At the very least, let's rename QbD "Intelligent Design." That way, columnist Emil Ciurczak quips, we can get faith-based government funding to teach it in U.S. public schools. 

For more on Quality by Design and the disconnect with some Pharma H.R. departments read Emil's latest column (posted below for the link-averse):

-AMS

The Perfect Storm*

I was perusing the “Positions Available� section of Chemical & Engineering News (just looking, I enjoy not showing up five days a week at the same place) and, as usual, grumbling about the descriptions. One that always gets me is the desire to place an Organic Chemist in charge of an Analytical department. I often see someone in charge of something and comment that I could easily DO the job, but that I could never GET the job. There is a tendency to advertise for the person currently holding a position, not for someone to do a better job. That might prompt a “You’re overqualified for the position,� from the HR department.

Think about that statement for a second. Were you to need an operation, would you tell a doctor, “No, you’ve performed too many heart transplants - you’re overqualified?� Somehow, I doubt it; but we seem to think chemists, pharmacists and process engineers become worthless when they have experience. Perhaps the quote should be, “No. I think we can find someone to work for less money.�

That got me to thinking about our narrow-minded industry. Years ago, while I was at Sandoz, the Colors and Chemicals division moved to South Carolina, leaving a number of employees to seek other positions. Since internal hiring was our practice, I suggested that a woman I knew to be a super chemist submit an application for our section. At the time, I was in the QC department doing my original NIR work (early 1980s). After several weeks, her application had not appeared. When I enquired as to its status, I was told by HR that she didn’t have the buzz words, “USP and routine tests� on her resume, so they ignored it.

She eventually got the job. She and I worked together and presented several NIR papers…but, not because of any help from the HR people. She was to be doing method development and those words don’t appear on any QC job description!  She was perfect for the job, but couldn’t get it.

Makes me wonder how we expect QbD and PAT to succeed. Since they are new, there are very, very few job descriptions with those “buzz words� included. Fewer still are resumes with QbD or PAT as accomplishments or goals. As a horse will run back into his burning stall when he panics, so, I fear, will management and HR fall back on “tried and true�  (or is that “tired�) descriptions and position-filling procedures. One problem with filling a position with someone who has dome nothing but that job is that there is no cross pollination. Since the paradigm has changed with QbD, doing the job the same way with the same personnel…well, refer back a few columns to the definition of insanity.

I fondly recall the cross-training I received at Ciba in 1970: one week making tablets, one week in sterile products, one week in clinical packaging, etc. When I started my “real� job I had an understanding of where my position fit into the overall scheme of things. While I was tasked with measuring package/product interactions, I had sampled a full-sized V-blender, made my own chewable vitamin C tablets, made pre-formulation compatibility samples for stability testing, and worked with the consumer products (like Binaca breath spray). Do companies take the time to do this cross training anymore? Whence cometh then QbD personnel, prithee?

Once more, with my firm grasp of the painfully obvious, I would like to make a simple suggestion. Would it be all that hard to do some cross-pollination within departments? On a larger scale, The Swiss giants (at the time still independent) Ciba, Sandoz, etc. had continuous exchange programs for US and Swiss scientists so that they could familiarize themselves with the other groups within the company. It was much easier to work from another continent when you knew the faces and job skills or your overseas colleagues.

Now, extrapolate this to QbD; wouldn’t it behoove a Physical Pharmacist, setting parameters for new APIs, to actually work on a compression line and see the potential problems? How about pre-formulation people actually being concerned with real stability issues? One immediate benefit of the cross-training program at Ciba was when a formulator (Glenn van Buskirk, by name) was reformulating a chewable Ritalin tablet. Before he proceeded to stability trials, he asked if the new ingredients might interfere with the current assay. In fact, the red dye (they were cherry-flavored, if I recall) interfered with the colorimetric assay, which developed a red color for spectrometric quantification. His awareness of another department’s potential dilemma allowed Analytical R&D to develop a new assay before it was needed.

How much better would a QbD program be run if all the members of the committee had a smattering of knowledge of each step in the production of a solid dosage form?  Unless we start to work as an organic unit, we may as well break out the slickers and life vests; it’s gonna get ugly before the weather breaks.

References:*From the book and movie of the same name: implying all (weather, in that case) conditions coming together to wreak more havoc than any one by itself.

There are no whole truths; all truths are half-truths. It is trying to treat them as whole truths that plays the devil.�b

      “Truth is rarely pure, and never simple.�c

      The news is again a-twitter with stories of another fallen hero: Avandia. While I have no need for the drug, it seems to echo the Vioxx and Celebrex stories of the recent past. I have arthritis, so those stories DID affect me. Having had to switch medications in mid-stream, as it were, I decided to take a closer look at the numbers being used. [Any of my readers who know my background know I have some interest in statistics and Chemometrics from my work in near-infrared (NIR) spectroscopy.]

As with any news story (e.g., “Man bites dog!�), seldom do the pundits read beyond the first paragraph.

The headline on the Today Show this morning was “Avandia causes 30% increase in heart attacks.� Let’s look at that first by going to the FDA website where the information was posted “for medical professionals,� as per the news. [Under the law, ALL citizens have access to the data, so don’t be put off.]

It seems that “8,604 patients on rosiglitazone (Avandia) [too bad “litazone� sounds so much like litigate] were compared with 5,633 patients randomized to a variety of alternative therapeutic regimens, including placebo.� The population seemed well dispersed among various lengths of disease occurrence, history of other problems and surgeries, etc. All but four of the 42 studies were of six months duration. The overall incidence of myocardial ischemia in the Avendia versus comparators was 1.99% versus 1.51%. This was seen as a 30% excess risk factor.

Now, I seemed to remember something similar in the 55 mile-per-hour national speed limit controversy, so I went back and looked at some notes. When Maine switched from 55 mph to 65 mph, the death rate doubled! That’s right, it doubled! It went from one to two for the year! Hence the title of this piece! So, let’s read farther…often newspeople and lawyers [there are already…same day as newscast…lawyers posting for patients taking Avandia] hope we have short attention spans and will not read further (it is, after all four large pages of print with no picture).

A Balanced Cohort Study used 33,363 patients in a managed care database for its study. “Propensity matching� was used to match risk factors (how novel) for cardiovascular disease and other considerations. The “composite cardiovascular endpoint� was hospitalization for heart attacks (myocardial infarctions) and bypasses (revascularizations). Patients in the study began use of the (dreaded) drug in question between 2002 and 2004. The groups were only rosiglitazone, metformin, or sulfonylurea; oral dual therapy combinations, and insulin combinations. The result?

 With a follow-up time of 1.2 years, the incidence of the composite cardiovascular endpoint was 1.75 events per 100 patient years for the rosiglitazone (Avandia)-containing regimen and 1.76 events per 100 patient years for the other treatments. Now, this is NOT a headline-grabber. Further studies also do not support the first stated study. This could be why the FDA voted 22-1 to continue the sales of the product and to allow doctors and patients to decide whether the risk is acceptable.

 This is all very interesting you say, but what does it have to do with process analytical technologies and Quality by Design (PAT/QbD)? Well, it seems the study that took ALL the factors into consideration was approaching Chemometrics…or, as we say, “Design of Experiment.�

When you use a portion of your data to support a conclusion (e.g., there is a better than 0.9 correlation between the rise and fall of the Mississippi River and the birth rate in Paris, France), you take a chance of using PAT to make your product worse.

When we attempt our first (or tenth for that matter) PAT project, it is critical to have enough inputs and use correct math to glean the causes of “good� v. “bad� product. If we merely look at, say, hardness versus dissolution rate, we totally ignore the distribution of lubricant or particle size of API or moisture distribution or etc., etc. etc.

Vis á vis the topic of this column, I could point out that 100% of the people who go bald drank water prior to baldness and anyone who breathes air will die. These are true, but what conclusions are you drawing from these statements?

The discipline needed for good science is not limited to the lab or the clinic or the production line. Good science and engineering are prerequisites at all stages of health care. But, since I have a limited charter, let it suffice to say, use all information when building a better product. May the force (a.k.a. Chemometrics) be with you.

References and Quoted Dignitaries

1. Benjamin Disraeli, 1804-81
2. A. N. Whitehead, 1861-1947, Dialogues, Prologue
3. Oscar Wilde, 1854-1900, The Importance of Being Earnest, I

By Emil Ciurczak, NIR/PAT expert and Contributing Editor, PharmaManufacturing.com. 

Comments, as always, invited.

PharmaManufacturing will soon launch its first Wiki.  It will cover the field of process analytical technologies (PAT) as it applies to pharmaceutical quality systems and  Quality by Design . We're looking for contributions from the pharmaceutical, biopharmaceutical and other communities using PAT (for example, API and fine chemicals, but even other sectors that are "ahead" of pharma in their use of PAT are invited to contribute material). We'll look for information on on:

Spectroscopy (NIR, FTIR, Raman, any type is fair game)

Particle Size Distribution

Effusivity

Sensor technology (any type useable in PAT)

Imaging

Chemometrics

Process Capability analysis and Statistical Process Control.

Design of Experiments

Process Control

PAT for Excipient Quality Control

PAT as an Anticounterfeiting tool

Simulation and Modeling to Improve Quality Control

Anything that falls under the "PAT" rubric will be fair game. The wiki will be moderated by editors and experts on our editorial advisory boards.

We hope that this forum will help encourage more people in the industry to share best generic practices and knowledge.  Remember, you can contribute anonymously.

If you'd like more information on this project please contact me at ashanley@putman.net

It's our blog and we can crow if we want to....We just learned that Emil Ciurczak's monthly column, Therapeutic Dose, is a finalist for "best contributed column" in the 2007 American Society of Business Press Editors (ASBPE) awards.

If you haven't read Emil's columns yet, you'll find them here and here (items #2-13).

-AMS

Like most pharma magazines, we've been covering e-pedigrees and RFID; although we'd like to say that we've been immune to the hype surrounding this subject, we've spent an awful lot of time covering the ins and outs of the frequency debate because very few companies will discuss what they are doing. It has been a bit like covering the much-hyped process analytical technologies (PAT) in that regard. Fortunately, PAT has developed more momentum and more pharma companies are open to talking about it.

But consultant Adam Fein, who has been addressing RFID hype for quite some time in his blog, recently cited a very fine "myth shattering" article in CSO that I wish we'd published (as well as a hype-riddled blurb from a trade journal e-newsletter that I'm relieved we didn't. )

In it, the author pinpoints the top five misconceptions about RFID technology as they apply to drug supply chain protection. Here is a link to the article by Sarah Scalet, a senior editor with the CxO Media Group.

Our contributing editor and editorial advisor Emil Ciurczak, an expert in NIR spectroscopy, did address some of the limitations of RFID in a recent op-ed entitled "You Can't Cheat an Honest Man."  As he suggests, PAT and powerful, inexpensive hand-held NIR and Raman spectrometers (while themselves the subject of quite a bit of hype) could be powerful weapons in the war against fakes.  China just bought boatloads of them last year.  Here's an excerpt from Emil's op ed.

Markers that use radio frequency ID (RFID) promise some relief. However, as with any defensive measure, the “enemy� is out there looking for counter-measures. Like hackers generating new viruses, drug counterfeiters are always seeking ways around security technologies. The problem I have with RFID tags is that they are on the bottle or case, not the product itself. Having worked in the industry longer than many of you readers have been breathing, I am aware of how easy it is to repackage products.

There is little to stop a group from hijacking a legitimate shipment of a controlled substance, emptying the product for diversion, and refilling the bottles with placebos (for insertion into the retail stream). These cases of bottles, still bearing the correct RFID tags, are distributed to pharmacies throughout the region, while the diverted product is sold to street pushers or made available online.

Before you start wringing your hands in dismay (who wrings their hands nowadays, anyway?), I have a humble suggestion. One of the benefits of PAT/QbD is the discovery of what is called the “process signature.� It is this process signature that allows us to predict a drug product’s performance vis-á-vis such things as dissolution, hardness, etc. This identifying characteristic of the product is our best defense against counterfeiters. With the advent of small, inexpensive, hand-held spectrometers (NIR and Raman), it is feasible for agents from the DEA, FDA, ATF, FBI or any other government entity to spot-check drug products in seconds.

Even if the miscreants were to invest the effort to use the correct APIs and approximate the excipients, they would seldom have the wherewithal to duplicate the large, modern tableting machines used by legitimate drug manufacturers. (It is not likely that counterfeiters would make knock-offs of generic products either, the profit being too small.) That makes the key element of the “Design Space� concept a key element in law enforcement, too. If another reason for PAT was needed, we may have just discovered it, "thanks "to the counterfeiters. . . .

News that industry and FDA relations are improving may elicit knowing looks from some quarters, particularly those politicians who say that the Agency's in industry’s pocket. But sour relations between FDA and the drug companies it oversees have contributed to the risk aversion and innovation gridlock that still prevents some drug companies from embracing new technologies and new ways of doing things (particularly QA and QC).The relatively slow rate of adoption of process analytical technologies PAT could be one indicator of the gap separating FDA and industry. But there are others: consider the "dispute resolution" process that FDA put in place several years ago. Anyone who disagrees with the results of a plant inspection can now put it in writing and have it reviewed. How many drug companies have even bothered to file anything? TWO (when I last checked).

Updating this picture is BIOCOM and PricewaterhouseCoopers’ survey on Industry/FDA relations, “Improving America’s Health IV,� which was released on Friday (a copy of which I just received). PricewaterhouseCoopers has been tracking the industry/Agency relationship for years---15 years ago, it was very strained, expectations were unclear and communications, poor. This resulted in a lot of very unscientific plant inspections and product reviews and a great deal of variability.

A total of 66 biopharma, pharma and medical devices companies responded to this latest survey, which was in progress at BIO 2006 (an indication of how difficult it can be to get the busy folks in the industry to take surveys of any length). Results show significant progress, but suggests a serious need for improvement in a few areas:

• More proactive communication from manufacturers when questions come up (examples could be questions about validation, new drug applications or the use of different approaches or technologies). FDA has become more open to questions and open communications but, apparently, some companies still aren't buying it, or approaching them early in the process with questions
• Agency staff turnover and lack of continuity in the reviewer or inspector assigned to a drug application or facility inspection.

Bullet point number two is particularly telling, since FDA activities have been underfunded for a number of years; travel and training budgets have been cut drastically, and presumably, morale has been an issue. This is one of the key issues that FDA's CMO Janet Woodcock and top Agency officials are addressing, as well as the need for more open discussion and debate (for more, from a March interview, click here).

You’ll find an executive summary of the BIOCOM/PwC survey results here.

But, in the meantime, here are some quick sound bites:

• 75% of respondents agree that FDA has made significant improvements since the FDA Modernization Act of 1997
• When asked about the overall impact of FDA guidance on drug development, 73% say they have a better understanding of FDA expectations, suggesting that, as a result, the quality of their new drug submissions has improved
• 60% described their Agency contact as extremely knowledgeable and responsive. However 43% found it necessary to “escalate the request above the original level of discussion"
• 31% of drug manufacturers and 46% of biologics manufacturers say that FDA changed its position during the review of a new product
• 43% say that FDA personnel changes resulted in a break of continuity in at least one of their reviews
• 68% say that FDA’s Critical Path Initiative is on the right track, but only 41% say it is focusing on the right issues
• Over 80% of respondents agree that pharmacovigilance is a key issue facing the industry, with most agreeing that a universal adverse event database would improve patient safety as well as the analysis of safety data.

We’ll be interviewing analysts and discussing results of this survey in our next issue and online. Stay tuned.

Chemical Engineering Progress just ran an interesting summary of the Society of Biological Engineering's first international conference on accelerating biopharmaceutical development, held in late March in California. Amgen's EVP of R&D, Roger Perlmutter, had a lot to say about the dearth of new drugs.  He mentioned the fact that there are only 16 new molecular entities. "The industry cannot continue down this path."  The environment has changed substantially over the past few decades.  In the past he said there were few interesting targets and strong IP. Today, he noted there are "thousands of new drug targets and rapid generic penetration,"  he said. He pointed the finger at weak preclinical trials, which, he said, provide poor predictive information.  He suggested that the industry focus on serious illnesses such as cancer and not on modest improvements to existing therapies. He also suggested that preclinical and clinical evaluations be integrated.

Following his presentation, Dr. Helen Winkle director of the Office of Pharmaceutical Science, FDA's CDER discussed manufacturing's role in the innovation problem, noting that the waste involved in drug manufacturing "can be as high as 50%."  In addition, she emphasized that industry must assume the policing of its internal quality control, rather than leaving that to FDA. "FDA's role is to do an initial verification and subsequent audits," she said. New drivers for industry, she said, are 21st Century GMPs, Critical Path Initiaative, Quality by Design and PAT.

In our next issue, Bikash Chatterjee, president of Pharmatech consultants, USP advisor and president elect of ASQ's Northern California chapter responds to an article we'd published in April on FDA's move to become more scientifically-driven.  It's a must-read; watch for it in June's issue.  Below, a brief excerpt

"In my 25 years as an industry professional I have seen many sound initiatives come and go;  JIT, TQM, QFD all failed to gain traction with [pharmaceutical] quality organizations.  Throughout this period the agency's response to the escalating drug complexity and associated public safety issues has been to step up the level of regulatory oversight. Consequently, the addition of risk-based cGMP guidelines for the 21st century has sent the industry reeling. Can we reconcile our history of controlling product safety through heightened quality oversight and incorporate these new scientific characterization requirements? Unlike previous failed initiatives that inhibited operational process innovation, the de facto consensus determined by the ISO, ICH and FDA swiftly validates the new risk-based approach as best practice.

So why has our industry, which has prided itself as being scientifically driven, struggled with the concept of QbD? Why has PAT not become the ultimate business trump card? Although Big Pharma and Biotech are beginning to embrace these redefined basic principles of process characterization and variation control, the remainder of the industry remains largely uncommitted. Lean Six Sigma initiatives are creeping into process improvement programs but have yet to propagate to the R&D phases of the drug lifecycle. I believe the problem lies in two places: Our motivation—or lack thereof—as  an industry for change, and secondly in the fact that much of the significance of the new initiatives lies at the characterization of process at the R&D stage, a place that traditionally has little regulatory visibility..."

Is Big Pharma heading down the road travelled by Detroit's Big Three automakers? API manufacturing expert Girish Malhotra asks that question as he examines the future of big pharma in an op ed that we'll publish next month.  The parallels might seem striking:  for years, U.S. automakers focused on design and other features and turning out "me too" models. They only addressed fuel efficiency when the government forced them to, and by then, Japan was miles ahead.

We all know the competitive pressures facing pharma today: Patent expirations and pressure from generics will create a $100 billion loss in revenues, at a time when the cost of R&D and commercialization have increased exponentially.

But some lessons could, and should be learned from an unexpected source: generics companies in India and China which are developing simpler, less expensive and greener manufacturing processes.  Improving API manufacturing innovation, Malhotra believes, will go a long way to strengthening Big Pharma's ability to continue to compete in the future.

"FDA clearly spelled out the situation that exists within the industry in its September 2004 report, "Innovation and Continuous Improvement in Pharmaceutical Manufacturing," he writes. "Developed countries have the highest medicine consumption requirements today. However, the needs for the developing countries are high. We are at the start on an exponential growth curve. Since the prices are controlled, generic companies from developing countries have the highest incentive to innovate, especially in the API manufacturing area and that could further alter the global pharma business."

What do you think? Please write in and let us know.

Many within the industry are more than curious about Michael Moore's new film, Sicko, which is expected to premiere in Cannes this summer.  Do any of you remember Mr. Moore's debut feature, Roger and Me, which immortalized his fruitless quest to interview Roger Smith, then president of GM, to discuss plant closings and their economic impact on Moore's home town.  (Since then, we've learned that Moore did interview Smith.)

For the record, even we tried to contact Moore, hoping that his allegiance to manufacturing might work to our benefit. Big surprise: It didn't.  (For more on this, read "The Scruffy Guy Cometh," which a former colleague wrote way back when Moore sightings at pharma plants were the news of the day. )

But I have been on a similar quest of my own for the past year and a half:  to secure an interview with Ajaz Hussain, now the head of drug development for Sandoz, the former deputy director of CDER's Office of Pharmaceutical Sciences, and considered by many to be the father of Process Analytical Technologies (PAT) in pharma, one of the first to advocate the drug industry's use of the tools and techniques that would test drug quality during, rather than after, manufacturing.

Our readers are all admirers of Dr. Hussain.  In fact, they appear to hang on his every word. And many are curious as to how the transition between FDA and industry, between concept and practical application, has been going. Requests for op eds on dissolution science and biosimilars were politely declined. ("This subject has already been addressed by peer-reviewed journals")

And the quest for a personal interview, which began at IFPAC 2006, and which has been promised to our readers, twice so far, continues. 

Dr. Hussain is now a key figure in the hugely complex and controversial area of biosimilars, and has testified before the Senate and just made a presentation at a panel discussion on this subject at BIO. But he also seems to be a very interesting human being, who is now living and working on two continents, a pattern that is becoming the rule for more people in this global industry.

After a  larger-than-life presence at FDA, Dr. Hussain appears to be avoiding publicity.  This is absolutely his right, and condoned by an industry that doesn't encourage people to speak to media of any kind. It would be impossible to accommodate requests for interviews or articles from every little trade magazine that's out there covering this space, especially with a grueling travel schedule, but it can be done.

The problem is that silence and the flat, safe and scripted Q&A's that have appeared in other trade magazines, fine publications that they are, may send the unintentional message, that it's much harder to put PAT into practice than it was to theorize about it.

We are not National Inquirer papparazzi or "60 Minutes,"Ajaz, but a little publication devoted to the message of modernizing drug manufacturing.  And you needn't even deal with "the press", but with one of your fellow PAT experts who has contacted you.  

Please do not worry. We won't harrass you further, but we haven't given up hope that you'll pick up the phone and make the connection when you can.