Possible sources and classification of impurities
Impurities are defined in ICH Q6A guideline as “Any component of the drug product that is not the chemical entity defined as the drug substance or an excipient in the drug product. The impurities in drug products can be originated not only in the drug substance or inert ingredients used for formulating a drug product; but they can also be brought into the drug product through the formulation process through the use of polymeric single-use materials or by contact with packaging materials. Impurites can cause toxicological problems. The presence of these unwanted substances, even in small amounts, may influence the efficacy and safety of the pharmaceutical products.
There exist different sources of impurities in Pharmaceuticals:
- Raw materials and reagents used in the manufacturing process. Either by impurities present in these materials, or due to their presence not being completely removed at the end of the process.
- Chemical processes used in manufacturing, which can give rise to impurities due to, for example, side-reactions or reactions that do not go to completion.
- External sources of contamination, such as atmospheric contamination during the manufacturing process or cross-contamination due to other processes being run in the same manufacturing line.
- Impurities originating from interaction with the Container Closure System.
- Leachable impurities originating from polymeric materials used during the manufacturing process or in the Container Closure System.
- Decomposition of the DS or the DP during storage – Some substances decompose on storing due to thermal, oxidative, hydrolytic and/or photodegradation processes. Also degradation impurities can occur due to interaction between the API and the excipients or other substances present in the product.
According to the ICH impurities are classified as organic impurities, inorganic impurities and residual solvents.
- Organic impurities may arise from starting materials, by products, synthetic intermediates and degradation products, as well as leachables from contact materials. These impurities are controlled by Guidelines ICH Q3A and Q3B. ICH M7 Guideline was later introduced to regulate those mutagenic impurities that can pose a risk at concentration levels several orders of magnitude below those described in ICH Q3A/B.
- In the case of leachables, ICH Q3E guideline is in development and there exist regulations such as EMA’s Guideline On Plastic Immediate Packaging Materials and FDA’s Guidance for Industry Container Closure Systems for Packaging Human Drugs and Biologics.
- Inorganic impurities may be derived from the manufacturing process and are normally known and identified as reagents, ligands, inorganic salts, heavy metals, catalysts, filter aids, and charcoal etc. These impurities are controlled by Guideline ICH Q3D.
- Residual solvents are the residues of solvents used during the manufacturing process. Of the above three types, the number of inorganic impurities and residual solvents are limited. These impurities are controlled by Guidelines ICH Q3C