaborations. Between the batch processes and the continuous and more case studies coming out and more manufacturing in the continuous manufacturing area overall, all of this will help in reducing the product development cycle times. Hopefully that means more products coming out. So yeah, thank you for listening to this session on the continuous manufacturing platform and I hope you have all enjoyed it as much as I've enjoyed talking about it. Thank you.