Drug products can be heavily impacted when raw materials cause variability – anecdotal evidence suggests that batches worth millions of dollars are sometimes discarded due to trace elements coming through the supply chain.
Not only does this increase costs and significantly impact production scheduling, but it could delay the manufacture of drugs that may, ultimately, impact patients.
Yet, despite these industry-wide issues, there is no harmonization or best practice and some companies have even optimized their methods for certain metals.
This galvanized BioPhorum to bring together a team of experts to investigate the reasons why variation happens and develop an industry-agreed solution.
The result is Media and hydrolysates, which gives you a strategy for a method development and outlines the process to detect trace elements in chemically defined media and soy hydrolysates.
“This has been an open secret in our industry for many years,” said Bala Ramanathan, Associate Director at Janssen and lead author of the paper. “I don’t think there’s a company, especially on the biopharmaceutical side, which has not been impacted by trace elements in upstream bioprocessing.”
A groundbreaking collaboration
The idea was formed at a BioPhorum meeting in Switzerland in 2019, where there was confusion around trace element characterization. Members wanted to know what methodologies other companies were using – without revealing their own.
This prompted the BioPhorum Raw Materials subteam to carry out benchmarking and design a test for trace elements using five samples – three commercial DMEM (Dulbecco’s Modified Eagle Medium) and two hydrolysis – and distributed them globally to 16 participating companies.
This groundbreaking BioPhorum collaboration shared blinded data and compared analytical methods between biopharmaceutical and media manufacturers. Anonymity was critical for companies to take part. The paper discusses the issues around trace elements and uses graphs to show the results of the project’s findings and the variability in identifying trace elements.
It looks at the fundamental issues you should consider when developing your method. Some of these are short-term, e.g., how much time, resources, and labor are available? And do you use contract labs with enough technological know-how? Others have a longer-term impact, e.g., if an issue is identified, how will you stop it from happening again? And will you just look at high-risk components in your media?
It also considers current best practices, which metals should be targeted, using inductively coupled plasma mass spectrometry, and key technical issues such as sample preparation, acid selection, and thermal hot block or microwave degradation.
The project was well received by US Pharmacopeia (USP), which has formed a Trace Metals Expert Panel to develop a new General Chapter to build on Chapter <233> for these applications. BioPhorum has also requested revisions to Chapter <233>, including changes to instrumentation, sample digestion, and polyatomic interference.
An updated Chapter means that anyone considering working with chemically defined media and soy hydrolysates can implement best practices and ensure they meet customer requirements. This builds on current guidance, which only focuses on small molecule products.
This is an excellent example of work to support the recent BioPhorum/USP letter of intent that signposted how the partnership will work together to advance scientific collaboration by harmonizing industry practices and incorporating these into pharmacopeial standards. “This kind of collaborative relationship is beneficial across the board,” said Aaron Mack, Senior Engineer at Biogen, “because it reduces costs, waste, testing and reduces time overall to better supply raw materials for all manufacturers.”