Ahead of this year's Extractables & Leachables Asia, we spoke with Dennis Jenke, Chief Executive Scientist at Triad Scientific Solutions,​ learn more about what he shared with us below!






Q1    What are the key challenges in designing standards and guidelines for E&L?
 
I will start with what I think is the most significant problem facing our community of practice.  Perhaps surprisingly, it is the name “E&L”.  The pervasive use of this name has produced the mindset that extractables and leachables are somehow joined at the hip, meaning that there must always be extractables plus leachables and that somehow extractables and leachables are intimately related.  In fact, I would suggest that there are circumstances, many of them commonly encountered, where there can be extractables but no leachables and also leachables but no extractables.  Furthermore, I can think of many cases, especially with aggressive extractions, where the logical link between extractables and leachables have been broken, for example when the conditions of extraction bear no resemblance to the test article’s clinical conditions of use.  
 
Moreover, the challenges in extractables and leachables are different.  In extractables, the challenge is all in the extraction; that is, how to perform the minimum number of properly designed and justified extractions in the shortest period of time to be able to forecast leachables. Extractables studies are generally designed so that the analytical testing can be accomplished.  In leachables, the challenge is almost always analytical, as the “extraction” in a leachables study is simply “age the packaged drug product over its shelf-life” or “leach the medical devise by a process that mimics the way the device is used clinically”.   The challenge of leachables is analytically complex and challenging drug products or body-simulating leachates, leachates that destroy the testing equipment, and unachievably low AETs.  

Secondly, we are, as a community of practice, risk-adverse.  There is much talk about “risk-based approaches” but when it comes down to it, we are willing to accept very limited risk.  This has two consequences.  The first is that we design studies for the worst possible case imaginable, knowing full well such cases are rarely encountered.  This occurs in the experimental design (most aggressive extraction possible), in the analysis (lowest possible AET adjusted with the largest possible uncertainty factor), and in the assessment (we safety assess for the infrequent  patient who requires an atypically large dose to manage an atypically extreme medical need). Thus, for the total study we have compounded worst-case upon worst case upon worst case, ending up with such complex studies that instead of doing a good job we are forced to make difficult decisions, adopt flawed generalizations, and  make unwise compromises.  
 
It is to address this worst-case upon worst-case upon worst-case that everybody is encouraged (required) to perform the same really difficult study (or series of studies).  In most cases, the circumstances are not nearly as extreme as the compounded worst case and people find themselves performing impossibly complex studies to address relatively simple situations and ending up with extractables profiles that have no relationship to the reality of leachables.  How can we as a community lament about how many unknowns we find when we continue to extract test articles with solvents and under conditions that they were never designed to handle and which they never encounter clinically? 

No, we must stop this mindset that says “everybody has to test to this challenging compounded worst-case standard”.  Rather, we must adopt a mindset that says “a vast majority of us can adopt a standard based on reasonable conditions of use and only those who finds themselves outside these conditions have to do more”.     
 
The second challenge is unnecessary and redundant testing.  It is a true statement that one encounters many innovative materials in packaging, medical devices, and manufacturing components.  However, it is also true that one encounters many of the same materials in these applications.  For example, as a consultant in this discipline I have had many occasions where I have clients who are all using the same stopper for their vial products.  It is illogical and unconscionable that each of these clients must perform an extraction study to support the use of a material that has already been approved and has a history of safe use, for a similar use in similar circumstances.  It is major shortcoming of our community of practice that we have not embraced the concept of materials that are “generally recognized as safe” and have not produced a mechanism by which such materials can be declared to be GRAS.
 
Lastly, perhaps the greatest challenge is out inability to collaborate.  I do not know why this is.  However, as a community we are talkers first and listeners second.  We let our egos get the better of us and fall into the “not invented here” and “I am smarter than anyone else” mindsets.  We fall into the trap of vested interests and cannot grasp the point that in fact we all have the same interest, developing inexpensive, effective, and safe medical and pharmaceutical products that improve the human condition.
 
Listen, there is no single person or organization that has all the answers.  Conversely, there is no problem that we face where someone has not figured out a really good answer.  If we could be patient long enough to find these people and just shut up long enough to truly listen to them, then what we find so challenging today would become so simple, so practical, so elegant, and so valid in the future. 

Q2    How do you balance scientific generalizations with the need for practical standards?
 
Scientific generalizations and practical standards are imbalanced only when (a) there is a disagreement in terms of the science supporting the generalizations and (b) when the standards are based on unnecessarily compounded worst cases.   In the case of (a) the “solution” is to be open to the reality that there is likely someone out there smarter than me and who has “a good answer” to the question I am struggling with, to actively identify and seek out those smarter people, to listen to those people when we have found them, and then to be willing to compromise to produce an outcome that is as equitable and manageable to all interested parties as possible.  We must understand that compromise does not mean ”I shout my opinions loudly and often enough that others let me have my way to just shut me up” or “it’s my way or the highway”.  Rather, compromise means sometimes you have to give a little to get a little.   
 
In the case of (b), we must understand that in many situations, safety is not a real issue and what we are doing by our testing is not establishing safety but rather confirming safety.  Surely the testing required to confirm safety is less burdensome than testing required to establish safety.  If we can develop reasonable standards that cover the most common case of confirming safety and require that safety be established only in the more atypical circumstances, then we will be able to balance scientific generalizations with practical standards.

I also want to comment how it is possible to distort science to the extent that the distortion results in unrealistic standards.  It is human nature, I believe, that we publish or present the most sensational cases.  For example, no one publishes the most commonly encountered studies where the outcome is “we found the same old extractables all at safe levels”.  How boring! Rather people publish the sensational cases where the extractables cause a profound effect, or were challenging to identify, or were unexpected.  Now please do not mis-understand me, there is nothing wrong with doing this communication and our community of practice benefits greatly from such shared knowledge and experiences.  However, it is possible to get a distorted sense of reality if one concludes that these rare exceptions are somehow actually the norm. With such a distorted sense of reality, one could develop standards and recommend practices that manage the exception and not the rule.

Q3    What advice would you give to young scientists entering the E&L field?
 
My first piece of advice will surprise everyone because I am going to tell these young scientists that they must remember that E&L is not all about the science.  E&L is not doing a Ph.D. thesis.  E&L is not the ideal world where one generates an overwhelming quantity of corroborating and unequivocal data to prove, beyond any reasonable doubt, the hypothesis that the drug product or medical device is safe for its intended use.   E&L is not a world where all the interested parties share an equal understanding of the essential scientific principles that “govern” E&L or even a world where these parties agree in terms of what these principles are or how they should be interpreted and applied.   
 
Thus, my first piece of advice is not about science but rather about effective communication.  I offer three points:  (1) that successful E&L is as much about how the story is told as it is about what the story is, (2) it is OK to think you are the smartest person in the room and that you know it all but in fact there likely is someone in the room who is smarter than you and no, you do not know it all,  and (3) you aren’t really listening to the other person if all you are doing is talking and you can’t be an expert if you ignore everything that others are doing.
 
My second piece of advice is to reiterate that E&L is a team sport.  There are a lot of very smart people in the E&L community of practice and one can learn as much about E&L by listening to them as one can by spending their lifetime in the lab doing experiments and gaining “the ultimate E&L knowledge”.  If you are one of those very smart people, then share your knowledge with everyone else.  If you meet with resistance, be humble but strong. But check the ego and the “not invented here” attitude at the door and the do not dwell, publicly or privately, on “why don’t they get this?”. 
 
Finally, the third piece of advice actually addresses science.  An E&L expert is not only an analytical expert, a toxicology expert, a material science expert, or a regulatory affairs expert. While an E&L expert may have a specialty or strength, the expert is, first and foremost, a jack-of-all trades, highly knowledgeable in these and other scientific (and maybe not so scientific) disciplines that all are involved in generating and interpreting E&L data.  Although a triathlete does not necessarily have to be a world class runner to succeed, I can guarantee you that the triathlete who sinks like a rock in the water will not win many events. The same is true of the E&L expert who can turn lead into gold only to find out that the only form of acceptable payment is silver.  What I mean by this is the following.  To be a successful E&L scientist, I do not need to be the smartest mass spectrometrist on the planet (for example).   However, I can never be a successful E&L scientist if my knowledge of mass spectrometry is deficient.