Douglas McCormick is a former Editor-in-Chief of 

Douglas McCormick

Most impacts of minor drug manufacturing are clinically undetectable. Many of us have probably caught ourselves thinking that from time to time, especially when trying to stay between the lines of a particularly twitchy specification. 

I'm not referencing my own late-night musings here, though, or recalling a whispered bar-room heresy. 

				This is, rather, what Janet Woodcock, MD, said in one of her first presentations as the US Food and Drug Administration's first Chief Medical Officer, delivering the keynote address to this year's IFPAC meeting (held in Baltimore at the end of January).			

We all worry, properly, about a 10% variation in API load, and dread a 15% error. But how, Dr. Woodcock asked, do manufacturing variations—the variations we spend so much time and money to control—how do they really compare with the errors built into the rest of the healthcare delivery system?  

Consider a fairly routine 1.5 × patient-to-patient variation in size or liver function. Consider the variations in uptake and excretion that come with age.  

Consider, she said, the 4 × variation in therapeutic effect stemming from genetic variations.  

And consider, finally, the variations in doctors' prescribing habits and patients' compliance (where some patients don't skip more doses than they take, while others take extra on the if-some-is-good-then-more-must-be-better principle).

Woodcock quickly pointed out that there are important exceptions, drugs for which close dosage control is critical (thyroxine, for example).

But the exceptions only underscore her larger point: before we can intelligently set the limits of process variation, we need to know what the clinical impact of that variation will be. 

And why is an intelligent approach to quality essential? Cost, of course. 

Mechanical engineers have a rule of thumb relating tolerances to cost: if it costs $1000 to get 90% in-spec, it will cost $2000 to reach 99%, and $4000 to reach 99.9%. As a first guess, you can expect six-nines, one-in-a-million reliability to cost $32,000.  

Quality costs. And, in today's environment—with pipelines running dry and the costs of clinical trials and manufacturing surging—is it right to make the patient pay for quality that has no impact on his or her treatment? 

"It looks like a train wreck," Woodcock told her IFPAC audience, "with [R&D] productivity problems going one way, and ... the healthcare [cost] crisis running on the same track, going in the other direction .... Society is very, very sensitive to the cost of pharmaceuticals. So something is going to have to give in this equation." 

The key is process knowledge at a level of sophistication few of us have dared to contemplate. And, in the end, manufacturing understanding has less to do with the chaotic behavior of bulk powders in a bin blender than it has to do with the final behavior of the active ingredient in the patient.  

The way to avoid the train wreck, Woodcock told her audience, is to modernize, moving even further away from "empirically derived, qualitative methods" to a rigorous, scientific approach focused on the patient.  

That, ultimately, is the fixed standard against which production performance will be judged. It will be a long time coming, of course, and current acceptance criteria will likely be with us for most of a generation. But it's like driving a car on a winding road: if you don't keep your eyes on the road ahead, you're sure to wind up in a ditch.  

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Before we can intelligently set the limits of process variation, we need to know what the clinical impact of that variation will be.

What Will It Mean to the Patient?

During the too-quiet week between Christmas and New Year's Day, I did a back-of-the-envelope analysis of Warning Letters issued by the US Food and Drug Administration during 2006. I devoted a couple of hours that dislocated week to downloading and categorizing the 455 Warning Letters with which the Agency gladdened the preceding year. 

I'm sure that many people celebrated the holidays by doing the same. 

Now, making that tally was not exactly a matter of clicking a mouse and getting a cross-tabulation. The agency's online database assigns each letter a subject, but there's little consistency from letter to letter. To take a fundamental example, the letters refer variously to "current good manufacturing practice," "current good manufacturing practices," "good manufacturing practice," "good manufacturing practices," "CGMP," and "GMP." A letter to device manufacturers, for example, might be captioned simply "GMP/Adulterated." Or it might refer to the "Quality System Regulation" or "QSR" or the "Reporting Requirements."  

All in all, the 455 admonitions carry 157 distinct subject classifications, most of them merely minor variations. 

What this exercise revealed (in addition to my urgent personal need for counseling and a rewarding hobby) is that we—the people who actually make pharmaceuticals—are extraordinarily good at what we do. 

FDA's 455 Warnings cover a wide cross-section of US manufacturing. One way or another, FDA regulates about a quarter of the country's economy—anything that's swallowed, injected, inhaled, or spread on the skin.  

In the final analysis, just 22 of these Warnings concerned the manufacture of human pharmaceuticals: Fourteen were issued for CGMP violations in finished pharmaceuticals. Four went to API producers. Three to medical gas suppliers. And one for a biologic. (Fourteen more Warnings went out to compounding pharmacies, as the Agency continued its campaign to bring them under GMP control, but that's a story for another time.) 

As anyone who has been on the receiving end can attest, even one Warning is about three too many. But compare the 18 Warnings for drug products and substances with the 37 letters sent to investigators, institutional review boards, and laboratories for clinical-trials missteps. Or consider 80-plus Warnings issued to medical device makers. Or those earned by drug marketers for making false and misleading claims or selling unapproved products. Or the 170 or so Warnings sent to various links in the food chain, from makers of medicated feeds to dairymen to seafood processors. 

Our industry manufactures billions of doses of medication each year. The Center for Drug Evaluation and Research's list of registered manufacturing facilities runs to more than 11,000 entries. The scope of the activity is mind boggling. Yet we seem to pull it off with greater consistency and integrity than any other sector FDA regulates. 

The disparity between the manufacturing and marketing sides of our own industry is particularly interesting. In manufacturing, we have clearly cultivated a culture of quality—though we equally clearly have far to go. It's not that we're unimaginative or uncreative. Rather, we can see only too clearly what will happen to our customers—our patients—if we cross over the limits, no matter how tempting it might be.  

Look at the damage done to our industry by pitchmen shading the facts for marketing advantage. Then look at the record on the manufacturing side. It's hard not to feel that the culture of quality is the culture that matters.  

We, the people who make drugs, are extraordinarily good at what we do.

Twenty-Two Warnings

of people, that I should never have believed 

Ninety million people live in California, Texas, New York, and Florida. Imagine that, sometime tonight, an unnameable catastrophe carries off everyone in those states over the age of 14. When the sun comes up tomorrow, only the children remain. Eighteen million children, left to care for one another or fend for themselves.  

Eighteen million orphans: That's Africa today. 

Last month, BD Medical (a division of Becton, Dickinson and Company, Franklin Lakes, NJ, 

) hosted a two-day conference in Lyon, France, on product life-cycle management. The keynote, presented by executive vice-president Gary M. Cohen to an audience of some 200 customers and prospective customers, was not about the company's products, however. 

Instead, he talked about his company's mission to provide appropriate healthcare to the world's most disadvantaged populations, taking as his text three of the eight United Nations Millennium Goals for improving the health of the world's poorest nations by 2015: 					

reduce maternal mortality rates by three-quarters;

halt and begin to reverse the spread of HIV, malaria, tuberculosis, and other pandemic infectious diseases (1).

Here are the dimensions of the problem: In southern Africa, HIV infects 40 million people and AIDS kills three million each year (the population of Chicago—gone). Malaria kills another three million (Philadelphia and Phoenix—gone). Tuberculosis kills two million (Houston—gone). In 2000, measles killed 850,000 (the children of San Jose, Detroit, Indianapolis, Jacksonville, and San Francisco—all gone). Maternal and neonatal tetanus, contracted by the infant or mother during childbirth on bare ground, killed 200,000 babies and 30,000 women (the children of Dallas—gone). 

The litany of suffering recalled former president Bill Clinton's address at the 2006 BIO Annual Meeting in Chicago. Though we've reported it before, it bears repeating:  

Keep in mind half the world's people live on less than $2.00 a day; a billion people live on less than $1.00 a day; a billion people go to bed hungry every night; a billion people never get a clean glass of water in their entire lives; . . . [each year] ten million kids die of completely preventable childhood illnesses that claim no lives in America...; and one in four of all the deaths on earth this year, all the deaths including from natural disasters, wars, accidents, crime, heart attacks, stroke, cancer, everything else in the whole world, one in four deaths will come from AIDS, TB, Malaria and infections related to dirty water, principally cholera and diarrhea-related illnesses (2).  

Our industry is doing much to help, and must do more. In 2003, industry delivered more than $2 billion in aid to fight AIDS, malaria, and tuberculosis in Africa—more than the World Health Organization or UNICEF (3, 4).  

Much of this aid, though, comes in the form of Western hand-me-downs: products designed and manufactured for developed-world needs and healthcare delivery systems. They are a start, but they don't precisely fit the real needs. The challenge, Cohen pointed out, is to design and provide products that are tailored to this market, however unprofitable they might be: drugs, devices, and supplies that are robust, easy to use, and inexpensive. And in this direction, we have very far to go. 

Health in the Millennium Development Goals 

www.who.int/mdg/publications/mdg_report/en/index.html

 2. D. McCormick, "Motion and Tranquility," 

 3. J. Breitstein, "AIDS in Africa: The Road Forward," 

 4. Pharmaceutical Research and Manufacturers Association (PhRMA), 

Millennium Development Goals: The Industry's Contributions

Ninety million people live in California, Texas, New York, and Florida. Imagine that, sometime tonight, an unnameable catastrophe carries off everyone in those states over the age of 14. When the sun comes up tomorrow, only the children remain. Eighteen million children, left to care for one another or fend for themselves.

Empty Cities, Outstretched Hands

 (Mumbai, India) has purchased two manufacturing plants from 

	On Wednesday, Sun announced it had agreed to buy Valeant's Bryan, Ohio, liquid and semisolid dosage facility. Last month, Valeant sold Sun Pharma a raw-materials and dosage-form manufacturing operation in Hungary.

	Valeant is a $680-million specialty pharma company focusing on neurology, dermatology, and infectious disease. The sales, says CEO Timothy C. Tyson, are part of the company's plan to consolidate manufacturing into four facilities by the end of 2006.

	Sun Pharma is the 5th-ranked Indian pharmaceutical company, specializing in psychiatry, neurology, cardiology, diabetes, gastroenterology, and orthopedics. Sun bought the plants to expand its generics business on two continents. The Ohio acquisition, said Chairman Dilip Shanghvi, will join Sun's US subsidiary, 

 (Detroit, MI), to strengthen Sun's American generics business and give the company capacity in liquid, cream, and ointment formulations. The Hungarian purchase expands capacity in bulk actives and product development, and will speed up product roll-out in Europe.
	
	–Douglas McCormick

Sun Pharma Buys US, Hungarian Drug Plants from Valeant