Getting Ready

forRisk-BasedGMPs

Getting Ready

Risk-BasedGMPs

Getting Ready

forRisk-BasedGMPs

Patrick Clinton

26 BioPharm International APRIL 2003

In the sweeping program of change currentlyunder way at FDA, perhaps no element hasgreater potential to transform the way compa-nies do business than the agency’s plan tomove the regulation of good manufacturingpractices (GMPs) in the direction of what FDAhas described as “a science- and risk-based

approach to product quality regulation incorporat-ing an integrated quality systems approach.”

Risk-based GMP regulation offers many po-tential advantages to the industry and the agencyalike — including potential reductions in inspec-tions, greater consistency, and coordination withinternational standards. But to date, for many inbiotech, it is just a set of ideas that give few cluesto what life under the system would be like.

For a better sense of what risk-based regula-tion promises — or threatens — we turned to adistinguished group of industry experts. Here iswhat they had to say:

ONE PROGRAM, MANY MO T IV ESThe first point to recognize about the risk-management initiative is that it has multiplemotives. On one hand, it is designed to improveregulatory procedures and respond to industry

concerns. On the other, it is clearly meant to copewith a crisis of resources at the agency.

“You have to keep in mind that to a largerextent than many people realize the agency isdiverted these days to a lot of bioterrorist-relatedinitiatives and the reformatting of CBER intoCDER,” explains Michael Petty, an FDA veteranand a partner of the Washington, DC, office of thelaw firm of Ropes & Gray. “Even before that, theagency was crying of resource starvation. Thereare a number of areas where FDA doesn’t meet thelaw. They’re supposed to review citizen petitionswithin 108 days. They’re supposed to inspectplants every so many years. There are all kinds ofplaces where if it were industry doing what FDA isdoing, they’d be under consent decree.

“But if you’re going to assume that there arelimited resources, and this is a serious issue forthe agency today and going forward, you wouldhave to prioritize based on something. Well, for apublic health agency, what would be better asthat ‘something’ than risk?”

Even if there weren’t a resource shortage,there are still issues of efficiency, focus, andappropriateness, explains Ron Johnson, a 30-yearFDA veteran, now executive vice president ofQuintiles Consulting. “I think it’s clear that FDAmanagement is concerned that the energy theagency invests in enforcing GMPs may not befocused on the most critical issues,” Johnsonsays. “A risk-based approach makes exquisitesense from the industry perspective, because ittries to separate the aspirin from the nitrogly-cerin, and that is something FDA historically hashad a difficult time doing.”

It’s not that FDA has been unaware of risk, orthat it hasn’t already tried to build risk assess-ment into its operations, Johnson says. “If youask anyone in FDA they will say, ‘All of ourplanning has been focused and based upon risk.’If you look at the compliance programs, theyidentify high-risk things — sterile drugs, forexample. But when it gets to the field office thosepriorities can get compromised. There are exam-ples where FDA has spent enormous amounts ofenergy and effort on an over-the-counter pharma-ceutical manufacturer. You have to wonderwhether that’s the most important thing in theworld, because it probably is not.”

If the point of the new approach to GMP regu-lation is largely to solve internal FDA problems,there is also a real focus on stripping awayunnecessary regulation for the sake of consumers.

Sandy Weinberg, professor of biomedical en-trepreneurship at Muhlenberg College in Allen-

Patrick Clinton

As FDA moves toward a

new vision of GMPregulations,

BioPharm Internationalasked industry experts

some key questions:What form

will risk-basedGMPs take?

What are the benefitsand costs for biotech?

Will the changereally encourage

innovation? And, most important,can FDA leaders get

field inspectors to buy into

the new approach?

BioPharm International APRIL 2003 27

town, PA, and head of the college’s BiomedicalRegulatory Tracking Project, follows regulationat more than a dozen agencies. He says, “There isincredible political pressure on FDA to find waysof reducing the cost of pharmaceutical drugs.You’ve basically got three kinds of costs. You’vegot the R&D cost. If you cut that, you end upwithout new products. You have profit, andalthough that sounds tempting to politicians, ifyou cut profits, capital flees to other industries,and again you have no new products.

“So you’ve got to find some way to cut produc-tion costs,” Weinberg continues. “Most of produc-tion cost in the pharmaceutical industry is qualitycontrol, and you don’t want to cut quality controlwhere it counts — so FDA’s new approach sug-gests a way to cut quality control where it doesn’tcount. The trend to consider cost as a factor inregulation is probably universal. This is the firsttime it’s been applied in this industry, but it’sbeen part of the process everywhere else.”

For Don Burstyn, vice president for regulatoryaffairs at Alkermes, a publicly held biopharma-ceutical company in Cambridge, MA, and amember of the PhRMA work group on GMPs,part of the point is to put science back in the dri-ver’s seat. “In manufacturing and setting up oursystems we try to take a scientific, very rationalapproach to things. It makes good manufacturingsense as well as good business sense to have ascientific rationale for what we’re doing. Today,unfortunately, we’ve gotten ourselves into a situ-ation where many manufacturers as well as manyinspectors, basically operate by dogma. They say,‘Things need to be this way because they’ve al-ways been done this way’ without thinking of therationale behind it.’ Those of us who have beenin the business for a long time and have workedat the agency understand that there are multipleways to approach the same problem. There aremany right answers. We have to be sure that theanswer we choose is right in the context of ouroverall operation, maintains product quality, andis efficacious.”

As a result, the risk management conceptseems to respond to multiple concerns at thesame time. “I think the way the industry isheaded and the way FDA is headed is to put moreemphasis on good regulation through good sci-ence,” says Tobias Massa, executive director ofglobal regulatory affairs for Eli Lilly and Com-pany and chair of the scientific steering commit-tee for the Product Quality Research Institute(PQRI). “The GMP and inspection processevolved in response to various issues that have

arisen over time. The GMPs have served a veryvaluable purpose. But now we’re saying, ‘Look,everybody needs to understand that there’s nosuch thing as zero risk. That being the case, howdo you apply the best science to controlling risk?’

“We and FDA are saying that the answer basi-cally relates to product quality and using the bestcurrent science to result in the best possible GMPprogram. It’s true that to some degree this is theresult of a resource issue, but I think it’s more aresponse to the question: What is the best thing todo relative to how we regulate medicine?”

MEASU R ING R IS KThe big question now is how the new concept forGMPs will be implemented. Some experts areanticipating that a full implementation will taketwo to three years, including the time it takes totrain inspectors. In the short run, FDA plans tomeet with industry and others to gather informa-tion, beginning with a workshop scheduled totake place 22–24 April in Washington, DC.

“There is conceptual agreement among every-one involved — FDA, industry, and various seg-ments of the industry — on where we’re going onthis whole concept of risk,” says Gerry Migliac-cio, vice president of global operations for Pfizer.“I think FDA has done a wonderful job of fram-ing the discussion. And now that everyone isstarting to use the same terms and understand thesame concepts, we can start quantifying it. That isthe task ahead.”

For Migliaccio, who serves on PhRMA’sGMP committee, that task is partly a matter oflearning to work with data the industry alreadypossesses thanks to technological developmentsin the past few years. “We have a significantamount of data on our products and processes,”Migliaccio says. “We have analyzed the data. Inmany cases we understand the capabilities of ourprocesses. And we’re doing more and more ofthat as time goes on. To me, it’s a matter ofworking with FDA to define the data set that’srequired to control risk. That is what we and FDAand academics have to develop jointly.”

Working out the nuts and bolts of quantifyingrisk will be a substantial task. And in truth, thereare probably still parts of the big picture that needto be filled in. “I don’t think we’ve come toagreement on what we mean when we talk aboutrisk,” says Tobias Massa. “I think we have tolook at risk from the perspective of what it meansto the patient. As we do our jobs from the per-spective of both the regulator and the regulatedhow are we viewing that? I think it’s pretty clear

28 BioPharm International APRIL 2003

where we stand as an industry: When we talkabout risk and quality, it basically means fitnessfor use. Are medications safe and effective? Arethey available? Are the directions for taking themedication easy to understand? When we talkabout fitness for use we’re not talking about howwell it meets minimum standards. We mean is aproduct safe, is it efficacious, is it readily identifi-able, and is it easy to use?

Availability may not be part of the conven-tional concept of risk, but it adds an extra dimen-sion to the analysis. A patient can be harmed bythe absence of a lifesaving drug just as surely ashe or she can be harmed by an adulterated drug.And availability is a part of the risk picture that isheavily influenced by regulatory practice. “Whatdoes it mean if a product is not available to theconsumer?” Massa asks. “Obviously that has todo with the intended use of the particular product.If you’re talking about acne medicines, the risk isat one level. If you’re talking about a lifesavingdrug, your considerations are different. Thosethings need to be taken into account.”

GETT ING INSPECTORS TO B U Y INThe risk-based approach to GMPs is part of asweeping campaign of reform at FDA, but thatdoesn’t mean that the concept behind it is a newone to the agency. Risk management has beenpart of FDA’s thinking for years. And some ex-isting programs may well give a clue to how theagency plans to handle GMPs — and whether itis likely to succeed.

For a number of industry experts, the mostcompelling example of an FDA risk-based pro-gram is the approach to medical device manufac-turing embodied in the Quality System Regula-tion (QSR), 21 CFR Part 820, which went intoeffect in 1997. Medical device manufacturers hadbeen subject to GMP regulation since the early1960s, but QSR brought a new set of ideas to theprocess. “I gave a speech to the Parenteral DrugAssociation seven or eight years ago, when I wasstill with FDA,” says Ron Johnson. “I said if youwant to know what your future is, look what’sgoing on in medical devices. If I were betting, Iwould bet that the GMP for drugs will move inthat direction.”

Muhlenberg College’s Sandy Weinberg ex-plains how the system works: “Anytime you haveany kind of submission for a medical device,” hesays, “you calculate the risk involved. You iden-tify the predicate events that might tell you whatkind of risks to expect, then you determine theseverity and probability of those events, andbased on that you classify them as high, medium,or low risk. Then, when you’re filing an applica-tion, or when an inspector comes, you say, ‘Wedetermine this to be high, medium, or low risk.Here’s why, and here’s our standard for what wedo to handle a high, medium, or low risk.’ It’s apretty efficient system, and it really lets you putyour dollars where they count.”

But although many in the industry speak wellof QSR, it hasn’t been a panacea for the medicaldevice industry. Larry Pilot, partner of the lawfirm McKenna, Long & Aldridge, and counsel tothe Medical Device Manufacturers Association,has worked with medical device companies underthe device GMPs and under QSR. He says that hehasn’t really seen a reduction in the number ofproblems.

“It’s the application of QSR by the agencythrough its inspection process that has caused dif-ficulties,” Pilot says. “The bottom line is at thedistrict level. Do they really care about risk man-agement? I can tell you that I’ve had experiences— past, recent, and current — where risk doesn’tmean anything. If the district wants inspectors toput a gun to somebody’s head, they’ll put the gunto somebody’s head. That’s inappropriate, it’s un-fair — and it happens.”

Pilot’s experience raises an important issue inregard to FDA’s current program of change —perhaps the central issue: Will the agency be ableto change its own culture, right down to the cru-cial level of individual inspectors?

“The Achilles heel in any new initiative atFDA has always been at the worker bee level —the investigator on the street is the person that’sgot to get in tune with the new thinking,” saysRon Johnson. “Historically FDA has not done agood job at corralling or managing itsinvestigators, particularly those at the nationalexpert level. That’s going to be the real acid test.The managers and the Washington headquarterspeople can do all sorts of things, but it gets exe-cuted at the field level.”

Part of the issue for individual inspectors is theability to control the inspection. In theory, a risk-management approach is supposed to focus theinspector’s attention on the highest-risk portionsof a manufacturing process. But inspectors have

“The Achilles heel

in any new FDA

initiative has

always been at the

worker bee level –

the investigator

on the street.”

30 BioPharm International APRIL 2003

been known to balk at systems that seem to tellthem what they should look at and what theyshould ignore. That emerged as a problem severalyears ago during a pilot program at the devicecenter that used a Hazard Assessment/CriticalControl Point (HACCP) approach as an alterna-tive to the center’s quality systems approach. “AnFDA inspector wants to look at everything,” saysJohnson. “He doesn’t want anything to be prede-termined. In a HACCP program you’re steeredtoward particular things, and I think some inspec-tors felt they were being denied access to infor-mation they needed to make a real evaluation.”

At the same time, Johnson says, inspectorsshould understand that the agency is changing.“If they just look around at the rest of the agency,most other FDA programs, with the exception ofbiologics have moved on and have adopted cur-rent scientific principles, whereas the drug GMPhas just stalled. Perhaps Janet Woodcock candrive that and Mark McClellan can drive it. Andclearly this is an initiative that resonates with theadministration.”

In light of these concerns, some of the addi-tional elements of FDA’s plan — such as the de-cision to remove authority for warning lettersfrom the district offices, or the new conflict reso-lution process — start to look like an attempt tomanage a cultural change within the agency. “Ifthe new initiative is successful, it will preventsome actions at the field level from coming tolight,” suggests Johnson. “A field observationwill go through triage in Washington, and theWashington people will apply the risk-based con-cept and will be in a position to say, ‘This is not ahigh-risk area, this is not a high-risk product,these practices are not high-risk. We’re not goingto permit you to do x, y, or z.’”

If that is the plan, it offers its own set of chal-lenges: Can Washington in fact manage this sortof triage? Can risk really be assessed away fromthe field? What will the impact be on the inspec-tors? But on the other side, there are real risks ifFDA attempts to impose the risk-managementsystem and fails.

“We’re talking about a very big fundamentalcultural change for both FDA and industry,” saysTobias Massa. “The industry is basically a skepti-cal, captive audience here, and I think there aresome folks who are saying in their own minds,

‘We have seen quality efforts come and go, andyet we still revert back to the most conservativeapproach every time.’ Maybe the industry fearsthat it will end up doing more things, but not seeany change in how it’s regulated.

“I don’t think that’s going to be the case. Ithink FDA has been very responsive to industry’sconcerns about consistency between the field andthe center, consistency in the field, consistency inthe centers. Industry has never said ‘we don’twant to be regulated.’ I think what the industryhas said is ‘we want science-based regulationsthat are consistently applied.’ If we don’t achievethat, then both industry and FDA have failed tomeet one of our fundamental goals.”

C H A NG ING TH E P LAY ING F I E LDAssuming that FDA can manage the transition toa new, more scientific approach to GMP regula-tion, there are still some important questions:Will a risk-based approach to GMPs create a two-tiered regulatory system, with some companiespractically deregulated, while others bear an in-creased regulatory scrutiny? Will smaller compa-nies be subject to a disproportionate share ofFDA attention? Will the system encourage inno-vation, as it is intended to, or will innovation beperceived as intrinsically risky, and thus to beavoided? And will what looks like an effort to re-duce regulation turn out to be something quitedifferent — an offloading of responsibility andcosts onto industry?

It’s too soon to answer most of these ques-tions, but some already seem reasonably clear. Atwo-tier system for instance? “I think my answeris yes, even though that’s not FDA’s intent,” saysRonald Tetzlaff, president of the consulting firmKMI/Parexel. “FDA is going to intentionallyinspect those facilities where noncompliance hasthe greatest risk to health, and of course biotechscertainly fall into that category for three reasons:FDA has listed three categories as being of spe-cial concern — sterile drugs, prescription drugs,and plants that have not previously been in-spected — and biotechs typically fall into thosecategories. Second, many biotech products areproteins and by their very nature represent moreof a challenge because they have relatively com-plex manufacturing processes and analyticalmethods, in addition to the fact that most biotechproducts by definition are derived from livingcells that are themselves inherently more difficultto control. And biotech-derived molecules areoften more difficult to characterize, because thereare a lot more product attributes that potentially

“FDA is going

to inspect facilities

where noncompliance

has the greatest risk

to health. Biotech

plants certainly fall

in that category.”

32 BioPharm International APRIL 2003

pose hazards to patients. Because there’s such alarge number of facts that have to be addressed,and the scientific expertise necessary to evaluatethose things is complex, you can expect FDA togive [biotechs] a lot more scrutiny.”

In principle, a two-tier system will come aboutbecause some companies will experience drasti-cally reduced scrutiny, and no one will experi-ence an increase in regulatory burden. Thatmakes sense, says Michael Petty. “There’s a con-tinuum of products here. On one end, you’ve gotrisky prescription drugs with potential liver toxic-ity, ‘black box’ drugs, all those kinds of things.At the other end, you’ve got over-the-counterdrugs (OTCs) that are not very problematic, andyou’re right on the line with cosmeceuticals or di-etary supplements. You could probably make anargument that there are several OTC productsthat should really be in the same playing fieldwith some dietary supplements, for instance, interms of their risk.”

Although biotech products will probably con-tinue to be scrutinized more heavily, some willprobably benefit from the new approach. “Not allbiotech drugs are created equal,” says Petty.“Look at the ones for which FDA is alreadyworking on monographs for quasi genericizing.They certainly think that they understand insulinand hCG. They’ve seen 12 different versions ofthem, and they all are safe and effective.”

“Pharmaceutical companies are usually wellestablished, and they have usually been in thebusiness for a long time,” says Massoud Lavian,assistant director for compliance for ClarkstonConsulting. “They have gone through a lot of in-spections. They are familiar with the basics.Biotech companies are generally smaller andoften newer, so they are not as familiar withGMP issues, with documentation issues, withhow to set up programs, and so forth. So yes, theemphasis will be on the biotech companies.”

Does this mean that the new system will makelife harder for young biotech companies? “In myopinion, no,” says Lavian. “They are supposed todo the same things they did before. The amountof work stays the same. It just becomes easier forFDA to find out if they have done it or not.”

There’s even a case to be made that smallercompanies will have some advantages in a chang-ing regulatory environment. “Today a smallercompany starting out has a better opportunity to

be ‘compliant’ than some of the larger compa-nies,” says Don Burstyn. “That’s becauseCGMPs evolve. You look at a company that’sbeen in business 30 years and has been doingthings a certain way, it’s very difficult to modern-ize or change things within the system. In addi-tion they have baggage. Companies that havegone through many inspections end up with bag-gage, like one inspector finding something orasking them to change parts of the system. Thesystems become very cumbersome, and it’s verydifficult to maintain consistency. A small com-pany starting out fresh, if it does things right, hasthe opportunity to put in best practices and scien-tific practices at the beginning.”

Innovation is a more complex question. “Intheory the new approach will allow companies toinnovate if they choose to and if FDA is flexibleas to how they interpret the GMPs,” says RonaldTetzlaff. “In the short term — the next two orthree years — I think many companies will take aconservative wait-and-see approach. Many, if notmost, will be unwilling to jeopardize their prod-uct approvals or invite delays in reaching marketwhile waiting for FDA to interpret or approve aninnovative approach.

“That will be especially true in the biotech in-dustry where it’s exceedingly complex, the sci-ence is very state-of-the-art, and it’s going to bedifficult to present the data in a manner that willsatisfy all scientists. In the short term at least,prudent management will look to see if there aresuccessful outcomes from other companies be-fore they invest heavily in a novel approach.”

At the same time, it seems clear that FDAunderstands that innovation may need support.Tobias Massa points to the Process and Analyti-cal Technology (PAT) initiative. “PAT is proba-bly the forerunner of the 21st Century initiative,”he says, “because what PAT is looking at is con-tinuous improvement and being able to introducetechnologies into the manufacturing process.”

To Massa and many others in the industry,continuous improvement and a quality systemsapproach are the real issues. “Quality systemsdrive you toward risk-based decision making,” hesays. “The whole effort here is related to productquality. If you look at FDA’s material, they’verenamed the program. It’s no longer ‘GMPs forthe 21st Century,’ it’s ‘Quality for the 21st Cen-tury.’ FDA is saying we need emphasis on qual-ity more than we need strict adherence to SOPsand so forth. Quality will drive everything else. Ifyou have quality in the design and control of yourdrug process and your testing paradigm, goodmanufacturing practices will follow.” BPI

Patrick Clinton is editor in chief of BioPharm International,

485 Route One South, Building F,First Floor, Iselin, NJ 08830,

732.225.9500, fax 732.225.0211,pclinton@advanstar.com,www.biopharm-mag.com.

“Today a smaller

company starting out

has a better chance

to be compliant than

some of the large

companies, because

the CGMPs evolve.“