I am thrilled to have Dr. Anurag Rathore share his QbD journey with our QbDWorks community. This is a followup to the previous post.
This is a part of QbDWorks interview series where we interview the thought leaders of Quality by Design to discuss what works and what doesn’t in QbD.
Welcome to our first interview with Prof. Anurag Rathore.
This interview covers:
- Anurag’s Personal Journey as a pioneer of QbD
- How QbD has changed since the beginning
- Challenges in adopting QbD and Lessons Learned over 10 years
- How QbD strategy should be different for small companies and big companies
- QbD implementation challenges for companies with limited resources and budget
- How big companies can align regulatory expectations with company strategy
- Why biosimilars need a specialized QbD adoption strategy and how to take advantage of their situation
- Why biologics/biotech took so long to get the first QbD approval – Gazyva
- Strategies on successful QbD filings
- How to deal with the discrepancy between FDA and local inspectors’ view on QbD
- Critical elements of QbD
- Regulatory Relief in Design Space and realistic expectations
- India’s QbD adoption: current status and its future
- QbD in the education space and the Indian Government’s role
Listen to the Interview:
Bonus: Also at the end of this page, you can download a Chapter 1 Summary of Prof. Rathore’s Book,
Quality by Design for Biopharmaceuticals
Sun: Hi Anurag!
Rathore: Hi, Sun.
Sun: Anurag, thank you for your time today. I’m thrilled to introduce Anurag, Professor Anurag Rathore from IIT Delhi. He obtained his Ph.D. from Yale in 1998 from United States, and then he joined as a Process Development Engineer at Pharmacia, now Pfizer, and then he moved on to Amgen. Now he’s back in India, teaching and evangelizing “Quality by Design”. [(QbD)] So…welcome!
Rathore: Yes, thank you, Sun.
Sun: So, take us through the personal journey of QbD. I know you were there from the very beginning, and you published many articles, as well as many books, so tell us from your side of the story.
Rathore: Yes, so the quality by design really started from-I think it’s 2004, which is when published the PAT guidance, and in that guidance, the basic aspects that basically formed quality by design. After that, I remember that that was the time that people in the biologics industry were not really thinking too much about QbD but a couple of years later I think 2006 is when the people in the biotech industry started with the idea of quality by design and focused on the technology. That was when we had the idea of doing this book on QbD. We started in 2006, we started-I remember-asking people to write chapters in 2007 and at the time it was still a very new thing. But, by the time the book came out in early 2009, I remember there was a huge demand for what QbD is and how to implement it. Partly because of that, and also the fact that we were lucky to have a very good set of [others], who were all scientific leaders in their respective areas, the whole thing-you know, the whole package-was very well received and the book did very well. Over the time and now, I think if I look back, I think today we have a come along way ahead on QbD. I think people know what QbD is, know what PAT is, and I think the kind of questions people are asking have changed. In view of that, we are planning a second edition of the book, to basically address the reality of today.
Sun: Fantastic. Yes, it has been changing since the first days of QbD. Before I go on to the recent challenges, can you tell us why you got involved in the first place, and what were some of the challenges as an early adopter of QbD and how you got involved, actually, from the very beginning?
Rathore: I think I remember attending a FDA workshop on PAT guidance, and I think just the concept and the thinking that was around that and the people who created the guidance, what they were thinking. Somehow that clicked, and that got me interested in the whole thing. Luckily for me I was in Amgen at the time and Amgen was also interested in, basically adopting QbD so I think part of it was being in the right place at the right time, and the company allowed me to interact with the developers and work with them towards implementation of QbD. So, that’s how I’ve been figuring out a lot of personal experience and QbD also the evolution of QbD over the next decade or so.
Sun: Right, and there’re still companies who are challenged with the adoption of QbD-I know most of the leaders in the industry have adopted QbD — so just going back to the old times, what were some of the challenges, and the lessons you’ve learned, to overcome them?
Rathore: Yeah, so in the early part-I’m talking about 2004 to 2007, those years-I think the question was more about the concepts that make QbD and also about how to apply QbD,-you know, for a molecule that is under development-so there was more of kind of a clarity kind of questions. (00:04:54) I think times have changes since then, because now if I look today, I think most of the major pharma-, as well as bio-pharma companies have already adopted most of these concepts, whether it’s risk analysis, or design of experiments, or any of these kind of tools. Pretty much everybody is already doing it today. Also, I think in general, people know what QbD is, people know what PAT is, but I think that questions that are there, first of all, are for smaller companies who have limited resources. You know, how do you go about implementing QbD, and because you have limited number of people with relatively limited experience then how do you get started on that? Obviously you have limited resources as well as limited budget. So, I think that’s one set of challenge. For the larger companies I think it’s more of trying to come to a point where regulatory expectations are aligned with the companies’ business strategy. I think we are slowly getting there, because now we have one finding, at least-the so-called QbD finding-which is approved. So I think companies now have a little better idea of what it would take to get an approval. Then they can make a decision whether it’s really worth it or not, so that’s kind of where the larger companies are, and then the third set I would say is people who are engaged in making biosimilars which are-as you know they are basically molecules which are copied from innovator drugs and companies that are doing that have a different mindset because they are working on very, very lean resources as well as there is a cost. So the question is-how do they implement QbD? Because I don’t see-you know, the biosimilar producers implementing QbD the same way are Amgen or Genentech or Biogen Idec would. So I think it needs to be kind of a different version, a different flavor of QbD, for that kind of a situation. So I think these are the threefold areas where problems will really happen over the next decade.
Sun: Very interesting. So, the one that was approved you’re referring to was Gazyva of Genentech. Is that correct?
Rathore: Yes, yes.
Sun: OK. Do you know anyone who’s involved in the filing, and why that was the different case for Gazyva (versus Perjeta) which is now approved for design space, but they basically had the same approach for filing QbDs?
Rathore: Yes, so, that-, I’ve been part of discussions and conferences-you know, people from Gazyva presented on that. I don’t want to comment specifically on what the differences are, but I think the point here is that like I said, there was-, for the larger companies understand the concept but there is still rationalization that needs to happen between the company, or between the industry and the regulators on what is required to get approval. I think it was more the reason why it took so long is because again, there is a back and forth that companies have to go-you know, with the regulators eventually to get to a point of consensus, which is what I think has been achieved now. So, I think going forward, you’ll see a lot more approvals happening this way, but again I think the company has to decide whether-, you know, what it takes to get such an approval… You know, is it really worth it or not? And I think that’s always going to be, I think, a company to company decision.
Sun: Hmm, interesting, so we see some leaders in the US. How is the climate in India for adopting QbD?
Rathore: Yeah, so when I moved here, I was not expecting many Indian companies to be adopting QbD, because like I said, many of them are engaged in biosimilars, you know, production of biosimilars and they work in a very different environment in terms of finance and resources, but actually what I’m seeing here is that, the companies that aspire to supply these drugs, such as fully get them approved, and developed countries-whether Japan, or Europe, or U.S.-those companies are adopting actually these methodologies, and doing actually a pretty good job. So I’ve, you know, I’ve seen some of these work forces at length and I think they’re doing a fabulous job of actually incorporating QbD into the systems. (00:10:08)
Sun: Interesting. So, when you mentioned biosimilars, and perhaps a different approach for QbD in this area, could you be a little more specific, you know, what should be different for biosimilars?
Rathore: Yeah, I mean, I think one is how to be basically more efficient about the whole thing, because having done it at Amgen and I think it’s the same how [Norash] is doing it, or [Barzanai] because that’s one way to do it, but I think as a biosimilar producer, doing it for basically a new drug is a little bit different from doing it for a biosimilar drug. Because for a biosimilar drug your target is kind of defined, so some of the studies, some of the activities that you would otherwise do for a novel drug that is already done for you. So, I think how go about QbD, you know, the stress is kind of more on compatibility, in this case. More on analytical technicalization, I think there’s a greater need on trying to create non-clinical ways of establishing compatibility, so I think these are basically kind of-goes into newer areas of innovation. Of course, your clinical data is much less than a typical innovative company has, so all these changes would require slight changes in the way you would implement QbD.
Sun: Huh. So, your first book on QbD was published-I think it was published in 2009? Is that…?
Sun: …QbD for bio-pharmaceuticals and I loved the book, I highly recommend it to our community. I know you’re working on the second edition of the book…what will you be covering on the second edition?
Rathore: For the second edition, I think we will retain some chapters from the first book because the basics kind of stay the same, but what I would like to do is to address more on, basically, what has happened in the last five years or so, which is basically more clarity on how to-I mean, what does it take to have a successful QbD filing? More clarity on-, basically have some of these people like I said there is some development, someone from a large biotech company talk about where we are with QbD, what does it really take to implement QbD? Some kind of a case study, or a mock study, or something. Another area that I would like few chapters, like I said, are from biosimilar producers. You know, about how they are approaching it, you know? What are the differences, you know, in how they are doing things versus how the innovators are doing things? And finally maybe a couple of smaller companies about–even in the U.S.-about how they are implementing it. So the idea would be basically about-half the book would be basically an updated version of the first edition, which is focusing on mainly on fundamentals and concepts, but the second half will be kind of new and will try to have case studies from all the key players to get more clarity on these topics.
Sun: Excellent. I really look forward to that book, when it comes out. So, what do you have in mind in terms of-, when you said what it takes for a successful filings for FDA. Can you share some of the things you plan to write about in the book?
Rathore: Yeah, I mean, for example, it will be great to have someone from the FDA team analyze the chapter you know, I mean, the experience, I mean, of course keeping it general-I don’t want-we can’t expect them to give out confidential information but I think someone could write a chapter on how their experience has been, you know, what have they learned over basically the last six or seven years of interactions with the FDA? And similarly someone from the FDA, you know write something on what are the kind of the issues they’re seeing with the QbD filings they’ve had? And what are the areas that the industry should focus on?
Sun: Right. So one of the common questions that come up all the time, and-including myself-is when we go to conferences and talk about QbD and all the directors-, Christine Moore and Rick Friedman, and so forth, they’re all enthused about QbD, but when you go to the sites-the local sites of the companies, the inspectors are not on the same level as the top level directors of the FDA and the EMA and they have different expectations. (00:15:15) Have you experienced that? And how do you deal with that? It’s one of the common questions that come up all the time.
Rathore: Yeah, for that heterogeneity will always be there because the FDA is also a large organization, and it is kind of unreasonable to expect that everyone there would behave exactly the same way, and ask the same questions. So, I think that will always be there, but I think what you see is, that, over time as more and more companies adopt these QbD principles, similarly they have had more and more reviewers and more and more inspectors are also kind of getting familiar with these practices and all the pitfalls. So, I think gradually-this really absolves these things. Similarly, the evaluators will also kind of go through the same learning curve, and eventually it will all work out.
Sun: Well that’s good to hear. I’m just curious-now you’re a professor at IIT, well you have been for many years now-in the education space, what do you teach these new to-be graduates on QbD?
Rathore Yeah, so that is a very good question. I mean, historically, we have not taught these things as part of the regular curriculum but what the Indian government-, actually I’m working with the Indian government to create a center on bioprocessing and part of that is actually to have modules on these types of practices, because QbD is not the traditional textbook kind of stuff and the reason you don’t have it as part of normal curriculum is that not everybody can teach it; I mean, you can’t just read it from the book and start teaching it. It’s based on-you know, people need to have practical experience. Before they can teach it and that really limits to how many people you have who can do that. But there is a plan that we have we basically we will have short courses because India is a country-and I think it’s probably the same in a lot of other countries-where you have a lot of people who are very smart and very capable, but they have not had enough training in this kind of area, and they need that. So the idea, is that government support will start the center and part of that initiative is to actually offer the short term courses to the industry, on topics such as QbD, process validation, scale of technology transfer, process and technical-, technology, things like that.
Sun: Excellent. I look forward to those graduates making a big impact, probably more in India and also more at the global level. Let’s see…going through the list, I want to go back to the challenge a little bit, because although many folks are very enthusiastic about implementing QbD, the reality-even at the big company level-is that the adoption is a challenge. There are two sides to the challenge at the macro-level. One is for the internal organization level-resistance of change in the way we develop therapies and products-drugs. At the regulatory level, can we go back a little and talk about those two challenges? And when you were working at Amgen and what kind of challenges you faced, and also working at the regulatory bodies, what you had to deal with and so forth?
Rathore: Okay, so can you repeat which particular challenges you are…?
Sun: Sure. Let’s attack the internal challenge first, internal resistance within the company-when you’re trying to start out QbD what were some of the challenges you faced, and what to do about it, basically?
Rathore: Right. I think the challenge that you have, whenever you have any new concept coming in-there is always going to be some resistance because people are not used to doing this a certain way or something that basically go against what they have been doing over the years. (00:19:57) That, I think was there at the start, but like I said, once an organization starts doing things they have a kind of tendency to start growing in the company and you see one product team applies this, and eventually the second product team applies it and then over some time-five years, or ten years depending on the size of the company-most of company is kind of aligned on how to go about it. So the industry in that sense is going-has already gone through that I would say so the larger companies I think more or less pretty much everybody is already on the same page. Because they are being exposed to these concepts one way or another, you know in their regular jobs. Like I said, the smaller companies are a little bit behind, but I think again as opportunity comes, gradually I think they will also start adopting this over time. From the regulatory side, again it’s kind of the same issue because everybody has a job and if you talk to the people that are there I think you will see they’re also extremely busy people-very long list of developers and everybody has their kind of work defined for them, so it’s not like they have plenty of time to learn about these new kinds of things. But, again like I said, I think as these things grow, as more and more companies are adopting these concepts, then obviously, gradually more and more reviews and more and more inspectors also learning. Plus I think FDA is pretty good about their internal training and other avenues to align amongst themselves, so I think basically everybody is going through a transition, but I think if you look at today I think all these major organizations have already achieved quite a significant amount of progress in this regard.
Sun: OK. That’s great insight. Going deeper into QbD-there’re a lot of elements of QbD-risk assessment, there’s the design space, control strategies, so forth. All of those many elements-what do you think is the core to make it a successful-, to get headway into the QbD program successfully?
Rathore: I think-, I cannot say anything one thing which is the core, because everything has to come together, everything has to work to make the system work, but a couple of things which are a little bit difficult to do, and they are critical in that aspect-for example, one is assigning criticalities to the different attributes. If a biological product has typically a lot of different quality attributes and of the biggest challenges for a company is to decide which of those are critical and which of those are relatively less critical…
Rathore: …and that definement, especially when you are a small company, or are working on a first product is very difficult because you don’t have experience to help you-and you are mainly relying on literature and obviously whatever they tell you is [generative] that is a pretty difficult part, I would say, of the whole exercise…
Sun: Do you have any tips on-, or your approach on how to define criticality?
Rathore: No, I think there are lot of tools that people have published, so there are people that I have seen in literature who have done a very good job of summarizing whatever literature exists already…
Rathore: …so I think these kinds of things are out there, but still the fact remains that if it’s the first molecule and you don’t have a lot of prior experience, then it’s going to be a very difficult exercise to do, because trying to get specifications for every attribute-why it is critical, or why it is not so critical-is not going to be easy because you’ll not have the [example] support each and every thing. So like I said, that’s a challenge that everybody kind of has to go through the first time, but it does get easier as you have second product, third product, as you go through the pipeline of your product, so I think it gets easier over time. So…
Rathore: So, the second issue I see is around the control strategy, because that’s such a thing which ties the whole process together so you are thinking-, you have start thinking from a unit operation perspective and then eventually thinking about integrating all unit operations into a single process and how to control everything together. (00:25:02) That actually becomes a little bit of a challenge as well. And so that’s another thing where I know companies struggle, but again, that’s one of those things the first time you struggle, but I think once you do it and once you understand the concepts behind it, I think the second time it gets significantly easier.
Sun: Yeah, very true indeed. The design space-when QbD first started big-, well the expectation was that we get a regulatory relief if we can prove the ranges we are operating have been proved safe and so forth. Do you think-, which hasn’t happened yet, for biotech yet-, do you think that will change anytime in the future?
Rathore: I don’t think so, because I think it all started from the ICH Q8 where the design space was defined, and it was said that ok, once the design space is approved then the company would be free to work anywhere in the design space without requiring the approval from the regulatory authorities. But in reality, if you look at how we develop those processes, most of our work is done on large scale, and whatever we do on manufacturing scale is generally everything is under very tight, small operating ranges, so you are basically running a very tightly controlled process in the plant, you are not qualifying the-whatever your design space is, in the manufacturing plant. So, that’s where the problem is, that if you are not doing that, what basically the regulators have a tough time is-, well if you are not running-, qualifying the workspace in the large scale, then we can’t give you a kind of blank check in the form of design space approval. I think that’s something which, we went through the whole cycle of the industry expecting them to get approved, and then design space is not getting approved and then I think now we are at the point where industry realizes really it’s not just about design space, it’s also the fact that if you do things this way, then you will have better understanding of the process, better understanding of the product, and that will help out dealing with process development eventually. So, kind of the perceived benefits of doing this have changed from just really a design space thing to more about process and product understanding.
Sun: Hmm, well said. I think that people are coming to the reality of what this QbD can bring. So, as a person, as an expert working in the space of QbD, what’s the future outlook of QbD look like in your eyes? How do you think it’ll change in the next five years, or maybe in the next ten years in the industry, and how will it affect the whole industry and the biotech?
Rathore: I think you can the industry into these three parts the larger companies are already getting-, I mean they know what QbD is, what PAT is, already incorporating most of these concepts and it’s a question of basically kind of just deciding what force should be and what would be acceptable to regulatory and just doing it over and over from different [?] so I think they’re already there and I think what you see more is ways to make the process more efficient-from a resource perspective, from a time perspective, that’s where the focus would be for larger companies. For smaller companies, it is more of looking at QbD, adopting it, and kind of a little bit customizing it to their needs, because they probably cannot do each and every thing that the larger companies can, but anyway depending on the application, depending on the product that they have in the works decides how to go about implementing QbD. And then finally the biosimilar producers where it’s a slightly different game that we are playing so again accordingly creating a version of QbD that kind of fits your needs as well as your requirements and then going with that.
Sun: Excellent. This has been such a great insightful interview, basically. (00:30:00)So, to wrap it up, do you have any tips for those just starting out QbD?
Rathore: All I can say is that, read the book-obviously there are a lot of good papers out there. You can do all that, and I think another thing is that I’ve got a couple courses that some of these professional organizations teach but that’s another good way to get familiarize with that but again, eventually you only learn once you start implementing; that’s the only way to learn and I’m sure everybody will struggle but I think you know if you keep at it, you can eventually figure out how to do it the right way.
Sun: Excellent. Thank you so much for your time, Anurag. Where can people find you if they want to reach out to you?
Rathore: I am pretty accessible, so you have my email and if you just Google my name I think it’s easy to find.
Sun: So I’ll list those on the resources…
Sun: OK. Excellent. Thank you so much for your time
Rathore: Thank you, Sun.
Sun: Thank you.
Rathore: Take care. Bye.
Sun: You too.
So Here’s the Book
These are great nuggets of wisdom from Anurag Rathore. When I began my QbD journey, I learned much from this resource so I highly recommend you read the book and use it as a reference.
Quality by Design for Biopharmaceuticals: Principles and Case Studies
In this book, leading authorities from the biotechnology industry and the FDA discuss concepts, applications, and practical issues of Quality by Design including topics such as:
- The understanding and development of the product’s critical quality attributes (CQA)
- Development of the design space for a manufacturing process
- How to employ QbD to design a formulation process
- Raw material analysis and control strategy for QbD
- Process Analytical Technology (PAT) and how it relates to QbD
- Relevant PAT tools and applications for the pharmaceutical industry
- The uses of risk assessment and management in QbD
- Filing QbD information in regulatory documents
- The application of multivariate data analysis (MVDA) to QbD
As a QbD evangelist myself, I highly recommend this book as a must-read to those starting QbD in Biopharmaceuticals.
The Book covers: (Chapters)
1. QbD: Basic Concepts (Terminologies)
2. Considerations for Biotech Product in QbD (Steven Kozlowski, OBP of FDA is a co-author)
3. Molecular Design of malaria vaccines
4. Risk Assessment to determine criticality of product quality attributes
5. Design Space for a Microbial Fermentation Step
6. QbD for Tangential Flow Filtration
7. Design Space for Purification Process
8. Viral Clearance: QbD and Design Space
9. Formulation: QbD, Risk Assessment and Design Space
10. Biologics: Fomulation and Process Development
11. QbD for Raw Materials
12. PAT Tools for Biologics
13. Evolution and Integration of QbD and PAT
Since each chapter is written by different co-authors, quality does vary chapter-by-chapter.
Even the way each author applied QbD tools (risk assessment, design space, etc.) varies.
Just like any other field, the practice of QbD has been rapidly evolving since 2009 and
therefore some suggestions in the book seem outdated.
Nevertheless, Anurgag and Mohin did a fantastic job of covering a wide range of key QbD topics in Biologics.
I would use the book as case studies and not as a manual.
I highly recommend this Book to any QbD professional.
If you are interested,
I have benefited much from Anurag’s book and have shared it with my colleagues. So I am happy to share slides of the chapter 1 summary with the QbDWorks community. Please consider it a bonus when you purchase the book.
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Thank you and please comment on how these interviews are helping you on your QbD journey!