No Regulatory Incentives for Quality by Design (QbD)? 10 Recommendations

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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)

1. Submission of knowledge-rich dossiers facilitates assessment and inspection activities by regulatory agencies.

2. The post-approval change management system should facilitate continual improvement of products, while providing appropriate regulatory oversight.

3. 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

4. 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).

5. 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.

6. Regulatory commitments should be defined in the approved dossier and differentiated from supportive information.

7. 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.

8. Post-approval change regulatory reporting categories can be differentiated based on the product and process knowledge communicated in the submission.

9. 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.

10. 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

submissions.

 

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-

innovative.

 

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

listed here.

 

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

problem.

 

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

possible.

 

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

afternoon.

 

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

past.

 

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

discussions technically.

 

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

unnecessarily raised.

 

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

controls.

 

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

management.

 

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

going forward.

 

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

regulatory oversight.

 

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

much oversight.

 

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

provide.

 

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

two.

 

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

commitments.

 

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

as questions.

 

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

management.

 

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

constraints.

 

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

forward.

 

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

for them.

 

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

different places.

 

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

as well.

 

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!