To better detect, characterize, identify, and quantify the impurities present in drug substances and products, scientists rely on robust analytical tools with high sensitivity and specificity. In this exclusive interview with Pharmaceutical Outsourcing, Rakesh Gupta, Technical Director – Quality Control for Gaelic Laboratories – a contract manufacturer with newly equipped laboratories offering pharma testing services – shares his advice on navigating this critical part of drug development and manufacturing, and the various techniques now available, based on his own recent experiences helping to set up this high-tech CMO.
What are the main impurities found in drug substances and products, and how much of a problem do they pose to pharmaceutical manufacturers?
Pharmaceutical impurities are the unwanted chemicals found in APIs or drug product formulations. The amounts of various impurities found in pharmaceutical substances determine the ultimate safety of the final products, so the identification characterization, qualification-quantification, and control of impurities are a critical part of drug development and manufacturing.
Pharmaceutical manufacturers need to deal with three main categories of impurity: organic impurities, inorganic (elemental) impurities, and residual solvents.
Organic impurities often arise during the manufacturing process or storage, typically hailing from starting materials, intermediates, unintended byproducts, or degradation products. Irrespective of their source, these impurities can result in undesirable biological activity or toxicity – including genotoxic impurities, which have their own particular guidelines and thresholds, and which have received particular attention from the FDA and EMA due to their mutagenic potential and carcinogenic risk.
Inorganic impurities are simply unwanted elements that tend to occur in drug formulations. Pharma manufacturers need to perform a risk assessment to ensure that these impurities are monitored and controlled in final drug products, and they need to assess potential sources from packaging, container closure, and drug delivery systems.
Levels of mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) – the four most toxic inorganic impurities – need to be measured in all drug products. These and other inorganic impurities arise from a range of sources – APIs, raw materials, synthetic additives, excipients, catalysts, production processes, or equipment.
Residual solvents are the volatile organic chemicals used in the synthesis of pharmaceutical products, several of which are known to have toxic or environmentally harmful properties. Solvents such as acetic acid, acetone, isopropyl alcohol, butanol, ethanol, and ethyl acetate should be limited by GMP or other quality-based requirements. Unfortunately, their complete removal can be difficult, and the situation is compounded by the fact that the final purification step in most pharmaceutical processes involves a crystallization step that can lead to the inopportune entrapment of solvents, causing residual impurity.
So, to answer your question, all of these impurities pose problems, and inbyCH and the guidelines of various regulatory authorities, they all need to be identified, characterized, qualified quantified, and controlled to ensure that drugs are manufactured to the highest quality standards, and that they are safe and effective for patient use.
How are these impurities best identified and characterized?
Put simply, they are best identified and characterized by making the most of modern analytical technologies. Pharmaceutical impurity analyses rely on robust tools with high sensitivity and specificity, Rakesh Gupta Technical Director – Quality Control Gaelic Laboratories such as spectroscopy, chromatography, and various combinations of these techniques.
Using these tools – and perhaps others too – laboratory teams can create so-called ’impurity profiles’ that effectively describe the identified and unidentified impurities present in any drug substance or product. This process of impurity profiling usually begins with the detection of impurities, followed by their isolation and characterization.
Whether dealing with organic, inorganic, or solvent impurities, manufacturers are required to develop robust impurity testing methods for their products, and at a later stage, those methods need to be validated and proved suitable for use in Quality Control testing. This is something that a lot of manufacturers can struggle with, and our team is always happy to help with method development, validation, and analytical method transfer when needed.
How do you choose the right technique for each situation?
Well, first you need to give your laboratory team access to a choice of equipment. This is why, over the past two years, we have upgraded our analytical technology base, so our laboratory team can always choose the best state-of-the-art instrumentation for the job. Some of our latest investments include HPLC, UPLC, Headspace Gas Chromatography (HS-GC), TOC, auto-titrators, UV-VIS Spectrophotometers, Fourier Transform Infrared Spectroscopy (FTIR), Raman spectrometers, a fully automatic hardness tester, dissolution baths, tapped density tester and muffle furnace.
Then, ultimately, the right technique is chosen based on the type of impurity and the level of information required. Generally speaking, various combinations of liquid chromatography, UV detection, mass spectrometry, GC, and capillary electrophoresis form the mainstay of impurity profiling, providing sufficient information in a time-efficient manner.
However, as shown in Table 1, particular combinations of these techniques can be applied to achieve precision, accuracy, linearity, sensitivity, robustness, and speed in the detection of organic, inorganic, or solvent impurity profiling.
Can we focus on genotoxic impurities for a moment – how would you recommend pharmaceutical manufacturers should test for these?
Several organizations have developed guidelines that specifically address genotoxic impurities in pharmaceutical products. The main concern related to these impurities stems from the potential to interact with human DNA to cause mutations and cancer, even at the lowest levels. Therefore, genotoxic impurities should be avoided, or at least reduced to levels below a defined threshold.
As with other impurities, the process of genotoxic impurity testing begins with method development and methodological validation, a crucial step in ensuring the accuracy and reliability of the testing process. Once the testing method is developed and validated, analyses to detect and quantify genotoxic impurities can be performed.
By FDA and EMA guidelines, potential genotoxic impurities need to be controlled at levels much lower than other impurities. This makes the development of analytical methods for genotoxic impurities quite challenging because the procedure should allow detection limits in the range of 1 to 5 parts per million. This demands highly sensitive analytical instruments, and also selectivity due to the presence of other organic compounds that might also be present in low concentrations.
All these requirements lead to the fact that a single analytical procedure is usually not sufficient, and a combination of analytical.
Author Details
Rakesh Gupta, Technical Director – Quality Control for Gaelic Laboratories, explains the importance of identifying, characterizing, and controlling impurities present in drug products, the latest techniques available, and some suggested solutions for the most common impurity challenges.
Publication Details
This article appeared in Pharmaceutical Outsourcing:Vol. 25, No.4 Oct/Nov/Dec 2024Pages: 24-25