Dr. Janet Woodcock (CDER, FDA) Speech at ISPE 2013

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Dr. Janet Woodcock is the director of CDER, FDA and oversees 4000 people and 10000 drugs. At ISPE 2013, Dr. Woodcock began with the statement –“Industry QbD adoption was successful. but QbD submissions were a mixed success. Culture of quality is not there yet.”

She also openly talked about the growth opportunities of FDA in adopting more systematic approaches in reviews and providing proper incentives to the BioPharmaceutical industry. Then she laid out plans for the newly reorganized–Office of Pharmaceutical Quality (OPQ)– to oversee quality throughout the lifecycle of a drug. Overall theme was culture of Quality (by Design), continuous improvement and how FDA will evolve to meet the new challenges. As usual, Dr. Woodcock was very open to suggestions from the industry and public.

 

Below is the raw transcript that I took from her speech. It may have some typos and I will edit further in the near future.

 

“…And also the reward and incentivize a culture of quality

and industry. The mantra that we had through the 21st century

was that our goal would be a pharmaceutical manufacturing sector

that could reliably reproduce high quality drug products with

minimal regulatory oversight. In other words, it was quality

driven and I don’t think we’re there yet.

 

I have been told by many of those in industry that an adequate

incentive structure is not put in place to really make that

happen. Likewise, I would say that on the regulatory side we

talked a lot about risk, but we failed to adopt a truly risk

based approach to review and inspection. Instead we continued to

review and inspect everything in a fairly uniform way, although

we have certain risk models for inspection and so forth. Really

not a true risk based approach, and that was something we were

aiming for.

 

Also, one of the things that we acknowledged when we started the 21st

industry initiative was that intense regulation was holding back

industry’s ability to continuously improve and innovate. That’s

because of the intense regulatory strutting over any changes,

and the timeframe required to get regulatory clearance for any

kind of changes. So we need to provide industry more freedom to

operate in return for when they have achieved a quality

production.

 

We also failed, I think, the achieve standards in all areas of

inspection, info review, that are very clear, and regress, that

we can review and inspect against. So that we’re predictable and

we’re consistent, because we have uniform standards that you can

read up on. You know what the goalposts are. We still aren’t

there yet, I would say.

 

And then finally what has been particularly perplexing for me is that

we failed to achieve an understanding of the state of industry

manufacturing, including the range and capability of different

establishments around the world. So if I would ask my team,

“Well, okay, how many establishments do we regulate, what are

they, how much do they make and what is their state of quality

of production?” No one could tell me the answers to those

questions.

 

So we really need to move further down the path of really getting a

grip on all of those questions, and I will talk about how we

plan to do that.

Now, as I said, we did this initiative between 2004, 2003 and ’04 and

’05 and so forth, but then it died down a little bit, and this

was for a variety of reasons, particularly the requirements of

the FDA Amendments Act, which was passed six years ago.

 

It was after some of the drug safety problems, including Vioxx and so

forth, and there was a tremendous emphasis on drug safety. The

agency was given a huge laundry list of activities it had to

accomplish, and so we had to turn our attention to that and not

press as hard on the pharmaceutical manufacturing. But now we

have completed that list of tasks and objectives, and we have

the new generic drug user fee program that we’re implementing.

Now is the time for us to take this up again.

 

The Generic Drug User Fee program in particular has emphasis on a

level playing field in manufacturing around the world. So we are

required under that law to make sure that we have equal scrutiny

of firms and manufacturing no matter where it’s going on around

the world if they are selling product in the United States. So

that’s very challenging. But we got considerable additional

resources to oversee facilities, and this is helping us in

setting up our new programs.

 

So what it could do for us, really, is give us an opportunity. But

there’s also an imperative. There is a tremendous backlog about

locations in the generic world, and if we cannot not modernize

we’re going to fail to achieve our GDUFA objectives. So we must

modernize the way we regulate manufacturing in order to achieve

the objectives of GDUFA.

 

We have a lot of challenges that have been growing over this decade,

and many of you, wherever your position might be in industry,

academia or whatever, you’re probably well aware of these.

Globalization as really resulted in a dispersion of facilities

all over the world. The majority of drugs that are used in the

United States are now manufactured outside of the United States.

So that’s a big challenge for us in making sure we manage this

global inventory.

 

And obviously there are suggestions we need to work with other

regulators, but that means greater harmonization, that means a

lot of work in getting our inspectional standards more uniform

and so forth.

 

Complexity. There are new manufacturing methods, there are more

complex products that we’re dealing with nowadays, and we have a

very complex supply chain, as many of you know. And we have to

factor that into how we regulate as well.

 

Dealing with shortages; I’m very grateful for SP for the work they

have done to help us on this issue. This continues to be a big

problem for the health care system in the United States, and

since CDER regards its mission making quality drugs available

to the product, if they’re not available we’re really failing in

our mission, and we have gone to very extreme efforts to try to

make these drugs available to people who need them.

 

As was mentioned, breakthrough therapies. We’re going to be seeing

those coming through, and they are on an accelerated development

pathway, often unexpectedly to the manufacturer, the innovator.

So we are developing special programs, because manufacturing may

well become the rate limiting step for these kinds of products.

Yeah, they’re usually for desperate conditions where people

really want to get their hands on, and they feel they may die if

they don’t get this therapy, one therapy or another. So supply

in manufacturing becomes really important.

 

Biosimilars. We have had a new product, and although we haven’t

received an application yet, we expect to. There’s a big

reliance there on quality, and the quality organization to make

sure those biosimilars, as far as their characterization, are

biosimilar. That’s a new program. It will put a strain on our

resources as well.

 

And then of course I already alluded to the need for harmonization.

The world cannot go on this way simply having all these

regulatory programs with different requirements, particularly

for manufacturing, but just burgeoning all over the world. So

it’s going to be very challenging, though, to figure out how to

harmonize these efforts, and my team and others’ folks are

converging on Japan towards the end of this week to have another

ICH meeting to talk about how we can actually modernize our CH,

and then how we can get some of this stuff done.

 

So let me discuss our proposed CDER reorganization, the office of

pharmaceutical quality. This is not a done deal. This is

something we will propose, and so it’s somewhat theoretical. But

we’re moving right down the road on this.

 

For OPQ we are making progress. We have completed a concept of

operations, and that’s what we do first, just say, “How is this

going to work? What do we want to do? What functionalities do we

have?”

 

Subsequent to that we completed an organizational structure that

would support that concept of operation, and now we’re working

on the HR type of activity, which is putting all the people into

the organizational structure. Then we’ll give that to HR and it

will have multiple sign offs. It would take six or more months

in the federal government to be signed off on and become real.

So that’s where we are.

 

Now why are we doing this reorg? What would it constitute and how

would it really affect you? Well, I think we’re planning to

change a lot of things, so I think it will be interesting for

all those involved in pharmaceutical quality.

 

The reorg is intended, number one, to have one voice for quality. So

whether it’s new drug quality or generic quality, OTC drug

quality, they are all going to be managed under one roof, one

organizational structure, whether there’s US sources or ex US

sources, uniform. That’s a requirement of GDUFA. Biotech, small

molecule. All right. Uniform.

 

And whether it’s an inspectional policy or quote “GMP” policy or

review policy, all within OPQ. So one voice for how US FDA

regulates pharmaceutical quality, and we’re working very closely

with CBER and [CBM], the other two centers that also do

pharmaceuticals, to make sure we’re all in synch on this.

 

There’s a new conceptual framework, as I said, of what we’re trying

to accomplish, and I’m going to go into that. We also want to be

very patient centric. We think that the critical quality

attributes of pharmaceuticals ought to be linked to patient and

customer, and what the customer needs, and same with the

specifications.

 

We are really going to do a risk basis this time and do risk

assessments, and that will be incorporated into the work flow so

that that will happen. We also are going to really work hard on

standards, make sure we have clear standards. We also plan to

reduce some of the redundant documentation that people do now.

 

Many of you, if you send in applications and then they are cut and

paste into a  review at our end, we want to focus more on

risk failure modes and things like that, and not on a lot of

documentation by our scientific staff.

 

So overall we want to simply achieve our mission better, which is to be

highly effective at making sure quality drugs are available to

the public. And to do that, one of the principle changes we’re

going to make in our structure and function, is we plan to

specialize staff and review and inspection.

 

So we plan to specialize. For example, we’re going to have units that

look at the API and look at all the APIs, and they are going to

do a risk assessment of that facility and that process. How

might the process fail? How might the API not be what it should

be? What is the controller mitigation strategy that’s put in

place, are the analytical methods robust, and so forth? Those

folks will specialize in that.

 

The goal here is to incorporate. We have a vast amount of knowledge

about API manufacture, because we regulate all the different

parts of the industry. We need to incorporate all that knowledge

and base our risk assessments on what we’ve learned over time

about what can go wrong. And in the generic product, the generic

product will be specialized. Biotech is already specialized, as

you know, but new drugs, and what we call life cycle drugs,

small molecule generics or drugs that have gone off patent will

be lifecycle drugs. All those product offices are going to look

at the drug product, what defines it, how could it fail, what

are the patient linked critical quality attributes? And they are

going to do risk assessment around that.

 

How do you establish critically relevant specifications? We had spent

a long time talking with clinicians and our clinical

pharmacology staff about what really matters.

 

And then we are really very interested across the board in looking at

statically valid approaches to testing. I know many in this room

use statistically valid approaches to sampling, but for testing,

but that isn’t uniform, and the USP tests, which are protocols

which are used for testing in the marketplace, marketed drugs,

are really not appropriate in this setting.

 

So we will be doing some more things about that. But primarily in the

drug product area it’s specialization. The new drug folks are

going to specialize by, as they do now, by clinical indication

so they are best aligned with the clinical staff. But the

lifecycle folks are going to be organized by dosage form. That’s

where specialization really can help, I think.

 

Then we’re going to have a group dealing with the process and the

facilities. We’re going to organize that, we propose, by dosage

form. Again, so specialize by dosage form. Again, we would like

to have risk assessment. Usually we’re going to have a fair

amount of knowledge about these facilities. I’ll talk about that

in a minute.

 

We’re also going to put all our micro staff together. They have been

doing an excellent job, but they have been in three different

locations and we want to put them altogether, and again, look at

whether the risks are adequately mitigated.

 

Now inspections, which is something of course we do routinely, and

many of you are used to, we have pre-approval inspections,

approval follow-up inspections, surveillance inspections, and

then for cause inspections. What we’re going to do is in

managing the first three types of inspections is going to be in

the office of pharmaceutical quality, and our complaints

organization will manage for cause inspections, because they are

going to be doing the enforcement actions, if any are needed.

 

We are partnering with ORA, because we want to move toward a team

review by these very specialists and with real time interaction

when an investigator is actually in the facility. So we’re

working with ORA.

 

Now inspection, we hope to have more focus on execution and

operational excellence of the firms and less on sort of the SOPs

and the documentation. We really want to know about the results.

 

So you’re going to hear later about metrics, a potential collection

of metrics by the FDA, and this gets into a new concept, a new

function or office that we will be standing up or proposing to,

which is surveillance.

 

What do we mean by that? Well, this is very important. Surveillance

establishes a concept that we have an inventory of facilities

that we regulate. Similar to those of you who are in quality,

okay, you have a portfolio of establishment, where you’re trying

to assure the level of quality, right?

 

Right now what we’re doing is working to identify stable inventory.

Who do we regulate? Where are they? How many are they, and so

forth? And then we want to attach to that, how are they

performing? And that’s where the metrics come in. Many of you,

or the quality organizations where you work, okay, they have

some type of measures that they follow to assess how well you’re

doing. Usually it isn’t, say, a six sigma type of measure, but

it’s some sort of assessment of the quality of production. And

we’re working with SB, and I really thank SB for working on this

and trying to think about what measures would be appropriate,

simple, somewhat clearly defined across the industry, reproduce

able and so forth.

 

But the surveillance function will do more. It will also pull in all

the other data we get, which is inspectional data, application

data, recalls, alerts, information from other

inspectorates from around the world and so forth, and build an

understanding of what is the status of that facility.

 

Theresa Mullin, who is our head of strategic programs at CDER, and

also is our ICH leading or ICH effort, is also leading setting

up this surveillance office. It will contain the group that

manages the surveillance inspections, and we hope to modify

those to make them more informative about what this overall

state of the facility might be. So we can put that in our

database.

 

So that’s a surveillance function. We also are going to run this

office on more administrative detail. We are going to run

centralized project management, having a very strong project

management industry style, project management model. We are also

going to use the work flow management tool, but we’re setting up

across CDER. We’re going to put it in this office, and as I

said, we’re going to do a team review, but we don’t plan to pile

big reviews on top of one another. We’re really going to have to

get lean and streamline the documentation part of review.

 

And we’re also finding, we’re going to set up a policy office that

will have a centralized policy function for CMC and CGMP for

pharmaceutical quality. It will not only do the guidances and

regulations, usually things, but it will also have an evaluation

function.

 

And we’re going to look at how we have cited the industry, either in

deficiencies or in inspections, and see if those citations align

with our policy, and if not, do we need more …

policy, or do we need more training, or what do we need? Because

I have gotten many, many complaints about lack of consistency

across these functions, and really, the only way, I think, to

drive for more consistencies to measure it. So the office of

policy would do that.

 

Now you were going to as, “Well, how can the FDA accomplish all of

this?”

 

We do have a program that instructs us to do much

of this, and don’t forget that the generic facilities are the

bulk of the inventory, so that’s a large piece of what we have

to do. But as part of this whole change we are building a new

decision support system that I call a pharmaceutical quality

platform. This is eliminating redundant databases, and many of

the manual data entry functions that we have right now listed,

or in the quality side.

 

We have completed an electronic orange book because we only had one

person working on the orange book, and if that person got sick

or something we wouldn’t have a way to have an orange book. So

we have done that, and that, of course, focuses on the product

itself and its dosage forms and so forth, what are they, who

makes them. So we have that.

 

Now we’re trying to move more toward the facilities, and we want to

use the … number as the unique identifier for each

facility, and then we can link to that the applications, what

firms use that facility and so forth, and try to start pulling

all this together. And then what products come out of product

made in that facility.

 

So we’re going to work on facilities next, and with that, then we can

start linking things like all these [fars] biologic product

deviation reports, inspection reports, recalls, facility

history, firm history, and the metrics we collect once we

collect them, and have all this information available to

everybody in the office of pharmaceutical quality so that we can

figure out, really, what is the state of the facility? Do we

need a preapproval inspection? Is that a high risk facility

because its metrics are failing and so forth?

 

We think this also is an innovation that will really help us. We’re

really excited about it, and we hope to get this done over the

next year and a half. It’s a very ambitious timeframe, but the

project is moving right along.

 

So what will you see with the office of pharmaceutical quality in the

next year, in 2014? Well, we plan to implement the reorg and

then stabilize the process, the team review process, with

centralized project management. Of course we have to get this

huge GDUFA backlog done and all sorts of things. We hopefully

will implement metric collection in the next year in some way,

and again, that’s going to be an iterative process.

 

We will implement modified review processes, and we’re going to work

on modified inspectional procedures. Additionally, though, we

have had a whole series of groups over the last year go more in

depth on different issues. These were technical advisory groups.

They looked at risk assessment. They looked at clinically

relevant specifications, knowledge management, governance of the

new organization, bio pharmaceutics, how do we manage that?

 

I think we have come a long way in our conception of that, but we

still have a way to go on the bio pharmaceutical piece, and how

we deal with the solution specs, and then how do we focus

inspections? So there’s a whole list of things that we will take

up in depth once we have the office up and running.

 

Now I wanted to say a few words about GDUFA, because it’s a huge and

important new program and impacts many people. The OPQ part is

both the quality of review and inspection program. Because we

have such a large backlog we have formed SWAT teams to try to

deal with each piece of the backlog and get these moving through

the system. We are having to calculate how many units we have to

put out each month in each of these categories to converge on

the goals that have been set forth in the program.

 

I was around, that’s how long I have been at the FDA, I was around

and actually running CDER at the beginning of the

implementation of PDUFA, which was 20 years ago, I think. With

that the backlogs were minuscule in comparison. There’s no

comparison to this, and there’s a lot of elasticity in the

system, whereas here, this year under PDUFA, we have to hire 50%

of the people, get them trained and then start getting all these

backlogs done.

 

So the coming year, 2014, is going to be extremely critical. But I

hope we’ll all see substantial progress occur, because this is

the engine that’s helping drive us to really reform how we

regulate pharmaceutical quality.

 

Now some of you may have heard about the agency group called the PAG,

or Program Alignment Group. The commissioner sent out a memo to

this staff talking about that. We’re trying to align agency

activities better. The agency now has so many programs. They

have tobacco, they have the new foods program, which is much

different than the older foods program, much more ambitious.

They have medical product programs and then a variety of other

activities they have to carry out.

 

I think the field is in the middle of all this, and so we’re working

on how we can manage all this, especially in the face of

globalization, multinational firms and so forth.

 

It’s clear that FDA is no longer a domestic agency. We are to protect

the domestic population, but we must go all around the world, or

collaborate with the whole world, in order to effectively

achieve our mission. Some parts of the agency are still more

focused domestically. So we are working on all of that within

this PAG, and hopefully over the next six months we will see

some more products out of that as well.

 

So in summary, the agency, in particular CDER, is trying to

modernize how we regulate pharmaceutical quality. It’s really an

extension of the thinking of what we did for pharmaceutical

quality for the 21st century, but I must tell you it is more

ambitious this time.

 

The Generic Drug User Fee program is a stimulus, because we can’t

keep doing things in this same way or we’re not going to achieve

the goals. The goal of regulation is really quality drug

products for the product, but without excessive oversight by the

regulatory side.

 

I think the mechanism of regulation where we really want to get to is

to ensure a culture of quality in the industry. That culture of

quality will then achieve reliable quality of production for

drugs, because that’s how those things work.

 

There are very few relatively regulators around the world compared to

the number of people who actually work in the manufacturing

sector or pharmaceutical companies. Look at the membership of

ISPE alone, all right? So that’s who makes the drugs. So really

the industry has to deliver here on the quality.

 

One of the points of this is that there is a cost to poor quality. It

has been shown repeatedly in many industries, and actually

published by some in the pharmaceutical industry on QBD, that

higher quality leads to lower costs. So this can be a win-win if

it’s done correctly. But this isn’t the same as compliance, as

the goal of simply complying with what the regulators ask you to

do. This is owning quality, driving quality, making it happen

and making real improvements that improve the whole cost

structure.

 

We need to set goalposts. We need to ensure the industry’s ability to

continuously improve. We are beginning to think in our

conceptive operations about how we’re going to do that, because

you can’t be required to wait two or three years to put in a

process improvement. You’re just not going to do it, and the

cost of that will be too high. You need to be able to make those

iterative improvements in order to get to a better quality

state.

 

So we need to both insure industry’s ability to continuously improve,

but then we also need to hold industry accountable in meaningful

ways if the quality isn’t there. I think these objectives are

really highly achievable, but they are going to require a lot of

change, both within the agency and then subsequently within the

industry.

 

I believe many in the industry are already going down this path, and

have been helping us. And I thank those of you who are working

with us, and I really look forward to working with you in the

future. So thank you very much.

 

Now, I have been told there are a few minutes for questions, if

anyone is interested. But you have to come to the microphones,

which are scattered around the aisles, I believe.

 

Yes?

 

Audience: I’m …from XX magazine. I

thought my do to list was pretty long, so that’s a pretty

impressive to do list to have. The one that I’m thinking of is,

you really hit the nail on the head with the FDA being a

national regulatory body that’s functioning as a global

inspectorate. So we have been talking about harmonizing for 20

years. What is your vision for real getting the harmonization to

happen? Could you maybe tell us how we might be able to help you

with that as well? Thank you.

 

Janet: I was asked this the other day also. Before we want to

harmonize externally we need to get our own act together. The

FDA needs some very clear standards of what we think inspection

should look like now or in 2014. What would that look like? What

would an ideal preapproval inspection look like? What would a

post-approval inspection look that? What would a surveillance

inspection look like?

 

Yesterday I heard from a number of international regulators who run

inspectorates in other countries, and they have really good

ideas. They rank the facilities. They look at the different

areas and point out where the deficiencies are. In other words,

they roll up their assessment into something that’s more or less

actionable. Like, you have a problem with your facility. Your

process may be great, but your facility is going down the tubes.

That’s something that can be understood, I think.

 

So once we get into this new structure and people more or less

staffed and assigned to do this, we need to see, what are the

benchmarks? What are the best practices in doing these things,

and then decide internally in FDA what we think we want to do,

and then engage the international community with the goal of

getting to something concrete that is actionable? We need to

work with the industry on this as well.

 

I have heard from the industry many times, “Please, just tell us what

you want.” I have also heard that you have ten inspectors in the

door every six month period, they offer them different regions

and they look at different things and they have different

laundry lists of deviations, and they actually inexpert

regulations differently, the GMP regulations.

 

So I think that in itself is a huge lift, but something we absolutely

must tackle.

 

Any other questions?

 

Yes?

 

Steven: Many people in this room offered

advice on a consulting basis to the manufacturers here. Does

your program include training or some method to insure that the

consultants have the current information and are offering the

best advice?

 

Janet: We are in the formative stages of what we’re doing, so the

answer is no. At some point, I think what we would like to do is

come out with guidance that is much clearer. What does success

look like? And if we benchmark these other programs in

inspection that would help, but I think what we would like is

for the industry to own quality more deeply, and that means

focusing on results. That’s why metrics are very important. Not

focusing so much on all the procedural aspects, but what are you

actually achieving?

 

And if you look at the quality movements, you know, the quality

movement over the past 30 years you can see that it’s really

about a dedication to quality form the shop floor all the way to

the boardroom. That kind of dedication.

 

There are a lot of groups out there that know about this and do these

sorts of things. I will have to see. I don’t think we know right

now. I’m not sure what is lacking. I’m not sure. We have

certainly seen from a number of firms who have come in and

talked to us, they have established metrics, they are

monitoring, they are continuously learning, and so those folks

are really on the path of the quality movement, which you should

be on, which is you measure, you improve, you re-measure and you

focus on your objectives.

 

I probably have time for one more question.

 

Deb: Hi Janet.

Janet: Oh, hi!

Deb: Nice to see you. XX from Ireland.

Question for you. The drug shortage strategic plan that the agency

released last week talked about the idea of releasing, the

agency putting out historical information about company’s

quality records, and using that to incentivize quality in

industry. I’m wondering if you can talk any more about what the

agency has in mind there.

 

Janet: I do not have that in mind. What I would like to do, as I have

said is, people do well with what’s measured. People respond to

what you measure. We would like to collect metrics from industry

on their production quality, all right. SB is working with us

and other organizations are going to give us

and so forth.

 

What does the industry measure now? What are feasible, simple,

relatively straightforward metrics that we could start with? And

what we would plan to publish out of that once we have it done

would be, what is the spread? That would help answer the

question I have been asking for many years, which is, what is

the state of the quality of manufacturing in the pharmaceutical

industry?

 

Now, I have asked certain consultants who work with the industry a

lot. They say, “Somewhere between 2.5 sigma and 3 sigma.”

 

But that’s not acceptable. I would like to publish a spread

of things so that individual companies can benchmark themselves

against that spread, but I don’t have any intent of publishing

individual submissions from companies. I think that would be the

kiss of death for this.

 

Deb: But would the agency consider something like a gold star plan for

manufacturers that really have an excellent track record, or is

that something that’s just not planned on CDER’s priority list

right now?

 

Janet: So the question was, would we consider a gold star, some kind

of reward or something?

 

I think we would consider anything that’s really a meaningful

incentive. I believe a more meaningful incentive would be to

provide those with a very good record with more freed to

operate, because that’s what’s inhibiting innovation.

 

But if gold stars and everything would turn people on then we would

certainly be happy with that. Whatever would incentivize people

to pay attention to this. I know many of the people in the

audience who are equality managers really understand what I’m

talking about.

 

We need the boardroom, as well as everyone in between, to be paying

attention all the time to quality. We need that to be front and

center, and we need to ability to continuously improve. So how

do you do that?

All right, well thank you all very much, and I look forward to

working with you.”

If you have any comments or questions, please let me know.