Active pharmaceutical ingredients (APIs) are the active ingredients used in pharmaceutical manufacturing and are formulated with excipients to create the finished drug form.
According to Cervicorn Consulting, the global API market was worth around $239.18 billion in 2024, and is expected to grow to $382.89 billion by 2034, with a CAGR (compound annual growth rate) of 4.82%. This growth is driven by an increasing demand for pharmaceuticals, expansion in the numbers of people with chronic and infectious diseases, and advances in research and development. Other drivers include growing numbers of prescriptions for biologics and biosimilars, as well as the increase in precision medicine. [1]
The importance of global quality standards
It is vitally important that therapeutics are manufactured to the highest possible quality and safety standards, particularly those that are used for very vulnerable patients. This includes preventing impurities that can risk patients’ safety, maintaining consistency between manufacturing batches, avoiding poor quality APIs that could affect the final formulation, and ensuring the correct levels of potency. All of these reduce the risk of production delays and regulatory actions and recalls, both maintaining the reputation of the company and making sure that there are no delays in getting drugs to patients. [2, 3]
In order to ensure the quality and safety of APIs, national regulatory authorities (for example the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) or the International Council for Harmonisation (ICH)), set strict guidelines for manufacturers. These guidelines affect all the steps of API manufacturing, from the sourcing of raw materials to manufacturing. [2]
The challenges for manufacturers
APIs can be sourced from many markets around the world. This has the benefit that it allows access to lower cost markets; it however means that there are potential vulnerabilities in the supply chain, and that the quality of the source material may be variable. [2]
While there are some requirements that are standard between guidelines, others will vary. Companies that are manufacturing drugs for different jurisdictions must be sure that they meet the regulations for each country where the drug is approved for market. [2, 3]
Sources for impurities in APIs
Contaminants that occur in pharmaceutical API manufacturing may be introduced from outside, or generated as part of the API synthesis and manufacturing process. Contaminants from outside include physical and biological contaminants such as dust, dirt, debris and microorganisms. These can be as a result of human error caused by inadequate cleanliness and hygiene or through handling mistakes. The manufacturer can also be at fault by not training staff correctly, not providing the right personnel protective equipment and clothing, not maintaining equipment, creating inadequate conditions or by poor process design. Solvents, reagents and catalysts used as part of the synthesis process can also remain as impurities (chemical contaminants). [4, 5]
Unexpected reaction byproducts can contaminate the resulting API, such as the creation of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), both carcinogens, in the manufacturing of valsartan and other sartans (angiotensin II receptor blockers), by a number of companies in 2018. [6]
Ensuring quality and building in quality-by-design
Best practices for manufacturing APIs that can meet global standards include: [3, 7]
Risk assessing the API manufacturing process
Assessing potential impurities that may be introduced during manufacturing
Employing current good manufacturing practices (cGMPs)
Ensuring that staff are appropriately qualified and trained
Ensuring a robust cleaning and maintenance program
Managing the quality systems
Validating processes
Testing API effectiveness
Ensuring that raw materials are properly sourced
Carrying out vali...
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