QbD Success and Challenges: ONDQA Implementation

Christine Moore
Dr. Christine Moore, Credit: ISPE

Dr. Christine Moore shared her perspectives on the current status of QbD. The talk was titled: ONDQA Implementation, QBD: the success and remaining challenges.

I am sharing my raw notes from her talk. Again, I will edit the article further after I return from my trip.

I encourage you to read the entire transcript below. Dr. Moore of ONDQA, FDA addressed many specific  Quality-by-Design questions, including topics such as, regulatory relief, design space, global harmonization, criticality, QbD adoption, etc.

Dr. Christine Moore is the Deputy Director for Science and Policy and currently Acting Director of FDA’s Office of New Drug Quality Assessment. She started at the agency in 2004 as the Branch Chief of the newly created Manufacturing Science group. Christine has been actively involved in FDA’s Quality by Design initiatives and was a member of the expert working group for ICH Q8(R). Prior to joining the FDA, she worked for 10 years in API process development and scale-up at Pfizer and Searle/Pharmacia. Her background is in chemical and biochemical engineering, with degrees from Northwestern University and Massachusetts Institute of Technology.

Here is a short summary of (paraphrased) points:

1. Innovator companies have found that by using quality by design, … provides them a business benefit. They improve product quality and process robustness. They decrease operational cost, and that pays for itself.

2. We see it becoming increasingly adopted by generics and biotech companies….there is a limited use of regulatory flexibility that we’re actually seeing in applications in terms of design space, real time release testing..

3. Definition of “criticality” from Q8(R2) … should be based upon the potential impact of the parameter and not the residual risk after the implementation of the control strategy.

4. FDA would  like to see the ICH terminology only.

5. We really think that quality by design, both science and risk based approaches has made great progress in industry. But, we also recognize that the regulatory post approval flexibility has not fully matured.

6. We have had very good success in our harmonization efforts between US and Europe and, surprisingly, including Japan as well. We have a high degree of similarity of regulatory expectations. We’re still working on aligning those even further.

Mentioned Links:

1. EMA-FDA pilot program for parallel assessment of  Quality-by-Design applications: lessons learnt and Q&A

resulting from the first parallel assessment  [Click]

2. Questions and Answers on Design Space Verification [Click]

Talk Begins

“Dr. Moore: Okay. First of all, I’d like to thank Previous Speaker for a critical look

at the industry perspective on QBD for small molecules. I

think the good news there is that none of what he presented

was a surprise to me and others in the agency.

 

Also, through some of the items that I’ll be presenting –

and I’ve seen Steve’s slides and talked to him about this –

I know that we’ll be addressing some of the points. But, we

do recognize that we will need to continue to work together

to fully advance and coalesce, really capture the full

potential of QBD.

 

Today I will be talking about, from a small molecule new

drug side, our perspective on the implementation of QBD in

terms of successes and remaining challenges. I’ll start

with just some quick background on quality by design and

then go into the current status.

I’ll spend quite a bit of time talking about our

collaborative efforts with our European regulatory

counterparts through our pilot for QBD and then some ideas

on next steps.

 

I’d like to start with a reminder of what the definition of

quality by design is. This comes straight out of ICH

Q8(R2). There are four points that I have listed here.

The first is that it’s a systematic approach to

pharmaceutical development and manufacturing. You start

with predefined objectives, and there’s an emphasis on

product and process understanding and on process control.

It’s based on sound science and quality risk management.

 

I thought it was important to start with this definition to

recognize that the, I’ll call it, textbook definition but

it’s really guidance definition, of QBD is about a science

and risk based approach.

It’s not about regulatory flexibility, however, by doing

QBD the presumption has been, and we’ve been trying to put

in place, systems that by having that science and risk

based approach certain regulatory flexibility followed.

Obviously, from Previous Speaker’s talk, we are not all the way there

yet.

 

But, let me go on and talk about what QBD is not. QBD does

not mean design of experiment, although you often use

design of experiments when you’re doing a QBD approach. QBD

does not mean design space. The two are not synonymous,

although, again, you can use QBD approaches to define a

design space. And, the use of QBD in development does not

automatically grant regulatory flexibility.

 

Rather, the applicant has to take that knowledge that

they’ve learned, that science and risk based approach, and

present proposals into the regulators about flexibility

that they’re looking for. ICH Q8(R2) defines a pathway for

flexibility in terms of design space.

The other ICH documents, as well as Q8(R2), talk about

flexibility such as real time release testing, and now

we’re going to move onto that discussion for other aspects,

such as comparability protocols, at least in the US and in

the European regions.

 

I have two circles here.

What you have in the blue circle there is science and risk

based approaches. That’s what the textbook definition of

QBD is. Then, there is a dotted arrow over to that blob of

flexible regulatory approaches.

 

The point is that one does not equal the other and that

there is a connection between the two, but it’s a dotted

line connection because additional actions have to happen

on the part of the applicant in terms of what you put into

your submission, what you claim, and how you justify those

flexible regulatory approaches.

Also, it’s a dotted line because there are not as many

pathways or not a complete pathway, and Previous Speaker touched upon

that right now to take that science and risk based

knowledge, those science and risk based approaches through

QBD, and turn it into full flexible approaches.

 

So, the state of quality by design. I think you’ll find

this is consistent with what the last speaker said. What

we’ve seen from our perspective, as well as what I’ve heard

in the many, many conferences I attend, is that the science

and risk based approaches of QBD are being embraced by most

innovative pharma companies for development.

Often, that dotted line’s not completed. So, they have the

blue circle. They did that work in development. They may or

may not have been fully transparent with that in their

application. That’s their choice. But, they’re not claiming

that regulatory flexibility such as design spaces.

 

On the other hand, as Previous Speaker mentioned this, the innovator

companies have found that by using quality by design, by

using those science and risk based approaches, it provides

them a business benefit. They improve product quality and

process robustness. They decrease operational cost, and

that pays for itself.

 

We see it becoming increasingly adopted by generics and

biotech companies. I don’t think that it’s as fully

embraced in those companies as it is in the innovator

companies, but it’s definitely growing. As also mentioned,

there is a limited use of regulatory flexibility that we’re

actually seeing in applications in terms of design space,

real time release testing, and other approaches.

 

I like to reference this paper. This came out just a little

bit over a year ago. I know at least one of the authors is

in the audience here. It was a survey of 12 companies, both

small molecule and biotech, regarding their experience with

quality by design. It came out over a year ago, so I would

imagine the survey was probably at least two years old.

 

(I’ll write an article regarding this paper soon)

 

Essentially, it was very positive in terms of the business

benefits of using QBD, and all of these different benefits

were listed in the paper in terms of improving your

product, improving your process, decreasing cost,

increasing speed to market, and increasing your

manufacturing capability. These are all positive aspects.

Also, some quotes from that paper talk about industry’s

perspective on the QBD.

 

Again, we’re talking about the blue box part here. From the

blue box part, again, it’s very positive where the people

who were surveyed in this work thought that QBD would

become more of the norm, and that it’s worthwhile doing,

and it’s already expanding its scope and will continue to

grow. If you haven’t read that paper, I suggest that you

do. That’s where we’re perceiving the industry is at.

 

We know at least for small molecules, the groups that my

office works with, they like the blue circle. They think

that it’s worthwhile to do that science and risk based

approach. That regulatory flexibility will get more to

that.

 

But, let’s talk a bit about how we’re responding to it,

what we’re doing, and what our status is, in terms of how

we review applications that contain quality by design

elements. First of all, we look at quality by design using

the standard application review process. We don’t have a

special process for these applications.

 

All of our review staff have been trained on elements of

quality by design in review through in-house training

opportunities and many, many external training

opportunities including some hands on training

opportunities for advanced methods.

We also have specially trained staff. We call them our QBD

liaisons that are trained very extensively. This was a year-

long training on and off on advanced quality by design

concepts. These folks serve as consultants and mentors, and

they’re available in every branch and division of ONDQA.

 

Another point of what we started when we started looking

intensely at quality by design is we started looking at

enhancing our team approaches of starting out with required

dedicated meetings where we get the whole review team

together. That includes the folks from compliance.

It includes investigators if they’re known at the time. It

includes other offices such as if we have microbiologists

reviews, et cetera, and defining the quality review team,

and looking at that interaction and enhancing and

continuing throughout the cycle of the review.

 

That approach has been very successful. We’ve now

standardized it for all of our new drug applications for

the last year, and we’re looking at extending that for all

of our applications and continuing that approach as we move

into the proposed office of pharmaceutical quality.

Recognize that the vision for office of pharmaceutical

quality is even more enhanced in terms of the team review

approach and focusing reviewers on areas of specialization.

The enhanced communication internally has been very

successful.

 

We’ve also transformed what we called at once our QBD

steering committee into a standing precedence meeting where

we consider new novel aspects and applications that might

be quality by design or other aspects, too. We do have

these discussions at the senior management level within

ONDQA so that we’re making unified decisions for the

office.

 

In general, what we see for our QBD review aspects is we’ve

moved from something we considered an extraordinary process

to a rather ordinary process. I’m not saying that your

application that you’ve worked very hard on is ordinary. I

am saying, however, that we do not have a special process

for reviewing quality by design.

 

Moving on beyond just FDA and ONDQA, I do have some

observations regarding some of the things Previous Speaker talked

about, too, and the global regulatory environment. I

recognize we can’t control other global regulators.

However, we can communicate with them and share our

knowledge with them.

 

In general, as I reflect upon those two aspects of QBD, the

blue circle should not be a problem. I would hope it’s not

a problem for different health authorities. They should be

able to understand review and appreciate that enhanced

science and risk based approaches.

 

But, we recognize, too, that the opportunities for those

flexible approaches might not be available in all regions.

That’s the pink blob over there, the regulatory

flexibility. There could be nonacceptance, or different

views of design spaces and the approaches to them,

agreements on using PAT or real time release testing.

 

Another area that we’ve been talking about and still are

working on is establishing clinically relevant

specifications. So, obviously, there could be different

expectations from different health authorities for QBD

containing applications and the amount and detail of

experience that they have in their ability to look at or

accept regulatory flexibility.

 

One of the things that we are doing to work on that is we

have a standing pilot between the European Medicines Agency

and FDA that’s called the EMA-FDA QBD pilot or the EMA-FDA

parallel assessment pilot. This has been going on for close

to three years now. You can find that information through

either the FDA web page or through the EMA web page.

 

The objectives of the program include to ensure consistent

implementation of ICH guidelines and to establish better

communication between our agencies to move towards more

consistency to have that collaboration.

Although this platform was meant for the review aspects, it

builds on previous platforms for joint inspections as well

as a program for scientific advice. The idea, though, is to

open communication pathways between the agencies, have the

discussions, and see what areas we can harmonize in.

 

The scope of the products that we have been looking for in

the pilot, we’ve accepted into the pilot, are those that

include quality by design or process analytical technology,

real time release testing sort of aspects. In the pilot we

explicitly excluded biotech products and priority review

applications although you’ll see in a minute we kind of

fudged on those a little bit.

 

There are multiple pathways in this program. It could be

for a simultaneous submission of either a NDA MAA, or a

supplemental NDA, or Type 2 variation in both regions.

That might qualify for the full parallel assessment. In

this pathway it’s requested by the applicant or the

sponsor, and, again, you’re submitting the application, the

supplement or the original application, to both agencies at

the same time or close to the same time.

 

The second pathway, which we found has become more popular

than the parallel assessment, is the consultative advice

pathway. In this case the application is only submitted to

one agency, and entry into the pilot can be initiated by

industry or by one of the regulatory agencies.

We’ve also thought of using this pathway for things that

were excluded by the parallel assessment, namely the

biotech and priority review applications. There’s also the

option of using scientific advice for CMC meetings, and

there is an existing program for that which we refer to.

 

What does it look like when something actually comes in as

a parallel review process? Separate reviews are conducted

by each agency, and then we have set points where we

exchange information, discuss the information, and see what

areas we agree on or do not agree upon. And, those are

based upon pre-established timelines.

 

This third bullet that is bolded is very important. There

is no change in the statutory review timeline. I know that

initially many companies were afraid if they went into the

pilot, the parallel assessment, that their applications

would be delayed. We’ve committed that that will not

happen.

 

Even though we’re looking to harmonize our questions or our

information request list of questions wherever possible,

we’re still using the current pathways by each of the

agencies. So, communications have been from the FDA to the

applicant and from the EMA to the applicant.

We just try and make those communications look the same as

much as possible. We strive, again, as much as possible for

a common list of questions or information requests. Then,

it’s also part of the pilot as outlined to have a lessons

learned meeting between the agencies at the conclusion of

the parallel assessment.

 

So, where are we today on this EMA-FDA pilot? We’ve done

one full parallel assessment and we’ve conducted four

consultative advice. Some of those are still ongoing. There

was also one biotech product in Steve and Jeff’s shop that

followed the same pathway for the consultative advice.

 

In addition to the specific applications, we’ve used the

relationships that we’ve established, the knowledge that

we’ve established, to have multiple discussions on quality

by design type elements in our review processes. We’ve had

multiple teleconferences both on applications and on

general topics. We’ve also had three face to face meetings

between EMA and FDA.

 

Regarding results from the pilot, we’re publishing now a

series of question and answers related to our outcomes to

the pilot. One of those questions and answers just

published on Monday, so I’ll talk about that in a minute.

Obviously, we’ve had many conference presentations.

 

An unexpected benefit of the pilot was that we had Japan

participate in many of our discussions, and they were

observers for the parallel assessment application that we

had. From our interactions they’re very keen on continuing

if not increasing that participation.

 

We are currently considering an extension of the pilot

beyond the current date that it expires which is March

2014. We have several companies that are interested in

doing the parallel assessment program.

 

So, regarding the communications we’ve had from this EMA-

FDA pilot, as I said, we’ve published two questions and

answers. ( Q&A 1 ,  Q&A 2) They can be accessed from either the EMA or the

FDA websites, or just Google EMA FDA QBD pilot and you

should be able to get the hit for it rather than typing in

these long numbers.

 

The topics that we’ve included in the Q and A are quite a

few. We’ve talked about the agencies’ expectations for

QTPPs, CQAs, criticality, and expectations for the level of

detail in the manufacturing process description.

We’ve also touched upon a growing trend we’ve seen in terms

of using quality by design approaches for analytical

methods, and there are certain terms that have arisen from

that sort of approach. The most recent one that was

published on Monday discusses design space verification.

 

I’m going to go quickly through these different topics just

to kind of give you an overview of where we’ve gotten in

terms of the questions and answers and the areas of

alignment. Again, I would refer you to the original

documents for more detail.

 

One of the first areas of agreement we came up with is QTPP

is quality target product profile, and CQA is critical

quality attributes. This one was pretty easy because we

want them in the applications.

In fact, if you look at ICH Q8(R2) it says they should be

in applications independent if you use an enhanced approach

or a more standard approach. That was a clear and easy area

of alignment between our agencies.

 

One area which was not as easy to come up with was that of

criticality. The FDA somewhat shifted their position in

this discussion. Previously, we were saying to ourselves we

don’t really care what you call things as long as you

clearly explain it. Then, after more discussions we

realized from a terminology perspective we get in trouble

by having too many terms and having companies use different

terms in different applications, because we have our own

knowledge management and communication problems.

 

I have listed here the definition of criticality from

Q8(R2) and that talks about the process parameter whose

variability has an impact on a critical quality attribute

and therefore should be monitored or controlled to ensure

the process produces the desired quality.

Criticality is also touched on through the points to

consider as well as the Q and A documents related to ICH

Q8, Q9, Q10. But, really the major point of agreement is

that criticality should be based upon the potential impact

of the parameter and not the residual risk after the

implementation of the control strategy.

 

Therefore, even if after you implement the control strategy

you can control that process well that doesn’t yield it as

gone critical. We’re looking off of the ICH definition.

We’re looking for consistency there.

 

We’ve also recommended that companies, at least in

discussion of their manufacturing process description, not

use terms like key process parameter – again, that leads to

confusion within the agency – and that only ICH terminology

be used.

At the same time we recognize that things such as key

process parameters are built into many organizations’

development approaches, and we do not object to the idea of

you using that internally or even putting that terminology

in your process development section.

 

But, please clearly define what you mean by your

terminology. We’ve seen other terms, too. Again, we want to

see that clearly defined. But, as far as in the

manufacturing processes description we’d like to see the

ICH terminology only.

 

We also have agreement on the level of detail in the

manufacturing process description. Previous Speaker touched upon this.

We expect that all relevant parameters both critical and

talked about here noncritically, though that’s not an ICH

term, are included in the process description and obviously

justify regarding their target values or ranges.

 

There is a difference between the agencies in terms of our

regulations here, because at FDA this expectation for the

complete description of the manufacturing process can be

satisfied in part through inclusion of the master

production record, more commonly know as the master batch

record or MBR, at commercial scale. There’s also a note

here that the requirement of the inclusion of the MBR is

required for both generic J products as well as V2

products. That’s by the regulations.

 

An area that was not anticipated when ICH Q8(R2) was put

together was the idea that you could take the same science

and risk based approaches that were being advocated for

evaluating processes and apply them to analytical methods.

We’ve now seen several companies do this. They tend to use

the terminology that I’m talking about.

 

There are some analogies between the quality target product

profile and what they’re calling the analytical target

profile as well as analogies between the design space and

what is being called the method operable design region.

 

So, this was part of our discussions in terms of

reharmonization with the EMA and, in general, we said we

were okay with that approach, with some caveats. We think

that using the idea of describing the analytical method,

the development, the robustness of the analytical method in

terms of ATP and MODR is an acceptable approach.

 

But, there are some limitations on what we think it should

be there. We do need some more experience to better qualify

those limitations.

 

One of the expectations, the second bullet on the ATP, is

we both agreed that this approach really would be

applicable to a single method of analysis. And, it would

not be applicable to, say, switch from a HPLC to a GC and

say well that’s under my filing because it’s defined in

that ATP. We believe you have to go through the standard

change management approach that’s laid out in other

guidances.

 

With the MODR that’s the analogy to the design space, we

again agree with that approach. But, in general, before we

put out more guidance in that area we would want to see

more examples from industry. The main point of the QBD for

analytical methods is that we’re amenable to looking at and

considering it, and we’d be willing to look at more.

 

This is the most recently published Q and A that just came

out on Monday. It talks about design space verification in

areas where we’re in alignment between EMA and FDA.

 

First of all, let me step back and talk about what is

design space verification. I do have the definition here.

That shows up in the Q and A. What we’re really looking at

is showing that the design space, which you may have

developed at laboratory or pilot scale, is suitable at

commercial scale and that it’s capable of manufacturing

quality product.

 

Now, what we came to agreement for initial design space

verification is we recognize the design space is typically

developed at laboratory or pilot scale. And, this is

specific to small molecules, so Steve or Jeff may have

something different about large molecules.

There are certain circumstances, limited ones, where we’ve

seen a design space developed and demonstrated at

commercial scale. And, some technologies like continuous

manufacturing allow that more readily.

 

But, in general we recognize that it’s developed at

laboratory or pilot scale and that often the initial

commercial scale demonstration is limited. It’s often at or

near where you would typically intend to operate that

product either within your normal operating ranges or

within a specific target ranges.

We also believe that it’s not necessary to repeat all of

those laboratory pilot experiments at commercial scale.

But, the initial design space verification really isn’t

enough to give us confidence of the change management and

the knowledge management throughout the product life cycle.

This is one of those gap areas that Previous Speaker spoke frequently

about. The way that we’re looking to help bridge this gap

is potentially through a design space verification

protocol.

This protocol could include things such as a definition of

potential scale-up risks, a recognition of which scale

dependent parameters you have that are unverified at scale,

and what is your control strategy related to those scale-up

risks and descriptions of any additional controls.

 

There are some important differences regarding the design

space verification part of, between the EMA and FDA, mainly

where we would like to see this information. The EMA

recommends that the design space verification be submitted

in the application in the regional information section. The

FDA, on the other hand, is recommending that if you choose

to have a design space verification protocol that it be

maintained at the manufacturing site.

 

We would also like to see a high level description being

provided in the application in some way saying that, yes,

we have this design space verification protocol, it covers

these topics, and you can find it available at our

manufacturing site.

 

Those are the areas where we’ve come to alignment with EMA

and that we’ve published on, but we do have some ongoing

discussions. We hope to be publishing additional Q and As

in the future.

 

Some areas that we’re still discussing include online

monitoring, namely MIR spectroscopy because that’s the most

common one that we’re seeing. And, some of the points that

we’re having the most discussion on include aspects of

calibration of the model, what samples do you have in that

calibration and at what scale, and how much of the

validation of the model do you need particular related to

from material manufactured at commercial scale.

 

We’re still discussing the level of detail in the

application regarding how much information the agencies

would like to see regarding the development of the design

space, your DOE, statistical data supporting it, et cetera,

and the level of detail regarding risk assessment.

Knowing that continuous manufacturing is on the horizon,

we’re also talking about regulatory considerations for that

technology that’s new to the pharmaceutical industry. Other

aspects are the approaches for large sample sizes, criteria

for content uniformity or the so called large M sampling,

and then utilization of protocols for post approval

changes.

 

I’m circling the last one although it kind of falls off the

page, because I’m going to talk about that a bit further.

Previous Speaker addressed that, again, we have the body of knowledge,

the science and risk based approaches, from QBD, but that

the regulatory systems are not yet in place to allow for as

much flexibility as industry would like to see.

 

I would say admittedly as regulators we would like to see,

too, regarding how to implement that regulatory, that how

to fully utilize the science and the risk based knowledge

that was gained during development. I don’t have a slide on

this.

But, if you heard Janet Woodcock speak on Monday, or if

you’ve heard her speak recently, you recognize that one of

the approaches we want to move towards in the future is by

using the combination of good science, good understanding,

as well as good manufacturing capability, good quality

systems to allow for improved regulatory flexibility.

 

I know Steve in his slides is going to touch upon that more

about how the two can work together. One of the limitations

we have is, first of all, we don’t have that quantitative

metrics on quality systems yet, but we’re working on

establishing that. The second is that we don’t necessarily

have the regulatory pathways to put it into place. But, one

regulatory pathway that we do have now are protocols.

That’s where I’m going to go to next.

 

For FDA these are the regulations under 314.70(e). EMA has

currently passed regulations for protocols, too. The point

of these protocols is that you tell us how you’re going to

make a change, how you’re going to evaluate that change,

what tests you’re going to do, and what the acceptance

criteria for that change is. You file that with us. We

agree to it.

\

It can allow reduced reporting categories, perhaps all the

way down to an annual report. By doing so you have higher

confidence that you will not have any regulatory hurdles in

terms of making that change, and also ease in terms of the

timing of the change and reducing the regulatory burden of

the reporting categories and waiting for approval, et

cetera. That, we think, certainly can help you in making

changes in a global environment.

 

The change protocols have the potential to enhance

regulatory flexibility and ease how you’re making those

changes. We really see this as one pathway, not necessarily

the only pathway, but one pathway to facilitate continual

improvement and process optimization. I really believe that

there’s a synergy with that risk based and science approach

that you learned about your product by doing a quality by

design approach.

 

The idea here is that you really want to understand the

relationships and the risks of your product all the way

back between the patient and the product and the

manufacturing process. One way to do that, you’ve probably

done if you’re doing quality by design, is to have risk

assessments. Those risk assessments can be supported by

laboratory or pilot scale data similarly to how you

would’ve supported your design space development.

 

There really is a potential to use change protocols to

support a wide breadth of changes in terms of optimizing

process, supporting continual improvement, and providing

flexibility in terms of scale and throughput. This is a

slight twist on how we had seen protocols used in the past.

It’s also somewhat in contradiction with our current draft

guidance on comparability protocols which seem to indicate

protocols are meant to be for narrow changes.

 

We’re trying to take that regulatory approach and broaden

it so that really we can provide the manufacturer with a

wide range of post approval changes that are supported by

their science risk based approaches and then implemented

under their quality system.

 

So, what are some considerations for these protocols? You

want to definitely understand the potential risks of any

changes you might be doing on the product attributes and

the quality of the product.

That not only goes for the unit operation where you may be

making that change, but downstream effects as well. It

could be possible to group together these changes in very

broad ways perhaps based upon unit operations or the

potential effect to a product critical quality attribute.

 

Really, an important consideration is how well can your

control strategy detect the effect of that change. If your

current control strategy, your standard approach, does not

detect a potential effect of risk of that change then you

would want to consider things such as enhanced sampling,

non-routine tests, maybe using advanced analytical methods.

 

But, what do you really need to do to verify product

quality? You also want to consider if by making this change

and if I have something like a design space approved not

only what’s the effect downstream but what’s the effect

with the rest of my approved areas of operation. That’s

what I have on protocols.

 

I’m going to talk a little bit about the next steps

regarding your work with EMA. As I mentioned, we currently

have several consultative applications ongoing. They

include newer technologies, continuous manufacturing, and

we also have several applications that were not part of the

pilot. They were pre-pilot. But, we got agreements from

the companies to include them in our discussions with EMA.

 

So, instead of just the five applications that I spoke

about, I think we have nine or ten in total that we’re

talking about based upon our experience with quality by

design. We’re looking at review approaches. That’s

especially useful for answering the question of what level

of detail we’re looking for in applications related to

design space and risk assessment.

 

As I mentioned before, we’re considering extending the

pilot beyond March. What we would really like to do is

advance the concepts I just finished talking about looking

at enhanced flexibility of post approval changes using

protocols as a pathway.

 

So, in conclusion, we really think that quality by design,

that blue circle, both science and risk based approaches

has made great progress in industry. But, we also recognize

that the regulatory post approval flexibility has not fully

matured. I think we’re in alignment with industry on that.

 

We have had, I think, very good success in our

harmonization efforts between US and Europe and,

surprisingly, including Japan as well. We have a high

degree of similarity of regulatory expectations. We’re

still working on aligning those even further.

 

We think that moving forward change protocols can be a

pathway to do that. It may not be the only pathway but it’s

one that we currently have available and we’re ready and

willing to implement.

 

That’s the end of my presentation. I want to thank you, and

I think we have some time for a few questions.

 

So, anyone have any questions?

 

Male : Alright, Christine. First of all, thanks, that was a fantastic

presentation. Regarding the change protocol, you had

mentioned that there are, let me look at my thing here,

regulations for the protocols. Were those regulations, is

that just the following slides right after that, or is

there somewhere where we can actually find…

 

Dr. Moore: No. See, you want to look in your 21CFR 314.70 (e)…

 

Male 1: Okay. Say that again.

 

Dr. Moore: 314.70(e).

 

Male 1: Okay.

 

Dr. Moore: And it’s just a paragraph there. Essentially what it says is

that you can propose a protcol. I have slides on this, but

not in this talk. The protocol can be part of an original

application. Or, it could be proposed as a pre-approval

supplement.

 

What the protocol needs to include is a description of the

change or potential changes, the method that you’re going

to use to evaluate those changes, so the test that you’re

going to do to evaluate the changes and the acceptance

criteria for the changes. You’ll also want to put in there

how you file it. There is comparable regulations in the

biologics. I don’t know if you know the number off hand.

 

Male 2: 601.12(e).

 

Dr. Moore: 601.12(e)?

 

Male 2: E.

 

Dr. Moore: B?

 

Male 2: No, E.

 

Dr. Moore: E, okay. 601.12(e) is on the biotech side. The language is

almost identical, with the exception that it doesn’t say in

that language that it can be included in the original

application, but we take them in the original application,

too. Yes?

 

Male 3: This question is maybe for both of you to touch upon. I was

really happy to see in your slides, Christine, the opening

talking about what quality by design is not. I think that’s

very important. In your bullet around quality by design is

not a design space that really hit home with me.

 

I think it would be very helpful for us to really engage in

what design space really means. I think we spent a lot of

time discussing design spaces and not enough time talking

about control strategies, and how those two are related,

and what those really mean.

 

From my perspective as a scientist, if I go off and do this

amazing work, and I generate multi variable analysis of

some step, and I understand my functional relationships

between parameters and control attributes, is there an

expectation now that I need to decide whether I’m going to

file design space? Or, in my past experience that would be

just an assumption that I would ask for a design space.

 

We’re getting questions now globally around why would you

file design space for a process that’s robust. So, there’s

a lot of confusion around whether we need a design space

for robust processes and how to use the design space. Is it

for compliance? Does it help with knowledge management?

And, is it really in fact a control strategy element in the

first place?

 

So, I really think your slide is important around quality

by design is not design space. But, I think we spent an

awful lot of time emphasizing the importance of design

space as apparent with the design space verification

protocol, the importance of that. I’d just like to get your

perspectives.

I think it’s really fascinating to me to see those two

different perspectives as to how and when a company might

choose to use the design space or propose a design space

when they have that full multivariate analysis in hand.

 

Dr. Moore: Okay. I was actually going to address a different part of your

question first. I might come back to that.

 

I think the point you said about getting questions from

regulators on why do you need a design space is something

that we need to work on from the regulatory thought process

side. Because I’ve heard, not necessarily with design

space, with other say post approval changes why is the

company proposing post approval changes.

 

I think that the regulators have to recognize that our

success is interdependent, that we have to allow you to

succeed in order to fulfill our public health mission. It’s

not just why do they have to do this, what was the problem

with it, but that your business reasons are legitimate

reasons for making changes.

 

That’s how I look at design space changes. If this provides

a business reason for you in terms of having flexibility of

continual improvement or optimizing your process, then

that’s a legitimate reason for us to do the work to

evaluate the design space. It shouldn’t necessarily be

viewed as a negative in terms of maybe you didn’t have a

robust process.

 

I forgot the actual question you asked.

 

Tim: It was a thoughtful question.

 

Dr. Moore: It was.

 

Male 4: Tim, I think what you want to know is what’s the advantage of

doing it, design space, and how would you characterize that

advantage, right. So, you actually, Christine, answered

what I would’ve answered. That if a company chooses for

business reasons to recognize a design space they would

recognize it in terms of what control strategy they

actually have.

 

Because at least at Pfizer, and I know at other companies,

we have decided that design space is one element of control

strategy. It could provide advantages if we characterize it

appropriately and can get it approved for post approval

change.

But, it may not always. We have had instances where we

don’t have truly multivariate interactions between

variables. We make the decision that it’s really not a

design space, so there’s no point in registering it. But,

our process is still robust and we have other controls that

can manage that.

 

Dr. Moore: Just to throw a teaser out there, I think that if we do a good

job putting additional flexibility in, however that pathway

is, through protocols, through qualifying or through

something related to the status of your quality system,

that there may not be a need to file and get a design space

approved and still have as much regulatory flexibility.

We’re not there yet, but I think that could be possible.

 

Tim: Any other questions?

 

Female 1: Thanks, Christine, especially for the protocols. This question

they asked also yesterday in the PAT session, because it’s

really burning now for all the companies that are doing

real time release testing. Recently we had the case where

we filed for real time release testing. We said it’s going

to be this spectrophotometer or equivalent.

 

The reviewers were adamant that we should take the

equivalent part off and that we should explicitly state what

kind of spectrophotometer we were going to use. From a

scientific point of view we know that we can actually get a

different spectrophotometer, and do the calibration, and

make sure that the calibration works, right, the same way

we calibrate methods.

 

So, the question is, if you have a filing, can you say that

this is my NIR, this is what I’m testing, this is what I

measure, but in the event that this spectrophotometer

breaks this is how I’m going to do my calibration to

another instrument, and this is my acceptance criteria,

therefore I don’t need to file for a variation?

 

Dr. Moore: Okay. There are two or three parts of that question. First,

regarding the interchangeability of spectrophotometers, it

sounds like from a scientific perspective that there’s a

difference of opinion between what the FDA reviewer thought

in terms of interchangeability versus what you’re thinking.

I believe that additional information – if you have

publications, et cetera supporting that interchangeability

– would be useful for us to learn from.

 

Regarding the alternative approaches if you have a PAT

method in place it comes down quite a bit to do you have

the same assurance of quality. That might touch upon

aspects such as validation. It’s really something that you

would want to bring in to have discussions with us for your

specific product, about the purchase that you’re proposing,

and then we can give you better advice. It’s potentially

possible, but it raises a lot of questions that we would be

better off discussing for specifics.

Female 1: You said this is what we brought you and we asked…

 

Dr. Moore: Yeah, we definitely are willing to talk about looking at online

monitoring or control in meetings and alternatives to your

standard purchase. Not a problem.

 

Male 5: Thanks, Christine. It sounds like lots of great dialogue going

on in the pilot between the different regions. That’s

really encouraging. But, some of the questions you had up

there around things like level of detail, I’m curious

whether you consider taking the dialogue in the pilot

beyond the initial approval.

 

Say into the first year or two post launch you can have

great discussions about the level of detail. But, if in the

year post launch you have to do variations. One region says

it’s no problem because [Inaudible 0:48:01] application.

But, another region says you’ve got a variation that takes

12 months to get cleared. By the time you go through such

questions, that may be insightful for the actual discussion

around the original approval beyond just getting it to the

goal line of approval. Because the theme that some of

Previous Speakers thinks raised around continuous improvement you

really don’t appreciate what the application brings in

until you actually manufacture it.

 

Dr. Moore: Okay.

 

Male 5: And are we losing an opportunity to put some things in the pile

by not carrying on the dialogue past launch?

 

Dr. Moore: We had not considered that, but we can. Alright. I know that

there’s going to be a Q and A session later, so shall we

cut it off?

 

Tim: Yeah.

 

Dr. Moore: Alright. Thank you very much.

 

Tim: Just a coda to what Jeff said. We had discussed extending the

original pilot but never got around to doing that. I think,

Jeff, that’s something we should probably talk about

considering in the future.”

What are your thoughts? Please share!

 

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