Pharma Buzzwords (IFPAC Day 2)

Bill Swichtenberg just filed the following minireport on today’s program

The one thing I’m learning here in
Baltimore at IFPAC is that PAT has a lot of buzzwords. The Organizational Transformations and PAT session may have used them all. The session looked at some of these changes at different big pharmaceutical companies.

 

Jay Jett’s talk “Right First Time” and “Operational Excellence” focused on Pfizer’s approach of reducing process variability and consequently improving process capability. Pfizer keys on the 5-15% of the process that is value-added. According to Jett (a black belt), Pfizer is committed to Six Sigma and the projects fall into one of four methods. Everyone at Pfizer is trained in method 1 which is the DMAIC method. Method 2 is run by Green Belts (5% of the company). Method 3 eliminates variations and is run by the Black Belts (1%). The master black belts (about 11 people) are trainers and look at method 4 which is finding efficiencies (QbD). Pfizer looks at processes first then looks to improve efficiency. “If not, you just make junk faster,” says Jett.

 

John Levins explained how Wyeth is building an integrated PAT program to transform their manufacturing practices across the Consumer Healthcare Division. Started in 2003, John virtually was the PAT program that looked at developing process analyzers for measuring “critical quality attributes” when it began.The start of this program was looking for simple change control. “Critical quality attributes don’t depend on scale,” said Levins.

 

Once this capability and methodology was in place, a leadership team was formed (in 2005) to guide the PAT initiative into a full systems approach. According to Levins, PAT requires an organizational change. Three guidelines he advocated were an initial strategy by upper management, a central manufacturing leader (with resources for PAT assigned by plant leadership and finally technical strategy set and then challenged by a leader.

 

At Merck, John Higgins described how they are using a technical approach to integrating PAT supported by a business justification. According to Higgins, there are many enablers needed to make PAT successful. These include an internal/external regulatory framework, a business case for PAT, technological development, communication and training and statistical data analysis. “The implementation and on-going performance of PAT methods often creates unforeseen challenges,” says Higgins. These challenges are not realized until real manufacturing takes place.

 

When deciding on PAT projects, Higgins said that Merck looks at five considerations. These include a strategic alignment with business priorities, financial analysis, resource requirements, the probability of success and regulatory implications/cGMPs.

 

According to this panel, PAT has grown beyond the why and what stage. Companies are now, more importantly, looking at the how and the institutionalization of the process.

 

While PAT always seems to focus on NIR equipment, it was refreshing to hear a speech on PAT that dealt with passive acoustics. What’s this you ask, it was piezoelectric sensors that recorded sound differences in a granulation monitoring application. Albert Alexander of AstraZeneca explained how he used this approach to correlate acoustic data to granulation. First this approach was used for dried granulations from different experiments (varying water amount, water rate, massing time) and related granule characteristics (size, porosity) to acoustic changes. This was used to assess the relationship between acoustic evolution and specific granulation mechanisms. The second part of the approach classified the data into clusters to determine endpoints. Granulations were then run using these endpoints with the resulting granules compared for similarity. It was found that this approach correlates well with wet mass characteristics. 

An interview with Duquesne’s PAT Guru, James Drennan (from IFPAC `07)

Emil Ciurczak spoke with PAT expert James Drennan III, Associate Dean of Duquesne University and Editor of the Journal of Pharmaceutial Innovation at the conference. IFPAC `07 Day 1.

EC – Let’s start with the journal first.  Tell me about that

JD – I was approached over 18 months ago by ISPE and they were interested in developing a journal and sought my help with chairing a task force of ISPE members to do that.  We kicked that off and spent virtually a year putting together a first issue, which came out in the Fall of 2006.

EC – And your publisher is…?

JD - The publisher of the first issue was Elsevier.  I’m not sure who the new publisher will be, going forward.  The goal of the journal is to create a forum for publication in an area that is unique right now compared to other journals out there.  We’re looking to provide an opportunity for dialogue in an area that is at the intersection between traditional pharmaceutical sciences and pharmaceutical engineering. And so the task team was made up of a lot of engineers from ISPE and some pharmaceutical scientists. We’ve put together a plan that will let us go forward with a peer reviewed journal that will allow us to address a lot of critical issues that the industry faces today, working at this interface between engineering and traditional science.

EC – I believe that I’ve already plagiarized several of the papers from your first edition in some of my columns. I was struck with the idea that we’re not measuring enough of the physical parameters. We’re only interested in whether something is clean and whether it’s the right chemical, and we do some compendial tests and is it heavy metals that are going to help us make a good tablet. Could you tell me some of the precepts of the papers in your first issue?

JD – We had a variety of papers there, looking at everything from novel software and approaches for product development, to try to speed up pharma product development to new analytical technologies like Teraherz spectroscopy to articles on PAT. 

The first issue had a real cross section of interesting topics.  We’ll look for significant variety in the future. I’d imagine us accepting articles on new technologies like nanoparticles and their value in developing new dosage forms, improving drug delivery, gene therapy, and we’ll look for more papers on some of the critical important topics like PAT. So, we’ll let the readers and the industry direct us in identifying critical topics for the journal, but I’d like to keep it focused on the cutting edge of technology.

FDA Deputy Commissioner, Dr. Janet Woodcock on the Critical Path: Focus on Your Customers (from IFPAC `07)

Dr. Janet Woodcock, M.D., Deputy Director and Chief Medical Officer of FDA, gave the keynote address at IFPAC’s plenary session, in which she made clear the connections between PAT, Quality by Design and the Critical Path Initiative.

 

Good morning. Ajaz asked me to talk about FDA’s Critical Path Initiative, and how that fits in with the goals that all of you are here to discuss, which really focus on optimizing pharmaceutical manufacturing, particularly through the application of process analytical technologies (PAT).

I’d like to explain how the Critical Path Initiative and other FDA initiatives such as Pharmaceutical Quality for the 21^st century relate to PAT, and talk about implications that Critical Path and quality initiatives have for PAT.

I’d also like to discuss how we can, in the future, link critical product attributes to clinical outcomes, to gain a better understanding of what we’re trying to control, in other words, to determine the attributes that determine a product’s good clinical performance.  At this point, this is something that we know very little about, except in the very broadest sense.

So the basis thesis behind FDA’s CP initiative, which really resonates across manufacturing, is that investment and progress in basic medical science has far surpassed investment and progress in the medical product development process.

And the analog in the manufacturing world is the fact that R&D investment by companies has far surpassed actual interest and investment in how to make product and actually get it out the door.

The development process is becoming a serious bottleneck.  Our theory at FDA, and we’ve said this publicly, across the board, is that we’re using the evaluation tools and infrastructure of the last century, and, in some cases, tools from very early in the last century to develop this century’s medical advances.

FDA would like to change this.

But all of this must be viewed within the context of this huge R&D investment, which  has driven heightened public expectations that we’re going to have all these novel therapies available based on new science. 

There’s been an explosion in new science.  There are ventures and labs all over the world that have all this great new stuff that’s going to cure more patients and meet medical needs. 

Novel drug submissions, however, have been flat…approvals last year were very low relative to performance in the 80s and 90s, and much less than what came out in the mid 90s.

Although investment in research and discovery has gone up tremendously, we’re not seeing this reflected in output of new products, even though the public is expecting this result. As a result, they’re getting mad at NIH and the pharmaceutical industry.

There’s been a definite plateau in the pharma development pipeline, and a lot of discussion and speculations in the literature as to its causes.  ‘Maybe we invested too much in genomics and it wasn’t ready yet,’ we hear,  and so forth and so on.  You’ve heard all this speculation.

But what we need to do is to work on things we can address and correct.  So the Critical Path focuses more on the development process

At the same time we’re that drug development today has a lower chance of success. That can’t be good news. So despite all the answers you have from science, as you move new products into preclinical and clinical development, their success rate is actually declining. Today,  new compounds going into Phase I have an 8% chance of success reaching the market, compared with 14% a decade and a half ago.

And, more ominously, the Phase III failure rate is now about 50% vs. 20% a decade ago. I say “ominous” because, by the time you get to Phase III you’ve sunk a lot of cost into the compound, and invested a lot of money. It’s very painful.  It also causes your stock value to go down, because you’ve told everyone that you have this great new compound going into clinical trials.

And of course you know, you read about it in the papers all the time, this program had to be abandoned, that program had to be stopped, etc. and all the disappointment that results. So the predictability of the process is not improving right now.

So we looked at all this at FDA a number of years ago.  We knew that these are all big problems, but we saw  that the societal investment on the R&D side has been huge. Investment was now needed in the development process; at FDA, we need to improve our standards and to use a lot of science to help us improve standards for manufacturing.

There’s a huge private and public investment in basic research, and huge investment in the development of specific products, but we don’t see the same kind of investment in “how” to develop an evaluation process. Academia has not been funded, and this is true in clinical trials, believe it or not, as well as manufacturing.

There’s been a little more funding for research in toxicology because of environmental issues.  FDA has done this type of work over the years, but Congress has not funded FDA to do any of this work.

In the private sector where many of you work, these efforts are often viewed as proprietary and confidential, and so knowledge is not generalized.  As a group, we cannot advance our development science as we should, all the way from manufacturing to clinical.

We need to explain this to the public. They’ve never heard about this before.  They think that when one of your scientists has a brilliant idea, in two years they should be able to hand a new drug using that idea over to the patient. There should be no problem, the public reasons, and if there is, then you’ve failed.  And your scientists think that too, by the way.

It’s never been explained that basic research is a long way away from having a product. We’ve adopted the term Clinical Path to explain the fact that this is a long and extremely technically challenging process.

And there’s research that we need to do to make this better.  Some people are talking about translational research and Phase I research along with Critical Path research.

 We tell Congress, the public and medical scientists that the science needed to enable efficient manufacturing is different from basic science, but it’s just as worthwhile, just as necessary to get new products out. There are three types of science:

Safety – to predict whether product will be safe enough

How do you predict how it will look?  Obviously we’re really bad at that. That’s why we have such a high Phase III failure rate.

Industrialization – How to turn an early scientist’s idea into something that can actually be manufactured, consistently, at commercial scale. That’s something that the public can try to understand. If you put it this way, people get it.

We say that each one of these areas faces many challenges.  We’re trying to build a case for everyone here, that we have to do this, we have to invest. And some of the people we’re trying to convert include the CEOs of big companies.

Patient groups are very interested, but just can’t figure out why their diseases, whether MS, ALS or cancer, aren’t getting cured. We’ve invested billions every year in basic research, and people can’t figure out why we don’t have products in hand to help their patients.

We explain how complicated the Critical Path is, how many disciplines are involved, and how all of these need to be improved.  This CP initiative we’re doing has a number of principles.

We’ve had no funding for this at all, specifically from Congress, so we’ve focused on establishing collaboration between government, academia, industry and patient groups, and we focus on developing new infrastructure and tools, not specific products. 

Everyone wants to focus on specific product development, which is viewed as glamorous.  We need, instead,  to focus on the tools that enable product development. We’re trying to build support for an academic science base.

In manufacturing, we talked to NAS and academia.  This is a major industry important to public health and important to biomed science and needs to be supported. 

We need to build opportunities to share knowledge and data instead of keeping it.  If one company implements PAT and nobody hears about it that’s not good

We need to develop enabling standards….standards for clinicals and for genomics. This is a very broad field.

We published an initial report and had open comment period.  We’ve also have multiple partnerships. We’re pleased that industry has stepped up to the plate. 

We’ve published a list of projects that need to be done, including major projects in manufacturing. .

Recently published a list of collaborators and we’re continuing to work…we have a major article that will be published in Clinical Pharacology Pharmacopeia on the Critical Path Initiative, and we continue to crest along

IFPAC `07, Day 1

 Where IFPAC has been held in a hotel in suburban Virginia for the past few years, this year’s conference is going on in Baltimore (click on the photo for more detail), near the Inner Harbor, a nice location offering more opportunities to get out after hours.   (Although temperatures are now hovering in the 20’s F)

Our senior editor, Bill Swichtenberg, who joined the magazine last October and is attending IFPAC for the first time, filed the following brief recap of Day 1 of the conference.

“…Being new to the industry, I’m finally beginning to see how these FDA initiatives fit together. Today at the IFPAC show in Baltimore, Mary., both Dr. Janet Woodcock and Dr. Moheb Nasr explained the Critical Path Initiative and Pharmaceutical Qualtiy for the 21st Century, focusing on quality by design. While I’m sure that neither of these talks would have been earth-shattering for PAT veterans, I found the talks interesting.

 Worthy soundbites of Dr. Woodcock’s speech were:
“Manufacturers should be trying to satisfy customers, not the FDA.”

“Dr. (Andrew C.) von Eschenbach is committed to move PAT forward.”

“PAT is a move from empirically-devised trial and error methods to a rigorous mechanistically-based and statistically controlled process.”

Dr. Woodcock emphasized that the FDA needed science to move pharmaceutical manufacturing along because there hasn’t been (and won’t be?) any additional funding from Congress. In addition, better linkage between clinical performance and quality parameters was needed.

Dr. Nasr picked up where Dr. Woodcock left off. He explained that the goal of the FDA was to create an efficient pharmaceutical manufacturing industry that can manufacture safe and reliable products without much oversight. Whether this happens or not is another story. He also stated that  “FDA is more interested now (in PAT) than ever before.”

He also said that FDA is heading toward a regulatory strategy that is specific to the product and/or process. This means manufacturers should stop worrying about directives and focus on ways to improve their products.

FDA’s CMC pilot project is currently looking at 11 projects with four already approved and another one to be approved shortly.

Known for his expressions, another ‘Nasrism’ seems to be these new initiatives are “not about reproducibility but about robustness.”

With all the talk about Six Sigma and Lean manufacturing, today I also learned about the theory of constraints. Dee Bradbury Jacob of The Avraham Y. Goldratt Institute, New Haven, Conn., explained that this method defined improvement as “acknowledging and managing inter-dependencies that exist within an organization through the entire supply chain.”

The key to improvement in this method is exploiting the systems constraints. “You need the right people on the right tasks in order to improve constraints.” According to Jacob, if you improve these constraints, real value will ensue. “Anyone can swing a hammer, the trick is learning where to hit and how hard.” Advocates  hope that PAT projects will make that hammer hit the bell…”

Bill Swichtenberg

USP Scientific Fellow Gary Ritchie on 1119 and General PAT Standards Development (from IFPAC `07)

 At IFPAC, Emil Ciurczak interviews Gary Ritchie, Scientific Fellow for Process Analytical Technologies (PAT) at USP, for a review of PAT standards development within USP, with a special focus on 1119, the general chapter for NIR spectroscopy.

EC – So, how many chapters have you worked on for the USP?

GR -  Let’s start with 1119.  I didn’t bring that one in, it was pre-existing but it needed some revision, and so we can count the committee work that ensued when I came on board with 1119, for NIR spectroscopy. 

Then there were the chapters that I did bring in  for Raman spectroscopy, acoustic emission, and effusivity. 

And now, we are looking at revising some of the waters chapters. 643 and 645 were originally devised as lab offline tests, but were revised to reflect the fact that you can do online monitoring.

One of the things that I recognized early when I joined the USP, with respect to the PAT initiative, was the fact that the USP actually had the first online general chapter for process monitoring for pharmaceutical waters, published around 1997. 

Other chapters now under consideration by USP’s general chapters committee focus on chemical imaging and chemometrics. 

EC -  I think you’re being a little modest about the work on1119.  After all it was back in 1998-99 when you held the meeting and brought people from industry, academia and the USP together to propose a chapter.

If I remember correctly, you browbeat them into coming up with a useable document for submission in nine months. Compared to some of the committees that work on such things through several ice ages, I think that was rather commendable.

GR -  Other than the science that I’ve always been involved in at the analytical level, I grasped very early the importance of understanding how people use a given technique and why they need to use that technique.

One of the things that 1119 had suffered from for many years was the fact that, while it was in the Compendium, it didn’t receive much attention.

That’s  because it focused mainly on system suitability or system verification.  It existed as a way for someone who wanted to implement NIR measurement, to know how to calibrate the wavelength for photometric accuracy and photometric precision.

That would have been great if a lot of people were using NIR. But when the chapter existed [in that form], not that many people were using NIR.

What they really needed to know, from an analytical point of view, especially if they were going to use the technique for pharmaceutical work, was “How am I going to generate and validate a method?” And the chapter really didn’t answer that question. It instead answered the question “I have an instrument.  Does it measure something?”

EC -  So the new chapter basically has some hints on how to do quantitative and qualitative validations?

GR - “Identification, all the things that you, in your early days, actually taught the industry about what the techniques were useful for. And my work at Purdue, and yours, answered the questions: “OK we know that NIR can be used to take this measurement. How do we validate it so that FDA and other regulators actually accept it?”

EC - The other thing was that you had been instrumental in getting the new NIR standards for USP because NIST had given up that standard.  They no longer make it, yet it is required to have some traceable standard for any technique.

The FDA really likes to have everything required for IQ,
OQ, PQ, for method validation.  For instance in chromatography, you need a USP standard to run against.  Now for spectroscopy you have a USP standard to run against.

GR  - Absolutely. When I joined USP it became obvious that we needed to make the standards more useful, so that they went beyond merely answering questions that regulatory agencies could have regarding a submission.  How could regulatory authorities independently verify that a person using the chapter and verifying suitability. 

How, for example, could FDA verify the fact that the suitability values reported back in some lab notebook stating that “on a certain date, a given wavelength was tested.” How could they verify that that the testing actually was done?

EC- They couldn’t.  It’s pretty much like standardized thermometers or anything else. “Traceable” is the key word.

GR  -That’s correct.  And the void that was left by SRM 1920A, the previous NIST NIR standard that you referred to, needed to be filled by an improved 1119 Chapter.  It really was a no brainer.

EC - So you’re doing this with multiple testing of standards on grating and Fourier Transform instruments?

GR -The specification has not changed, it’s actually been expanded. When the original 1920A standard spec was originally tested, during a round robin of collaborative studies involving six equipment vendors, it specified three wavelengths, and established 1 nm and 1.5 nm wavelength specifications.

What we’ve done in the certification of the new standard that will be coming out shortly, is that we’re actually certifying standardizing seven wavelengths.  The user, depending on which portion of the spectrum that he or she wishes to operate in, or even the whole spectrum,  can choose any three wavelengths for qualifying any instrument for its intended use in measuring a process or product.

EC You’ve added talc to get a peak above 2000 nm?

GR Some say that this may not extend the standard’s usefulness. I’ve heard opinions, both pros and cons on the additional band above 2000, but its usefulness remains to be seen.  I know that, for fiber optic work, you generally don’t want to read anything above 2100 nm or so because of internal attenuation you get with the energy on the fiber optic material. If you go ahead and use this area of the spectrum for calibration sometimes you’ll get a lot of noise and scatter.  But that’s only a problem with fiber optic work.

If someone is using a model for even, say, qualitative work, but using a direct hemispherical detection system, that end of the spectrum is useful up to 2500nm.  I think they get an additional advantage with this extra peak.

Stay tuned tomorrow for reports on Day 1’s general sessions and keynote speeches from FDA’s Deputy Commissioner Dr. Janet Woodcock, Dr. Ajaz Hussain and Dr. Moheb Nasr.

 -AMS

Former WHO flu vaccine chief, Klaus Stohr, to head up Novartis’ flu vaccine development program

This article, from the New Scientist, with the news.

USP Releases Free Standards to Ensure the Safety of Medicines for Neglected Infectious Diseases

The United States Pharmacopeia (USP) has released free documentary standards for medicines used outside the United States to treat neglected infectious diseases. The standards are available on USP’s Web site at http://www.usp.org/internationalStandards/ . “Public standards for such medicines are urgently needed to help ensure that patients in all parts of the world have access to good quality medications,” said Roger L. Williams, M.D., USP executive vice president and CEO. “These international standards will make it easier for healthcare organizations in countries without sufficient regulatory and pharmacopeial resources of their own to ensure the quality and purity of medications.”The World Health Organization estimates that 1 billion people – one sixth of the world’s population – suffer from neglected tropical diseases. Widespread counterfeiting and distribution of sub-standard drugs has worsened this situation. The initial two drugs included in the International Standards program are used in the treatment of HIV-AIDS: Abacavir Sulfate, and Efavirenz. These monographs are posted in draft form, with a 90-day period for public comment that ends on April 30, 2007. Instructions for submitting comments are at http://www.usp.org/internationalStandards/ . Monographs for drugs used to treat malaria will be added shortly as part of the ongoing program. USP’s standards are widely recognized internationally as authoritative, science-based, and credible. They are developed through a process that is transparent and open to public comment. As the world’s only private pharmacopeia, USP has the unique ability to work across borders, giving it the ability to set voluntary standards for medicines used outside the United States.The worldwide public health benefits of the International Standards initiative include:§ Supporting the effort to provide quality drugs to patients with the greatest need;

§ Helping ensure that medicines for neglected infectious diseases in international commerce meet a high standard of quality

This is a very important initiative, as the industry wrestles with effective ways to promote the development of more effective treatments for “neglected diseases”. 

For an interesting interview with Rachel Glennerster (executive director of MIT’s Poverty Action Lab) and Michael Kremer (Gates professor of developing societies at Harvard University), whose book, Strong Medicine, came out about three years ago, click here.

- AMS 

Stay Tuned Next Week for Our Report on 2007’s IFPAC Conference

Interest in process analytics is increasing within the pharmaceutical industry, spurred by FDA’s  endorsement and support of “Process Analytical Technologies,” and now the Agency’s broader Quality by Design framework.

As a result, the IFPAC conference, devoted to the use of process analytics in various industries, has evolved.  Although it still covers developments in electronics, environmental, chemicals, petrochemicals and food processing, the program now places a special emphasis on pharmaceutical and biopharmaceutical applications.

What began as a clubby audience of engineers and scientists is broadening, as more managers and senior managers explore PAT’s potential return on investment, and consider how process analytics and modern manufacturing methods can combine to impact the bottom line, and reduce manufacturing waste .

We have covered this important conference for the past few  years, and included a bit of digital coverage last year, but never tried to “report” on it. 

This year, though, NIR and PAT expert Emil CIurcak and senior editor Bill Swichtenberg will be at the conference reviewing the latest technology and interviewing thought leaders from the industry, for an online review of the program that will be posted on our web site later this month. 

But we’ll also try to provide some short snippets and daily reports in this blog, for those who can’t attend the conference this year, or who are curious about QbD, PAT and process analytics and how they might practically be applied, to everyday drug R&D, manufacturing and QA/QC operations.

In the drug industry of the future,  industrial pharmacists and quality professionals will need to “get geekier”  and to think more like engineers.  IFPAC offers a variety of practical case histories and best practices.  And not all of them are from control and instrumentation specialists, either. Some of the most interesting come from  pharmaceutical industry professionals and managers who have made or are making that adjustment in thinking, themselves.

-AMS 

Interview with Henry Schein’s CEO Bergman from Davos Conference

Stanley Bergman, CEO of flu vaccine distributor Henry Schein BLOOM (BLOOM), National Wed 24 Jan 2007 03:36 PM EDT From Bloomberg’s coverage of the World Economic Forum in Davos, Switzerland, an interview with the head of the largest U.S. distributor of flu vaccine

Johns Hopkins research finds coated nanoparticles a drug delivery solution

This just in from the Baltimore medical research hotbed:

The layers of mucus that protect sensitive tissue throughout the body have an undesirable side effect: They can also keep helpful medications away. To overcome this hurdle, Johns Hopkins researchers have found a way to coat nanoparticles with a chemical that helps them slip through this sticky barrier. During experiments with these coated particles, the researchers also discovered that mucus layers have much larger pores than previously thought, providing a doorway that should allow larger and longer-acting doses of medicine to reach the protected tissue.The team’s findings were reported this week in the Early Online Edition of Proceedings of the National Academy of Sciences.The discoveries are important because mucus layers, which trap and help remove pathogens and other foreign materials, can block the localized delivery of drugs to many parts of the body, including the lungs, eyes, digestive tract and female reproductive system. Because of these barriers, doctors often must prescribe pills or injections that send drugs through the entire body, an approach that can lead to unwanted side effects or doses that are too weak to provide effective treatment.

“Mucus barriers evolved to serve a helpful purpose: to keep things out,” said Justin Hanes, an associate professor of chemical and biomolecular engineering who supervised the research. “But if you want to deliver medicine in a microscopic particle, they can also keep the drugs from getting through. We’ve found a way to keep helpful nanoparticles from sticking to mucus, and we learned that the openings in the mucus ‘mesh’ are much larger than most people expected. These findings set the stage for a new generation of nanomedicines that can be delivered directly to the affected areas.”