cGMPs / QRM Process

Dr. Moheb Nasr's IFPAC Plenary Speech

Here we provide a transcript and a two-part audio file of Dr. Nasr's keynote address at IFPAC 2007, in which he emphasized FDA's continued interest in PAT and its importance in a Quality by Design framework.

The transcript of Nasr's plenary speech follows. Click here to hear an audio file of Part 1 of this speech, and click the Download Now button at the end of the speech transcript to access the "Part 2" audio file.



Good morning and thank you. This is my fifth time at IFPAC. I’m here to … make it very clear that we at the Agency are committed to the continuation of our initiatives in pharmaceutical manufacturing and PAT.

I will focus on how these activities relate to the initial premise of advancing science-based pharmaceutical manufacturing. There’s a unique opportunity at IFPAC, since pharma is only one section of many here, and there is an opportunity to learn from those in other industries about other approaches [to applying PAT concepts].

I’d like to share with everyone my own perspective on where we are today as it relates to pharmaceutical manufacturing.

I want to:

  • make it clear how we define the design space;


  • discuss pharma quality initiatives as a subset of the Critical Path;


  • focus on QbD and how the PAT initiative hits QbD; and


  • share with you where we are today.

…The industry is under attack today… The question is: are [drugs] affordable? Should we worry? There is a lot of discussion in Congress regarding Medicare and… purchasing strategies. In short, there are a lot of challenges facing industry.

What about us as an agency? There’s quite a bit of public concern…

In the last couple of years, more so than before, this is highly visible — the high cost of pharmaceuticals, will we be able to monitor drugs after approval? There is resistance to importation from Canada and outside the U.S., and there are other issues regarding specific drugs.

Resources are very tight. [But we must ensure the] adequacy of expertise for every change in science in technology. We need expertise and it is very important that we have the right staff and expertise [for our programs]. We cannot expect industry to provide us with this info…

We have been working tirelessly over the past few years to ensure international harmonization [of regulations]. There’s discussion about variations … as they relate to manufacturing changes. We’re involved in quite a few activities.

But there are still a lot of public concerns. There are unmet medical needs, questions about costs, managed care issues, insurance questions, the issues of counterfeit drugs, questions about the safety of importation. And there are public opinion issues, along with drug safety, speed of drug approval, perceived lack of enforcement (at times), criticism about approval times, and questions about our relationship with the industry.

So where are we today with pharma manufacturing? The industry’s level of quality is adequate. But QA can be quite painful, and in general, drug manufacturing is not as innovative and efficient as other industries.

Manufacturing is expensive and efficiency is not as high as it could be. Here is low factory equipment utilization.

And amazingly, there’s quite a bit of reliance on FDA’s regulatory oversight. This industry is too reliant upon the FDA. We don’t like that and don’t want the seat of power to be with us. We think that industry should be empowered to manage most of its QA and QC functions.

In short, the bottom line is that our industry not as innovative and efficient as other high-tech industries. It is overly conservative, and there is a lack of coordination between key business units.

These challenges impact PAT. Since we’ve recommended harmonization, it’s challenging. We see frequent manufacturing failures and more reliance on outsourcing.

And that reliance, in itself, becomes more challenging, not only because of our concern about the well-being of the U.S. pharmaceutical industry, but because of the Agency’s limited resources, and our ability to reach beyond our nation’s borders to ensure that GMPs being implemented.

A recent report by George Washington and Washington Universities … found that this industry wastes $50 billion each year because of lack of manufacturing efficiency. Think of how that money could be used to develop drugs that could meet unmet medical needs, and potentially, to reduce the cost of pharmaceuticals in our country.

So where are we with our Desired State? Dr. Woodcock spoke about the… meeting in Washington, where we defined the Desired State for agency and industry. Simple definition indicates where we need to move: to maximum efficiency and flexibility in drug manufacturing, producing products of high quality without extensive oversight.

This sounds simple, but is difficult to do. In order to get there, we need three pieces:

  • Quality By Design (QBD), as spelled out in ICH Q8;
  • Robust, reliable pharmaceutical quality systems, as spelled out in ICH Q10;
  • The use of quality risk management tools as in ICH Q9.

The harmonization efforts and efforts within Agency on Q8-10 will take us where we need to go to reach the desired state. This effort is very tedious, difficult, even painful at times, but the only way to move forward.

So, where are we with pharma quality initiatives, QbD and PAT?

In September 2004, we published the 21st Century Quality Initiative and also issued the PAT guidance document.

This guidance came after almost two years of intensive efforts by FDA's hardworking PAT team, of which I’m proud to have been a member...

We’ve been working on ICH… made quite a few changes in our office. We had some challenges with our generics review process, came up with question based review.

We also finalized quality systems guidance. We held a workshop in 2005; that’s where Janet spoke on the final Desired State.

We’ve scheduled a workshop next month on all pharmaceutical quality initiatives in Bethesda. We will be talking about PAT, QbD, biologics, CDER, quality systems, etc. If you can attend, it will be extremely valuable.

So what about QBD? What’s it all about? ICH Q8 was finalized over a year ago, in 2005, and became regulatory guidance in spring of 2006. Q8R, an extension, will provide a way to facilitate implementation of QBD.

People are asking, "Whatever happened to the PAT initiative? Is FDA not interested anymore? Where does PAT fit in with QBD? How is the Agency dealing with QbD and PAT applications?"

We want to deal with questions. We have so many things going on at the same time, at the Agency, different guidelines, so I thought it might be helpful to summarize and address some of your concerns.

If you think about product, process design, manufacturing and process monitoring as a representation of what goes on from discovery through full-scale manufacturing, ICH Q8, finalized last year, deals with pharma development from product design through full-scale manufacturing.

The PAT guidance published in September 2005 addresses manufacturing, process design, manufacturing design, monitoring process improvement.

Q9 provides the ability for using modern formats to address quality risk tools, from design to full-scale manufacturing.

Last September, we published the guidance for Q10, and we’re aiming for completion in May, 2007.

So what is QbD? Well, consider the word “design.” It implies creation, conceiving, planning, having a purpose, devising something for a specific function. In design, one has to think, develop a concept, and plan… These are design’s key elements.

I would like to share our current view of QBD.It’s a system that starts by defining the desired product up front.This requires identifying and defining critical quality attributes. The first step is thinking about:

  • What is the product needed for?
  • What are the clinical relevancies?
  • What type if population is the drug for? For example, is it for pediatrics?

Once that type of thinking takes place, then the design of formulation and the manufacturing process can take place. Now that you know what the critical quality attributes are, you can reduce problems and issues based on those quality attributes. You’re defining the requirements in advance. That should automatically lead to the design of a better formulation and process, because process and product development is the goal.

Basically, you take a systematic approach and plan with the end in mind, before you start working on process optimization, quality and manufacturing. But once you do that, there is a need to understand the effect of material attributes such as raw material attributes on process parameters, on those critical quality parameters and attributes that are needed for the drug to work.

You need to identify and understand the sources of variability in raw materials… and processes, that is where PAT can be very critical. There is a need to continue to monitor processes to ensure consistent product quality.

This is where further use of risk analysis, risk mitigation and modern process control and product QC and management are important. You build requirements in advance and understand variability to improve monitoring and control.

QbD is a holistic risk-based approach. It is a deliberate design effort from product conception to commercialization, and requires total understanding of the impacts of product attributes on performance and quality, allowing analysis of performance and quality.

QBD is not simply formulation and process optimization or experimental design for demonstration/justification of critical quality attributes. These are all desirable things to do, but these are only parts of what you need to do in order to achieve with QbD.

It is interesting to contrast traditional and Qbd approach.The traditional approach isn’t bad, but the QbD approach is better and provides opportunity for innovation and for using good science for the assurance of quality. At times, in some of today’s manufacturing approaches, some QbD elements are being utilized.

Drug development is traditionally empirical, using univariate experimental data, one experiment at a time. QbD is systematic; it uses multivariate experimental approaches.

In the traditional framework, the manufacturing process is fixed… Under the QbD approach, the manufacturing process is adjustable and there’s continuous vertification and focus of quality strategy.

Now consider process control today. Today, in manufacturing, you have some limited in-process testing, basically intended for "go/no go" decisions. We start the process, take samples, we wait for results from lab, then decide whether or not we can move on to the next step.

Under QbD, PAT is utilized for feedback and feed-forward control … that’s where PAT fits into the holistic and systematic modern approach to pharmaceutical development and manufacturing.

Let’s consider product specifications. Today they are the final means for quality control and for analyzing daily batch data. Under QBD, they are only part of the overall QC strategy that must be achieved for desired product performance.

Moving on to control strategy, today it is mainly accomplished by intermediate and then product release testing. Under QBD, better utilization of risk [assessment] is made, and control shifts upstream, and where opportunities for real-time release can be realized.

Finally, consider life cycle management. Today, we chase things only in a reactive way when we have problems or we have OOS results and changes. Under QBD, we have to continually go back into the designed space to improve the process and product. Note that I use "continual" improvement, rather than continuous, here.

The design space is defined in ICH 8 as involving multidimensional combination and interaction.

So what does this DS tell you, that we are we making a big deal of it?

We have a DS approach in place now. In some way it’s limited. But the concept of design space offers opportunity once we understand the process.

If we understand all about product and process, understand how process parameters can potentially combine or interact to have an impact product quality. We talk about variability, in terms of material of use, and process parameters, so we have to understand this concept.

We have to understand, in order to move to that characteristic QbD system, and multivariate approaches are needed.

There is regulatory flexibility, provided that you are working within the design space. And working within the design space is not considered a change. The more you do advance, the more you know, the more flexibility you will have in manufacturing in the future.

It is important to know this in our definition in ICH Q8, the design space for a given product/process is proposed by applicant and subject to regulatory approval.The applicant has complete flexibility to look at the approach and devise a solution, but then the applicant must ask us to look at their approach and evaluate it.

So how do you come up with a design space? I think it’s important that there are many approaches.

The most highly desirable one is usually the most difficult to find. Mechanistic first principle approaches, here a combination of instrumental and mechanistic knowledge, chemistry, chemical engineering is used to model and predict process performance.

Statistical DOE allows for efficiency in determining parameters and interactions.

Scale of correlations is a fairly common approach used to evaluate different scales and pieces of equipment.

Which one do we expect the industry to use? Combination of all is useful.

We want industry to try out [these methods] and improve the knowledge base…

We’ve been making a big fuss over the manufacturing processes. It is important that any process be not only reproducible, but robust. Robustness is very important.

When you look at manufacturing processes and putting stuff into containers you have some parameters, some raw materials and variables, that change from time to time. Process output is measured by evaluating statistical quality attributes.

So, to ensure stability, we have tried very much to have fixed conditions — this concept drives batch process validation too … using the same operator, the same material, the same equipment. We don’t change a thing.

This is okay. That’s what we’ve agreed upon and we’ve had some success with it. But the problem is that this approach doesn’t last long. You have to make changes or are forced to make changes. That’s why you should focus on building robust manufacturing processes.

With a robust process, it is okay to have different inputs — different equipment, operators or raw materials.

You study the variability, and you adjust the process to adjust to variables in equipment, etc. to have desired output [given any] available equipment and resources.

Designing robustness into a process is very important. If you look at the relationship between process understanding and process control, the more control and understanding you have, the more you understand and control your process, the more robust it is. The less robust it is, the higher the chance of potential failure.

PAT enables both a high level of process understanding and process control, and that’s why PAT is critical in order for QbD to be realized.

PAT and process monitoring are critical for process understanding . . . for manufacturing — they ensure robust operations.

So, in response to the question, "Isn’t FDA interested in PAT anymore?": We are more interested in PAT than ever before, because we realize that PAT is critical to process development, to developing a mechanistic understanding [of a process] and correlation-enhanced process understanding. PAT is also critical to the establishment of the design space.

Under manufacturing, PAT ensures robust operations, process control and allows continuous improvement. Historical data trending, having and applying such knowledge and information allows continuous improvement. Statistical Process Control is also critical, as Ajaz has said.

I hope you are all more convinced than ever that PAT is critical to QbD. It’s just that QbD encompasses earlier issues and clinical issues too, not just manufacturing.

So, what have we done? We established a new CMC recruitment office to [recruit experts to help us review] new drug applications that focus on science and critical quality attributes and how they relate to safety and efficacy. Starting in November 2005, we established a manufacturing science branch with engineers, pharmaceutical engineers and pharmaceutical scientists. We established a project management staff, and decided to handle post-approval differently than other CMC agency reviewer groups in our office.

We developed a pilot program. We have been talking with industry, seeing some applications. . . determining our expectations, and asking if information submitted to the Agency has a certain thrust, whether we have the capability and expertise to deal with it.

Our program offers industry the opportunity to submit CMC info but using a QbD approach. Applicants use their own approach. Some of the concepts were design space and real-time release. So we wanted to see how these concepts were applied in some applications.

It’s very easy to talk about these concepts in a PowerPoint presentation, but it’s very difficult to use these concepts to develop drugs. We want to use these concepts and see how they translate into real drugs, and to seek public input in developing guidance.

We started this journey in July 2005, and the deadline for first submissions was March 2006. I thought we’d have a thousand applications. We received more than 12 requests, but we have accepted only 11 people so far — nine original releases and two supplements.

Four are under review, others have been submitted. But now, as an agency, we have real “hands-on” experience in how all these concepts impact drug development.

In summary, so far we see that all pilot applications use some elements of QbD, but none of them so far has used the total systemic approach that I have outlined. Some use PAT, identification of critical quality attributes in formulation development, risk assessment, DOE. We see examples of process development that define critical process attributes and design space.

We are shifting the focus of what we do from reviewing batch records to reviewing science.

Some other observations: Process stability information is there, but we still would still like to see more information on process robustness. PAT is used more in development, but not for robustness, in some cases.

One thing that really bothers me as a scientist is that, at times, firms are doing good work, they have good development processes, good information and they put all that in the development section of the application, but there remains a disconnect between using good science to provide better, more robust quality control. This is something we need to work on.

People have heard about new flexible regulatory approaches. The question is, what do I take? With one client, they gave us science, but [their approach was still], "Okay, this is just for show and tell." So we challenged them; we asked them, "How can you use this good science to develop a better model for a more flexible regulatory strategy?"

We challenged them, and flexibility is resulting in different approaches, such as in-process testing using assay identification with NIR instead of in product testing, in-process testing of dosage uniformity by wave dilution, PAT for some innovations, real-time release, the annual reporting of post-operational changes … These strategies are being used for participants in CMC pilot program.

In general, the blanket of review flexibility depends on the level of knowledge and process understanding. The solution is regulatory agreement, [which is] under development — that is, a mechanism for applicants to propose a specific strategy for a specific product and process. Applicant commitment is everything that is put into that application.

You need to change your concept of obligation commitment for regulatory agreement, the next step between what you put in the application and what you’ll be responsible for once it’s approved. This will facilitate continual improvement.

We’ve discussed the financial impact of post-manufacturing changes…

In conclusion, QbD is not a requirement right now. The current system is adequate for regulatory submission, but I would argue that QbD is a desired approach, assuring product quality, enhanced manufacturing efficiency and flexibility…The Agency’s focus remains on the development of safe, effective pharmaceuticals for the public.

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