Pharmaceutical Quality by Design Book – Practical or Theoretical? [Interview]

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A new book on Quality by Design was recently published. When I read such a book on QbD, I ask – “is it merely theoretical or actually practical?”

As a scientist who deals with the reality of messy biologics and constraints of time and resources at the office, I strive to separate the wheat from the chaff for my busy fellow scientists who are also applying QbD.

So I let the editors of the book – Walkiria and Mark – answer this question.

I wanted to hear the behind-the-scenes story and share them with you – QbDWorks community.

So is this pharmaceutical QbD book for you? 

Find out by listening to the QbD book interview.

Here’s the Pharmaceutical QbD Book interview with Walkiria Schlindwein and Mark Gibson!

 

Here are the topics we cover:

• What is covered in the book
• Background of the co-authors
• Rapid Risk Assessment – Lean QbD
• What FDA, MHRA and EMA thinks of post-approval design space
• Tools for PAT and in-line measurements
• Future of QbD and PAT
• How to change an organization from Quality by Testing to Quality by Design
• How a management can be convinced of QbD benefits
• Upcoming DeMontfort conference – what to expect

And controversial topics

• Should we use  KPP (Key Process Parameters) in addition to CPP (Critical Process Parameters)?
• Should we use  CMA (Critical Material Attributes)  in addition to CQA (Critical Quality Attributes)?
• What do regulatory agencies recommend and how to find a middle ground

The link to the book from the Wiley publishing company. (QbDWorks does not receive any profit from the book.) 

 

A sample chapter from the book:

Table of Contents

1. Introduction to Quality by Design (QbD)

 

If you prefer to read (rather than listen to) the conversation,

sign up and read the interview transcript!

 

Sun: Good morning, Walkiria and Mark. Welcome to the QbDWorks Podcast, we have today a very special guest from UK, Walkiria and Mark. Now, we met– I met Walkiria at the conference a few years ago, and we talked about the De Montfort University that she leads right now and Mark as well in one of the conferences. And recently, they published a book on QbD and we always try to support those who are leading the programs in various parts of the world of QbD.

So, that’s a quick introduction of Walkiria, she received her PhD in Polymer chemistry at the university of Leicester, and she’s the program leader associate professor of pharmaceuticals in De Montfort University program in QbD, quality by design. Mark has received his PhD in University of Bath in pharmacy, focusing on analytical studies and drug formulations, employing microorganisms. And currently, he is an independent pharmaceutical professional consultant in AM Pharma services limited as well.

Welcome, welcome to the talk today, thanks for your having me taking your time out of your schedule to join the conversations

Mark: Morning.

Sun: So, let’s begin on the story of how you first got involved with QbD from the very beginning. Now you’ve been in the Pharma industry for the life science industry in general for some time, starting with your graduate studies but how did you first went in and how did you first get involved QbD, powered by design.

Walkiria: Hi Sam, It’s a pleasure to be talking to you today. So my first contact with QbD, with the QbD world was quite a while ago, back almost 10 years, in 2009, and I have to say there were two people there that were quite important, that planted that speed that grew to what we have today and these were Jeff Smith’s, my colleague from De Montfort and then Mike honey. At that time, Mike was the VP at AstraZeneca in Macclesfield in England. So those two came back to this conference that’s they attended and they said well, there is an opportunity there to start a course on QbD and really this is where things started back in2009 and then following that, I went to my first QbD training course with the famous Bruce Davies and Line Lundberg and this couple has been my life since 2009, so, they were really what catalyzed the course that was put together and this is how he started really back in 2009.

If I may– we have also at that time we managed to get some funding to develop this, what we call at that time a postgraduate certificate course with the industry and Bruce helped me to gather a steering group from the industry and I was responsible for the academic side and we set up this group that was mainly consisted of people from the MHRA–our regulators, Medicines Healthcare Regulatory Agency in UK, five Axes Anika, GSK, BMS and some people also from the supply chain camel and jump the surface supply so that’s where we started really.

Sun: Excellent and how long did that process take roughly to kick off the program.

Walkiria: The first consultation that we had obviously was to identify the content of the course and joined up by the main Pharma as I said before AstraZeneca, GSK and BMS and as soon as we think we have identified the champions, we call them at that time, they were responsible to recruit within the companies people with subject knowledge, a specific subject knowledge to write the content for us so this took about a year and the program was finally validated in 2010 as a postgraduate certificate and really when we had this idea, well everything was kind of going really well and lots of good ideas from the different companies and people really wanted to share good practice and things. It went really well but when I got the material actually, we realized we have much more for a bigger course and then the second stage of development started from 2010 to 2012 where we revalidated it into a full master’s course that we will deliver it now.

Sun: Yeah I met and I’ve started to connect with those graduates now. It’s been a few years since they reached out to our community and they joined the QbD works community as well.

So, it’s a joy to see them the fruits of your labor from the early days and now that they’re going into industry, the students, early students are going to industry contributing back to the QbD society or the community so Mark, could you tell us about how you began your involvement with the QbD?

Mark: Yes and hi son. Yeah I got involved that’s what’s going back quite a few years. When you introduced me, you talked about my PhD which is probably not related to anything to do at QbD-

Sun: (Laugh)

Mark: -and also my recent role as a consultant I’ve been doing that for about the last four years but in between that I’ve worked in the pharmaceutical industry for 30 years with AstraZeneca, the last company that I worked for and my involvement with yeah so my involvement QbD comes right back from the beginning probably to my company AstraZeneca were very keen to be involved in ICH QA pharmaceutical development includes with the development of the guidelines but then implementing QbD within the organization and actually applying QbD to product developments. So my role in the industry was very much to do with developing new medicines, product development and then also later on with clinical trial manufacture and manufacturing processes including continuous manufacture.

So, I was very keen on QbD working in the industry. When I finished four years ago I took early retirement, I sent myself up as a consultant and was very keen to continue working in this aspects and I joined up with De Montfort University with Walkiria and we’ve done quite a few things together-

Walkiria: Yeah.

Mark: -to support the program here at De Montfort and develop it.

Sun: Excellent! I mean I just have to thank you. Again, you could have comfortably retired yet you wanted to contribute all your experience and knowledge back to the younger generation and those who are trying to transform the industry together and move forth so, you’ve definitely left a big legacy.

So let’s talk a little bit about the book. What made you write a new book on quality by design and what was your angle? We have some resources on quality by design for many different groups. How could you say this book is different from other resources that’s already out there?

Walkiria: If I can start, this was really madness that people write books if you could agree with me but it was really serendipity I would say, I met Dennis from University of Greenwich at the conference and then he came to me, “How about writing a book on quality by design?”

He is the main editor of the advances in pharmaceutical technology series from Wiley publisher and I said, “Ok, let me think about it” and then obviously this idea grew into something that now is there as an outcome which we are very pleased with it but my idea to begin with was we have this wealth of content and knowledge that was given to us to do the course from companies that actually could share examples that were very applied to the quality by design and say well let’s try to build the content of the course into a book more structured which will be easier for the students actually to follow and this was the idea, to capture the content of the course into a book and the contributors that we have there actually they recorded most of the lectures that we have on the different learning course.

So, in principle was a quite easy idea, “Ok, we have all the material there, let’s just write” but in practice, all it takes longer than the you think-

Sun: Absolutely.

Walkiria: -Joe brought her and I must say she was also worked for AstraZeneca for many years and she helped me at the beginning to structure the content and contact people and get them signed up for it and later on Mark got more involved with editing side of it and Joe unfortunately, well fortunately for her she got busier and the had to drop but that’s where we started. So we really want this to be focused on the practical approach so hopefully there will be– there are some good case studies there that people can use for their own situation or where they work and try to apply those concepts.

Sun: Absolutely, yes so I had a chance to read some of the excerpts from the book and it’s very extensive content. So when publishing a book or publication you have to make choices on what to include and what not to include and there are some stories or rich details that you wish you could convey but you couldn’t publicly in a book.

Now are there some of those examples of stories that maybe you can share through this conversation that you really wanted to transfer the knowledge or some funny stories or some of the unofficial stories?

Mark: I think one particular story is interesting, in that we did involve authors and contributors from different companies and backgrounds and therefore we have slightly different views on what was an acceptable approach. For example, with key process parameters which is a term one company uses but and in fact parental drug Association uses in their guidance but other companies were saying, “oh no we you shouldn’t use that, the regulators don’t accept it. It’s not in the I CH guidelines” and we had a lot of debates about this whether to include mentioned key process parameters or not.

So, there is something in the book but there is a sort of cautionary notes about the use of that terminology but we did have a lot of discussion about this. Companies like Pfizer, GSK, AstraZeneca, all got involved in the discussion-

Walkiria: Yes

Mark: -about whether we should be including it or not.

Sun: Now I do know that that’s a hot topic and even in my experience with my former employers when I work with other pharmaceutical companies that I’ve seen that KPP or Key Process Parameters is usually there in the poly documents and I know that many folks if not most use it yet when we went to the conferences with the regulators they were discouraging folks from using terminologies that were not in the ICH. I know that’s a hot topic, so was there any consensus after informing them or discussing through this topic? I know it’s not easy to change terminology of a company organization quickly.

Mark: Well, I think what we’ve tried to do in the book is we’ve tried to explain that you can use Key Process Parameters but you need to explain what that terminology is and what it actually means versus but to warn that probably not to include it in a regulator submission. It probably won’t be accepted by the regulators or they probably won’t take it seriously. That was the consensus that we reached, come from the people who were involved in the discussion.

Walkiria: I think it also, it’s same applies to critical materials attributes and I think Elena and I had some discussions around there as well and how people perhaps don’t use that correctly and yeah I think, we were quite aware of make sure that the harmonization of terminology was used correctly and in accordant in line with the guidelines.

So, this was one of the major concerns that we had to be coherent and this story has to be the same and that’s what we’re trying to do.

Sun: Got it, so what about the curriculum material attributes? What points of disagreement or contention were there?

Walkiria: To look at the guidelines. We should be referring to the quality, critical quality attributes of materials and the CMAs should be avoided and if possible.

So, if the critical quality attributes often that you rather than using the CMAs but most people will use CMAs and at the beginning I did as well and she until Elena said:” No, this is not correct” and we had quite extensive discussions around that.

Sun: Yes.

Mark: One of the challenges for Walkiria and myself as editors of the book was to ensure consistency across all the chapters and we did pick up that in some chapters we were contradicting ourselves, you know? I still got to find examples off the top of my head but it took a long time to go through the material and talk to the authors and then ensure that we got a clear understanding, clear messages coming out from the book. So, we didn’t confuse people by saying different things in different chapters.

Sun: Right and that is a very important role of an editor of a book.

Mark: Yeah, I think from our experience trying to apply QbD, we’re still learning all the time. We’re still trying to apply the principles in a consistent way and we do come across many times situations when we have different views, you know? On how it should be done, different ideas so, it was quite an interesting thing to go through the book entirely and make sure we were being consistent.

Sun: Absolutely.

Walkiria: One has been asked of some aspects of the book related to risk assessment that hopefully we’re going to cover disseminate at the Edison College in March if hopefully Roger Weaver and Alan will be able to share with us this new way that Pfizer is trying to do risk assessment development risk assessment, development risk assessment strategies for rapid full of development and a manufacture. I mean we all know how long the proper risk assessment takes-

Sun: Absolutely.

Walkiria: -and indeed sometimes can you get lost into this massive initiative or massive effort that goes into risk assessments.

So, I’ll be looking forward to see what they have developed in terms of simplifying risk assessments in a way that is still very effective but it doesn’t really hinder the development of products in a way that people want to be more flexible when rapid.

Sun: Right and that’s why we’ve been preaching that message to them in our community and that’s why our QbD works committee came up with the link should be the risk assessment for the development folks and I encourage many folks to as well as our scientists encourage many folks to do the rapid type of quick iteration of risk assessment specifically for the development stage because that makes a lot of sense to get to the design space, design experiments quickly and iterate and so forth. So, yes I look forward to seeing that too and we have a lot of stories on the link, QbD software as well for those who are actually practicing, who have been practicing the kind of rapid prototyping or a rapid risk assessment on the stage as well.

I want to jump to a little bit about the regulator for the actual progression of QbD. Now when QbD originally began, first began there was a lot of enthusiasm and of course there are a lot of critics too, pessimists-

Walkiria: Yeah.

Sun: -and I’m sure you get that question a lot. Now it’s been almost around 10 years since maybe QbD actually first began I ICQ 8 for published and I have seen work with the industry and academia and the students that are out there. What can you say about the reality versus the principal or the theory of QbD? How much it promised in the beginning? How much we accomplished so far? How was the ROI of that the reality gap between the reality and actual first big goal of their QbD?

Mark: Well maybe I should say that from an industrial perspective working for AstraZeneca, we are at the beginning thought there were some opportunities with QbD. I think we were already implementing a lot of the tools, the risk assessments and tools such as experimental design which have developed further over the years and you know can be quite sophisticated now also multivariate analysis which is good scientific practice as much as anything. I think you know we were wondering whether with design space there were great opportunities to reduce or give us more scope and flexibility once our products were approved and on the markets and if we wanted to change something but in reality, I think a lot of people certainly I’ve spoken to and lots of the people that have been involved in our book, some of the examples and their interactions with regulators from their company’s perspective, they’ve found that it’s been more difficult to us to achieve this beneficial design space and actually use it in practice. We have at the symposium that Walkiria mentioned regulators involved in the discussion and every year we try and get feedback from them in terms of how come we you know benefit, mutual benefit from QbD design space from a company perspective as well as from the regulatory perspective and you know I think there are limitations and I think it can be quite challenging to actually have an opportunity within the design space and use it in practice.

Walkiria: I think the regulator’s, they defer obviously, the FDA and if you compare the EMA with MCA and all the territories some more– well they work in a different way but my experience here with it with the MHRA, we have an understanding between they have helped us to move some of these barriers and between the regulators and the industry and academia.

I think the nice thing about this is a neutral platform where I can bring both regulators and industrialists in a more comfortable way. I mean they don’t eat it in neutral territory and we have had discussions that I think benefit both sectors and the one thing that I think we need to work more is really when it comes into processing are digital technologies and in line measurements and the data, multivariate analyses and from a regulatory point of view this our reality here I’m not saying the FDA is the same I think again there are some experience there.

Our reality here is there are a lot of things to be done in my view in terms of education and in terms of understanding what is required of submissions when you go into in line measurements and you have massive amount of data to show to the regulators. So hopefully very soon we will have some more interactions with the MHRA trying to move on towards a better understanding of what is needed from a regulatory point of view so my experience is this is really something that will take sometime to move on into some area where benefits are seen clearly from both sides.

Sun: Absolutely, yeah that I know that every conference have those conversations between the regulators and the industry folks on trying to close in the gap. So, that their expectations are more aligned because for industry honestly, the time is very important and the resources are limited and the more the regulators require, the more cost the industry companies have to bear in coming up with some of the efforts required to do QbD or PAT efforts.

So, where do you see the QbD and PAT going forward from now on, I know since the ICHQ 8 and not Q 9, 10, 11, 12 has been drafted and shared and disseminated. Where do you think where the next steps are or the next trends are?

Walkiria: Yeah that is a very good question and I think from my point of view in terms of education and research, education stroke research, we are entering a 3rd stage of our QbD initiative here which is really trying to apply what we’re teaching. For that we have developed this center of innovation for rapid and adaptive medicine the development and manufacture at De Montfort where we have capabilities of continuous manufacture and inline process monitoring and hopefully in future process control.

I know there are several centers of excellence around the world that those things more focus on the research and I think what I’m trying to do here is to disseminate from the education point of view and practical point of view, bringing companies here to work with us in a way that in many case will be a bespoke training that we can develop for them to get them thinking QbD from beginning and I think the challenge is there. You get it or you don’t, there’s no halfway. There’s no point to develop a product and then do QbD afterwards.

So, which is the many cases happen so I think this is my next stage from my perspective in terms of combining a practical aspect with education and also research around some of these issues, PAT is one of them. So inline process monitoring control, it’s a big area and I think that’s where we need to do more to help regulators and industry.

 

Sun: The very good point. Mark from coming from the industry point of view, do you have anything to add to what the next areas our focus should be?

Mark: My experience especially since leaving the industry four years ago and becoming an independent consultant and also working with De Montfort University, mentoring individuals who are working in different companies with different backgrounds and doing QbD qualifications, master’s qualifications,

I’ve realized that the actual a lot of companies are still catching up. I’ve been lucky enough to work for a major global pharmaceutical company and there are a lot of other companies still catching up and got quite a long way to go to build in the QbD principles and culture.

I know it’s not directly answering your question, where’s the next step with QbD? Where does everyone go from now but I think a lot of catching up to do and different types of companies even Cosmetic companies, we’ve got individuals who are formulating and making products who wants to know more about QbD and realize the potential of it but their organizations haven’t fully bought into it and it’s not just the individuals working on the bench of scientists and developing the products but it’s the management and the whole organization getting buy-in to be able to use an applied QbD.

So, I think it’s a lot of work to be done, you know, to actually bring other companies outside maybe in the major regions of the world, you know, in some other countries as well that are still catching up.

Walkiria: I think if I can add to this as well, the essence for me is really the definition of QbD really says it all. The good science and the risk based approach, I think when people get that everything will follow.

Sun: In moments of your teaching or conferences or interacting with the network that you have, what do you think helps them get it? Is there a certain point of knowledge or a certain point of information that really clicks, that makes them get that make a transition from the traditional approach to risk based in science and risk based approach to drug development?

Walkiria: My point of view that the students have been through the course, definitely converters that try to influence their workplace and their managers but when the managers get it from I mean as if they get it, the life is much easier for everybody-

Sun: Of course.

Walkiria: -so still I struggle, I think doing changes from the bottom up is much harder and it takes much longer and we are having in the past 10 years I’ve worked with vice presidents from different companies that some of them get it and things go very well, I mean one person that has helped me and it has made a huge difference while of course I have to say and the thank him is for the [unintelligible 00:30:29] from GSK and it is amazing how this makes it different.

So, the students are good ambassadors, I think and they help I think, the companies to convert the people that are the blockers If I can say that way because I just feel a lot of reluctance and the misconceived the ideas that QbD is expensive and those kind of things that go around but If you go back to basics and if you know your science and technology that you’re using well, if you are able to assess criticality, I think doing a design of experiments make easier and the rest follow.

So, by there, that is no magical one-

(Laughs)

Sun: That’s what we all are looking for, silver bullet.

Walkiria: -but I am very optimistic and I’m a fighter. If people that know me and know that is very much the truth and I keep going and I never give up and I think that’s the way forward and eventually we will get there.

Mark: Practical hands-on experience of QbD and also I think it’s difficult sometimes for companies to interpret the ICH guidance and understand how to apply it without discussing or looking at the practical examples which case studies which are out there and that’s where again where we hope that our book will help companies to be able to follow simple case that is to apply QbD to the real situation.

Sun: Could you give us a list of some of the case studies that are specifically mentioned in the book?

Mark: Most of them most of the chapters that are written in the book contain case that is, we didn’t think should we put all the case that is at the end of the book and then decided to include them in the chapters.

So, the book is structured so each chapter has a topic which is related to QbD. If you look at the different chapters that are in the book; quality risk management for example, tools an introduction to risk analysis well that contains several case studies around risk management and risk analysis. Quality systems and knowledge management again there are some case studies and then we divide up chapters into developing drug substance manufacture, drug product manufacture and also analytical methodologies.

A separate chapter which came in a little bit later when we thought it was an important area and there quite a few case studies associated with each of these chapters and then the chapters on D.O.E, Design of Experiments and multivariate analysis, that’s very hands-on practical explanations of applying these things to the real world, real case studies, they’re involved in the chapters.

Walkiria: Yeah we decided to the process analytical technology chapter, we’ve included our bespoke case study that we’ve developed for GSK and although it’s a very brief introduction of the case study, we will– we are in a process of publish the details of the results that we’ve collected but that is a good illustration of how we’re actually with for example, the UV rays that we have in line we can very quickly screen optimize and propose design space that it can help you to the next stage of scale up that way so there are some very good effective in my view, case studies that can be used as an example so people can sort of relate to their own situation on their own workplace but it is not that easy. I think my job here this particular case study that we’ve developed so we deliberately selected an API that will show some fantastic changes as you did dramatic things with the API for example, going close to the edge of failure and then moving from there and you can very quickly optimize your system with the tools that you can have available in life for example, but the clarity of the example should be there and I think to deliberately show how this way of thinking can be effective and the methodology can be used in a more effective way so it’s our responsibility as educators and the university people I think should be thinking about designing the examples in a way that people will get it and this is what we want reading.

Sun: Right, well thank you for that example. Before we end I want to have a chance to talk for you two give us a quick introduction to the upcoming conference or the program that’s coming. So if you could tell us our community what your conference is about and who will be there or what the theme is for this year?

Walkiria: Ok, well the let me just talk about little bit about the history of this conference. When back in 2013, when we get all these people, this steering group, very high up senior people coming every year said well how can we keep going let’s just do a symposium and that’s the way I keep the steering group active and helping us so that is to catalyze this interaction between regulators industry and academia.

So, this year is the first the number six and the theme is medicines manufacturer, roadmap to innovation and this was really inspired on some documents that were published by the government and there’s a huge initiative from the UK government to incentivize medicines manufacture and innovation is the key there.

Now, with this in mind, the symposium always split into three parts. The main part is I tried to invite people that had influence in companies and big companies like GSK for example. [unintelligible 00:37:32] was a senior VP for GSK for many years and he was heavily involved with the medicines manufacture in the through partnership. Again an initiative from the government to try to stimulate that sector and so I have the first session is will be people that would experience in applying QbD. Alistair Cooke also will talk about continuous technologies and regulators are always important.

Carolyn from AstraZeneca will talk about when innovation meets regulation which I’m looking forward to her talk so and the second part is always an open forum where we—this is very a stimulating actually discussion, we spend about an hour and a half discussing and promoting this debate, where we are in industry and regulators and academia and what we are doing and where to go next.

I always leave opportunity for the young people that are actually our students from the course from industry and they can showcase what they are doing at their own company and how they are applying QbD in their own companies. So, we have people from Germany this year, from UK talking about their experience and this is an API systems, API manufactures, also interesting today this year we’ll have a talk from Reckitt Benckiser and in applied QbD to be doing fast-moving consumer environment which is a good sign because though various is deceived not to be difficult to the applied QbD.

Sun: Very interesting.

Walkiria: Yeah that’s I’m looking forward to that as well and then the final session obviously I’ve mention already, Roger is going to talk about these new ways of the risk assessment for a rapid product development and the final session is dedicated to innovation in technology and we have some case studies there. Professor Axel from Cambridge is doing a tremendous work on measurement of porosity of tablets using Terahertz and this is the intention is to have this as a real-time with this testing for dissolution I say.

Following that we have case studies for– this also extremely important I think development where you combine techniques or in line measurements we have talks from Kopeck and contribution from Simak and in Glasgow Stratford University where Cameron is going to talk about digital twins and micro-factures for future manufacture coupled with also people from perceptive engineering that are going to showcase what they are doing in a hot-melt exclusion from the process control and process monitoring.

We’re going to end up, the grand finale is going to be in the hands of the [Dave Rudd?] and he works for GSK for a long time and he’s going to talk about his title of the talk is time for change, a brief guide to innovation including how, when and who. So it should be great fun and he’s an excellent speaker so everything I think will be convinced in a way that we give opportunity to young people to showcase what they are doing. We also have very senior people from industry sharing their experience and the innovation in technology is the focus of this podium this year.

Sun: Excellent! Thank you for giving us a rundown. I look forward to seeing the output of the symposium in March 21st 2018 in Leicester. Do you have anything else to say to our listeners although links to the conference and the book will be included in the QbDworks.com.

So please go and check out the links so thank you so much for your time today, Walkiria and Mark for joining us today. Please continue to produce many good students at De Montfort University as you’re educating the next generation for call by design for the life science industry.

Walkiria: Thank you so much, pleasure to talk to you.

Sun: Thank you.

Mark: Thank you.