Introduction: What is a KSM?

Key Starting Material (KSM) term is used for intermediates in pharmaceutical industry. These are building blocks of drug industry. India imports KSM for many medicines from China and Xena Organics is planning to take the step to be #AtmaNirbhar for India by supporting the #MakeInIndia Initiative

The Guidelines on Chemistry of New Active Substances of the Committee on Medicinal Products for Human Use (CHMP) points out that the starting material should contain significant structural fragments of the structure of the active substance and should mark the beginning of a detailed description of the new active substance during synthesis [9]. ICH Q7 states that the appropriate GMP defined in Q7 should be applied in all manufacturing steps of the API when the raw materials enter the manufacturing process of medicines. At the very least, the sponsors are likely to provide a robust specification of the starting materials of the last drug intermediates to demonstrate the quality of the built-in active ingredients during synthesis.

ICH Q7 provides guidance on best manufacturing practices for medicinal products, but not specific guidance on the selection and justification of a raw material. The starting material is defined as a raw material or drug intermediate used in the production of a drug substance containing the most significant structural fragments of the structure of the substance. Although Q11 says that the ICH Q7’s best manufacturing practice (GMP) provisions apply to all branches of pharmaceutical manufacturing, the process begins with the first use of the raw material

As discussed above, agencies seeking to limit impurities in a drug substance may require a longer API for synthetic pathways, define a route for the synthesis of precursors, or identify a single supplier of precursors. Changes in the reaction process, including the start materials or changes in specifications or testing methods are likely to affect the quality of the drug substance and require prior approval by the PCA. Processes and active ingredients for the development of active pharmaceutical ingredients may contain a primary component called KSM (key ingredient) or intermediate product.

Starting materials from multiple sources can be analyzed for impurities and their content during the manufacturing process of APIs. This approach aims to take advantage of the due diligence carried out by manufacturers and suppliers to prevent a raw material supplier from adopting a different synthetic path that involves novel contaminants that cannot be detected by existing analysis methods or that cannot be removed by the current cleaning process. Regulators should ensure that any new proposals or policy changes allow sufficient time between the submission of the MAA and the development of analytical processes and data to support the proposed changes.    

As described in ICH Q11, the selection principle of significant structural fragments is intended to help distinguish reagents, catalysts, solvents and other raw materials that do not contribute to the significant structural fragment from the molecular structure of the active substance or material. Chemical compounds that are processed from raw materials into active substances are called intermediates. In this process, the API that goes through these ten types of intermediates in one process when it transforms from a raw material to an API is purified until it reaches a high degree of purity and becomes an API.

Companies in other parts of the world and around the world have begun to shift to other product areas and limit their operations, leading to a further concentration of global sales to China and, in the case of India, to intermediates and APIs. India is currently dependent on China for KSM and APIs (70-80%), commodity imports to produce certain life-saving antibiotics such as cephalosporin, azithromycin and penicillin and dependence on Chinese imports is up to 90%. To boost domestic production and independence the government has announced an incentive program to produce about 50 key APIs, but import dependency is still high. The increase in raw materials for products such as anti-ulcers (PPI, CVS, CNS) seems to be costly in the near future, according to experts.

When China began to take measures to reduce pollution, this began to affect certain zones and manufacturers, and this had a domino effect, as it was these areas which maximized market supply and their loss of production affected prices and supply along the pharmaceutical and chemical value chains. First, China sourced and produced many of the basic chemical intermediates (APIs), and these intermediates gained a high market share over time, given cost competitiveness. The KSM was used for self-consumption and the production of API.