In pharmaceutical drug substances and drug products, impurities are developed during the synthesis. They remain with the active pharmaceutical ingredients (APIs) or sometimes develop during the formulation or upon the aging of both active pharmaceutical ingredients (API) and formulation of APIs to medicines.
The consequences of impurities
Impurities may bring about incompatibility with other substances; impurities may bring down the shelf life of the substances and also may cause difficulties during formulation and the use of the substances. Sometimes impurities also change the physical and chemical properties of the substances.
Impurities present in a solid organic compound tend to have effects on the melting point. Firstly they tend to lower the overall melting point of the compound versus the value for pure material; secondly, they tend to increase the range of the melting point values.
The presence of these impurities even in small amounts may affect the efficacy and safety of the pharmaceutical products. These impurities are commonly known as byproducts, degradation products, intermediates, interaction products, related products, transformation products, or penultimate products.
Sometimes the presence of impurities in the compound may affect its potency. Impurities may affect the drug substance as its chemical nature and can interact with drug substances. You must keep in mind that impurities may develop in the drug substance during any of the stages like the manufacturing process, or purification stage, or may be due to storage conditions.
The definition of impurities in pharmaceuticals
An impurity is considered as any inorganic or organic material or residual solvents other than the drug substance or ingredients that arise out of synthesis or unwanted chemicals that remain with APIs.
Impurities that are genotoxic at trace levels are also of great concern due to human carcinogen and their detection at trace levels are of increasing concern in pharmaceutical industries and regulatory agencies. Genotoxic impurities may induce genetic mutations, chromosomal breaks, or chromosomal rearrangements and may have the potential to cause cancer in humans. So the exposure even at low levels of such impurities present in the final drug substance in the drug product may be of significant toxicological concern. So it is important for process chemists to explore possible opportunities to avoid the use and generation of these genotoxic materials in the manufacturing process.
Health risks in pharmaceutical products
The effect of elemental impurities in drug substances and drug products may arise from several different sources like residual catalysts that were added intentionally in synthesis or may be present as impurities. Undeniably, the presence of elemental impurities does not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. Long-term exposure even to low concentrations of impurities can cause many adverse health effects and even toxicity.
Summarizing the effects of impurities
We know that to get almost pure substances is very difficult and some traces of impurities are always present. So the impurities present in the substances may have the following effects.
- Impurities may bring about incompatibility with other substances.
- Impurities may lower the shelf life of the substances.
- Impurities may cause difficulties during formulation and the use of the substances.
- Sometimes impurities change the physical and chemical properties of the substances.
- The therapeutic effect can be decreased.
- Shows the toxic effect after a certain period.
- Injurious when present above certain limits.
- It may change the odor, color, the taste of the substance.
- It may affect its potency if the compounds have foreign matter or impurities.
How to prevent impurities?
To prevent these impurities many tests such as limit tests are carried out to lower the impurities to make the pharmaceuticals safer.
Once a drug product has been formulated it is possible that traces (low levels) of impurities will remain but that’s not an automatic indicator that a drug product quality is terrible. The key concern is the type and level of those impurities for manufacturers, regulators, and patients.
Regulatory agencies and standards-setting organizations like the U.S. Pharmacopeial Convention (USP) spend a great deal of time and effort establishing limits on allowable levels of impurities in medicines to help ensure that they do not pose a threat to public health and that product quality meets or exceeds the public’s expectations.
The various regulatory authorities such as the International conference on harmonization (ICH), the United State Food and Drug Administration (FDA), and other agencies are emphasizing the purity and identification of impurities in active pharmaceutical Ingredients (APIs), further different pharmacopeias like United states pharmacopeia, British pharmacopeia, and Indian Pharmacopoeia have incorporated the limits of impurities present in APIs and Drug product.
Impurities in medicine
Medicine has its kind of quality standards that must be maintained before it can be given to patients and failure to meet them may result in poor-quality medicine. The standard involves is good manufacturing practices (GMPs) and failure to meet that quality standard often occurs in GMP processes. Many drugs are manufactured in batches of more than a million tablets and GMPs are intended to ensure that through rigorous manufacturing controls, all tablets within a batch are of consistent quality.
The other type of standard defines the chemical and physical properties that each drug substance, drug product, and excipient must be able to meet. These kinds of standards are developed by USP. They describe how to measure and ensure that:
- A drug product contains the drug substance it is supposed to;
- A drug product has the right amount of the drug substance and
- A drug product does not contain unintended levels of impurities.
In the pharmaceutical industry, the characterization and isolation of impurities are compulsory for acquiring and evaluating data which discloses the need and scope to perform impurity profiling. Nowadays various analytical techniques are used to isolate and quantify the impurities.
In Pharmaceutical drug products and drug substances, impurity is a critical quality attribute. Impurities do not show any therapeutic benefit but sometimes they are potentially toxic and controlling the impurity is a very critical task, especially during process scale-up.
The percentage of impurities present in a drug substance finally determines the safety of the final drug product, so therefore it is very important and critical to quantify, identify and control the impurities during the drug development process.
- Pilaniya, Kavita, et al. “Recent Trends in the Impurity Profile of Pharmaceuticals.” Journal of Advanced Pharmaceutical Technology & Research, vol. 1, no. 3, 2010, pp. 302–10, https://doi.org/10.4103/0110-5558.72422
- “Shedding Light on Impurities in Medicines | Quality Matters | U.S. Pharmacopeia Blog.” Usp.org, 2014, qualitymatters.usp.org/shedding-light-impurities-medicines. Accessed 27 Jan. 2023.