Impurities are extraneous compounds that are not the drug substance but remain with active pharmaceutical ingredients (APIs) or arise during the synthesis, extraction, purification, or storage of the drug. The presence of these unwanted chemicals, even in small amounts may influence the efficacy and safety of the pharmaceutical products so understanding the origin, control and measurement of impurities is critical to the production of high-quality drug substances.
In addition to guidances from the local authorities of many countries, a series of guidances developed in recent years by the Expert Working Group of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, commonly known as ICH, have been increasingly accepted by the pharmaceutical community. According to ICH guidelines on impurities in new drug products, identification of impurities below the 0.1% level is not considered to be necessary unless the potential impurities are expected to be unusually potent or toxic. In all cases, impurities should be qualified.
Thresholds
Impurities generally fall into three main categories: process impurities, degradation impurities, and contaminant impurities. Additionally, enantiomers and polymorphs may be considered impurities under some circumstances.
n Process impurities arise during the manufacture of the drug substance.
n Degradation impurities arise during the storage of the drug substance.
n Contaminant impurities are not drug related but are inadvertently introduced during processing or storage, and are not part of the synthesis, extraction, or fermentation process.
Process impurities
These include inorganic impurities, organic impurities and residual solvents.
Organic impurities may be unwanted by-products of a chemical synthesis. They may arise by many different routes, for example, by the reaction of an intermediate with the solvent rather than the desired substrate, by cyclization in the wrong direction. Organic impurities can also arise from impurities in the starting materials, for example, traces of propylamine in butylamine may lead to the propyl analog of the drug substance or they may be reagents used during the reaction. Unreacted starting materials and intermediates may also be present as impurities in the drug substance. In some cases, enzymes are used during a chemical synthesis.
Inorganic impurities include water, salts from buffers, reagents, ligands, catalysts, heavy metals, or other residual metals and inorganic compounds used in processing, such as filter aids and charcoal. Inorganic impurities can also arise by leaching from equipment as a result of the unit manufacturing process.
Residual solvents are organic volatile chemicals used during the manufacturing process or generated during the production. Some solvents that are known to cause toxicity should be avoided in the production of bulk drugs. Depending on the possible risk to human health, residual solvents are divided into three classes.
n Class I, viz benzene (2 ppm limit), carbon tetrachloride (4 ppm limit), methylene chloride (600 ppm), methanol (3000 ppm, pyridine (200 ppm), toluene (890 ppm) should be avoided.
n Class II, viz N, Ndimethylformamide (880 ppm), acetonitrile (410 ppm).
n Class III solvents, viz acetic acid, ethanol, acetone have permitted daily exposure of 50 mg or less per day, as per the ICH guidelines.
Degradation impurities
Normally, degradants are chemical breakdown compounds of the drug substance formed during storage. In rare cases, degradants are formed when the drug substance chemically interacts with other compounds or contaminants. In addition, degradants may also be formed by physical degradation, for example, aggregates of proteinaceous material, dimers, trimers, and so forth, of synthetic compounds, polymorphs of synthetic compounds.
Ester hydrolysis can be explained with a few drugs viz aspirin, benzocaine, cefotaxime, ethyl paraben, and cefpodoxime proxetil.
Oxidative degradation of drugs like hydrocortisone, methotrexate, hydroxyl group directly bonded to an aromatic ring (viz phenol derivatives such as catecholamines and morphine), conjugated dienes (viz vitamin A and unsaturated free fatty acids), heterocyclic aromatic rings, nitroso and nitrite derivatives, and aldehydes (especially flavorings) are all susceptible to oxidative degradation.
Photolytic cleavage includes example of pharmaceutical products that are exposed to light while being manufactured as solid or solution, packaged, or when being stored in pharmacy shops or hospitals for use by consumers. In ciprofloxacin eye drop preparation (0.3%), sunlight induces photocleavage reaction producing ethylenediamine analog of ciprofloxacin.
Degradants may be chemically identical to process impurities. However, the levels of degradants will increase during storage, while the levels of process impurities will remain constant. The rate of increase of degradants resulting from storage is dependent on the chemical nature of the drug substance. The degradation of penicillins and cephalosporins is a well-known example of degradation products on storage. The presence of a ß-lactam ring as well as that of an a-amino group in the C6/C7 side chain plays a critical role in their degradation.
An understanding of the potential degradation pathways of the drug substance will lead to optimization of the storage conditions and will result in fewer impurities.
Contamination impurities
Contamination impurities are unexpected adulterating compounds found in the drug substance.
Current manufacturing technology has reduced many of the contaminant impurities observed in drugs prepared decades ago. For example, heavy metals like lead that leached from pipes or manufacturing/storage tanks gave rise to the commonly used limit test for heavy metals in the drug substance. Current pipes and tanks are primarily stainless steel or glass-lined to reduce this concern, although the type of material is ultimately dependent on the nature of the reactions, the nature of the drug substance, and the nature of the manufacturing unit operations. Other contaminants could be, but not likely agents sprayed to improve the environment in the manufacturing plant or accidental droppings like human hair or paint chips from walls.
Other impurities
Different polymorphic forms may be categorized as impurities in the drug substance. Different polymorphs may be generated by changes in the manufacturing process or by seeding effects if a new polymorph arises.
Based on the realization that the nature of structure adopted by a given compound upon crystallization could exert a profound effect on the solid-state properties of that system, the pharmaceutical industry is required to take a strong interest in polymorphism and solvatomorphism as per the regulations laid down by the regulatory authorities.
Polymorphism is the term used to indicate crystal system where substances can exist in different crystal packing arrangements, all of which have the same elemental composition.
Whereas, when the substance exists in different crystal packing arrangements, with a different elemental composition; the phenomenon is known as Solvatomorphism.
Mutual interactions may lead to the formation of impurities. Most vitamins are very labile and on aging they create a problem of instability in different dosage forms, especially in liquid dosage forms. Degradation of vitamins does not give toxic impurities; however, potency of active ingredients drops below Pharmacopoeial specifications.
Because of mutual interaction, the presence of nicotinamide in a formulation containing four vitamins (nicotinamide, pyridoxine, riboflavin, and thiamine) can cause the degradation of thiamine to a sub-standard level within a one year shelf life of vitamin B-complex injections.
- The author is with SRIPMS, Coimbatore