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The Pharma Quality by Design blog at this URL will no longer be active. We've moved all of our posting to our redesigned PharmaQbD home page. Please visit us there for daily updates on things happening in the QbD world.

Regards,

The PharmaQbD Team

QbD Pioneer Afnan to Leave FDA

One of the true thought leaders behind pharma's PAT and Quality by Design movement, Ali Afnan, PhD, has decided to leave his post at FDA. In today's On Pharma blog, Agnes Shanley looks back at Afnan's key role within FDA, and muses about his reasons for moving on.

QbD Comes to India

Two good QbD seminars have been slated for March in Hyderabad and Mumbai, featuring consultant Line Lundsberg and Dhaval Trivedi of Intas Pharmaceuticals. Click here for more.

Design for Six Sigma: A Model Partner for QbD

When the concept of Six Sigma was developed at Motorola in the 1980's, its practitioners soon realized it had an inherent flaw that would preclude many manufacturers achieving six sigma levels of performance. Once a process reached five sigma levels, there was often little financial incentive to push ahead to the six sigma threshold. As consultant Murray Adams explains in our recently posted article, "Design for Six Sigma: A Potent Supplement for QbD", "financial gain of further improvement is frequently outweighed by the cost of implementation." The dilemma was called the five sigma barrier.

In a heavily regulated industry such as pharma, however, settling for pretty good will not do. Adams continues: " . . . a 5 sigma process may not be sufficient for many critical process steps. In fact, in the pharmaceutical industry, even the 'world class' six sigma standard (3.4 dpm) is inadequate with respect to the occurrence of some critical defects. Given the limitations of the 5 sigma barrier, how can we achieve an appropriate level of process performance while maintaining a competitive operating cost?"

The answer that the Motorola folks came up with was to adapt some of the tools of Six Sigma for the early stages of product design--thus, Design for Six Sigma was born. There isn't a good understanding of the differences between DfSS and Six Sigma in the drug industry, Adams believes, but pharmaceutical development teams would be well served to incorporate more DfSS into their practices. Once they do, he says, they'll find that many of its tools--such as Monte Carlo Simulation, Parameter Design, and Tolerance Allocation--complement Quality by Design concepts and support initiatives being undertaken under the QbD umbrella.

Those interested in learning more on Monte Carlo Simulation should also read "Leaning on Six Sigma and Predictive Modeling in a New Industry Paradigm," by Oracle's John Danese and Fred Ciochetto. This PharmaManufacturing.com article also includes references to other resources on the topic.

IFPAC: Analyze This

If you're into PAT and QbD, you'd be hard-pressed to find a trade show with more relevant sessions and productive discussion than the annual IFPAC show. Over the years IFPAC has gotten more and more pharma-centric, and this year's Baltimore event is no different, with GSK's Theodora Kourti getting things started, followed by FDA's Vincent Vilker and Helen Winkle, and then a host of other pharma presenters over the next few days. Click on the preliminary program link on the IFPAC home page.

Is Tech Transfer Broken? Can the Principles of QbD Fix It?

While scant data exists to suggest how efficient, or inefficient, technology transfer is within drug manufacturers' development efforts, it's pretty clear that most companies hardly have tech transfer down pat, and still others just don't get it at all. That's a recurring theme in a podcast posted on PharmaManufacturing.com yesterday, in which tech transfer experts Stephen Perry, Russ Somma, Emil Ciurczak, and Paul McKenzie offer harsh criticisms of the tech transfer projects they've witnessed first hand. And thankfully they offer advice as well.

Sometimes the problems are simple--development teams just fail to write critical information down in their notebooks, "something they should have learned in college!" Ciurczak says. But the experts also make clear that practices associated with Quality by Design--namely, proactive risk assessment and data management--can eliminate problems in the early stages of development and facilitate later transfer. Perry notes how developers typically send data on successful process studies to their partners, but not data from failed studies that can be just as enlightening.

Perry is the author of Pharmaceutical Manufacturing's January cover story on doing tech transfer the right way, and he suggests that one thing that often dooms tech transfer projects (internal or external) is the inability of the technology sender to share necessary information with its partner:

There is no such thing as “too much” or “too detailed” information. Such dedicated tools as assay summaries, detailed process descriptions, and bills of materials should be created and used . Other information from the sender, such as regulatory submissions, development reports, raw data, validation reports, etc., can be extremely useful. This work would have to be done anyway as part of the future process validation and to support regulatory submissions.

One of Somma's mantras is simplifying tech transfer, which seems to run counter to the idea of providing as much detailed information as possible. He, as well as Oracle's Arvindh Balakrishnan, explain how this paradoxical challenge can be overcome in a podcast which is now the lead feature on our PharmaQbD.com site.

Finally, Centocor's McKenzie is a proponent of recipe-based development as a means of ensuring consistency throughout scaleup and as handoff occurs between partners. Here is a summary of McKenzie's philosophy from last fall's Bioprocess International conference, as well as a blast from the past: Pharmaceutical Manufacturing's September 2007 cover story featuring McKenzie in his days with BMS.

The success or failure of tech transfer is hard to measure, but that doesn't mean that it shouldn't be a key focus of initiatives to accelerate and lessen the costs of drug development.

QbD for Biotech in Three Parts

Biopharm International has just published the third installment of a three-part series on Quality by Design for biotech products, written by members of PhRMA's Biologics and Biotechnology Leadership Committee. Links are as follows: Part 1, Part 2, and Part 3.

QbD News Delivered to Your Desk

For those unaware, PharmaQbD.com's pharma QbD Enews is a twice-monthly electronic newsletter that features QbD-related news items plus a few feature articles. Here's today's issue, with a special focus on best practices in tech transfer from Stephen Perry of Kymanox and Suraj Mathew of Tefen.

Looking for a Few Good Authors: QbD "From Theory to Praxis"

PAREXEL's Siegfried Schmitt is looking for chapter authors for a book titled, "Quality by Design: From Theory to Praxis," to be published by PDA. You may contact Siegfried via his LinkedIn posting, or directly at siegfried.schmitt@parexel.com.

The following are some parameters that Schmitt has shared with us:
• Authors may write part or a whole chapter (or several)
• Authors should outline either in bullet points or in prose what they want to cover (structure and contents of their contribution) by mid-February 2010
• Schmitt will provide feedback and suggestions
• Drafts should be completed by June 2010
• Revisions are expected by the end of August 2010

Authors may include text from existing publications, Schmitt says, provided they have been adapted for this publication. References should be listed in a separate table.

Tufts Center: Approval Times Have Dropped, But Is It Enough?

For those of us who work in and follow the drug industry, winter is always made a bit brighter and warmer with the coming of the annual Outlook paper by the Tufts Center for the Study of Drug Development. The Tufts report is one of the definitive measures of where we are, where we're heading, and what hoops we have to jump through to get there.

This year's report (here's the Center's summary; the full Outlook 2010 will be made available to non-subscribers this spring) has plenty to chew on, but here are a few of the more relevant points that drug developers and QbD professionals need to consider:

--Few drugs make it to market, but it's important to remember that of those that do, only 3 of 10 generate enough revenue to sustain R&D.
--Drug developers don't just need to improve time to market, they need to dramatically change what they're doing--to "transform the way they conduct research and development over the medium and longer term to be more efficient and productive."
--Collaboration is critical. R&D success will depend upon how developers engage their partners at critical points in the product lifecycle.
--Risk management will continue to balloon in importance. With FDA and global regulators limited in their resources, it will be left up to developers to show expertise via Risk Evaluation and Mitigation Strategies (REMS)
--Biotech products will boom, but take longer to get to market due to increased clincial trial requirements.

Just a few thoughts to warm your winter.

Visualizing the Golden Batch with S88

ISA-S88 is a standard for batch control that many proponents of Quality by Design are adopting. S88 is a design philosophy for processes and recipes (see here for Wikipedia’s pretty good summary) that is becoming more and more relevant in the pharmaceutical industry.

One S88 believer is Centocor’s Paul McKenzie, formerly of Bristol-Myers Squibb. McKenzie, who spoke at the Bioprocess International Conference last fall, explains the value of S88 as follows (as related by Agnes Shanley, who was in attendance):

Each process will have its own raw materials, quantities, process parameters, recipe procedures, and equipment requirements. . . . With a portable recipe, equipment is separated out as its own class, and you assign an equipment class to each area, a good approach for when a process is changing, McKenzie said.

The approach allows users to create a series of recipes. Everyone collects data in the same way, he explained, so that tech transfer becomes ownership of that recipe. As it moves along, you have a master recipe and then a control recipe specific to each actual unit you run. . . .

This in turn facilitates a QbD approach.

“I don’t want people innovating on what they call something in a MS word doc,” McKenzie said, but in terms of parameters, using a common global language to describe process and product.” With this approach, one recipe can be used across the world and global facilities, he said. The method makes it easy to link to regulatory filings and to visualize the “golden batch.”

For the full summary of McKenzie's talk, see "Paul McKenzie's Recipe for Success with QbD".

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.