Are there any regulatory incentives for Quality by Design (QbD)?
The Pharma Industry is disappointed about what FDA and ICH hinted as a benefit of QbD (Quality-by-Design) — Regulatory Flexibility.
“While QbD concepts described in ICH Q8(R2) and Q11 are… well accepted by FDA and Pharma, recent regulatory experience suggests that the implementation of QbD has created divergent perspectives and expectations.”
The Result? “Little regulatory incentive for industry to pursue continuous improvement,”
is what Roger Nosal (VP of Global Chemistry, Manufacturing & Controls at Pfizer) began with at the ISPE talk on “Industry’s view on the regulatory challenges when implementing QbD.” Based on his experience in QbD submissions of NCE’s, Roger began by stating the current issues with regulatory agencies:
Lack of clarity on how industry should define and manage “risks”
Inconsistent delineation of regulatory commitments in NDAs and BLAs
Absence of clear risk-based CMC review and inspection activities
Lack of trust for post approval change management
This type of conversation between the industry and the regulatory agency is healthy and should be encouraged. QbD is still in its toddler stage and will have growing pains. As more stakeholders embrace the QbD mindset, we can and will calibrate the approach and the expectations. I have faith that both the Industry and the Regulatory Agencies will work out the differences as the QbD practices and culture evolve over the next few years.
As I was observing the conversations between the industry and the FDA, I must commend the FDA officials’ willingness to listen to what the industry had to say. Coming from a different cultural background, I can attest that very few regulatory agencies around the world do this.
So how did the FDA respond to the Industry’s frustration? Please read This Article.
Roger’s presentation referenced a whitepaper co-authored by PhRMA LDKITT. The team consisted of authors from Pfizer, Takeda, NovoNordisk, Endo, Eli Lilly, PhRMA, Bayer, Merck, Amgen, BMS, GSK, Biogenldec, AbbVie, BI and Novartis.
After delving deeper into the regulatory challenges in Quality-by-Design, The LDKITT team presented 10 recommendations to both the FDA and the Pharma Industry. (Ref: PhRMA LDKITT Whitepaper)
Submission of knowledge-rich dossiers facilitates assessment and inspection activities by regulatory agencies.
The post-approval change management system should facilitate continual improvement of products, while providing appropriate regulatory oversight.
A regulatory commitment represents the specific description of the manufacturing process and quality assurance / control of the product that is defined in the regulatory dossier, and that is subject to a regulatory action if changed after approval
Clearly defined regulatory commitments and any regulatory action needed to change them should be commonly understood by a company and regulatory agency. (Comparability Protocol or a Post Approval Change Management Protocol or other).
Where appropriate, a Comparability Protocol or a Post Approval Change Management Protocol (PACMP) delineates how a change or changes to an approved Regulatory Commitment(s) will be implemented.
Regulatory commitments should be defined in the approved dossier and differentiated from supportive information.
Regulatory commitments defined in an approved dossier should, in general, be those details of the product, manufacturing process description and associated control strategy that are demonstrated to be critical to assure the quality of the product.
Post-approval change regulatory reporting categories can be differentiated based on the product and process knowledge communicated in the submission.
More flexible approaches to post-approval change are possible for enhanced submissions supported by a comprehensive, robust change management system within a company’s pharmaceutical quality system.
Further development of regulatory tools for post approval changes, e.g., PACMP could support and encourage the utilization of enhanced development approaches and knowledge-rich submissions by industry.
Here are the rest of my raw notes. To save you time, I bolded the keywords:
“…So far Industry was able to submit a number of Quality-by-design submissions. We’ve
been fortunate enough to gain a fair amount of experience. What I’m going to
talk about today is where we are and predominantly about where
Pharma has put together some recommendations for moving forward
with the implementation of quality by design and regulatory
The contents of the talk are, what is the problem with QbD from
a regulatory perspective? What are the barriers of innovation
and continual improvement? The status of the regulatory
implementation of QbD and recommendation based on the white
papers that Pharma has generated.
Then, some brief discussion on global harmonization.
Nicholson Price is an attorney who is up in Boston and he has
done a fair amount of scholarship and research on what the
problem is with quality by design. Recently, put a draft paper
in place that I happened to read and these were quotes from him
and he said,’ basically contrary to widespread perceptions, drug
manufacturing is typically expensive, inefficient and non-
Making matters worse, regulation actively impedes innovative
changes to manufacturing methods through substantive and
procedural varies across the lifespan of a drug.’ He issued a
number of references that contain numbers about product recalls,
shortages, problems with products in the industry that are
And is estimated and it has been estimated, and McKinsey did
some work on this and I think these numbers are a bit soft, but
they estimate at about $50 billion a year in waste attributed to
these recalls and these problems.
As a result, the industry has been kind of going in a circle. I
think most of us in industry looked in quality by design as an
opportunity to improve the way we would do innovation and get
innovation submitted in regulatory submissions.
So you had an old or underdeveloped manufacturing process and
you could be in the position where you might even be doing a
drug recall or you might have a shortage or an inventory
You might consider doing some manufacturing innovation to
increase the robustness of your process to avoid that and you
would look at that as an opportunity to gain some flexibility if
QbD kind of offered that to us initially. That’s where we
thought we were going initially. Innovation design for
regulatory compliance though became the mantra and not for
quality, specifically. We were looking poorly at whether or not
we could be compliant. That didn’t give us much incentive.
As a result, many companies have chosen not to improve a lot of
their older process, particularly for their older products. And
as you can see this is a bit of a circular discussion.
Could quality by design be the cure? I think, initially, most of
us thought because its science based, its risk based, it’s
prospective, it could be. But how much effort and how much
difficulty there may be where the challenges lay was really what
would determine whether or not it was going to be successful.
Now, purely from a physical implementation, actually doing
quality by design, most industry believes that it has been very,
very good to do quality by design. None of have said that it
isn’t, because it’s the right thing to do.
You’re looking at your process in advance; you’re trying to
figure out how to design that process so that it will not fail.
And we spent a tremendous amount of time making sure that we can
justify the process and the product knowledge that we have and
use it as well as we can.
I think where we have had the issues and the challenges is the
misunderstanding between what we do and what we provide to the
regulators and then what they see and what they don’t see.
That’s what I’m going to talk about next. That was part of what
Pharma focused on in their two white papers. Christine Moore is
in the audience, Christine Moore and this is a quote from her
from the gold sheet, “That QbD has really caught on in industry.
Science and risk based approaches to QbD being appraised by
innovator companies.” That is absolutely true.
Janet however, has said, “A quid pro quo.” A quid pro quo in
this case, would be regulatory flexibility would really sweeten
the deal for us. And that’s true, that would make it easier for
us to file post approval changes based upon increased
information and robustness in our processes.
But in fact, there has been a fairly large degree of challenge
from regulators about what we are doing and how we are doing it.
That has forced us to look at our processes and our systems and
determine whether or not that we can provide that kind of
information. That’s kind of put us where we are.
So what’s needed? The pharma team that I led recently looked at
this from a number of angles. We came to the conclusion that we
needed better transparency on regulatory commitments. What are
they, how are they used, what would they represent and how they
would facilitate post approval change?
We also recognized that change and knowledge management were key
to this discussion. Because frankly, the regulators when they
ask us questions, a lot of those questions are related to, how
do you do change management? Does the knowledge of a process
through the life cycle, stay retained with the product and the
company? Those are fair questions. Quite frankly, industry
didn’t have a lot of good answers.
In addition, cultivating improvement of quality can be a
competitive advantage and I think most of us in industry believe
that to be the case.
The more that we invested in talking about and looking at
quality, the better we feel our products are placed in the
marketplace. But what about and I’m going to pose this and this
is a bit of a teaser in a sense, what about regulatory
exclusivity for manufacturing innovation?
We have exclusivity for pediatric medications; we give
exclusivity for other things. Is there an opportunity to provide
an incentive like this for companies to look not only at their
new products for continual improvement, but some of their old
products? I’ll leave that with you, we can talk about it later,
probably could be the subject of part of the summit this
So what is the status of regulatory implementation? In the
pharma white papers and the first white paper, the purpose was
to describe the current status of implementation and identify
where the opportunities for implementation and application of
QbD in a regulatory submission were. And then provide some
options for reconcile any different perspectives.
Now we’ve had a number of discussions with FDA and we’ve had a
number of discussions with other regulators on this and we have
determined that there are some differences in perspective but
also, just some lack of transparency.
I think on the industry’s part, as I said, before change
management and knowledge management were two areas that the FDA
was really interested in and industry was not able to provide
what I would consider to be satisfactory responses. But there
were four problems associated that we identified.
Four problems that we felt we really needed to look at. One is
the lack of clarity of regulatory expectations. And this affects
us whether it’s a QbD submission or not frankly. And the
inconsistency in the delineation of what those regulatory
commits are in a submission was also something that we have been
grappling with and struggling with.
So also an absence of clear risk based CMC review and inspection
activities. We were getting inconsistent responses from
inspectors and reviewers for the same products sometimes and we
weren’t sure from an industry perspective what that meant. It
did lead to in some cases to some confusion.
The lack of trust on post approval change management. If we did
QbD, if we got a design space approved, what kind of post
approval change management would be accepted and what would it
look like? And by the way all four of these, this is not about
blame; this is about observations between differences in
perspective between both FDA and industry.
Understanding variability was kind of the key to quality by
design. If we didn’t improve on our understanding of variability
we have a better understanding of our process capability and the
reliability of our manufacturing. We’d be able to reduce our
manufacturing problems and we’ve seen this.
Frankly, industry has seen this across the board since
implementing QbD. Most of the companies that I’ve worked with
and within my own company, we have recognized that we don’t have
the number of deviations or failures that we’ve seen in the
Quality by design has allowed us at the very least to understand
where the certainty is and where the variability is and to
correct for it as necessary. A line process parameters and inputs
with quality attributes, of course was one of the fundamental
tenets of how quality by design was rolled out.
You identify your critical quality attribute and then you align
your process parameters with them and improve quality
assurance, and by embracing the technical merits of QbD, we
think that that is one area that we do not have any kind of
divergence with the FDA.
I believe that to be the case because we’ve had a lot of
discussions on the technical application. There are differences
in terms of what we should be doing and how much we should be
doing, but those are reasonable and I think we’ve had good
However the application of QbD was not intended to change or
increase regulatory standards of product approval in the
industry’s mind. And what we have been sensing over the past few
years is that those standards have actually increased a bit and
that’s a bit of a cause for concern on the industry’s part.
So we’d like to get back to a reconciliation of understanding
what it is we’re doing and how we’re doing it in a way that
would allow us not to feel that those standards have been
The industry promotion has been that if we increase relevant
data and we demonstrated the enhance process of understanding
that QbD afforded. We would give regulators confidence in our
process and confidence in the rigor behind our manufacturing and
By improving that that confidence, we should be able to do
things more easily post approval. So, continual improvement
should be something that we will be able to do relatively easily
and not difficultly, and ideally, continual improvement would
largely be managed within our pharmaceutical quality system.
Remember, I said that this is industry’s presumption and these
were the presumptions that at the time we embarked on quality by
design. At the root of the divergence is really an understanding
of where our risks are. I think industry naively felt for a long
time that our risks were managed.
We understood our products, we invested the energy up front to
do prospective work and we demonstrated we felt reasonably well
that our processes were robust. I think on the FDA’s side, their
concerns were, I don’t understand how you’re doing change
If I don’t understand that, how can I be assured that if you do
a change, are you doing another risk assessment? Which are
legitimate questions and questions that need to be answered.
What has happened I think is that we have gotten to a stalemate
where there’s been little incentive for many of us to pursue
design space Or to do things to change design space because we
have been concerned about whether or not we’re going to have
additional hurdles. think that’s the root of the discussion
So pharma came up with a number of recommendations, ten of them
and I got all of them here and I’ll briefly go through them.
The first one is that if the submission of knowledge rich
dossiers facilitates assessment and inspection activities by
regulatory agencies, we believe that is indeed the case and that
it is true. I think regulators do as well.
Post approval change management system should facilitate
continual improvement of products while providing appropriate
There are three or four on regulatory commitments here. I often
refer to how the Japanese do regulatory commitments and I’m not
saying that is the perfect system.
But when you file a JNDA, you include all of your regulatory
commitments in your application form. And when you do that, it’s
very clear that those commitments are what you’re agreeing to
operate to. In the west and Europe, it’s not that clearly
articulated and there are some differences of opinion about what
regulatory commitments truly look like.
In terms of post approval change, there have been a tremendous
amount of talk about comparability protocols and about
post approval change management protocols. The industry and FDA,
I think, has looked at this as an opportunity to possibly
clarify how we would use regulatory commitments to actually do
post approval change much more easily.
With quality by design, because of the amount of complicated,
sometimes tremendous volume of information, that would be very
useful. If we use those protocols, we would be able to delineate
change or changes to the commitments and implement them
effectively without it, what we would call inappropriate or too
Regulatory commitments should be defined in the approved dossier
and differentiated from supportive information. So we put
together a tremendous amount of data now in a quality by design
submission and there is a tremendous amount more that we don’t
Risk assessments for example are huge, huge documents of
information. And so differentiating what a commitment is from the
data is really kind of important so that we don’t confuse the
Regulatory commitments defined in an appropriate dossier should
in general should be those details of the product, its
manufacture, control strategy, all demonstrating that the
quality of the product has been assured.
Post approval change regulatory reporting categories could then
be differentiated based on product and process knowledge that we
actually put in the submission and then are captured in those
And interestingly enough, many companies when they thought about
quality by design in their minds thought that we could file only
those things that were critical. So our process descriptions
were very, very small. It was not very helpful to the FDA and we
recognized that. In doing that, we excluded an awful a lot of
information that the FDA needed to effectively evaluate whether
or not we actually had a robust process.
So, again, defining what that commitment should look like and
why is key to moving forward with post approval change. More
flexible approaches to post approval change management are
possible with enhanced submissions and we believe that and we
have seen some evidence of that.
But, it hasn’t been consistent. I think that is one of the areas
that we’d like to move forward with. And further development of
regulatory tools for post approval changes like the post
approval change management protocol would be helpful. There are
a number of operational challenges and I have them listed here
These may be some of the questions we can talk about this
afternoon or talk about during the day today and I’m not going
to go through them here. You’ll notice though that there are a
fair number on risk and change management and knowledge
Those are areas I think we need to help the FDA understand what
we do and why. So they are assured that through the lifecycle of
the product that we have a good handle on our processes and our
products. So let’s reconcile divergence by reducing those
We feel that we can develop a framework for identifying the
commitments and submission. Perhaps it’s the quality overall
summary, could be something similar to what we do in Japan.
Enhanced risk based approaches to regulatory oversight of post
approval changes are something that we think that the FDA could
be looking at to adopt as part of their review process.
And then ultimately we’d like to foster some enhanced
information sharing collaboration between the offices and I
think that’s already happening through OPQ. We’ve seen some
evidence of that at this meeting and we’ve talked about it with
the FDA recently and it looks like it’s moving in a direction
that will provide the appropriate alignment consistency as we go
I was gratified to hear that much like OBP, reviewers in the
small molecule area will probably be going on inspections as
well from time to time which I think is actually very valuable
So I’m going to speak for a minute on global harmonization
because one of the reasons that quality by design is also
attractive to industry is we thought we could use it as the
basis for harmonizing globally the variety of request we get.
Again, divergent requests from different countries around the
world. So this is a real example, it’s a product at Pfizer and
it’s a product that I’ve been involved with for a number of
years. We have right now 24 separate sets of requirements for
the same product globally. They’re just differences of opinion
of what should be in that product and why.
This creates a tremendous amount of complication for industry.
If you register a product in 50 markets or 100 markets and you
have to maintain 24 separate or maybe more sets of criteria,
you’re inventory is very complicated.
And if your inventory is very complicated, it makes it much more
difficult and much more challenging to be able to manage that.
So we don’t think that this sustainable.
If you’re a company that only makes one product, it may be
sustainable. But many of the larger companies in particular we
manufacturer a tremendous number of products. So the
complications are becoming even greater.
Inspections, in 2012, we had a 175 inspections at our
manufacturing sites, 29 of them were preapproval. We had 4 new
products that were approved and for 1 product we had 5 PANs from
different agencies around the world.
We know that [Pix] is moving in a direction to try to harmonize
and we think that’s the right direction. But again, sustaining
that number of inspections is a tremendous burden on industry.
Again, QbD might be one answer because we’re going to be opening
up and being more transparent about a lot of what we do and that
should alleviate the need for as many inspections as possible.
And again, I think the FDA is moving in the right direction
based on what I’ve heard this week and even previous to this
week. It looks like there is some progress in this direction.
Supply chain complexity. We’re getting our raw materials from
around the world. We are converting those into APIs, or
components, starting materials that convert the APIs into
We’re doing drug product manufacturing in different places.
We’re packaging in different places and we’re distributing in
different places and our supply chains are getting more and more
complicated as well.
If you go back to the example that I gave where we have 24
different control strategies for 1 product and then you overlay
that on the supply chain complexity for that product, you can
see that it gets very complicated very quickly. I know this
worries the regulators and it worries us as well.
In order to maintain this, we have to be very, very careful
about where our inventories are and what they look like.
As a result industry has grave concerns, but on the other hand
we see the opportunity to harmonize. And if we can harmonize
using something like quality by design, we feel it’s an
appropriate way to go.
With that, I would like to thank the Pharma LDKITT that was put
together to discuss quality by design implementation and put
together the two white papers. Those white papers have been
issued by Pharma, but have not been issued broadly.
They have been issued to us to be able to share and that’s why I
shared the output today and we hope to share that in the future
And with that I will entertain a couple of questions before we
go onto the next speaker thank you. Any questions?”
What are your thoughts? Please Share!