Why aren’t leachables treated the same as other pharmaceutical impurities?

For this month’s blog, I thought I would discuss a topic area which from time to time discussed but really (at the moment) has not been resolved - Why aren’t leachables treated the same as other pharmaceutical impurities?

Unfortunately, if you are looking for a clear answer it is probably best that you stop reading now! Nevertheless, I will attempt to present some of the arguments and feel free to comment.

I guess I should begin with some context, impurities in pharmaceuticals are mostly covered in two ICH Quality Guidelines. ICH Q3A(R2) – Impurities in New Drug Substances and ICH Q3B(R2) – Impurities in New Drug Products (both last updated in 2006). I say mostly since, if you read these documents, there are a remarkably large number of items which they say they don’t cover this includes:

  • Biological/biotechnology

  • Peptides

  • Oligonucleotides

  • Radiopharmaceutical

  • Fermentation products

  • “Extraneous contaminations”

  • Enantiomeric impurities

  • Impurities arising from excipients

And most importantly for this blog, “…extracted or leached (impurities) from the container closure system are not covered…” – taken from scope section of ICH Q3B.

You can also add to this solvents, metals and mutagenic impurities as these are covered by ICH Q3C, ICHQ3D and ICH M7 respectively.

So guess that is problem #1 Existing guidance on impurities says it's not applicable to leachables

Now we have that out the way we can begin to discuss the main point why aren’t leachables seen as the same as other pharmaceutical impurities. Well I suppose another point to add is sometimes they might be.

Problem #2 Leachables can cover a very wide variety of substances

If a leachable is a solvent or a metal, chances are that they will be captured and covered by those existing ICH guidelines, the reason for that being it may be very difficult to assign an impurity to a source and as far as the patient is concerned is unimportant because they are still be exposed to them regardless of source. Another interesting example is where a leachable reacts with the API, in that situation the substance is treated as an impurity and would be covered by ICH Q3A or B.

Problem #3 Existing guidance is somewhat contradictory

ICH Q3A classifies impurities in several ways such as:

  • Organic impurities

  • Inorganic impurities

  • Residual solvents

The last two are captured by there own ICH guideline, the first one is then sub-divided further into manufacturing process and/or storage of the API:

  • Starting materials

  • By-products

  • Intermediates

  • Degradation products

  • Reagents, ligands and catalysts

I also want to stop here and talk about mutagenic impurities. It was realised that some of the impurities used in the synthesis were potentially mutagenic and others were not, many of these were small organic substances used in the synthesis. That sounds a lot like molecules we find as extractables and leachables doesn’t it?

ICH M7 was introduced to clarify what approach and thresholds were needed for mutagenic impurity because it was felt ICH 3A/B did not adequately address the risk.

In fact, leachables are much less likely to be the same as the very reactive substances that are potential mutagens. The universe of leachables may rarely include some potentially mutagenic substance but the large majority are low toxicity substance used in materials which are low hazard and widely used in other areas such as food and medical devices.

So, what is the argument for not treating them the same as drug impurities. Well there are a number of points

1. Some of the impurities will be chemically very similar to the API (but not all) – this leads to the view that any toxicology for these impurities will be similar to API, unlike leachables

2. The drug impurities will likely be included when the drug is tested pre-clinically and clinically so toxic effects and adverse events will cover these substances, unlike leachables which may introduced later from final container closure systems or modified manufacturing process

However, many of the starting materials and reagents are very different from the API (like leachables) indeed if antioxidants are used or solvents, they might be the same exact substances.

So coming back to mutagenic impurities, ICHM7 is intended as a complementary guidance to Q3A and B. It provides risk-based threshold limits below which these types of especially toxic substances are considered to present a negligible risk to patient exposure. M7 points out that is generally considered that non-mutagenic substances have higher limits of action. Indeed, the TTC concept has very large and conservative uncertainty factors and its lowest intake is set at 1.5µg per day exposure assumes a lifetime of exposure.

So, what should be the right mechanism of control for leachables? If you followed the existing ICHQ3A/B approach that could see an acceptable intake for leachables at 1mg per day but this limit is for a biological assessed (and qualified ) impurity and definition which needs clarification for leachables.

If ICHM7 is deployed, you are using assumption which potentially significantly overestimate the risk from a substance, especially from substances which have been fully identified established to be absence of toxicologically significant structural features.

Several groups have worked to define safety thresholds for substances (most notably PQRI), and these are typically centred around knowledge and understanding of physiochemical properties and the chemical

structure and well as existing databases of toxic substances. It is clear that, this is a complex and demanding area since no-one wants to put patient safety at risk. But the calculation of actual risk, can be very challenging when information and knowledge is limited.

Unfortunately many substances have limited or no safety information particularly if they are not considered hazardous with the drive to less animal testing not more, it unlikely that direct testing toxicity testing will be done. So a threshold based upon a structure–activity relationship (SAR) that is the relationship between the chemical structure of a molecule and its biological activity seems a likely way forward but these approaches are still being developed and currently do not adequately cover every toxicological end-point

So to summarise:

  • Existing guidelines struggle to cover leachables as impurities in pharmaceuticals

  • The guideline scope does not cover all of the dose forms in which leachables might be found

  • The guidance, might be appropriate for some kinds of leachables but the published guidelines do not explicitly cover them

  • The general lack of toxicological information means threshold concepts such as used for mutagenic impurities are probably needed, but there is currently no one agreed approach

So, I would conclude this blog by expressing the hope that the upcoming work on ICH Q3E, considers a balanced approach which focuses them on alignment, consensus and clarity when they write their guideline. Leachables are clearly impurities (nobody wants them to be present) so it's very important that existing and new approaches are considered for inclusion in a definitive guidance which covers leachables of all kinds.

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