From a wet-chemical procedure including color comparisons leaving room for interpretation to the most modern measuring methods such as microwave digestion followed by ICP MS measurements. This change of technologies is currently taking place to protect human health from elemental impurities. After around 10 years of discussion and adjustments, new regulations for all pharmaceutical products will be valid from January 2018 at the latest.
Elemental impurities constitute a toxicological risk for the patient. They are divided into two categories: elemental impurities can either be intentionally added (for example as catalysts for the synthesis of the active pharmaceutical ingredient) or not intentionally added, in which case they result from impurities in the drug product components. Additionally, elemental impurities may be introduced during the manufacturing process or during storage from the container closure system.
Up to now heavy metal analysis was performed via the reaction of heavy metals with thioacetamide. The color change due to the precipitation of metallic sulfides was compared with a lead standard. This method has several drawbacks such as matrix interferences, losses during the sample preparation and being dependent on the analyst for the interpretation of the color change. For these reasons, the discussion of new regulations started in 2008. According to the relevant pharmaceutical regulations (USP <232>, USP <233>, ICH Q3D step 4, Ph. Eur 5.20) the consideration of elemental impurities will be mandatory for all products from January 2018 at the latest.
A deeper insight into the regulatory background
The ICH is the leading platform for global pharmaceutical regulatory harmonization. The ICH publishes guidelines which combine the regulations from Europe, Japan, USA and Canada. The related guideline, ICH Q3D step 4, classifies elemental impurities based on their toxicity and the possibility of their occurrence in drug product components and drug products. According to the respective dosage form, such as oral, parenteral or inhalation, PDE (Permitted Daily Exposure) limits are defined for each element. For class 1 impurities, called the “big four”, the following limits are given:
|Element||Class||Oral PDE [µg/day]||Parenteral PDE [µg/day]||Inhalation PDE [µg/day]|
The manufacturer has to evaluate within a risk assessment whether the relevant PDEs could be exceeded for a specific product. Depending on the outcome of this evaluation, a control strategy has to be defined, which can range from no required analysis to periodic studies up to the routine test of each finished product batch.
The demands placed on the measurement method (ICH refers to the pharmacopoeias) are challenging in regard to the performance characteristics specificity, limit of quantification, precision and accuracy. For the elemental analysis, the USP <233> states Inductively Coupled Plasma either with Emission Spectroscopy (ICP OES) or with Mass Spectrometry (ICP MS). However, even these modern measuring techniques do not provide good quality data without a reliable sample preparation procedure.
Pharmaceutical products have different and sometimes very complex matrices. To transfer them in a liquid, analyzable form requires a robust sample preparation technique such as microwave digestion, a modern representative of closed-vessel digestion listed in the USP <233>. The sample is decomposed with concentrated acids under pressure, resulting in a clear aqueous solution. The achievable high temperatures (the temperatures are not restricted to the boiling point of the acids) enable the shortest process times and a low residual carbon content which minimizes measuring interferences. Reproducible and comprehensibly documented results are achieved by controlling and monitoring the temperature in the digestion vessels.
At the latest by January 2018, the safety of all pharmaceutical products in regard to toxic elemental impurities is ensured by employing modern sample preparation and measuring techniques. Pharmaceutical companies are currently equipping their labs to fulfill the regulations. As time is short, we support them by providing a microwave digester, ready-to-use tested methods, method development (if required) and comprehensive documentation in full compliance with current GMP requirements enabling our instruments to be ready for operation in one to two days.