In any pharmaceutical formulations the all ingredients and materials need to be pure. However, it is almost impossible to get an absolutely pure material, as impurities get incorporated into them either during manufacture, purification or storage.
Impurities in pharmaceuticals are unwanted substances that can contaminate the active pharmaceutical ingredient (API) or the final drug product. These impurities can affect the safety, efficacy, and quality of medications. Understanding the types of impurities and their sources is crucial for ensuring the integrity of pharmaceutical products.
Impurities in pharmaceuticals can arise from various sources during the production, formulation, storage, and distribution processes. These sources of impurities were critical for ensuring drug quality and safety. Here are the primary sources of impurities:
• Starting Materials:
Impurities can be present in the active pharmaceutical ingredients (APIs) or excipients sourced from suppliers. If the same equipment is used to process multiple raw materials (or different products), cross-contamination can occur, where residues from one material contaminate another. Low-quality materials may contain higher levels of impurities due to inadequate quality control in their production, storage, or transportation. Raw materials, particularly those sourced from natural environments (e.g., plants, minerals, or even water), may contain trace amounts of heavy metals (like arsenic, lead, cadmium, or mercury). For example, some herbal supplements or traditional medicines may contain trace amounts of arsenic or lead due to contamination from soil, water, or improper processing.• Reagents and Solvents:
Chemicals used in synthesis or formulation may contain impurities. The solvents used in synthesis are also likely to involve a number of impurities that may extend from trace levels to critical quantities that can react with various chemicals used in the synthesis, Solvents used in the extraction or purification of raw materials (e.g., ethanol, acetone, or methanol) can leave residual traces in the material. If not properly removed, these residues become impurities.• Solvent Residues:
Residual Organic Solvents: In the production of pharmaceuticals, solvents are often used in the synthesis and purification of APIs. These solvents can remain as trace impurities if not fully removed. For example; Acetone or methanol may remain in a product after the extraction process, which would be considered residual solvent impurities. Chloroform or dimethyl sulfoxide (DMSO) can also be residues in the final drug product if not thoroughly removed, and these can have toxic effects if present in significant amounts.• By-products:
Unwanted chemical reactions during synthesis can produce by-products that contaminate the final product. For example, during the synthesis of aspirin, other compounds like acetic acid (a by-product of esterification) can remain as impurities.• Incomplete Reactions:
Residual starting materials or intermediates can remain if reactions are not fully completed.• Degradation Products:
Chemical degradation of the API can lead to the formation of new, potentially harmful compounds. For example, hydrolyzed forms of a drug like captopril (an ACE inhibitor) can degrade into disulfides, which may be considered impurities.• Oxidation:
Some drugs, especially those with sensitive chemical structures (e.g., vitamin C or adrenaline), can undergo oxidation, leading to impurities. For example, dopamine or norepinephrine (used in critical care) can oxidize to form quinones or other related compounds.• Hydrolysis:
Drugs containing ester or amide bonds, such as aspirin or lisinopril, may undergo hydrolysis (reaction with water) to form acidic by-products, which can cause impurities in the formulation.
• Cross-contamination:
Mixing of different products in shared facilities can introduce impurities. For instance, an antihypertensive drug could become contaminated with trace amounts of a different drug like paracetamol during production if cleaning procedures aren't properly followed.• Equipment Residues:
Inadequately cleaned equipment may leave residues from previous batches or products. If multiple products are manufactured in the same facility, cross-contamination could occur due to inadequate cleaning or improper handling.• Excipient Interaction:
Interactions between active ingredients and excipients can lead to the formation of new compounds. Paracetamol can react with hydrogenated vegetable oils or polysorbates (such as polysorbate 80) in the formulation, leading to the formation of toxic by-products like benzene derivatives. Ibuprofen, in its amorphous form, has better solubility and bioavailability. However, certain excipients like magnesium stearate or sodium lauryl sulfate can induce a polymorphic transition, causing ibuprofen to crystallize into a less soluble form, which could reduce the drug's absorption and therapeutic efficacy. he use of benzalkonium chloride (a common preservative) in ophthalmic preparations can react with the corticosteroid, leading to the formation of benzalkonium chloride-drug complexes or oxidative degradation products.•Stability Issues:
Certain formulations may be inherently unstable, leading to degradation and impurities over time.• Light Exposure:
Some drugs are sensitive to light, leading to photodegradation and impurity formation. Ascorbic acid is highly sensitive to light and oxygen. Improper storage in light-exposed or humid environments can cause it to degrade into dehydroascorbic acid, leading to color changes in tablets and reduced efficacy.•Stability Issues:
Certain formulations may be inherently unstable, leading to degradation and impurities over time.• Leachables:
Chemicals from packaging materials may leach into the pharmaceutical product. Impurities can leach from the packaging material into the pharmaceutical product. For example, plasticizers like phthalates from PVC containers can leach into oral formulations or injectable drugs, posing a potential health risk.• Contaminants:
Particles from packaging materials can also contaminate the drug. Certain packaging materials, such as glass, aluminum, or plastic, can interact with the drug product and introduce chemical impurities. For example, styrene or bisphenol A (BPA) could leach from certain plastics, especially if the packaging is exposed to high temperatures or is stored improperly.• Transport Conditions:
Fluctuations in temperature and humidity during transportation can affect product stability.• Handling Practices:
Poor handling practices can introduce contaminants from operators or the environment.• Bacterial or Fungal Contaminants:
Pharmaceutical products, especially biologicals, injectables, or oral liquids, can become contaminated with bacteria or fungi if not properly sterilized or if there is improper handling during manufacturing. For example, an injectable drug like insulin could potentially be contaminated with Escherichia coli (E. coli) if bacterial contamination occurs during manufacturing.• Host Cell Proteins:
In the production of biopharmaceuticals, impurities from host cells used in production may remain. Bacterial proteins, such as chaperones or ribosomal proteins could remain as host cell proteins in insulin and Growth factor preparations.• Viruses and Endotoxins:
Contaminants from cell culture processes can include viruses or bacterial endotoxins. Endotoxins are toxic substances released from the cell walls of Gram-negative bacteria (such as E. coli), which can cause severe reactions, especially in parenteral (injectable) drugs. Even small amounts of endotoxins can lead to fever or shock when administered to patients.