Quality Risk Management: Looking North

Kevin North is a busy guy. As President and CEO of software and solutions provider Dyadem, he's no doubt got a lot on his plate, and has overseen the growth of a company whose products have been winning awards and winning converts among pharma Quality professionals. North was also a finalist this year for Ernst & Young's Entrepreneur of the Year.

All of which meant that I wasn't surprised when my list of questions to North about Dyadem and its pharma initiatives went unanswered for a few months. He did, however, promise that he would answer them when he could. True to his word, North followed up with me this week. Here is our conversation on Quality Risk Management, and we'll also be following up with Dyadem in the future about another of its core competencies, FMEA.

If there's one thing that strikes me about his replies, it's that the solutions that Dyadem offers are beyond what many manufacturers have even considered as a means of improving QRM and complementing Quality by Design programs. He says:

"Most FDA-regulated companies will tell you that they believe in the FDA’s QbD initiative, but they have a hard time putting it into practice efficiently, especially since many haven’t updated their risk management procedures since the advent of spreadsheet software. Many companies use Excel spreadsheets or customized software for each department and then spend hours trying to cut and paste information together to represent quality for the whole company. Companies that take Quality Risk Management seriously need software that was designed for risk management, not accounting."

In the EU, Funding for Those Who Strive to Eliminate Bottlenecks

The Innovative Medicines Initiative, a project started jointly by the EC and EFPIA, has announced another round of funding for projects that aim to speed drug development, including those that solve data management dilemmas. Click here for more.

A-Mab Case Study: Read It and Weep?

Now that the A-Mab Case Study has hit the streets (click here), the next question is just how much of an impact it will have upon the arc of QbD. If you're fairly new to Quality by Design and how it might be implemented at your facility or company (whether you're in biologics manufacturing or not), A-Mab will: a) give you loads of exciting concepts and data to ponder, hopefully opening doors to innovative QbD work; or b) intimidate the heck out of you and cause you to break down in tears.

A-Mab is 278 pages of intense concepts, data, and charts related to how QbD can be applied throughout the development of a typical biologics molecule. Where do you start? Where do you find what is truly relevant for your operations and applications?

I posed these questions, separately, to two people who were integral in shepherding the A-Mab project through--Sam Venugopal of PRTM Management Consultants, and John Berridge, a consultant and project manager for ISPE's PQLI initiative. (Click on their names to read summaries of our talks.) Both men admit that manufacturers will have to work hard to digest the document and assess how it applies to them. But both also see the document for what it is--a milestone for Quality by Design and unlike anything else that's been done previously.

Workshops focused on A-Mab will be held throughout 2010 by ISPE and CASSS.

GSK's Peterson Has Just What Your Design Space Needs

In case you missed it, we recently posted an article on multivariate predictive distribution by GlaxoSmithKline's John Peterson, director of the research statistics unit in the company's drug development sciences department. (The article will also appear in the Nov/Dec issue of Pharmaceutical Manufacturing magazine.) When we first approached Peterson--a highly accomplished statistician, among other things--about writing an article, it was with an eye towards explaining Quality by Design and the concept of a design space from a statistical viewpoint, but for readers who are non-statisticians. Peterson willingly assented and, if you read the article, I hope you agree that he has not only done as planned, but has also put forth some pretty heady concepts that statisticians involved in drug industry Quality by Design projects will benefit from tremendously.

The article seeks to encourage us to, as he says, "understand randomness and think stochastically." It's a testament to the power of statistics to help manufacturers understand and control their processes, in the name of making drug development smarter.

Great appreciation to Dr. Peterson for sharing his vision for us. I hope that you get as much from the article as I, a non-statistician, have, and we'd love to hear your comments.

Are You Innovating and Imaginating All By Yourself?

One of the many people I spoke with this past week at the AAPS show in Los Angeles was Ted Grasela, CEO of Cognigen Corp., which advises manufacturers on model-based drug development. Grasela delivered a presentation on the importance of modeling and simulation to development, and on strategies that pharmacometricians and statistical experts can use to influence drug development in a positive way. It's time for modeling and simulation to take its rightful and significant place in drug development decisionmaking, Grasela said.

Most importantly, statistical modeling can be a kind of glue that binds the entire drug development process and the people involved. “People are innovating and imaginating all over the place," Grasela says, "but often these islands of innovation that never get linked with one another.”

Here's my full writeup of Grasela's presentation. I stopped by the Cognigen booth afterwards for a chat with Grasela and Cognigen colleagues, and came to appreciate their ideas of bringing more science to the development process. Here's the Cognigen home page for those interested.

Looking Ahead to IFPAC

As PAT and QbD have taken hold, IFPAC (the International Forum for Process Analytical Technology) has become an increasingly relevant, and well attended, trade show, and has become increasingly dominated by pharma-focused content. 2010's show begins January 31 in Baltimore, and the agenda is now available online.

The Henry Ford of Drug Development? Have We Heard This One Before?

Quote of the day: "This device is to drug discovery what the assembly line was to the automobile or the silicon chip to information technology." I'm sure this device to inject proteins into cells to accelerate drug development is useful, but could this McMaster U. researcher be prone to just a bit of exaggeration?

Merck's Clark: Merger with S-P Will Increase Not Just Size But Innovation

Upon completion of Merck's merger with Schering-Plough, CEO Richard Clark shares thoughts on "Merging into the Fast Lane of Drug Development" in today's Huffington Post.

Push vs. Pull: Finding Better Ways to Incentivize Development of Antibiotics

There's an excellent, balanced summary of the pros and cons of "push" and "pull" forms of incentivizing drug development (focused on antibiotics), by Kurt Karst on the FDA Law Blog. Karst quotes and links to a London School of Economics paper that urges governments to take more proactive roles in working with industry to establish viable incentives for those who develop promising antibiotic medicines, in light of "superbugs" and the issue of resistance to current antibiotics.

The report itself is exhaustive but worth a look. Don't be put off by the "Confidential" label at the bottom of each page, since the PDF is easily found in many places on the web.

Treasure Trove: Merck, Lilly, Amgen, Pfizer, and More from EMEA/EFPIA London Workshop

Milestones in the evolution and acceptance of Quality by Design were the recent meetings/workshops in London and Frankfurt bringing together regulators, industry professionals and other concerned parties (namely, EFPIA) to discuss the challenges confronting QbD and, more importantly, drilling down and assessing how QbD will play out for specific types of drugs, specific processes, and specific manufacturers--a growing recognition that there is no one-size-fits-all QbD--far, far from it.

What's also encouraging is that plenty of materials and presentations are being shared with the industry. The mock QbD examples that were the focus of the Frankfurt meeting (sponsored by PDA and EFPIA) will be made public in the coming months, following final revisions. (Click here for my discussion with PDA's Volker Eck on the key learnings from Frankfurt.)

Now, the key presentations from the EMEA/EFPIA meeting in London have been posted to the web. (Thanks for Alicia Tebar Perez of dTC Consulting for calling our attention to this.) Included are contributions from Gert Thurau of Merck, Pfizer's Liz Coulson, Wyeth's Graham Cook, Lilly's Martin Diller, and others. Enjoy!

Should We Call It an ELNLIMS?

We won't call it the holy grail, but the announcement by Thermo Scientific and Symyx regarding the release of an integrated LIMS/ELN product is a significant step towards a fully integrated, electronic laboratory. Researchers should have more power and functionality at their fingertips, with fewer obstacles towards accessing and sharing data. That spells more efficient development efforts.

In a press release last spring announcing the Thermo-Symyx partnership, Symyx president Trevor Heritage boasted that lab professionals will have the “ability to record and execute experimental protocols, capture results, access and analyze data, build reports and collaborate with colleagues seamlessly."

Given that it's now just six months since the partnership was announced, clearly there will be bugs to be worked out of the new offering, but that's to be expected.

Another intriguing question: What do we call something that combines a three-letter and four-letter acronym? ILMS (Integrated Lab Management System)? I'll have a chance to speak with representatives of both

Lessons Learned from 20 Years of Drug Development

Have the past 20 years been a bit hazy for you, or perhaps you'd just like a reminder of what we've learned from drug development's successes and many failures? Deloitte is hosting a free webinar on Nov. 10 on the lessons of the past couple decades.

--Paul Thomas

Pharma IT Moves Further Into the SaaS Era

Symyx has announced that it will begin offering its electronic laboratory notebooks in a hosted, software-as-a-service (SaaS) model. The company's press release suggests that this move is in response to economic pressures to offer cheaper, more flexible options, but the trend towards web-based IT offerings is one that will dovetail nicely with pharmaceutical companies' needs for better ways of integrating the work of their scientists worldwide.

The hosted Symyx Notebook will enable "medicinal chemists, synthetic chemists and biologists to manage, explore, share and reuse experimental information and intellectual property (IP). Using a hosted ELN service, R&D organizations can deploy and leverage the electronic notebook quickly and efficiently without added IT infrastructure and resources while collaborating more effectively with partners in today’s information-driven R&D environment."

Information security is a key concern, of course, which Symyx addresses in its announcement.

--Paul Thomas

The Challenges of Developing Alzheimer's Therapies

A quick note: From this month's Nature, an insightful look at the complexity of Alzheimer's Disease and the challenges (and limitations) of developing drugs that target the disease early enough in its progression to make a difference.

--Paul Thomas

Where Lies QbD's Competitive Advantage?

I've had the good fortune of speaking this week with Volker Eck, senior director of science and technology at PDA, and a day later with Graham Cook, Wyeth's senior director for process knowledge/Quality by Design. Both men were integral participants in late September's workshop in Frankfurt,  hosted by PDA, to unveil and discuss EFPIA's mock examples of Quality by Design implementation.

By all accounts, the mock examples were well received and the meeting was an important step toward helping manufacturers not just interpret ICH guidances but grasp how QbD might look for their products and processes. The mock examples are now being finalized, following input from the Frankfurt meeting and one earlier with EMEA in London, and are expected to be made public later this year.

You can read my summary of Eck's take on the meeting here, and I hope to have a podcast of my interview with Cook available within a week or two. Eck was insightful in that he said that many manufacturers at the Frankfurt meeting were still clearly struggling to "translate" the ICH documents, and the mock examples, to their own operations. With QbD, manufacturers can only truly learn by doing and thus will have to dive in

Studying Dogs Alongside Humans, to Develop Cancer Drugs for Both

National Cancer Institute researchers are undertaking a project to conduct comparative oncology drug trials in humans and dogs, with the hopes of providing an improved perspective upon how clinical drugs will perform in later-stage trials. An offshoot of the project is to accelerate the development of efficacious cancer drugs for dogs. The Comparative Oncology Trials Consortium maps out its mission in the Public Library of Science online. Here is some of the rationale behind their work:

Current drug development pathways are frequently unidirectional. Novel agents are assessed in conventional preclinical models of efficacy and toxicity before moving into human clinical trials where they either fail or succeed. Particularly with novel targeted therapies the conventional paradigms of toxicity studies conducted in healthy animals followed by Phase I and Phase II human trials leave unanswered many important questions on the “best use” of these drugs [6]. Translational drug development studies in pet dogs with cancer provide an opportunity to answer these questions by serving as an intermediary between conventional preclinical models and human clinical trials [7]–[9]. In these dogs, cancers develop naturally in the context of an intact immune system and with a syngeneic host and tumor microenvironment. Similar environmental, nutrition, age, sex, and reproductive factors lead to tumor development and progression in human and canine cancers. They share similar features such as histologic appearance, tumor genetics, biological behavior, molecular targets, therapeutic response, and unfortunately, acquired resistance, recurrence, and metastasis.

--Paul Thomas

QbD for Generics: Considerations and Questions

Quality by Design has great relevance for generic drug manufacturing, and this article is a summary of discussions held last summer with FDA's Lawrence Yu (of the Office of Generic Drugs) and Helen Winkle, and representatives of the generics industry. Most of the discussion deals with general thoughts and questions, and thus it's a useful overview of current understandings and questions surrounding Quality by Design for non-generics manufacturers as well.

--Paul Thomas

S-P'S Hassan: Small Developers Losing Clout, and Risk Losing Innovative Spirit

Speaking recently, Schering-Plough's Fred Hassan lamented the fact that small drug developers are not only seeing their market valuations decline, making them easier, less expensive takeover targets, but also that they face the prospect of losing their "innovation power" once they are swallowed up by larger companies. The comments were part of a longer speech by Hassan on the need to create more flexible pathways to bring cancer and other critical drugs to market sooner.

--Paul Thomas

What Lessons Will We Take Away from H1N1 Vaccine Development and Approvals?

Cutting Edge Information specializes in paid research reports for pharmaceutical decisionmakers, but yesterday sent out a press release not plugging a new report but simply opining on what lessons will be learned from the rapid and, it appears, successful development of new vaccines to tackle the swine flu pandemic. And what's to be gleaned from how quickly these drugs were approved by global regulators?

CEI raises some salient issues: if H1N1 vaccines can be successfully fast-tracked, shouldn't this open the door for more rapid and favorable regulatory review of oncology drugs and other products that clearly

What's on Your QbD Calendar?

Some great events taking shape this fall for Quality by Design, in case you hadn't heard:

Practical Solutions to PAT and QbD Workshop, Oct. 20-21, London

Process Chemmistry in the Pharma Industry (with Special Emphasis on Continuous Manufacturing), Nov. 2-4, Durham, N.C.--James Evans of the Novartis-MIT Center has put together a great panel on continuous mfg.

AIChE QbD Topical Conference, Nov. 8-13, Nashville, TN--the QbD thread runs throughout the event.

Eastern Analytical Symposium, Nov. 16-19, Somerset, NJ

AAPS and ISPE meetings in early November (both in Southern California) will also have plenty of QbD on tap.

--Paul Thomas

Global Outsourcing of Clinical Trials: Patient Concerns and Hope for Change

I've seen a number of news items come across my desk of late about Western companies forging partnerships to outsource clinical trials around the globe, particularly to India. Today's OpEd piece from UK's Guardian looks at some of the growing concern over fair treatment of patients as this trend plays out. The primary concern: "informed consent" can look good on paper but not necessarily be honored and practiced in situations in which trial patients are severely economically disadvantaged.

There are positives about the continued trend towards outsourcing trials overseas, of course. It's an opportunity to speed drug development, and to increase the availability of medications for "local diseases" around the world.

--Paul Thomas

One Man's Experience: Integrating SQL*LIMS with an ERP

A nice case study/best practices article from Jeff Vannest of J and R Consulting on integrating SQL*LIMS with an ERP system, in this case Oracle.

--Paul Thomas

ICH Guidelines Show Their Age (and Difficulty)

Throughout this year, our contributing editor Emil Ciurczak has undertaken a series of articles on the need to update ICH guidances--as, he points out, most of them were developed before the PAT/QbD era in pharma. Emil looks at the guidances through a PAT/QbD lens and offers up ways that they'll need revising (when ICH has time to get around to it).

Thus far he has tackled Q2 (R1), Q7A, and Q6A.

His latest analysis is of ICH Q8. We know what you're thinking--Q8 is one of the seminal documents of QbD. True, says Ciurczak: It's not so much that it needs revising, but that it needs ongoing interpretation. Few in the industry read Q8 in full, he notes, and it seems that few interpret it in quite the same way.

If Ciurczak is game, to be continued . . .

--Paul Thomas

FDA Initiates Study of QbD for Lyo Protein Product Manufacturing

FDA has released a synopsis of a project to study the development of QbD for lyophilized protein parenteral manufacturing. The parties involved in the one-year project include Baxter Pharmaceutical Solutions, Purdue University, University of Iowa, and University of Connecticut.

--Paul Thomas

Good for Mice, at the Expense of Moths

Researchers are investigating the use of insects for preclinical testing, which could relieve mice and other common lab animals of their traditional duties.

--Paul Thomas

U.S. vs. EU: Who's Better at Getting Drugs to Market? Does It Matter?

Joseph DiStefano of the Philadelphia Inquirer looks at the recent research of Dr. Donald Light, a visiting professor at Stanford, with an eye towards the debate over whose system of drug development, Europeans' or Americans', is the more productive.

Light reassesses the work of researchers Henry Grabowski and Richard Wang, who concluded a few years back that enhanced free-market conditions in the U.S. had allowed pharma and biotech companies here to get more drugs to market more quickly.

Not so fast, says Light. In his work, Light figures in the sheer amount of money spent on development (much higher in the U.S.) and whether or not the drugs that got to market really made a difference beyond what drugs were already available to consumers--or, as is often the case, they simply added one more product to the mix.

Dollar for dollar, Light says, and despite more prevalent government cost controls, European development is the more efficient system. (PhRMA wholeheartedly disagrees, as DiStefano's article notes.)

Regardless of which side of the pond you're on, and which public-private system of drug development you lean towards, the research from Grabowski, Wang, Light, et al. points to a greater need, everywhere, for increasing the quality and efficacy of drugs approved. Says Light about the U.S., "only about one in seven new drugs are better than existing drugs." Even if you question his methods, motives, or accuracy, it's a sobering statistic to consider, and a reminder that Quality by Design thinking is needed to keep our attention on what's important--getting truly better drugs to market, faster and cheaper than before, everywhere in the world.

--Paul Thomas

What is Your Favorite QbD Analytical Tool?

There's been an interesting (albeit slow to develop) discussion of late on the Quality-by-Design LinkedIn group regarding users' favorite QbD analytical tool. It would seem a very subjective topic (akin to your favorite flavor of ice cream), but the answers have ranged from NIR imaging to Excel spreadsheets ("It's great for getting agreement between teams prior to selecting process analytical techniques") to HPLC to terahertz imaging. What's yours?

Contributors to the thread offer some useful links to read more about their favorite tools.

(Apologies to the non-LinkedIn readers out there!)

--Paul Thomas

Drug Development, an Interactive Tour

Hadn't seen this video before on PhRMA's Innovation.org web site, but it's well done. A bit sappy (cue the piano music), but it's a good step-by-step look at how drugs get to market. A good one to send all your friends and relatives who wonder: a) how drugs get to market; and b) why it takes so darn long to get there. It's also good for explaining to them what you do--e.g., "See that guy talking about submitting IND's to the FDA--that's what I do all day!"

--Paul Thomas

Got QbD Education? Tell Us About It

We've begun to assemble a comprehensive list of legitimate, ongoing educational opportunities for Quality by Design (and PAT), including university degree courses, career development training, online webinars, and other resources. Visit our QbD Education Resources link on PharmaQbD.com, and let us know if you have items or organizations that you think should be added to the list. Vendor-sponsored opportunities are fine as long as they promote QbD learning and not any specific product or solution.

--Paul Thomas

EFPIA Ready to Roll Out Its QbD "Concept Cars"

In anticipation of its QbD workshop in Frankfurt on Sept. 22-23, PDA has released a special report on the impending EFPIA "Mock QbD" examples that will be summarized and discussed at the meeting. In the report, Wyeth's Graham Cook, Merck's Robert Schnepf, and Abbott's Brian Withers discuss the thinking behind, and importance of, the EFPIA examples, which will focus on terminally sterilized injectables, lyophilized injectables, small molecule API's, and monoclonal antibody API's.

Cook explains: You could compare the Mock documents to a concept car that you might see at a motor show. It has the look and feel of the future model, but not necessarily all technological parts are fully developed or built in to enable it to operate at full performance. Creating scientifically credible stories for the development of the hypothetical drug substances described in the Mock documents is not easy and so, in many cases, the team members would base the sections they were writing on real examples from within their companies and change them to fit the story we were trying to tell. When the groups had to decide what process steps or unit operations should be discussed, the principal selection criteria was to show examples that could be used to illustrate ideas and the use of tools, and perhaps provide a model for others.

Thanks to Parexel's Siegfried Schmitt for calling our attention to this on the Quality-by-Design LinkedIn group.

--Paul Thomas

It's (Un)Official: QbD Moving at a Snail's Pace

Okay, 17 responses to a poll does not a scientific study make. But our highly unofficial survey of blog visitors on the progress of QbD does at least suggest that the QbD movement is taking its own sweet time, in your opinion. Here are the numbers:

What's your assessment of QbD in the pharma industry now?

Moving at a snail's pace (12): 70%
Has a healthy momentum (3): 17%
Really starting to snowball (0): 0%
Moving, but in the wrong direction (2): 11%

We'll do some more unofficial polling over the course of the next few months to explore the reasons that QbD as snail is triumphing over QbD as snowball.

--Paul Thomas

Tech Transfer: Good Science and a Common Sense Approach

The role of tech transfer in pharma has traditionally been to generate information. Under a QbD umbrella, however, tech transfer must generate a "knowledge store"--a database within in which you can manage and leverage your company's intellectual assets and resources. So says Russ Somma in the new series of video snippets on tech transfer that we've recently posted on PharmaQbD.com. Another of Somma's mantras: Good science and a common sense approach. To view the video series "Tech Transfer in a New Light," click the "Somma on Tech Transfer" tab above the video player on our home page.

--Paul Thomas

Can Microsoft Fix What Ails QbD Efforts?

As QbD matures, so do IT offerings that bill themselves as the answer to drug manufacturers' drug development prayers. Manufacturers' challenge is clear: how do we take all our disparate, siloed R&D data from past and present and (cheaply and easily) use it to leverage our ongoing development efforts? As the ability of software to integrate and manipulate data from multiple formats improves, this massive challenge becomes more of a reality.

Of course, there is money to be made in bringing order to chaotic drug development data, as is evidenced by the companies getting into the market. Last week, I talked with Arvindh Balakrishnan about Oracle's efforts, and before that spoke with Blue Reference's Paul van Eikeren about his company's QbD IT consortium.

Microsoft looms large as well, and today we posted my interview with Jim Karkanias, Senior Director of Applied Research and Technology for Microsoft Health Solutions Group, about its Amalga Life Sciences solution.

Amalga is Microsoft’s attempt to make drug R&D data readily available, integrated, and robust, with the advantage that it leverages the Office format that is familiar to virtually everyone within a given organization. In the interview, Karkanias uses the example of a multidisciplinary team that is tasked with performing a gene expression study of a certain disease to illustrate how R&D will realize Amalga's potential. The fact that Amalga integrates relational and graphical data is what sets it apart, Karkanias says.

Merck is one of the companies helping Microsoft to develop Amalga LS. We'd love to hear more from anyone who's had experience with those solutions from the companies mentioned above, or other companies in the QbD IT space as well.

--Paul Thomas

For QbD and PAT, Are You Part of the In-Crowd (or Outside Looking In)?

Consultant Jack Carroll (one of our editorial advisors) sent in this commentary on a few things that are holding back PAT and QbD, based upon what he's gleaned from the people attending his training courses. From the attendance at these courses, Carroll says, it's clear that there are currently two factions operating in the QbD/PAT sphere--the mavens and learners. In other words, the in-crowd and the outsiders who are looking in (but may have little financial or corporate support for their initiatives).

Carroll writes: "We find a big disconnect between the PAT and QbD in-crowd and those trying to learn the “art.” The principles are sound, obviously, but the buzz-words are understood differently between the mavens and learners."

--Paul Thomas

Oracle's Balakrishnan: Towards an Integrated QbD

Another person who has his finger on the pulse of QbD, and whom I've spoken to a few times in the past six months, is Oracle's Arvindh Balakrishnan. We spoke again last week to touch base, and the focus of our discussion was Balakrishnan's belief that QbD is at a turning point in that many manufacturers have gone beyond the "hodge podge" approach that defined earlier QbD efforts and now have coordinated, corporatewide QbD programs.

Here is the audio of the interview.

--Paul Thomas

What is Your QbD Pain Point?

I had a chance to catch up again with Blue Reference's Paul van Eikeren last week, to talk about the progress of QbD in pharma, and about IT solutions to meet manufacturers' QbD needs. I've been following Blue Reference closely for the past year since van Eikeren is a proven innovator and business success--as founder of electronic lab notebook pioneer Intellichem (now part of Symyx)--and it's clear that he now aims to make a big splash with Blue Reference by leveraging the synergies between its software and the Quality by Design movement.

Through its QbD product development consortium, Blue Reference is working closely with manufacturers to codevelop novel QbD-focused solutions, and van Eikeren now feels that he has hit upon something that will make a difference: what he calls Paradigm Discovery, software that aims to mine manufacturers' R&D data from the past, find useful information, and put it in a format that can assist current QbD efforts. Manufacturers' major QbD pain point, van Eikeren says, is not being able to draw upon years of data from the past, and get return on investment for drug development studies that may never have led to a marketed product. Since the product is still in early development and hasn't been demo'ed for clients yet, van Eikeren isn't saying too much about how it works. Here is the summary of what he was willing to share with me.

Stay tuned . . . I aim to follow up with van Eikeren every so often, since Blue Reference is one of those bellwether companies by which to gauge the progress of QbD itself.

--Paul Thomas

FAQ's from ICH: What's Your Take?

Some discussion has started up around ICH's Q&A document on our LinkedIn group. If you're not a registered LinkedIn user, my apologies. I will summarize these responses some time soon. In the meantime, I would love to hear other thoughts about the value of ICH's document, and any answers that you take issue with.

--Paul Thomas

FAQ's from the ICH Quality Implementation Working Group

ICH regularly receives industry's questions regarding the implementation of Quality by Design. (Have a question? Submit it to ICH here.) Granted, not all the questions are worthy of response, but those that are are compiled in one Q&A document and made public, as part of the ongoing (and neverending) effort to educate the industry on QbD's finer points.

Some intriguing questions contained within, though perhaps few surprises if you've been following QbD for a while:
--Is there a regulatory expectation to develop a Design Space? (No.)
--Are GMP's different under QbD? (No.)
--Do traditional sampling approaches apply to real-time release testing? (No.)
--What happens when you wander outside of the DS? (It's a deviation under GMP.)

The Q&A's should tide you over until the Trivial Pursuit Quality by Design Edition hits store shelves.

--Paul Thomas

Webinar: Constructing a Design Space from a Mechanistic Model

A heads up: This Aug. 20 webinar promises to "review how to construct a design space from a mechanistic (e.g. kinetic) model, taking account of parameter uncertainty and lack of fit." Sponsored by DynoChem, but should be a good technical program for anyone (and it's free).

--Paul Thomas

Putting a Dollar Value on Pharmacogenomics

Few would argue that pharmacogenomics (using genomic markers to predict drug response in patients) will play a role in targeting drug leads and getting compounds to market faster. Researchers (consultants with NERA consulting and the University of North Carolina) have taken steps to quantify the impact that pharmacogenomics could have. The greatest economic benefits could result from the ability of pharmacogenomics to identify successful preventative medicines and thereby reduce overall healthcare costs, the researchers say in their new report on the economics of pharmacogenomics. They also suggest that their work justifies giving pharmaceuticals a larger slice of the overall healthcare financing pie. The full report can be downloaded free of charge.

--Paul Thomas

FDA, EMEA Harmonize Around Clinical Practices

FDA and EMEA announced today a broad collaborative effort in the area of Good Clinical Practices. The joint effort bodes well for continued cooperation between the agencies on many fronts, and in the sharing of resources that is imperative if global regulatory authorities are to get the most out of their limited resources. The agreement also represents a significant step toward the agencies' recognizing each other's inspections as valid and binding, and toward reducing the regulatory burden upon drug companies who operate trials worldwide and must satisfy the requirements of multiple regulatory authorities.

--Paul Thomas

Does Bing Have More Bang for the (Life Sciences) Buck?

If you're a researcher or pharma professional, should you prefer Bing to Google? Microsoft's Life Sciences IT expert Les Jordan (not surprisingly) thinks so. His latest blog entry details what Microsoft is up to in life sciences, but also takes a closer look at how Bing might have advantages over the "G" search engine for the industry's professionals:

Sponsored Targeted search by Therapeutics. Try this side by side with the “other” large search engine. Type “Diabetes” into Bing (http://www.bing.com) and into the “G”. I won’t give you the link ;-). Notice the difference:

“G” – gives you News on Diabetes as the first link. News! Who wants news on their disease? I need treatments, symptoms, diet, prevention, etc.

Bing – The first link is a definition (from content provided by Bing Health from Mayo Clinic), but notice on the left: Articles, Symptoms, Diet, Complications, Prevention, and Test – that’s what people are looking for! Also notice the related searches right under that - “pre-diabetes”, “Diabetes care”. Helps you sub-set your search instead of pouring through the “blue links”. Powerful.

Sponsored Targeted search by drug name. Again try this side by side between Bing and “G”. Let’s stay on the theme of diabetes. Type in Insulin into the search. Notice the differences:

“G” – A “Wikipedia” entry. Better than news, I’ll give you that…but still, it isn’t an authoritative source, and I’ll need to dig more to get the info I need, like “what are the side effects”, etc.

Bing – The first link is an authoritative article on insulin on “Bing Health” from Mayo Clinic. But notice the left side: Articles, Side Effects, Ingredients, Drug Interactions – that’s the kind of information people are usually looking for.

My first few experiences with Bing have been good ones. Would be interested in hearing your thoughts.

--Paul Thomas

Can PCMO and PQLI Work in Harmony for Paradigm Change?

PDA has stepped up its efforts to get its training and technical reports more in tune with ICH and a more risk- and science-based industry. These efforts have been underway, says PDA's Rich Levy, but the Paradigm Change in Manufacturing Operations initiative puts them into focus.

PDA has drafted a dossier around four key themes: Life Cycle Approach, Quality Systems, Process Management, and Quality Risk Management, and will use this dossier as the umbrella under which ongoing efforts will be undertaken.

In this article from my recent discussion with Levy, he goes out of his way to emphasize that PCMO is intended to complement, not counter, PQLI efforts already underway at ISPE.

--Paul Thomas

ADAPT Agenda Set; Throckmorton to Speak

The final agenda is available for September's ADAPT (Accelerating Development and Advancing Personalized Therapy) congress in Washington, D.C.

A quick summary of the tracks:

Track 1: Optimizing Clinical Trials
Track 2: Implementing Personalized Medicine
Track 3: Advancing Cancer Therapy
Track 4: Bridging Silos in Biomarker Development

Featured speakers include FDA Deputy Director Douglas Throckmorton; J. Carl Barrett, VP, Global Head Oncology Translational
Medicine, Novartis; Nicholas C. Dracopoli, VP, Biomarkers, Centocor R&D, Johnson & Johnson; and Giora Feuerstein, AVP, Head,Discovery Translational Medicine, Wyeth Research.

--Paul Thomas

QbD Presentations on Parade: DynoChem's User Meeting

DynoChem has made available presentations from its user group this past May. Registration is required to access the content, but among the materials available are:

Roles of Mechanistic and Empirical Modeling/DOE in Achieving Quality by Design, by Paul Stonestreet of GSK

Practical Insight on New Model Development: Filtration and Centrifugation, by Rich Ballenger of Abbott

Process Modeling Based Approach Towards Quality by Design for an API Synthetic Step, by Shawn Brueggemeier, Emily Reiff, Olav Lyngberg, Lindsay Hobson, and Jose Tabora, BMS

Practical Aspects of Distillation Modeling in DynoChem, by Carolyn Cummings of Amgen

An Example from GSK's Design for Manufacture Initiative: Use of Dynochem in Conjunction with Lab and Pilot Scale Data to Advance Process Understanding, by Dharmesh Bhanushali of GSK

How Process Safety and Environmental Lab Can Guide Process Development, by Viviane Massonneau of Merck

Lean and Green: The Value of API Process Design, by David am Ende, Pfizer

--Paul Thomas

How Varian Complements Agilent for QbD

Agilent's purchase of Varian should give the company much more prominence in the QbD space. As Investor's Business Daily put it, "Varian's products are used to help design new therapeutic drugs, while Agilent's products help analyze the causes and cures for diseases."

Here are a couple white papers out from Agilent this year:

Using Design of Experiments for HPLC Method Development

Using Fiber Optics to Speed and Simplify Formulation and Method Development

--Paul Thomas

QbD for Biopharma: New Course at PDA FDA Joint Conference

This year's PDA FDA Joint Regulatory Conference in D.C. in mid-September has an excellent program top to bottom. (Here's the agenda.) It will also feature a new course by Anurag Rathore (see yesterday's post on his new book) on QbD for Biopharma.

Rathore has just posted the tentative outline for the course on our LinkedIn group. If you're not a LinkedIn member, here is his overview--comments are welcome as the program is finalized.

Critical Quality Attributes (Patrick Swann): Potential CQAs for Mabs; Biological Activity Matrix; Product-related variants; Characterization of variants and setting limits (ICH Q5E); Clinical pharmacology studies; Specifications (ICH Q6B); Biological characterization

Design Space (Anurag Rathore): Clinical design space; Product design space; Process design space; Case Study I – Establishing process design space for a Pichia fermentation product; Scale down modeling; Failure Mode and Effects Analysis (FMEA); Design of Experiments (DOE); Parameter-parameter interactions; Worst case studies

Group work I (All): Group discussion to identify and list gaps attendees see with respect to molecules under commercialization at present and also legacy products.

Risk Assessment and Management (Patrick Swann): Review of historical approaches; ICH Q9 guidance; Quality risk management process; FMEA

Regulatory Aspects (Patrick Swann): OBP QbD pilot program; Observations based on review of proposals for categorizing quality attributes

Establishing Control Strategy and Lifecycle Management of Design Space (Anurag Rathore): Creating control strategy; Process validation; Filing; Process monitoring; Raw material management; Process analytical technology (PAT); Case Stud II – Multivariate analysis for a mammalian cell culture step

Group work II (All): Group discussion of gaps identified earlier

Wiley Publishes QbD for Biopharma, Edited by Rathore and Mhatre

Wiley and Sons has published the 288-page "Quality by Design for Biopharmaceuticals: Principles and Case Studies," edited by two of biopharma-QbD's leading advocates, Anurag Rathore and Rohin Mhatre.

Expect the book to become one of the definitive resources for QbD, given the impressive list of contributors. For those who don't have the $125 for the cover price right now, the Introductory Chapter by the editors may suffice; it's available here (scroll down to "Product Samples"). It's an excellent overview of basic QbD concepts such as CQA's, Design Space, raw materials and their impact on QbD, and PAT.

--Paul Thomas

What Is the Real Meaning of Pharma Innovation?

Britain’s NICE (National Institute for Health and Clinical Excellence) is charged with providing guidance on promoting good health among citizens of the U.K. Unfortunately, NICE has had a contentious relationship with the drug industry in general, and has often been viewed not as a promoter of public health but rather an impediment to innovation which might benefit the public. One way to put it: “Pharma sees NICE as a barrier to its ambitions to bring products to patients. NICE sees itself as the guardian of the public purse and of all patients.”

The above statement is from Sir Ian Kennedy, who was hired by NICE earlier this year to review the organization’s procedures and make recommendations for how it might turn things around—i.e., “make nice” with pharma while still protecting the public interest. Kennedy has issued his final report, "Appraising the Value of Innnovation and Other Benefits," with a laundry list of recommendations for NICE. But, for those of us outside the U.K., we might find most compelling Kennedy’s ruminations on the meaning of innovation within a pharma context. Here are some of those thoughts, from the report:

“ . . . It will come as no surprise that, while everyone was content to use the word [innovation], and everyone agreed that it was a good thing, it was not easy to identify what was being discussed. In fact, as is common in policy-making, the absence of any hard centre of meaning allows people from all quarters to appear to be in agreement, without the need to nail down what it is that they were agreed on.

4.8 There is no shortage of definitions of innovation. Their very number suggests an amorphous concept. It is clear to me that the notion of innovation has a range of connotations which are, to a degree, context-specific. And, the world of pharmaceutical products is one such context. As a first step, it may help to know what Sir David Cooksey had in mind when he called for this study. When I spoke to him he referred to innovation as connoting “different ways of doing things which bring improved outcomes”. This helps. There is the idea of difference, or newness, and the idea that it represents an improvement on what went before. . . . it should be clear that something more than newness (or difference) plus some degree of improvement in effectiveness may be necessary to qualify as innovation in this specific context. . . .

4.10 Where innovation becomes important, therefore, is when Pharma states that a product meets three initial criteria, in that the product: But, they will not warrant any special treatment. Only if they are priced in a way that meets NICE’s established approach, will they warrant approval. Such products may be described as innovative, but the claim alone will cut no ice, nor bring any special treatment.
• is new
• constitutes an improvement on existing products
• offers something more: a step-change in terms of outcomes for patients

Kennedy agrees that “step-change” is in itself amorphous as well, but this is what we should by striving for as an industry, and this is the concept around which NICE and pharmaceutical companies can coalesce to expedite products to market that are truly “innovative.”

--Paul Thomas

Snooping Around: A Peek at Quality Management at Sanofi

Found on the blogosphere is this summary of Sanofi Aventis' take on Quality Management, from one of its teams in Union, N.J. The recommendations at the bottom of the posting are the most intriguing, and suggesting that manufacturing may be underappreciated and QbD underutilized:

Sanofi-aventis is still struggling with on-time delivery. Management mainly sees manufacturing as a cost center. About 40% of the plant equipment is over 10 years old and some are manually operated. Elements in the operational excellence toolkit, such as Quality by Design, Process Analytical Technology and advanced process control are being underutilized. Models are not yet flexible enough to adjust production capacities based on demand. In addition, regulatory compliance and plant safety were lower this year. . . . If Sanofi-aventis wants to increase the benefits of quality, company leadership must make operational excellence a priority.

--Paul Thomas

H1N1 Puts Onus on Industry to Embrace QbD and FDA's Risk-based Dream

If ever there were a time for the industry to embrace QbD, it is now, as the threat of an expanding H1N1 pandemic looms and manufacturers scramble to develop and manufacture significant volumes of vaccines to counter the spread of the virus. In this his latest article (also published in the July/August issue of Pharmaceutical Manufacturing), Pharmatech's Bikash Chatterjee puts the threat in perspective (looking back towards the bird flu and even Spanish flu of 1918), and makes an impassioned case for the adoption of Q8 and Q9 principles as a means of accelerating development and helping to reduce or even extinguish the danger that H1N1 presents.

He concludes:

For an industry that has had its fair share of bad press in the last few years over public safety concerns, this is our chance to step up to the plate and show we can deliver when we need to. If we fail, the FDA can look to another long, slow transition as it struggles to enforce its new policies on risk-based process development and quality assurance.

--Paul Thomas

Can QbD Help Build Better Partnerships?

As far as I know, no one has looked into how to apply Quality by Design to outsourcing situations more than Russ Somma, president of SommaTech consulting. Russ has published on the topic in the past, and was the lead speaker on our recent webcast on outsourcing excellence (available on-demand here and also featuring Rakesh Kishan of UMS Advisory and Ron Perry of Wyeth Consumer Healthcare).

Here is the printed summary of Russ's webcast presentation. His underlying premise: "QbD does not become the driving factor of partnerships, but it becomes the philosophy against which one sets up strong partnerships."

Also, here is a related article by Russ and colleague Andy Signore from Contract Pharma last year.

--Paul Thomas

Risk Management Strategies for Extractables and Leachables

FDA's Ingrid Markovic has just published in American Pharmaceutical Review on risk management for extractables and leachables. Here's a link (subscription required), and here is the abstract:

Extractables and leachables (E&L) are chemical entities, which can be released into intermediate material or final therapeutic biologic protein product at various times during upstream and/ or downstream manufacturing steps, packaging operations and/or storage. These substances may pose a safety risk to the patient by causing toxicity, carcinogenicity, immunogenicity and/or endocrine dysregulation. They may also alter product physico-chemical properties via direct interaction with the active pharmaceutical ingredient or, indirectly, by interacting with the excipients in product vehicle, thereby adversely affecting the product quality. Current paper will address a risk-based approach to conceptualizing, evaluating and executing identification and characterization of E&L along with regulatory considerations regarding the impact of these impurities on product quality, patient safety and clinical efficacy. Selected case studies are presented and discussed.

The QbD/Six Sigma Connection, Revisited

I had a good talk a few weeks back with Patheon CEO Wes Wheeler about initiatives he's undertaken to increase performance across all sites, and to use performance indicators to drive marketing for new business. (Article here.) I also e-communicated with Patheon executive VP and CTO Paul Garofolo about the company's Patheon Advantage Lean Six Sigma and its ongoing progress. You can read that Q&A here, but I thought Garofolo's take on the QbD/Six Sigma overlap helpful:

PhM: Where is Patheon in terms of adhering to FDA’s vision of Quality by Design, and what role does QbD play in the PA program?

P.G.: We’re making great progress. It’s all about culture change, on both fronts. The fundamentals of Lean Six Sigma support the fundamentals of QbD. Some tools, particularly Quality Function Deployment, Design for Six Sigma and Design of Experiments are particularly well-matched with QbD. We’re finding that the methods we’re developing and the culture change we’re building with PA support fully our move to QbD.

--Paul Thomas

Mulling Adaptive Clinical Trial Design, and Hula Hoops

Can accumulating clinical trial data be used to adapt trials in their earlier stages to either optimize them or suggest that they ought to be terminated? That's the premise of adaptive clinical design; this article from Applied Clinical Trials ponders the question of whether adaptive trials are here to stay or will go the route of the hula hoop.

Thanks to the Agile Clinical Development blog from Health Decisions for passing this one along.

--Paul Thomas

Biosensors in Clinical Trials: More from John Lowry in Ireland

I blogged a few weeks ago about the potential of biosensors to be used to monitor neurochemical brain activities in clinical trial patients in real time, from the work of Irish researcher John Lowry. Yesterday, I spoke with Lowry to dig further into why companies like Lilly are interested in his technology, and what obstacles exist before biosensors might be used in human trial subjects. Here is the summary of that interview.

--Paul Thomas

QbD in a Nutshell

A good, succinct overview from today's Pharma Compliance Blog of QbD's past and where it stands today, from Gary Miller of CIS Partners.

--Paul Thomas

White Paper: Operational Efficiency in Clinical Trial Management

Good reading: A multi-article white paper from Oracle, including Accenture’s Henry Levy on enabling technology, Genzyme’s Jennifer Hunt on implementing a trial management system, and several leading consultants on clinical trials management of the future. While the paper promotes clinical trial management systems such as Oracle’s Siebel offering, it’s a strong overview of the current data management climate in general.

--Paul Thomas

Innovation: Are You in a Dynamic Ocean or Shrinking Pool?

Where will the innovation of the next century take place? McKinsey and Co. has put together an interactive innovation heat map which gauges global hotspots based on their size, diversiy, and momentum, as a means of estimating where future innovation will reside.

Click continue at the bottom of the landing page to view.

--Paul Thomas

On the Horizon: Drug Discovery and Development Week

Drug Discovery and Development Week, a collection of five conference themes around one exhibition, is slated for the first week of August in Boston. Among the highlights: In the Drug Safety Strategies to De-Risk Compounds event, William Mattes, former director of toxicology for the Critical Path Institute, will deliver a keynote on Skirting Drug Safety Potholes in the Critical Path to POC, while FDA senior scientific advisor Wendy Sanhai will discuss Biomarker Development and Clinical Qualification. The Cancer Drug Development track will feature a debate on the effectiveness of current methods of development via cancer stem cells. There's plenty more on hand, of course, including a keynote by Daiichi Sankyo president and CEO Takashi Shoda, on the challenges of building a global drug company in today's market.

--Paul Thomas

How QbD Can Leverage Outsourcing Partnerships

Forgive the self-promotion, but today I've been reviewing our recent webcast on Operational Excellence for Building Better Partnerships, and think it's a fantastic overview of how Quality by Design and principles of operational excellence can be applied to pharmaceutical contract relationships, for the betterment of everybody involved. In particular, consultant Russ Somma discusses how challenging QbD concepts such as Design Space can be simplified and applied to outsourcing relationships, and the ideals of QbD can be shared with partners. Consultant Rakesh Kishan gives a good talk on keeping core employees in mind in all outsourcing situations, and Ron Perry of Wyeth Consumer Healthcare details his company's innovative supplier quality excellence program.

The webcast is free; registration is required.

--Paul Thomas

Pharmaceutical Allies: QbD and Six Sigma

A rather lengthy but good PowerPoint presentation from an ISPE breakfast seminar on the link between QbD and Design for Six Sigma, courtesy of consultant Murray Adams.

--Paul Thomas

Quality Risk Management in Jersey

Roche and Dyadem have put together a program on Quality Risk Management for the end of this month in Princeton, N.J. Dyadem's offerings are well positioned for the QbD movement . . . should be an interesting program.

--Paul Thomas

Progressive Collaborations: GSK Gets First Contributor to Patent Pool

Another exciting collaboration speeding development: Alnylam has become the first company to jump into the patent pool that GSK has established to aid development of drugs to confront tropical diseases. Alnylam will contribute some 1,500 current and pending patents, tripling the number that GSK has already contributed itself.

GSK CEO Andrew Witty: “The key objective of the pool is to make it easier for researchers across the world to access intellectual property that may be useful in the search for new medicines to treat neglected tropical diseases. The more companies, academic institutions and foundations that join the pool, the more effective it will be. Alnylam’s announcement today is therefore a welcome and significant step forward.”

--Paul Thomas

Public and Private: Janssen Alliance for TB Drug Development May Serve as Model

An interesting note from a few weeks ago on an agreement between Janssen subsidiary Tibotec and the not-for-profit TB Alliance to share resources and expertise. Says the alliance's president and CEO Mel Spigelman, “Since the TB Alliance was founded, we have assembled the largest pipeline of new TB drugs in history . . . " It's a great model for collaboration, cost sharing, and bringing needed drugs to market that otherwise would not have gotten the full resources and backing they deserve.

--Paul Thomas

Real-Time Neurochemical Monitoring of Trial Patients?

A good article in the Irish Times detailing some of the work in the Emerald Isle to speed drug development. The lead is about the work of John Lowry at the National University of Ireland Maynooth. Some of Lowry's research is available online. Here is a journal article detailing his team's efforts to enhance the selectivity of its biosensors. And here is a thorough video on Lowry and his biosensor work.

--Paul Thomas

Microsoft's Les Jordan on DIA 2009

Microsoft's IT Life Sciences specialist Les Jordan offers up a nice summary of his experience at DIA last week, including photos and (for romantics) a shot of the San Diego sunset.

--Paul Thomas

Blue Reference's Van Eikeren Outlines QbD and Other Strategies

A good interview with Blue Reference's Paul Van Eikeren regarding the company's strategy, including a brief mention of its consortium with big pharma companies to develop a QbD enterprise solution based upon its Inference for R platform. (Here is the press release on that consortium from a while back.)

--Paul Thomas

What Sapphire and SQL*LIMS Customers Can Expect from LIMS Merger

LabVantage announced today that it is purchasing Applied Bio's SQL*LIMS business. While he couldn't comment at length yet, LabVantage VP of Corporate Development Ron Kasner offered a few thoughts via email:

PharmaQbd: What is the plan for integrating SAPPHIRE and SQL*LIMS? How quickly will this happen?

R.K.: Until the closing date, both companies will operate in a business-as-usual mode. More information about the integration plan, including product integration will be available post closing.

PharmaQbD: What will SAPPHIRE customers likely to get that they didn't have before, from a technology standpoint? What will SQL*LIMS customers get?

R.K.: All of our customers will gain access to a broader portfolio of software products and services, with our ongoing commitment to world-class customer service. We will continue to execute against our strategic product direction for SAPPHIRE. Our intent is to expand functionality within SAPPHIRE™ by leveraging the SQL*LIMS team’s domain knowledge and the robust product functionality within SQL*LIMS. At the same time, we will maintain our commitment to support the SQL*LIMS product and customers.

Forbes: Scale is the Real Reason for Big Pharma Mergers

Interesting article from Forbes, which posits that the real reason that big pharma companies are merging is not to shore up their weak pipelines, but to increase their scale in order to increase the likelihood of bringing more products to market, faster, and in more parts of the world. No longer is approval by the U.S. FDA the preeminent goal for any drug, but rather getting approved in many markets as quickly as possible.

--Paul Thomas

PDA Releases Dossier for Paradigm Change Initiative

PDA has instituted a new "Paradigm Change in Manufacturing Operations" (PCMO) initiative, based largely on encouraging ICH guidance within its organization and the industry. Here is the PCMO dossier, and we'll be following up with PDA in the near future.

--Paul Thomas

Tech Transfer Blues: U of Iowa Sues Abbott Over Humira

The University of Iowa's research arm has filed an intellectual property lawsuit against Abbott Labs, saying that the company had "willfully and deliberately" infringed on its patents that have been essential in the manufacturing of Humira. Abbott, not surprisingly, says it has done no wrong and will "vigorously defend" itself. GenomeWeb has the story. Stay tuned . . .

--Paul Thomas

Put Nashville in November on Your QbD Calendar

Over the years, AIChE's annual meeting has developed one of the strongest lineups of QbD sessions around. This year, from Nov. 9-13 in Nashville, is no different, headed by a plenary session featuring FDA's Christine Moore and Eli Lilly's Kevin Seibert. Here's a rundown of the QbD in Pharmaceutical Development and Manufacture sessions on tap: http://aiche.confex.com/aiche/2009/webprogrampreliminary/TI.html.

--Paul Thomas

How Conformia Will Help Oracle

Oracle's purchase of Conformia is sure to further enhance Oracle's growing reputation in the life sciences space. Here's one account of what the marriage will mean, as well as some thoughts from Agnes Shanley on Conformia's resurfacing after a dormancy.

--Paul Thomas

Explorations in QbD and Lab Automation

Tunnell Consulting's Sandy Weinberg has written a very nice two-part series for Scientific Computing on QbD for the laboratory:

Here are Part 1 and Part 2.

--Paul Thomas