Exclusive interview with Dr. Dennis Jenke, Baxter Distinguished Scientist, Baxter Healthcare

15 November 2011

1. As a chair of the PQRI PODP chemistry team you are in a key role with respect to the paradigms of this project. As this group is moving forward - what do you consider as crucial issues and their impact for the community once the work result will be published?

Firstly, I will point out that the PODP team is working closely with other organizations that are considering the many aspects of chemical safety assessment and thus what the community should be looking forward to is not the outcomes of the individual groups but rather the molding of these individual outcomes into definitive and actionable science-based strategic and tactical guidelines and recommendations.

Nevertheless, the mission of the PODP team is to translate, or extrapolate, if you will, the recommendations related to the generation and toxicological interpretation of chemical data from one specific dosage form category (OINDP) to another dosage form category (PODP). One aspect of this mission is to identify, generate, as necessary, and interpret the scientific information upon which such recommendations are based. Thus members of the PODP chemistry team are in the lab right at this moment examining how such variables as extraction solvent, extraction method and analysis method impact the apparent extractables profile of materials commonly utilized in PODP applications. One can anticipate that such information will be utilized to support best demonstrated practice recommendations that define how to perform effective and efficient extractables studies for PODP. Shortly, the team will go back to the lab and study the leaching of a model packaging system constructed from several of the materials that had been assessed for extractables. Such a study will provide insight into the nature of the correlation between extractables and leachables.


2. Demonstrating the safety of a container closure system for a given drug product affords conclusive guidance and strategies for various fields like binding and non-binding regulations (recommendations), chemistry and toxicology. What are currently, from your perspective, the most significant gaps which need to be closed?

I think there are several strategic and scientific gaps that need to be closed. The strategic first gap is the understanding that E&L is not a single step in a product development process but rather is a key part of the product development process. That is to say that E&L is not something that happens as a specific event on a timeline in the product development process. Rather, certain aspects of E&L most logically occur at different points in the product development process. If these aspects are allowed to occur at their logical points in product development, safety risks can be retired early and the safe assessment process can become more effective and efficient.

The second strategic gap is our own fault at using "lazy" terminology. The term "E&L assessment" as opposed to "chemical safety assessment" is harmful in two strategic perspectives. Firstly, it fails to recognize that there is a third quantity, intentional and unintentional additives, which is a precursor to, and an early predictor of, both extractables and leachables and that an effective and efficient safety assessment strategy includes a step where ingredients are specified and evaluated. Secondly the term E&L implies that if there is an extractables assessment then there will always be (and there always must be) a leachables assessment. One can envision situations where extractables assessments are an end unto themselves and would not require supporting leachables work to effectively and appropriately establish safety and, conversely, where leachables assessments could be effectively and efficiently implemented without rigorous and comprehensive extractables studies.

The two historical gaps in the science of E&L have been "how low do you go?" and "how do you know when you are done?" As the "how low do you go" question is being actively addressed by several ongoing efforts, I suspect that a widely applicable and useful answer will be provided shortly. I see the second question to be the more significant because it is not being actively debated. That is to say, that E&L assessment is almost universally practiced in the following manner. Multiple orthogonal analytical methods are utilized to screen extracts and/or drug products for "extraneous" substances (e.g., extractables or leachables). Certain analytical methods are almost universally used in this task; for example, GC/FID/MS, LC/UV/MS and ICP. These analytical methods are developed to be broad in scope and sensitive and are implemented so that that all relevant responses are addressed and run to ground. At the completion of the analytical exercise it is concluded that the extractables (or leachables) profile has been effectively and completely elucidated.

However, this thinking is self-serving in that it assumes that the applied methods are intrinsically capable of responding to all extractables (or leachables). As the universe of materials used in pharmaceutical applications is large and diverse, it is reasonable to conclude that the universe of extractables and leachables is also large and diverse. It is thus illogical thinking to conclude that a screening exercise will capture all potential extractables and leachables. Thus a gap in current extractables/leachables studies is doing the testing, or collecting the information, that provides the evidence that nothing eluded detection and "fell through the cracks"

3. What is your personal vision of the E&L world in 2015 and beyond?

Beyond 2015 I see an E&L world that is clearly structured in terms of the process of assessing the direct safety impact of packaging systems and which enjoys unprecedented collaboration between material vendors, drug product vendors and regulatory authorities. By 2015, industry-driven organizations such as the PODP, ELSIE, BPSA and others will have completed their missions and will have published not only best demonstrated practice recommendations but also the foundational science upon which recommendations will be based. Consistent with their mission, these and other organizations will compile informational databases which will greatly facilitate and serve to standardize the entire safety assessment process, including the generation and interpretation of chemical data. By 2015, these organizations will have had the opportunity to work out any minor inconsistencies in their recommendations and will have found a way to weave their individual works into a comprehensive, consistent, effective and efficient means for assessing safety. Acting in concert with these industry-driven organizations and benefiting from their own knowledge and experiences, regulatory agencies, including the USP, will publish guidance that is actionable, specific, rigorous and equitable, meaning that the guidance will properly balance the desire to minimize risk with the recognition of the practical limitations of even the most rigorously practiced science.

At the same time that E&L science is solidifying, the absolute need for E&L assessment will decrease. Let me explain what I mean here. In the past, E&L horror stories have surfaced as "older" existing material formulations have been characterized. As such formulations may have been developed with little or no regard for E&L, it is logical that such horror stories would exist and thus that the regulatory environment would adopt a strategy of "we cannot let that happen again". However, as the issues related to E&L have been recognized and discussed, it is now the case that (a) new, "low extractables" materials are more common in the marketplace and (b) material vendors more routinely supply high quality extractables data with their materials. As the foundation of ensuring the safety of packaging is (a) to use safe material and (b) to use materials that are well-characterized, the industry is moving to a place where E&L testing is more a means of confirming the accepted fact that the packaging is intrinsically safe and less a means of minimizing the risk that the packaging might be unsafe. Thus I see that E&L testing will evolve away from the means of identifying, managing and, where necessary, eliminating "bad actor" materials and more towards the means of systematically confirming that materials are as safe as they were intentionally developed to be.

While the assessing of the direct impact of leachables on patient safety will be a well-understood and a well-managed process in 2015, the assessment of secondary interactions will still be very much a work in progress at this time. While it is well-recognized and well-documented that such secondary interactions exist, the state of the science with respect to understanding, predicting and managing these processes is not at a point where the issue of secondary actions can be effectively managed. For example, while one can confidently predict the direct safety impact of leachable x found in drug product y, it is not possible to predict that leachable x will react with the ingredients in drug product y to either make them (a) subpotent or (b) unsafe. At the current time, such incompatibilities are addressed retroactively based on precedent. In the future, such incompatibilities will proactively be predicted based on sound scientific principles.


Dr. Dennis Jenke will be presenting insights into the identification, qualification and utilization of external resources for E&L studies and into the genesis and use of the Safety Assessment Triad.

Find out more on his presentation and other topics being discussed at E&L 2011 from the full agenda.

View further details on all speakers at E&L 2011.