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January 2019 - Current Topic

Note:  This document expresses Dr. Jenke’s personal views and opinions and is not a position established and supported by Triad Scientific Solutions LLC.  This document is not professional advice and does not constitute a professional service provided by either Dr. Jenke or Triad Scientific Solutions.       


Thoughts on What Constitutes Good E&L Science in 2019

Although it seems that the world of E&L is in constant and continuing flux, I believe that we have reached the point where our community of science can adopt standard practices that once seemed to be more of a dream than a reality, specifically in the area of analytical screening for organic extractables or leachables.  

It was not too long ago that objective observers of E&L practices would note three areas where screening extracts for extractables (or drug products for leachables) were sub-optimal:

  1. Too often, screening strategies failed to provide useful information about extractables/leachables either because:

    1. The strategies failed to respond to all extractables (or leachables), or

    2. The strategies failed to produce information from which the extractable’s identity could be inferred or the extractable’s concentration could be estimated.

  2. The identifications secured by screening strategies were predominantly tentative.

  3. The concentrations secured by screening strategies were more estimated and less quantitative. 


We are now at a point where we are capable of better and in fact where we are expected to be better.  In this “new reality”:

  1. It will be rare that screening strategies fail to provide useful information about extractables/leachables either because:

    1. The strategies will to respond to a vast majority of the most commonly encountered extractables (or leachables), and

    2. The strategies will almost always produce information from which the extractable’s identity could be inferred or the extractable’s concentration could be estimated.

  2. The identifications secured by screening strategies will be predominantly confident and often-times confirmed.

  3. The concentration secured by screening strategies will predominantly be semi-quantitative and more frequently fully quantitative. 


In considering the details of the transformation from past to future practice, it is appropriate to consider what served as the transformation’s catalyst.  Yes, there have been advances in analytical practices, better individual methods and better use of orthogonal and complementary methods to “fill in the gaps” that exist in even the best individual methods.   Yes, instrument vendors have produced better, more powerful instruments with greater information content, greater sensitivity and greater selectivity.  But these are not the catalyst, they are merely enablers.  The true catalyst has been … experience.  Each time we got a “bad TOC reconciliation” (for example) and used alternate methods to find the missing extractables, we went back to the screening approach and “filled in the gap”.  Each time we encountered an unidentified substance, secured an identity and then collected the information necessary to support or confirm the identity, we added one more compound to the “list of confident or confirmed IDs” and shortened the list of “tentatively identified (or unidentified) substances”.  Each time we injected an authentic standard and obtained a relative response factor, we transitioned from a “concentration estimate” to a more accurate and precise “semi-quantitative concentration”.  The more studies we did and the more times we took these actions, the closer we became to being able to embrace the future state.

However, the mere generation of this information is an inefficient enabler of the “new reality”.  The true transition from past to future is possible only when the information is collected, collated and archived in a format that facilitates its use in routine analytical practice. This format is termed, for lack of a better word, a database.

Again, it was not too long ago that laboratories, both internal and external to traditional pharmaceutical companies, could establish their “degree of competence” based on whether they even possessed some sort of E&L “database”, regardless of its size, contents and form (how many of you remember the individual “cheat sheets” we used to have on ID’s and response factors?).  Today, it is the size, the contents and the format of the database, both in terms of information content and information credibility, that is the measure of a “state of the science” analytical capability.

It stands to reason that the assessment of the impact of a leachable (or the potential impact of an extractable as a leachable) is “better” the more confident we are in the leachable’s experimentally determined identity and concentration.  Some organizations have the information and the tool(s) to provide more and better identities and concentrations with a higher degree of confidence.  As more studies supported by this information and these tools are performed and reported, what was once “nice to have” will become “necessary to have”.  This transition from “nice to have” to “necessary to have” will itself serve as a further catalyst for the development, population, proliferation and application of larger, more information-rich and more robust E&L databases.  And the industry we support, the drug products and medical devices we produce and the patients we serve will be better off because of it. 


 At a high level, two circumstances must exist for a packaging system to be a relevant source of elemental impurities in a packaged drug product:

  1. Packaging systems must contain sources of elemental impurities in the first place, and

  2. Those elemental impurities that are present in the packaging must leach out of the packaging and into the drug product during system/product contact.


Considering these circumstances, a team of authors representing the Extractables and Leachables Safety Information Exchange (ELSIE) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) published a review of published extractable metals data for plastic and glass packaging systems and concluded that:

  • Unless the elemental entities are parts of the materials themselves (for example, SiO2 in glass) or intentionally added to the materials (for example, metal stearates in polymers), their incidental amounts in the materials are generally low.

  • When elemental entities are present in materials and systems, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products.


These conclusions reinforce what I believe is a common opinion among E&L experts, which is that “there is generally a low risk of adverse product effects arising from metals leached from packaging systems” and thus that “monitoring or qualifying packaging systems with respect to extractable metals is, in many circumstances, unwarranted and unnecessary, especially if the packaged drug product is going to be assessed for elemental impurities anyway”.  


While I would not necessarily disagree with this point, I would make two counterpoints.  Firstly, it is my opinion that while the dataset supporting this conclusion was comprehensive, it reflected only that information which had been published at the time the review was written.  Personally, I am not 100% convinced that the information contained in the article is sufficient to be the sole basis of such an impactful policy as “no extractable metals testing required for packaging”.  Perhaps a larger and more complete database of information will allow the scientific community to draw a conclusion, one way or the other, with respect to extractable metals testing of packaging.

The second point I would like to make is that “low risk is not no risk”.  In fact, certain elements in certain circumstances can leach from packaging and can have an undesirable impact on a key product attribute.  I do not know how to properly respond to individuals who ask “in the absence of testing, how are you going to reveal known or currently unknown and unanticipated product – leached metal interactions?”.  But I know this: no one wants to be the next case study that everybody is talking about on the E&L circuit in terms of “we do E&L testing to prevent this from happening”.


Let us imagine the situation where it has been established that extractable metals from packaging is such a low risk that packaging systems and/or their materials and components of construction do not have to be screened for extractable metals.   The question then comes up “how will this conclusion be captured in the “official” guidelines, guidances and standards?” For example, as it currently stands, USP <661.1> contains mandatory extractable metals testing for polymeric material used in packaging.  Would it be proper for the USP in either <661.1> or its companion document <1661> to state that “extractable metals testing is not necessary” by either directly making this statement or indirectly by removing extractable metals testing? 


My opinion is that this would not be proper because it is not <661.1> that establishes the need to consider metals leached from packaging in the context of elemental impurities.  Rather, it is Q3D and <232> that establish the packaging system as a potential source of elemental impurities and requires that packaging systems be assessed to control elemental impurities.  Thus, if it were ever decided that the risk of extracted metals from packaging (or packaging material and components of construction) is so low that testing packaging (or materials or components) for extractable metals is not required, the proper place to capture this point would be the very documents which raise the issue in the first place, meaning Q3D and <232>.   In such a circumstance while it might be proper for both Q3D and <232> to mention packaging as a potential or theoretical source of elemental impurities, it would also be necessary for the same documents to note that the risk is low and thus that routine screening is not required.

Alternatively, let us imagine a situation where it has been established that the risk of extracted metals becoming elemental impurities is sufficiently high that packaging systems and/or their materials and components of construction must be screened for extractable metals.  In this case, four questions are relevant:

1.    What articles should be testing? (e.g., materials, components, and/or packaging),

2.    How should the articles be tested? (e.g., digestion or extraction and under what conditions),

3.    What elements should be targeted in the testing?  (e.g., “The Big Four”, the “entire periodic table” or something in-between),

4.    How should the results of the testing be reported and interpreted?  (e.g., specification limit, reporting threshold and at what level).

 At times I think it would truly require the wisdom of Solomon to provide answers to these four questions which are (a) scientifically valid, (b) practically implementable and (c) acceptable to the many and varied stakeholders who have a stake in this subject.  For those individuals and organizations who are trying to find that wisdom, I say good luck and god-speed and I thank them for their efforts.

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