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There may be several sources of elemental impurities in drug products, which may be residual catalysts intentionally added during synthesis, or may be present as impurities (e.g., impurities from the interaction of the drug with processing equipment or container/closure systems or impurities present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits.
The United States Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) are regard these impurities as risk factors for the pharmaceutical industry and pharmaceutical-related industries. They have established relevant regulations in the United States Pharmacopoeia (USP) and various international standard specifications to control the elemental impurities.
USP is the US government's technical regulations on drug quality standards and testing methods, as well as the legal basis for drug production, use, management and testing. As early as the beginning of the last century, the USP controlled the heavy metal elements in medicines by establishing USP<231> to ensure the safety of medicines. However, the sulfide precipitation method has low-sensitivity, non-selectivity, low reproducibility, poor experimental operability and poor resolution. If this method is used to detect the content of heavy metal, important heavy metals sometimes cannot be detected, and even above-limit levels of mercury also cannot be detected. Based on the above problems, in 1995 USP began to modify this method, which has been used for nearly a century, and to introduce advanced detection technology to detect the content of heavy metals. After several modifications, the USP officially implemented the new General Regulations <232> "Elemental Impurity-Limit" and <233> "Elemental Impurity-Method" on May 1, 2014. In June 2016, a guiding principle issued by the FDA stipulated that starting from June 1, 2016, all newly declared new drugs or generic drugs must conduct risk assessment of elemental impurities in accordance with the ICH Q3D guidelines. Beginning January 1, 2018, the FDA required all US Pharmacopoeia drugs (NDA, ANDA, and OTC) to meet USP<232>/<233> requirements, whether these drugs are commercially available, under review, or to be released. For non-US Pharmacopoeia drugs (NDA and ANDA), ICH Q3D requirements for inorganic elemental impurities must be met.
Which products need to be controlled?
This guideline applies to pharmaceutical preparations and biopharmaceutical products, including pharmaceuticals and their derivatives, synthetic peptides, polynucleotides, and low-proteins and peptides containing purified proteins and peptides.
Drugs that not applicable to this guideline include drugs that are not suitable for use in clinical research, botanicals, radiopharmaceuticals, vaccine cells, metabolic products, DNA products, blood products, dialysis solutions, products with therapeutic effects, and genetic therapeutics, cell therapeutics, tissue regeneration drugs, health care products, veterinary drugs, and total intravenous nutrient solutions.
Which elements need to be controlled?
The elemental impurities in pharmaceuticals may come from equipment, raw materials, excipients, solvents and packaging materials used in pharmaceutical processes. Inorganic element impurities are classified into three categories based on the daily allowable exposure value (PDE) of the inorganic element impurities and the possibility of occurrence in solid drugs, injectable drugs, and inhaled drugs.
|Class 1||Arsenic, Cadmium, Mercury and Lead||They must be assessed for risk.|
|Class 2 A||Cobalt, Nickel and Vanadium||A risk assessment of the potential sources of all elemental impurities and all routes of ingestion is required.|
|Class 2 B||Silver, Gold, Rhodium, Ruthenium, Palladium, Platinum, Rhodium, Iridium, Selenium and Tellurium||If these elemental impurities are intentionally added in the production of APIs, excipients or other ingredients of the drug, these impurities cannot be excluded from the risk assessment.|
|Class 3||Antimony, Chromium, Copper, Lithium, Molybdenum, Niobium and Tin||For oral intake, these elements do not need to be considered in the risk assessment unless they are intentionally added. |
For injection and inhalation of drugs, unless the PDE of the route of administration exceeds 500 μg/day, the possibility of the presence of these elemental impurities also needs to be evaluated in the risk assessment.
|Others||Aluminum, Boron, Calcium, Iron, Potassium, Magnesium, Manganese, Sodium, Tungsten and Zinc||Some elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guideline.|
Permitted daily exposures of elemental impurities
Permitted daily exposures represents the maximum allowable amount of an element in a drug that is administered at the maximum daily dose. Since the PDE value only reflects the total exposure of the drug, it is more practical to convert the PDE value to concentration, making it a tool for assessing the elemental impurity content of the drug or its components. There are four conversion methods in the guide. We introduce one of them here.
This method assumes that the daily intake (amount) of the drug is 10 grams or less, and elemental impurities identified in the risk assessment (the target elements) are present in all components of the drug product. Using equation below, and assuming a daily intake of 10 grams of drug product, this method calculates a common permissible target elemental concentration for each component of the drug. This approach, for each target element, allows for the determination of a fixed commom maximum concentration in micrograms per gram in each component.
Concentration (ug /g) = PED (ug/day ) / daily amount of drug product (g/day)
How to evaluate the effect of elemental impurity in inner packaging material on liquid and semi-solid preparations?
Potential leachable elemental impurities that may be introduced from the inner packaging material should be evaluated based on possible interactions between the drug and other packaging materials. If the inspection of the structural materials proves that the inner packaging does not contain any elemental impurities, no additional risk assessment is required.
The possibility of inorganic elements leaching from the inner packaging material to the solid dosage form is very small and does not require in-depth consideration in risk assessment. However, for liquid and semi-solid dosage forms, it is more likely that the elemental impurities will leach from the inner packaging material into the medicine during the shelf life of the medicine. At this time, the element impurities that may be leached in the inner packaging material should be studied after sterilization, radiation, etc., and it is generally necessary to focus on the impurity of this type of material in the evaluation of the inner packaging material of a drug.
In short, the FDA, USP and ICH have clearly requested that the risk of inorganic impurities in all listed and declared drugs must be evaluated to ensure the safety of the drugs.
Alfa Chemistry Testing Lab is the world’s leading third-party testing company, which provides one-stop pharmaceutical impurity analysis testing solutions for manufactures, suppliers, retailers, and consumers.
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