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It's been a little while since my last E&L blog and the world of extractables and leachables (E&L) continues to evolve. For example the United States Pharmacopeia (USP) has published revisions to their chapters on Biocompatibility Testing through its PF Online forum. It should be noted that these documents in PF Online are not official and not suitable to demonstrate compliance. They may never become official but represent a possible future chapter. So, in reviewing these chapters I thought it would be interesting to reflect on the changes they are attempting to introduce. The revision I am discussing was published to PF47(4) in July 2021 and is open for commenting until end of September 2021.
There are a number of chapters which they are considering revising (USP <87>, USP <88> and USP <1031>). In particular USP <87> and <88> have remained without significant revision for the last 40 years. In reviewing the two chapters, it is evident (to me at least) that the scale of their problem in revision is quite high.
For those which are unfamiliar with each chapter I will do my best to summarise but I do suggest you read each for yourself.
USP <87> is a collection of in-vitro tests to determine if a material or extract from a material might show "biological reactivity". This reactivity is judged by a graded scoring of the appearance of mammalian cell cultures after contact with afore mentioned material or material extract.
USP <88> is an in-vivo version, whereby extracts are injected into animals in a various ways and the responses are once again graded. Additionally, there is provision for surface implantation of plastic parts to assess reaction.
As of Dec 1st, 2020 USP <1031> provides guidance (it is a > 1000 chapter) for biocompatibility in different systems, the suggested revision published to PF47(4) in July 2021, attempts a significant revision in several places including:
A change in title to “The Biocompatibility of Pharmaceutical Packaging/Delivery Systems and Their Materials of Construction.”
An Expansion in scope to encompass plastic materials of construction and plastic and elastomeric components
A removal of the classification system linked to USP <88>
Introduction of a risk based approach to the evaluation of biocompatibility
So, returning to why these chapters are in need of revision. As I previously stated both <87> and <88> reflect both test methods and approaches unchanged for 40 years.
For example <87> is in no way a quantitative measurement, the graded system relies on opinion as to whether "biological reactivity" is present and indicated from observation. Using words such as slight, mild, and severe. The general requirement is a monitoring of cytotoxicity. Surely there are now better methods?
USP <88>, has perhaps an even wider range of issues. The very fact that it is an in-vivo based method raises questions. Is it really necessary to use in-vivo test methods to assess pharmaceutical packaging when there are alternatives available? That aside, the assessment criteria in the main, once again seem very subjective and thus not useful enough to justify the use of laboratory animals. End points which point to grading redness of the skin (ertherma) and swelling (edema) are perhaps not particularly inciteful or impactful in justifying the need for testing. The implantation test is similarly reliant on acceptance criteria which judges an encapsulation width scoring of a period of 120hr. Is this really of any benefit in determining a prediction of implant biocompatibility?
Does this really reflect the principles of 3R (Replacement, Reduction and Refinement)
Thus USP <1031> seeks to introduce alternatives but they have not dealt with the faults in <87> or <88> which seems to me a missed opportunity. I applaud the attempt to revise these chapters, particularly the removal of classification system that had the un-intended consequence of seeing most pharmaceutical material tested to Class VI regardless of application. However, more effort is needed to modernise the overall approaches in this area. Well though out leachable risk assessment is for me the answer. USP <1031> has started to suggest this but needs more added to bring clarity and reason to change.
If you feel the same or differently, I suggest you comment on the USP proposals in the forum or here.