Why does the management of impurities scare people?

A recent survey suggested that out of all CMC topics the one at the forefront of many people’s minds and concerns is that of impurity control.  Why might that be the case? After all there is a strong framework provided by ICH in the form of ICH Q3A / Q3B (Impurities in drug substance and products), ICH Q3C (solvents) and the most recent guideline ICH M7. In my mind this is because however good the framework there is always the need for interpretation, examples of this include:

  1. ICH Q3A / Q3B have defined qualification limits, within ICH Q3A for drug substance where the dose is <2grams these are: 1mg or 0.15% whichever is the lower. These however relate to lifetime limits, what about during clinical development where study durations are << lifetime? Beneath this also sit a series of fundamental questions regarding the actual conduct of preclinical studies – e.g. study duration / animal species / impurity or drug substance spiked with impurities – all these and many other questions exist.

The issue of durational limits was examined for the first time in a paper by

Harvey, Teasdale et al. Regulatory Toxicology and Pharmacology 84 (2017) 116-123.

  1. ICH Q3C – How do a define a limit for a solvent currently not addressed in ICH Q3C?
  2. ICH M7 – where do I start within the synthesis / how does M7 apply to anti-cancer treatments, what is a probable impurity?

These and many other questions are addressed in a recent book, ICH Quality Guidelines – An implementation guide – Edited by Teasdale, Elder and Nims (see link) published by Wiley and Son.  They are also addressed in a two day intensive course run by Andrew Teasdale (see details) which look at all key impurity areas and looks to define how a systematic approach to impurity risk assessment and control can be developed and applied.

Also of note is the tremendously exciting breakthroughs within medicines, the shift from treatments that address symptoms to those that are truly disease modifying.  Many of these involve new modalities that involve novel therapeutic agents such as Oligonucleotides, mRNAs, Antibody drug conjugates.  These bring unique challenges, particularly in the context of impurities, in some cases introducing the need for a completely new mindset as to how to define even what an impurity is.  A recent paper issued under the banner of the Oligonucleotide Safety Working Group examined this in relation to Oligonucleotides, defining for the first time a systematic means by which impurities could be grouped, classified and qualified, Capaldi et al, NUCLEIC ACID THERAPEUTICS

Volume 27, Number 6, 2017, DOI: 10.1089/nat.2017.0691.

Despite the concerns and the new challenges we face I remain of the view that impurities can be readily controlled at appropriate safe levels provided a clear, systematic, risk based approach is taken and it this I have tried to convey both through the book and courses described.