“Organic Impurity Profiling” for Drug Products versus “Leachable Studies”

Dr. Piet Christiaens, Scientific Director at Toxikon Europe, speaks exclusively to Smithers Rapra on “Organic Impurity Profiling” for Drug Products versus “Leachable Studies”:


Organic Impurities are critical quality attributes of drug substances and drug products because they have the potential to affect safety and efficacy.

Organic Impurities in drug products can originate from:

  • Expected & Unexpected degradation of the Active Ingredient (AI degradation compounds)
  • (genotoxic) impurities, present as a result of the synthesis of the active ingredient. (solvent residues, catalysts, reaction products in synthesis, intermediate synthesis compounds...)
  • Chemical Compounds, introduced into the drug product as a result of an interaction between the primary packaging and the drug product (Leachables).
  • Chemical Compounds, introduced in the drug product as a result of the contact between processing materials and the product stream (storage bags, filters, tubing materials...)
  • Secondary Leachables, being formed as a result of a chemical reaction between a leachable and drug product components (Active Ingredient, Excipients, Adjuvants, Preservatives...).
  • Leachables, coming from the secondary packaging (label, ink, adhesive, overwrap, cardboard boxes...)
  • Impurities, introduced into the API during intermediate storage. (Leachables from drug substance containers)
  • Drug product ingredient impurities (Active Ingredient, Excipients, Adjuvants, Preservatives). These could be - but are not limited to - processing impurities, catalyst or solvent residues, degradation compound of the ingredient and leachables of the containers used for storage of the ingredients.

The origin of the impurity may also determine which guidelines (and associated control limits) to follow in the final evaluation of the drug impurity. Relevant guidelines may include ICH Q3A (Impurities in New Drug Substances), ICH Q3B (Impurities in New Drug Products), ICH Q3C (Impurities: Guideline for Residual Solvents), ICH M7 (Assessment and control of DNA reactive impurities in pharmaceuticals to limit potential carcinogenic risk), or PQRI-PODP (under development), PQRI-OINDP, EMA (Guideline on plastic Immediate Packaging materials; 2005) or FDA (Container Closure Guideline; 1999) when it comes to Leachables.

Although there is some guidance on how to perform an (Organic) Impurity Profiling Study, this assessment is often based upon:

  1. An evaluation of the process and the potential impurities that may arise as a result of a certain process step. As a result, these impurities that may "potentially" be present are listed, and suitable analytical methods are developed to verify their presence in the drug product. In other words, this approach becomes a "targeted" analysis approach.
  2. For a lot of Analytical Investigations (eg ICH Q3A and ICH Q3B), the pharmaceutical industry mainly still relies on HPLC-UV in the assessment of Impurities (API related), which may not always be the best suited technique to verify the presence of organic impurities at trace levels.

Because of the targeted nature of the Organic Impurities profiling, and methods employed in performing such studies, it is obvious that one may potentially miss the presence of unexpected organic impurities at low concentrations.

Leachable Studies, and in particular "screening" leachable studies, may assist in establishing a broad organic impurity profile for drug products, at low concentration levels.

Typically, when performing a (screening) leachable study, the composition of the blank drug product (that was not in contact with the container/closure system) is compared with the composition of the drug product that was in contact with the container/closure system for a certain period of time. Every peak that is present in the Drug Product and is absent in the blank solution, is considered as an impurity, being introduced into the drug product as a result of a prolonged contact with the container/closure system.

However, a drug product could also be evaluated as a "stand alone" sample, without any reference to a blank solution. In this case, every compound detected and identified in the drug product would be reported. This "untargeted" organic screening approach could - in combination with the targeted analysis (eg analysis for genotoxic impurities, API degradants (ICH Q3B)...) substantially assist in understanding the impurity profile of a drug at low concentration levels. Looking at the results of a leachable study from a different perspective could assist in identifying gaps in the risk based approach in Organic Impurity Profiling.

From an analytical perspective, the standard chromatographic techniques used in (screening) leachable studies, such as Headspace GC/MS (Organic Volatiles), GC/MS (Organic Semi-Volatiles) and UPLC-HRAM (High resolution Accurate Mass) (for Organic Non-Volatiles), could be very well suited to perform this initial screening. The identification can be performed by using in-house developed (which renders the screening much more targeted and sensitive) or - alternatively with commercial databases. The chemical structure of the remaining unknowns could be further elucidated by using the high end mass spectral techniques, such as GC-Q-ToF or a UPLC-Q-Exactive Orbitrap.

Why could a re-evaluation of the (screening) leachables data potentially be interesting and relevant?

  • Know your drug product: safety and quality impact of the impurities, present in the drug product
  • Assess the Unknown Impurities from the Production Process of API
    • Synthesis Impurities
    • Residual Solvents, Monomers
    • Residual Catalysts
    • Intermediates, Byproducts
  • Assess the Unknown Impurities from the Drug Product Ingredients
    • WFI
    • Excipients
    • Buffers
    • Adjuvants
  • Assess Known and Unknown API Degradation Compounds
  • Assess the Impact of Intermediate Storage Materials/Single Use Systems on Final Impurities Profile of the Drug Product
  • Assess of Secondary Leachables and Interaction of Leachables with API, Excipients, Adjuvants...
  • Of Course: Assess the Leachables from
    • Primary Packaging
    • Secondary Packaging
    • Ingress of Environment
  • Have an idea on what stays under the radar... Proactive Information when QC HPLC-UV unexpected peaks show up...

It should also be stressed that not all drug products are amenable to this kind of approach. For aqueous based drug products, this approach could be more relevant than for drug products that are very complex in their composition (eg nutrition solutions, or drug products highly loaded with organic material). An evaluation of different types of drug products will be made.


At E&L USA 2015, Dr. Piet Christiaens, Scientific Director at Toxikon Europe will address 5 different case studies to show what could be learned from the raw data of a screening leachables study, when the drug product - which was in contact with the container closure system - would be interpreted as a "stand alone" test article, rather than in a comparative assessment with a blank drug product solution (not in contact with the C/C-system).