How Trace Analysis Ensures Product Safety
By Michael Tikhonov, Group Manager, TAPI Analytical R&D
To protect patient health and the world’s drug supply, drug manufacturers go to great lengths to ensure their drug products are safe, effective and meet stringent regulatory requirements before going to market, as do active pharmaceutical ingredient (API) suppliers for such drug products. In recent years, companies have adopted more advanced analytical techniques and invested in state-of-the art instrumentation to make sure their products are as pure as possible.
TAPI uses trace analysis techniques to test active pharmaceutical ingredients for impurities that could be harmful, even in very small quantities. Researchers have different interpretations of what constitutes a “trace” amount. Some define it as a concentration of less than 1ppm; others view it as a concentration that is low enough to make accurate analysis difficult. At TAPI, a trace amount ranges from the ppb level to a few tens of ppms.
Patient drug dosages typically include a mg level of APIs per day but usually do not exceed 10g per day. In such a “worst case” patient exposure scenario, 10ppm of an impurity in a 10g per day API dosage would correspond to 100µg of impurity per day.
Why trace analysis is so important in APIs
Pharmaceutical impurities originate from several sources. Some could be toxic, while others are not. They can occur naturally in raw materials, be created during the manufacturing process, or form during drug product shipment or storage. Regulatory agencies worldwide continually evaluate and update their guidelines to ensure drug products are as safe as possible before they are approved for market.
The dangers of toxic impurities – especially genotoxic impurities – were widely publicized in 2007 when the HIV drug Viracept (nelfinavir mesylate) was recalled worldwide. After patients complained the tablets had a strange odor, the manufacturer launched an investigation and found elevated levels of Ethyl methanesulfonate, a known alkylating agent that is harmful to DNA and can cause cancer. The incident also exposed a weakness in regulatory guidelines in effect at the time. As a result, tighter controls were instituted.
Quality is the foundation upon which TAPI is built and we take extraordinary measures to ensure we produce high-quality APIs for our customers. All TAPI products are routinely evaluated and tested for impurities to ensure they are safe and meet or exceed regulatory standards worldwide.
When trace analysis is performed, there are two possible scenarios:
- Routine analysis performed by the Quality Control Department (QC). This can take place after method development at R&D, followed by validation. In this case, the method must be as simple and as robust as possible.
- Analytical R&D evaluation. Such methods may use the most advanced techniques and the most exotic preparations. Hyphenated techniques like liquid chromatography coupled with mass spectrometer (LC/MS), supercritical chromatography coupled with mass spectrometer (SFC/MS) or gas chromatography coupled with mass spectrometer (GC/MS) are especially useful in such cases.
Detecting organic and inorganic impurities require different approaches
Generally speaking, all chemicals are divided into two groups: inorganic and organic. Obviously there can be combinations of both such as organometallic, but from an analytical chemistry perspective, substances can be categorized in these two basic groups.
When it comes to trace analysis, the approach to inorganic impurities is relatively simple. Almost all of them can be analyzed by Inductively Coupled Plasma – Mass Spectrometry (ICP-MS) as explained in this article by TAPI R&D Associate Director Mislav Runje.
However, analysis of organic impurities is much more complex. They may be classified into the following four groups:
- Genotoxic: an impurity with a high risk of causing genetic mutations or cancer
For example, sulfonyl chlorides are very useful reagents in organic chemistry for hydroxyl activation, but products of such activation (sulfonate esters), are known to be genotoxic and should be treated according to ICH M7 guideline to ensure that traces of such compounds are not carried over to the API.
TAPI carefully evaluates all products for genotoxic impurities in the development phase to ensure we consistently deliver high-quality products to our customers. Highly-trained synthetic chemistry experts use computational toxicity prediction tools as part of the process.
- Highly toxic: impurities with a known toxicological acceptable limit that might be lower than the TTC (Threshold of Toxicological Concern) or even not genotoxic
Well-known toxic materials may be assigned to this group such as Cyanide, mustards, certain phosphorous compounds, and many other chemicals that might be very useful in synthetic chemistry but are also very toxic to living organisms. Sometimes Ion Chromatography is used effectively to measure trace amounts of these substances.
- Class 1 residual solvents
These highly toxic solvents that could cause cancer or pose an environmental hazard, and should be avoided in pharmaceutical manufacturing.
TAPI does not use class 1 solvents in the manufacturing process, however other common solvents may contain class 1 solvents as impurities. For example, toluene, acetone and ethanol (and some other commonly used solvents) may contain benzene as an impurity, and dichloromethane may contain carbon tetrachloride as an impurity. Regulations for residual solvents, which are based on toxicological considerations, are described in the ICH Q3R guideline and its amendments. Headspace Gas Chromatography (HS GC) equipped with mass spectrometer (MS), flame ionization (FID) or electron capture detectors (ECD) are the most suitable techniques for this type of analysis.
- Others: an impurity that is not necessarily toxic, but trace levels need to be determined
Sometimes trace analysis is required, not because of toxicological concerns, but because analytical chemistry is addressing impurities as weight/weight. In some cases when low molecular weight (MW) reagents or impurities and high MW main product are involved, traces reported as weight/weight correspond to a large amount of unfavorable molecules. In other words in certain cases, trace level impurity, which is negligible from a toxicological point of view, is actually very significant due to its ability to lead to a large amount of by-products.
TAPI’s analytical expertise helps to ensure customers receive safe and high-quality APIs
Trace analysis provides the greatest challenges in analytical chemistry and the most innovative solutions. Decades of experience have taught us that the right technique combined with proper sample preparation is the key to success.
TAPI is committed to consistently delivering high-quality APIs, and trace analysis is a crucial step in achieving those results. We maintain a highly-regulated work environment that aligns with ICH and MOH guidelines and requirements around the world. Every process we follow and every action we take is done with our customers’ best interests in mind. TAPI’s culture of continuous improvement motivates us to find ways to make our processes even better, so our customers – and their patients around the world – can be confident their drug products will continue to be reliable, safe and effective.
Michael Tikhonov is a Group Manager at TAPI Analytical R&D in Petach Tikva, Israel. He has more than 10 years of experience in analytical development, especially in trace analysis.