The market for API manufacturing is competitive and costly, so there’s no doubt that organizations want to find ways to get to the end-goal – product commercialization – as quickly and cost effectively as possible. So, when impurities are found in scale-up, even the best laid-plans can be sent packing. Since impurities in raw materials are a fact of life, how can an organization make sure these set-backs don’t break the bank? The key is to balance risk with actual cost and practice good analytic methods.
Impurities are chemical substances inside a confined amount of a sample which differ from the chemical composition of the material or compound of interest. Impurities are either naturally occurring or formed during the synthesis of a chemical compound. It’s actually impossible to have a molecular substance that is 100 percent pure and free of impurities. A molecular substance that falls in the 99 percent range of purity is considered very good quality.
Chemical impurities can appear in two different ways. From raw materials or during process manufacturing. Most CMOs work with only properly vetted suppliers to ensure quality materials, and also perform sample tests before purchasing them to determine the level of impurities. Yet, once the raw materials pass muster, the chemical process itself can cause the molecules to undergo a chemical reaction which can alter the composition.
So, given the prevalence of impurities, how can you minimize their impact on cost-over-runs?
Practicing developing good analytic methods every step of the way is probably the best way to minimize the risk of chemical impurities causing costly over-runs or jeopardizing commercialization.
Analyzing the levels of impurities and the physical, structural and behavioral attributes of these impurities in APIs helps to identify the potential cause of variations in the finished product.
Implementing good analytic methods at every stage to uncover impurities is key. Impurities found during small scale manufacturing can delay a project and require new materials, but at so much less of a loss than when they are found in scale-up, when much larger batches of the materials are lost, and other production stages and scale-up facilities have already been invested in. When you realize that one week of plant time is worth $75,000, you realize that any investment in analytic method development can save significant costs.
To ease the impact of process impurities in large-scale manufacturing, here at PCI Synthesis we run batches in the kilo lab and look for any process impurities generated.
As they say, practice makes perfect, when chemical impurities are identified, good analytic methods can help you identify the source of the impurity and when it occurred, as well as what process chemistry may have worked to remove it. Once you understand where they came from and how they were removed, then you can set new specifications on that level, so new batches will have no more of the impurity.
The impact of failed approvals because of excess chemical impurities is far-reaching. Not only can investments of $20-to-$30 million be lost, but more importantly, clinical trials can be put in jeopardy, as well as any potential antidote to life-saving treatment.
Spending time to identify impurities in every critical stage of production, through properly vetted suppliers, and quality analytic methods and processes, not only facilitates successful FDA approvals and safe and effective drugs, but it can save significant costs in the long-run.
For other articles about impurities, check out Identifying Impurities in APIs, Controlling Impurities In Drug Manufacturing, and At what stage of API development should you start to think about ICH guidelines? For more info about impurities, guidelines or other aspects of API manufacturing, give us a call at (978) 462-5555.