There are stringent regulatory demands on the pharmaceutical industry regarding elemental impurities stipulating the control and documentation of elemental impurities in drug products, drug substances and excipients.

In compliance with USP <232 & 233>, EP (2.4.20) and ICH Q3D, all components, processes, packaging and final product must be risk assessed or tested for the presence of elemental impurities. Inductively coupled plasma mass spectrometry (ICP-MS) is widely recognised as the most suitable technique to meet the requirements of these, and future, regulatory requirements.

Almac’s dedicated elemental impurities analysis team has already worked with many pharmaceutical companies to address the challenges of these regulatory guidelines and has invested in a state-of-the-art elemental impurities analysis laboratory which incorporates incorporate industry-leading ICP-MS instruments. An example of our work was published in the Journal of Pharmaceutical and Biomedical Analysis.

Inductively coupled plasma mass spectrometry (ICP-MS) technology is used within mass spectrometry to ionize a sample. Almac’s investment in a state-of-the-art analysis laboratory incorporates incorporate industry-leading ICP-MS instruments; Thermo iCAP RQ C2 and Agilent 7900, in addition to MARS 5 and 6 microwave digesters.

Investigative analysis arises in all drug development programmes. It is essentially an exploration of the compounds present in a test article. Typically the aim of this investigation is to elucidate and characterise an unknown within a mixture, who’s presence is causing issues. Investigative analysis can be hard to describe, as by its very nature is complex . This is probably one of the most challenging aspects of NMR activities, but our very experienced team of spectrometry scientists and organic chemists are able to utilise a range of platforms to track and quantify unknowns.

Almac has extensive knowledge in testing wide ranges of compounds, including small molecules, peptides, biologics, drug products and excipients. The team has access to a huge catalogue of library methods, and intricate knowledge of methods for detection of metals, solvents, nitrosamines, and polymorphs. By drawing on this vast pool of knowledge we can quickly and efficiently narrow the search, and our state-of-the-art spectroscopic suite, and highly trained scientists can pin down the ID of an unknown using techniques such as NMR, LCMS, and MSMS to provide full structural elucidation when required.

Our spectroscopy expertise combined with in-house synthetic chemistry knowledge can help determine the likely source of impurities. We also have the instrumentation and synthetic capabilities to isolate or manufacture samples of impurities that can be used as reference standards. Being part of an extensive discovery, development and manufacturing organisation, we know the challenges which can arise and are on hand to tackle these with you at all times.

Critical to the drug development process, is the ability to identify and quantify levels of Genotoxic impurities. These levels can play a major role in the quality and ultimately the safety of both drug substance and drug product. Confirmation of these levels and subsequent regulatory compliance is achieved using the following techniques:

• ICPMS
• LC-MS
• HPLC
• GC and GC-MS

Following an industry wide issue in 2018 the FDA has put a focus on the quantification of nitrosamines in medicinal products. These are typically split into small molecule nitrosamines and NDSRI nitrosamines formed from drug substance related impurities.

Almac have robust analytical methodology for the quantification of small molecule nitrosamines, including the “cohort of concern” down to appropriate low levels per FDA guidelines and can apply these methods to API and drug products at any phase of development.

With NDSRI a more bespoke approach is required as these impurities are unique to the API and related impurities. However, Almac have a template approach to method development for nitrosamines that can be applied to each case to streamline the project.

Nitrosamines refers to a class of compounds which have been detailed as high risk with set exposure levels. It is worth noting that these are potential genotoxic impurities and Almac’s previous experience in this area stands us is in good stead to support this.

Two-dimensional chromatography can be used for the identification of unknown impurities found during release testing or stability studies. Enhanced separation is achieved using 2 separate HPLC columns with different elution conditions.

Almac typically employ this technique where the original HPLC method utilises a non-volatile buffer (such as phosphate) that cannot be directly injected into a MS detector.  This means that client chromatography can be reproduced on the first system and the unknown peak of interest can be diverted to the second system utilising a MS compatible mobile phase for MS or MS/MS analysis.

This saves time redeveloping the client method with MS compatible methods and ensures that elution order is maintained.  Impurities can be identified faster and without the complexity of changing mobile phase composition.