Industry Perspective on API Quality–A Conversation with Niamh Lynch of Lonza Small Molecules

Pharmaceutical Technology spoke with Niamh Lynch, Executive Director, Global Head of Quality, Lonza Small Molecules, Basel about best practices for API quality and the impact of the nitrosamine contamination situation.

PharmTech: How crucial is it for pharma manufacturers to ensure the safety of APIs? What are the possible repercussions of low-quality and/or ineffective APIs?

Lynch: What is really important for API manufacturing is to ensure that the specifications are appropriately set, especially for any impurities that might be toxic in nature. The repercussions can be huge, with the worst being patient impact—either because the drug is not doing what it should, or is doing something that it shouldn’t, reputational damage for the company, and access to the markets where medicine is needed.

PharmTech: What are the steps an API manufacturer must take to ensure quality throughout the development and manufacture of an API?

Lynch: It is essential that all possible impurities are defined during development, and toxicological assessments are performed. Of particular importance are any genotoxic impurities. These will need to be controlled or eliminated throughout the processing of the API, so that the product meets all the required specifications.

PharmTech: What are the steps sponsors should take to ensure the quality of APIs sourced from a supplier used in final products?

Lynch: It is important that the sponsor chooses the right outsourcing partner. It should be one who has a mature quality set-up, with a good quality mindset, and a willingness to continue to move with the regulatory trends. It is more important to get it right and manage changes than purely look at cost: if a problem is found further down the line, the costs will be far higher.

PharmTech: The International Council for Harmonisation’s Q7A GMPs forAPIs touches on all aspects of API production from facilities to equipment to materials management. Of all the areas the guidance covers, is there one particular aspect of API manufacturing that is more crucial for ensuring API quality?

Lynch: One area where we commonly find quality issues is with incoming materials. This might be solvents, raw materials, or even processing aids. Another big concern is when changes are made to chemical processes without adequate checking. Whether this is a shift to a new raw material supplier, a change of solvent, or even the use of different equipment, if the effects of the changes are not assessed appropriately, this can cause huge problems, particularly with the formation of additional, unexpected impurities.

PharmTech: What methods are available for testing the effectiveness and safety of APIs?

Lynch: Many different methods are available, but LC-MS [liquid chromatography-mass spectrometry] and GC-MS [gas chromatography-MS] are particularly important.

PharmTech: What has the industry learned from the nitrosamine contamination problems in blood pressure medications?

Lynch: The industry has learnt that, even though a supplier can state that it has performed an assessment against the regulatory requirements, it is extremely important that the manufacturing authorization holder performs not only a paper assessment, but analytics in addition. It also became apparent that if a change is made to a process, whether to solvents, catalysts, or a new supplier of starting materials, it can result in the formation of additional impurities.

PharmTech: Have regulators and industry resolved the nitrosamine problem, or is it continuing? What steps can be taken to ensure a similar situation does not occur in the future?

Lynch: The regulators reacted very rapidly to this issue, which started back in 2018. They were quickly on board, assessing the products in question and the suppliers manufacturing them, as well as identifying further nitrosamines that were being formed. They also set appropriate specifications for industry to follow. Industry has also reacted appropriately, implementing the necessary assessments and analytical methods. To ensure we do not have similar situations in the future, it is important that the drug developer also performs appropriate assessments during development, and the drug manufacturer assesses changes appropriately during the lifecycle of the product.

PharmTech: Are there other broadly used API groups that might cause a similar problem to nitrosamines? Are there other types of testing that can avoid this kind of situation with other APIs?

Lynch: How nitrosamines are formed is well known, and well documented. All manufacturers, therefore, need to perform an assessment of all of their products. LC-MS and GC-MS are the key techniques that should be used to identify the presence of any nitrosamines in the products.