Elemental impurities :The new regulatory compliance challenge in pharma :
New regulatory requirements for elemental impurities control in pharmaceutical products started to be implemented since Jan 2018. The harmonized compliance guidance — United States Pharmacopeia (USP) <232>/<233> and International Conference on Harmonization (ICH) Q3D – now require the pharma manufactures to address a much broader array of elements for impurity control based on different administration route. The classified 24 elements include not only the most toxic metals, but also a number of elements that could introduced intentionally duringproductionprocess. The new regulations also require significant low limits for the big four toxic metals (As, Hg, Cd, Pb) than the previous limits for heavy metals. The lower limits and more elements to address lead to the needs to use more advanced technologies and significant changes in elemental impurity testing in pharma industry. The new regulation requirements and new technologies also bring new challenges for the pharma companies such as more instrument investment and running cost, requirement for skilled operators, new process for method development and validation, etc. Other foreseeing challenges are continuously updating compliance, the new PDEs for alternative intaking routines, and speciation analysis requirement for toxicity of different valence states and molecular forms.
According to the new USP chapter <233>, two ICP based technologies– optical emission spectroscopy (ICP-OES) and inductively coupled plasma – mass spectrometry (ICP-MS) – are explicitly recommended in elemental impurity procedure due to their high sensitivity, low detection limits, multi-element analysis capability and wide dynamic range. Apart from the mentioned advantages, the new testing techniques also bring challenges such as the lengthy sample preparation process involving sample digestion and dilution, more complicated to operate, and the needs to develop new analysis methods. Typically, all 24 elements of the ICH/USP classes can be analyzed using the ICP-OES or ICP–MS techniques. However, the potential interferences could cause false positive testing results, e.g. the overlapping wavelengths in ICP- OES and identical isotope/mass in ICP-MS. The various permitted daily exposure (PDE) limits also required methods developed must balance matrix effects with instrument detection limits to monitor the elemental impurities at the required levels.
The breakthrough of the TOC analyzer in the pharmaceutical industry for validating cleaning :
As a means of minimizing or eliminating cross-contamination in production facilities, the operating regulation for pharmaceutical companies to clean their production facilities in accordance with stipulated procedures (cleaning SOP, standard work instruction) and to regularly demonstrate, i.e., validate (cleaning validation and revalidation), the effectiveness of these cleaning procedures by the use of analytical measuring techniques.
This means the residual substances auxiliary materials, cleaning agents, as well as their decay and reaction products, are to be tested for using a representative and validated sampling and analysis technique. Cleaning validation usually includes a test of this type in three consecutive batches, as well as a corresponding revalidation after a prescribed period of time. The difficulty entailed in this analysis is that contamination of a still tolerable level generally lies within the order of magnitude of the detection and determination limits of the analysis techniques used.
TOC analytics play an outstanding role in cleaning validation, especially for complex products or combinations of products with a large number of possible cleaning agents. As carbon is a component of all organic compounds, TOC determination allows the measurement and quantitative determination of organic residues of substances, auxiliary materials, reaction products, and cleaning agents in the trace range at around 50 ppb and below and is therefore predestined as a screening parameter. TOC determination is a pharmacopeia technique in accordance with PharmaEur. 2.2.44 and USP <643>, which is otherwise used to characterize organic load for water and ultra-pure water, and the cost of validation is lower than the other analysis technique.

1. to learn New regulatory requirements for elemental impurities control in pharmaceutical products
2. to learn using TOC analyzer for cleaning validation in the pharmaceutical industry.

elemental impurities, ICP-OES, ICP-MS, permitted daily exposure, PDE, TOC analyzer, cleaning validation

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