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Recent Events 

On Tuesday evening, November 15th, Michael Drues, Ph.D introduced pharmacogenomics at the Genzyme Science Center in Framingham after presenting the same topic at the Product Show the previous month at Gillette. Genzyme provided a smaller, more personal forum better suited to a spirited discussion on the future of medicine. After refreshments and networking in the lobby, the group moved into the "classroom" to listen to this pedigreed professor talk about a subject that touched many from both a technical and personal nature.

Attendees enjoy a lively networking reception before the presentation

Before launching into his topic, Michael started with a brainteaser to get the mental "juices" flowing, and then just kept going for the following hour and a half. He started with how we got to this point and noted that pharmacogenomics (aka personalized medicine) is not really new since doctors have been practicing "personalized medicine" for centuries. So what's different now? Until today, we have been practicing medicine from a "phenotypical" perspective but in the future, we will be able to practice medicine from a "genotypical" perspective. To illustrate how this is becoming a reality, Michael described development of the "frost-resistant tomato." Instead of engineers looking at heaters to prevent tomatoes from freezing, researchers put the anti-freeze protein (gene) from an artic char (a popular food fish adapted to life in the frigid arctic waters) into a tomato and achieved the desired results genetically. This is reality, not science fiction!

The presentation continued with Michael explaining that the average efficacy for drugs (their ability to do what each product states on its label) is 20 to 40 percent - only slightly better than a placebo (which is typically 30 percent effective). A new drug to market does not need to be better than other drugs already existing and being sold; it just needs to be better than nothing (e.g. a placebo). To say the least, this opened the eyes of many attendees! Michael went on to comment that this low level of success would not be acceptable for automobiles starting or planes flying. He then likened the traditional approach to medicine to buying shoes at a store with only one size available and contrasted it with pharmacogenomics which provides a custom "shoe" built specifically for individual patients.

Presenter Michael Drues with Chapter Board Member Janet Tice

Michael explained that, moving forward,   the question becomes: What is the FDA's role in personalized medicine since the FDA does not regulate the practice of medicine? It would appear that genetic tests and diagnostic tools would be a much better way to get the right drug to the right person at the right time. He then introduced the concept of pharmacogenomics as applied to medical devices - absolutely possible and with distinct advantages over what is being done currently. As an example, a real concern in the use of stents is the formation of deadly blood clots shortly after a stent is implanted. Currently, doctors cannot predict which patients are vulnerable to forming clots. However tests are available to identify people at risk, i.e. those who have genetic factors associated with early stent thrombosis.

So how do we practice medicine more intelligently than we do today? Do we use companion diagnostic testing and genotyping during clinical evaluation before prescribing a drug? Using Plavix (a drug that functions like an anticoagulant) as an example, Michael continued. Many patients cannot metabolize the drug so the question is: Why wait for a patient to swallow the drug to see if it is going to work?

Regarding clinical trials with their long timeline, if personalized medicine is going to impact medicine sooner, it may need to utilize "platform technology," that is, new technology that could potentially be used for many applications, both existing and in ways that haven't been dreamed of yet. For example, currently variability is managed at the trial's back end by using statistics; the new paradigm would be to manage variability at the front end using inclusion/exclusion criteria which would increase the probability of the trial's success. Then the ethical question becomes: Who pays for genetic testing before a trial vs. after? Another ethical question: If we are able to identify people with genes that respond to placebos, can we exclude them from the trial so that we require fewer patients and thus make the trial more efficient? Do we use placebos in medical device trials (i.e. sham procedures) to measure efficacy? Is this ethical?

Product development is costly and time consuming. In the past, most drugs came from discovery (e.g. the Amazon jungle), not invention. In the future, the new drug development paradigm can be changed to an engineer and chemist fabricating a molecule in silico (i.e. on a computer or via computer simulation). Another personalized approach to medicine could be using high tech compounding. Instead of just manufacturing millions of pills in a factory somewhere, pharmacogenomics is the engineering equivalent to stereo lithography. Michael used examples currently available in the consumer marketplace to further illustrate the concept: Coca-Cola Freestyle, custom-blended ice cream flavors and personalized orthotics - all created on the spot to satisfy the customer's requirements and delivered by a vending machine.

By this point, our heads were spinning with all the new concepts and possibilities. Michael suggested the idea of a "poly-pill" as a combination therapy - not a combination product (after all, the FDA doesn't get involved if a patient takes five pills). This could make a reality of a combination of drugs and biologics prescribed and produced right in a doctor's office (high tech vending), customizing the medication to the patient's specific needs.

Michael finished with some food for thought:

• Companion diagnostic - narrows market for drug but may enable higher margin?
• Clinical trial duration can be long if testing the whole population - more efficient if database of existing information is used to find applicable genetic types.

...and words of wisdom:

• If we don't have evidence that does not mean it didn't happen.
• Don't be afraid to fail.
• Don't go where a path may lead, go instead where there is no path and make a trail.

This session - with its focus on possibilities for the future - was definitely different than the typical ISPE event but provided an inspiring and thought-provoking learning experience. The evening flew by and left all of us thinking about the myriad of possibilities on the near horizon of medicine...and our next doctor's visit. Thanks to Michael Drues for taking us into the future!

Worcester Polytechnic Institute (WPI) has officially become the newest ISPE Boston Area Student Chapter.  With over 15 members and officers, the Chapter has hit the ground running with a plant tour of Abbott (more on this to follow) and is already planning for guest speakers and other educational and professional events in the semester to come.

The Chapter was founded in 2010 by a small group of student professionals. The motive was a strong drive to learn more about the pharmaceutical and biotech industry, especially by connecting with industry professionals. The intent to serve fellow students in the Worcester area with similar interests was also of great importance and ultimately facilitated the startup of WPI's Student Chapter. With over eight colleges and universities in the Worcester area, the WPI is the only local ISPE Student Chapter.

The partnership between ISPE and WPI is a logical step that was a long time in the making. As the biotech sector continues to grow and engineering schools recognize that students will be choosing careers in R&D as well as manufacturing, professional societies like ISPE benefit both students and industry. WPI opened its first life science building in Gateway Park in 2007, combining academic research with "incubator" companies developing next generation therapies.  With plans to further expand Gateway Park in the future, we expect ties between ISPE and WPI to strengthen further in the years to come.

On December 1st, just days after being officially recognized by ISPE, WPI students attended a plant tour at Abbott Bioresearch Center in Worcester.  Attendees represented a range of majors including Biotechnology, Biochemistry, Chemical Engineering, Biomedical Engineering and Mechanical Engineering.  As one of the participants put it, "a behind the scenes tour of Abbott was very insightful and educational. The Student Chapter is deeply grateful to ISPE Boston as well as Abbott for providing us with this opportunity."

The tour took the students through the process for culturing mammalian cell lines, beginning with raw materials and ultimately overseeing the purification steps.  Clean steam, water for injection, and purified water were some of the basic GMP utilities introduced to the students. The tour guides described the differences in purity, quality and price between the municipal tap water and Abbott's purified plant steam, attesting to the effective water purification methods used by the plant. Moving on through the plant to the upstream equipment, the tour included a look at some of the seed reactors and larger 3000 liter reactors.  CIP and SIP cycles were touched upon, as well as the differences between harvesting methods such as centrifugation and depth filtration.  Some of the modern, price effective technologies used in various stages of the production process were also highlighted and discussed.

Tour guides Joshua Froimson, Mike Doucette and Lorraine Mathis of Abbott generously donated their time and made the tour a huge success.  Being aware of commonly used acronyms such as CIP, SIP, WFI, etc. will give the students a leg-up when they begin interviewing for careers in the biotech industry in the months and years ahead.  On behalf of WPI and ISPE we thank our tour guides and Abbott Bioresearch, Inc.

The WPI Student Chapter has many more tours, professional speakers and educational conferences to look forward to in the months and years ahead. All of these events and more will facilitate the professional development of its student members and the greater WPI community. With the rapid expansion of the biotech and pharmaceutical industries, the partnership between ISPE and WPI will help foster the education of young professionals and feed more talented, well-prepared individuals into the marketplace. 

E2500 Integrated C&Q Draws Standing-Room-Only Crowd to Genzyme
Articles and photos by Joyce Chiu, CPIP, Honeywell Safety Products 

 

On the evening of December 15th in the Genzyme Cambridge auditorium, packed full with almost 100 attendees, Jack Greene gave an interesting and stimulating two-part presentation, titled "Integrated Commissioning & Qualification: Saving Time and Money without Compromising Quality."  This topic came about because of the recent publication of ISPE's "Applied Risk Management for Commissioning and Qualification" Good Practice Guide.  Although his presentation was reviewed by the ISPE Community of Practice on C&Q, Jack developed his presentations primarily based on his own 15 years plus experience in this area.

 

Presenter Jack Greene (second from right) joins friends during the networking reception.

 

As envisioned during the design of the program, the audience was very much part of the evening as they were encouraged to ask questions, share experiences and thereby help create a full interactive learning opportunity for all.  The presentation consisted of a historical perspective and a current state, peppered with interesting anecdotes based on personal experience and pearls of wisdom.

 

The historical perspective started with an overview of nomenclature - what are Commissioning (IC/OC) and Qualification (IQ/OQ/PQ) - and how FDA justified cGMP in 1979 and issued guidelines on process validation in 1987.  These resulted in two models of C&Q.  Model 1 did complete C and Q, essentially replicating two identical sets of activities by two separate groups of people, Engineering and Quality.  Model 2 skipped commissioning and went straight to qualification, with the rationale that since qualification was going to repeat commissioning, why not just do qualification?  Each model had its benefits and pitfalls; neither was ideal.

 

Before Jack started part two, he got the audience engaged.  Many shared their own experiences and the challenges they faced, and asked pointed questions.  Jack then started introducing E2500, an updated approach toward C&Q significantly different from previous practice and a risk-based model that focuses efforts on areas with the greatest impact on product quality and patient safety.  Only five pages long, E2500 is a high level guidance that provides a philosophy on C&Q, supported by ISPE guidance documents that show "how" to deploy such a philosophy.

 

Chapter President Brian Hagopian provides a Chpater update prior to the presentation.

 

E2500 philosophy says there is nothing special about validation, where the starting point follows ICH Q8 whereby a product is assigned a series of CQAs (Critical Quality Attributes) and the manufacturing process that makes it a series of CPPs (Critical Process Parameters) to control the CQAs.  Those CPPs in manufacturing (components, instruments, process control elements, alarms, data, etc.) are then identified and designated in accordance to ICH Q9.

 

This then presents an entire continuum between two extremes.  On the one hand is the traditional full commissioning followed by a full IQ/OQ/PQ, and on the other is the fully integrated verification ASTM E2500 advocates.  Most companies, in reality, adopt an approach somewhere in between.  Jack then presented scenarios that have been used, especially when "disaster" strikes.  All integrated C&Q models require that a project follow Good Engineering Practices (GEP), thus the number of changes during C&Q should be relatively small.  However, this requires that both the design and change management scheme be robust.

 

How does one implement a good E2500 based integrated verification model?  Again, Jack offered two models that have been used.  Model 1 is the Repeat Protocol model.  In this model, commissioning is assessed, protocols are written and placed under change control, and the work summarized in reports.  During qualification, only discrepant portions of commissioning are repeated after a review of the commissioning package.  Jack gave an example of using a 5% AQL level, whereby 5% of the commissioning was repeated.  The audience discussed the pros and cons of such an approach, which then led to Model 2.

 

Audience interaction adds another dimension to the information   exchange.

 

Model 2 is the Risk Based Scheme, which still uses the commissioning package as a starting point, with analysis and assessment, but the qualification is based on the Critical Aspects traceability matrix to guide the testing.  The testing can still be at the 5% level, however, it is now selected and prioritized based on criticality, namely, risk.  Assuming good commissioning, qualification should be fast and result in a package that demonstrates everything was properly commissioned and all CPPs have been achieved.

 

For each of these models, Jack presented a case study.  He also asked questions about how a full E2500 implementation would work.  This seemed to pique the interest of many in the audience, especially those who are at the forefront of using this approach.  Because of the newness of E2500, there have not been sufficient data gathered in the industry to show "what is the payoff" and "how to do we justify our recommendation to our clients?"  Because ISPE C&Q CoP members were also present in the audience, they got this feedback to take back to their community for further expansion and discussion.

 

Jack ended the lively evening by sharing the valuable lessons learned in his C&Q career - when to perform certain tests at critical junctures in a project based on GEP and common sense, tips on commissioning protocols and - possibly the most important lessons of all - successful C&Q starts with good, smart design.  Do not skim on design reviews, which should engage all subject matter experts and encourage healthy rigorous debates, collaborative and clean handoff from design to construction to commissioning and qualification (no tossing over the wall) and do not outsource commissioning but rather use it as a training opportunity to retain the expertise in house.