The sources of impurities in pharmaceutical drug products and drug substances can be assigned to the drug substance or inert ingredients which are used for the formulation of a drug product. Sources of impurities can also be brought into the drug product during the formulation process or through contact with the packaging. The impurities formation may take place either in drug substances, drug products, or during the formulation of the products. The sources of impurities may be from the intermediate step or from the route of synthesis.
The source of impurities in drug products and drug substances comes from various sources and may occur at different stages of the synthesis process and during the preparation of pharmaceutical dosage forms. The majority of the impurities are characteristics of the synthetic route of the manufacturing process.
According to the ICH (International Council for Harmonization), impurities are classified as organic impurities, inorganic impurities, and residual solvents. Q3A (R2) refers to the impurities in the new drug substances. The guidelines address the impurities, chemistry, listing of impurities in specifications its threshold, qualification, and identification. Further Q3B (R2) refers to impurities in new drug products and it defines those impurities which might arise from drug substances as a degradation product or from the interaction between excipient and drug substances or the primary packing materials (components).
According to the ICH guideline impurities are classified as:
Organic impurities – Impurities that occur due to starting materials, by-products, intermediates, degradation products, reagents, ligands, and catalysts.
Inorganic impurities – 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, charcoal, etc.
Residual solvents – Residual solvents are the impurities introduced with solvents i.e. Class 1- Solvents To Be Avoided, Class 2 – Solvents To Be Limited, Class 3 – Solvents with Low Toxic Potential.
In the above three types, the number of inorganic impurities and residual solvents is limited. These are easily identified and their physiological effects and toxicity are well known. For this reason, the limits set by the pharmacopeias and the ICH guidelines guarantee that the harmful effects of these impurities do not contribute to the toxicity or the side effects of the drug substances. The situation is different with organic impurities, such as Active Pharmaceutical Ingredient (API), prepared by multi-step synthesis resulting in various impurities, meaning that the number and variety of their structures are almost unlimited and highly dependent on the route and reaction conditions of the synthesis and several other factors such as the purity of the starting material, method of isolation, purification, conditions of storage, etc. In addition, toxicity is unknown or not easily predictable. For this reason, the ICH guidelines set a threshold limit above which the identification of the impurity is obligatory.
Sources of impurities
- Impurities in starting materials and Intermediates: Starting materials and intermediates are the chemical building blocks used to construct the final form of a drug substance. Unreacted starting materials and intermediates, particularly those involved in the last steps of the synthesis, can potentially survive the synthetic and purification process and appear in the final product as impurities. For example in the synthesis of the Tipranavir drug substance, aniline is the intermediate in the last step of the synthesis. Due to the similarity between the structures of aniline and the final product, it is difficult to totally eliminate it in the subsequent purification step. Consequently, it appears in the drug substance at around 0.1%.
- By-products of the synthesis: All chemical reactions are not 100% selective; the side reactions are common during the synthesis of drug substances. By-products from the side reactions are among the most common process impurities in drugs. By-products can be formed through a variety of side reactions, such as incomplete reaction, overreaction, isomerization, dimerization, rearrangement, or unwanted reactions of starting materials or intermediates with chemical reagents or catalysts.
- Products of over-reaction: In many cases, the previous steps of the synthesis are not selective enough and the reagents attack the intermediate not only at the desired site. For example in the synthesis of nandrolone decanoate, the last step of the synthesis is the decannulation of the 17-OH group. In the course of overreaction, the reagents also attack the 4-ene- 3 oxo group leading to an enol ester-type impurity (3, 17β- dihydroxyestra-3, 5- diene disdecanoate).
- Products of side reactions: Some of the frequently occurring side reactions (which are unavoidable in drug synthesis) are well-known to synthetic chemists; other side reactions that lead to trace-level impurities have to be detected and elucidated during impurity profiling. The formation of a diketopiperazine derivative is a typical side reaction in peptide synthesis.
- Impurities originating from degradation of the drug substance: Impurities can also be formed by degradation of the end product during the manufacturing of bulk drugs. Degradation products resulting from storage or formulation of different dosage forms or aging are common impurities in medicines. The definition of degradation product in the ICH guidelines is a molecule resulting from a chemical change in the substance brought about by overtime or due to the action of light, temperature, pH, or water or by reaction with the excipient and/or the intermediate container closure system.
- Enantiomeric impurities: The majority of therapeutic chiral drugs used as pure enantiomers are natural products. The high level of enantioselectivity of their biosynthesis excludes the possibility of the presence of enantiomeric impurities. In the case of synthetic chiral drugs, the racemates which are usually marketed, if the pure enantiomer is administered, the antipode is considered an impurity. The reason for its presence can be either the incomplete enantioselectivity of the syntheses or the incomplete resolution of the enantiomers of the racemate. Although the ICH guidelines exclude enantiomeric impurities, pharmacopeias consider them as ordinary impurities. A single enantiomeric form of the chiral drug is now considered an improved chemical entity that may offer a better pharmacological profile and an increased therapeutic index with a more favorable reaction profile. However, the pharmacokinetic profile of levofloxacin (S- Isomeric form) and ofloxacin (R- isomeric form) are comparable, suggesting the lack of advantages of a single isomer in this regard. The prominent single isomer drugs, which are being marketed, include levofloxacin (S-ofloxacin), levalbuterol (R-albuterol), and esomeprazole (Esomeprazole).
- Reagents, ligands, and catalysts: These chemicals are less commonly found in APIs; however, in some cases, they may pose a problem as impurities. Chemical reagents, ligands, and catalysts used in the synthesis of a drug substance can be carried over to the final products as trace-level impurities.
Impurities in pharmaceutical drug substances:
Impurities are defined as foreign particle that affects the purity of a substance. Usually, impurities occurring in many pharmaceutical or medicinal preparations may be of different types.
- A Foreign particle that brings about adverse or toxic reactions when present in excess beyond its limits. Examples: lead, heavy metals, arsenic, etc.
- Impurities may not cause toxic effects but bring about deterioration of the activity of chemicals. Example: hard soap containing an excess of water.
- Impurities that cause incompatibility of the active ingredient with other substances or which reduce the properties of the active ingredient.
Several factors affect the types and amount of impurities present in the chemicals or Pharmaceutical substances:
What are the Sources of Impurities in Pharmaceuticals?
Several factors affect the types and amount of impurities present in the chemicals or pharmaceutical substances, such as:
- Raw materials used in the manufacture – Impurities known to be associated with these chemicals may be carried through the manufacturing process and contaminate the final product.
- Reagents used in the manufacturing process – If reagents used in the manufacturing process are not completely removed by washing, these may find entry into the final product.
- Method/Process used during manufacturing – Drugs and chemicals are manufactured from different raw materials, using different methods or processes. The impurities are incorporated into the material during the manufacturing process. The type and amount of impurity present vary in the drugs/chemicals.
- Chemical processes used in manufacturing
- Atmospheric contamination during the manufacturing process
- Intermediate products in the manufacturing process
- Defects during manufacturing
- Manufacturing hazards
- Particulate contamination – The presence of unwanted impurities can arise from dirt, dust, glass, porcelain, or plastic fragments or from product containers.
- Process errors – A number of active ingredients in the product & its pharmacopeial limits may affect the manufacturing process and may create process errors.
- Cross-contamination – The handling of powders, granules, and tablets in bulk creates air-borne dust, which can lead to cross-contamination of the product.
- Microbial contamination – Many liquid preparations and creams are susceptible to bacterial and fungal contamination.
- Packing errors – Improper labeling or destruction of stock of unused labels may constitute a packing hazard.
- Inadequate storage conditions – Reactions with the content material or the occurrence of changes in the physical form of the drug due to temperature.
- Decomposition of the product during storage – Substances may decompose in storage due to the presence of air, light, and oxygen leading to the final product being contaminated. Decomposition products appear as impurities in the substances.
- Accidental substitution or deliberate adulteration with spurious or useless materials – many pharmaceutical chemicals are adulterated with cheaper substances.
The control of pharmaceutical impurities is currently a critical issue for the pharmaceutical industry. ICH has created guidelines regarding control impurities. The other various regulatory authorities also emphasize the identification of impurities and purity in the APIs. Thus, impurities testing for pharmaceuticals is necessary for creating a quality product for the market.
According to the ICH (International Conference of Harmonization), impurities are classified as organic, inorganic, and residual solvents. The Q3A (R2) refers to the impurities in the New Drug substance. The guidelines address the impurities, chemistry, listing of impurities in their threshold, qualification, and identification. Further, Q3B (R2) refers to Impurities in New drug products, and it defines those impurities which might arise from the drug substances as degradation products or the interaction between excipient and drug substances or the primary packing materials (components).
The Impurities are classified as inorganic impurities, organic impurities, or residual solvents. Organic impurities may arise from starting materials, by-products, synthetic intermediates, and degradation products. Inorganic impurities may be derived from the manufacturing process and are commonly known and identified as reagents, ligands, inorganic salts, heavy metals, catalysts, filter aids, charcoal, etc. Finally, residual solvents are the impurities introduced with solvents. The number of inorganic impurities and residual solvents of the above three types is limited.
The sources of impurities may arise from inorganic impurities, organic impurities, and residual solvents. Organic impurities may be from the starting materials, as a by-product, stages of intermediates, and also degradation products. Inorganic impurities may be through manufacturing processes which are normally identified as reagents, inorganic salts, ligands, heavy metals, charcoal, catalysts, etc. Residual solvents impurities are residual solvents present in the manufacturing process.
The factors affecting the impurities in the drug substances or drug products may be due to the synthesis process or manufacturing processes, degradation, storage conditions, excipients, container, or contamination.