From January 1, 2018, the United States Pharmacopeia (USP) requires that all new drugs and generic drugs, whether they are on the market or under review or to be declared, must meet the requirements of the General Principles for the Control of Elemental Impurities Limits (USP). To perform elemental impurity analysis, below are some necessary steps that should be considered.
The first step: Determine which elements to be verified
Before all verification work begins, the element impurities that need to be tested must first be clarified. For different routes of administration, the regulations stipulate the corresponding elements that must be evaluated. Among them, the 7 elements of Type 1 and Type 2A apply to all products. For other non-mandatory/not actively added elements, pharmaceutical companies can decide whether to include them in method verification based on their potential risks.
Step 2: Pre-processing methods
After clarifying the metal elements to be analyzed, it is necessary to confirm the most important part of the method verification, namely, sample pretreatment.
Different from the guiding principles of , USP makes clear provisions for the four applicable pre-treatment methods. It needs to be emphasized that most of the verification data deviations and subsequent method development challenges come from the pre-processing stage.
Although each method has its characteristics and is suitable for different sample types, in general, the direct dissolution method has certain advantages in the ease and safety of operation and the stability of the results, and are thus the first steps to try. For example, since some pharmaceutical intermediates are easy to directly dissolve in organic solvents (such as isopropanol, dimethyl sulfoxide, etc.), the high-temperature and high-pressure reactions are avoided.
For compounds that cannot be directly dissolved, the indirect dissolution method can also be selected. Among them, the microwave digestion method in a closed container is the most mainstream choice, and the parameters involved are more complicated than that of direct dissolution.
Step 3: Pre-experiment
After finding a method to completely dissolve the sample, a simple preliminary experiment can help the laboratory confirm the stability of the digestion solution, the approximate range of the accuracy, and the precision of the instrument parameter settings.
Step 4: Method verification
After the previous pre-experiment steps, the method parameters have been confirmed. Therefore, at this stage, it would be very simple to conduct the final method verification.
However, it needs to be emphasized that the system adaptability requirements of the element impurity experiment are different from the traditional liquid phase method. Among them:
System adaptability can be achieved through daily tune.
Mass resolution can be achieved by mass tuning once a month.
For trace metal analysis, “repeat 5-6 injections and keep the RSD at 2% NMT” is difficult to achieve.
The linear range of ICPMS is very large, and conventional quantitative analysis is generally done at 0.5J and 2J.
About Elemental Impurity Analysis Method
USP general rules recommend the use of the ICP-AES method (or ICP-OES method) and ICP-MS method. At present, modern instrumental methods that can be used for the analysis of metal elements include FAAS and GFAAS methods of atomic absorption spectroscopy, inductively coupled plasma spectroscopy such as inductively coupled plasma (ICP), ICP-AES or ICP-OES, ICP- MS method, and X-ray fluorescence spectrometry (XRF method). The advantages and disadvantages of each instrumental analysis method are very obvious.
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