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Impurities !!BETTER!!

In chemistry and materials science, impurities are chemical substances inside a confined amount of liquid, gas, or solid, which differ from the chemical composition of the material or compound.[1] Firstly, a pure chemical should appear thermodynamically in at least one chemical phase and can also be characterized by its one-component-phase diagram. Secondly, practically speaking, a pure chemical should prove to be homogeneous (i.e., will show no change of properties after undergoing a wide variety of consecutive analytical chemical procedures). The perfect pure chemical will pass all attempts and tests of further separation and purification. Thirdly, and here we focus on the common chemical definition, it should not contain any trace of any other kind of chemical species. In reality, there are no absolutely 100% pure chemical compounds, as there is always some minute contamination. Indeed, as detection limits in analytical chemistry decrease, the number of impurities detected tends to increase.[2]



Impurities are either naturally occurring or added during synthesis of a chemical or commercial product. During production, impurities may be purposely, accidentally, inevitably, or incidentally added into the substance.

The levels of impurities in a material are generally defined in relative terms. Standards have been established by various organizations that attempt to define the permitted levels of various impurities in a manufactured product. Strictly speaking, then a material's level of purity can only be stated as being more or less pure than some other material.

Impurities can be destructive when they obstruct the working nature of the material. Examples include ash and debris in metals and leaf pieces in blank white papers. The removal of impurities is usually done chemically. For example, in the manufacturing of iron, calcium carbonate is added to the blast furnace to remove silicon dioxide from the iron ore. Zone refining is an economically important method for the purification of semiconductors.

However, some kinds of impurities can be removed by physical means. A mixture of water and salt can be separated by distillation, with water as the distillate and salt as the solid residue. Impurities are usually physically removed from liquids and gases. Removal of sand particles from metal ore is one example with solids.

No matter what method is used, it is usually impossible to separate an impurity completely from a material. The reason that it is impossible to remove impurities completely is of thermodynamic nature and is predicted by the second law of thermodynamics. Removing impurities completely means reducing their concentration to zero. This would require an infinite amount of work and energy as predicted by the second law of thermodynamics. What technicians can do is to increase the purity of a material to as near 100% as possible or economically feasible.

Impurities play an important role in the nucleation of other phase transitions. For example, the presence of foreign elements may have important effects on the mechanical and magnetic properties of metal alloys. Iron atoms in copper cause the renowned Kondo effect where the conduction electron spins form a magnetic bound state with the impurity atom. Magnetic impurities in superconductors can serve as generation sites for vortex defects. Point defects can nucleate reversed domains in ferromagnets and dramatically affect their coercivity. In general impurities are able to serve as initiation points for phase transitions because the energetic cost of creating a finite-size domain of a new phase is lower at a point defect. In order for the nucleus of a new phase to be stable, it must reach a critical size. This threshold size is often lower at an impurity site.

The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids. As a result of chemical synthesis or subsequent degradation, impurities reside in all drug substances and associated drug products. While ICH Q3A Impurities in New Drug Substances (Revision 2) (Q3A) and Q3B(R2) Impurities in New Drug Products (Q3B) (Refs. 1 and 2) provide guidance for qualification and control for the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive.

Impurities in pharmaceutical R&D and manufacturing are a fact of life. New manufacturing processes, more complex drug formulations and increasingly complicated global supply chains for materials and ingredients are making it more difficult for companies to assess and control for impurities. In addition, a spate of recalls due to unsafe levels of impurities has prompted regulators to scrutinize impurities more critically than ever and regulatory actions related to impurities continue to grow.

Finding and addressing impurities earlier in R&D and process development can reduce the risk of unsafe impurity levels later in manufacturing processes, helping you stay on time and in compliance with regulatory expectations.

Under U.S. law, drug products marketed in the U.S. are expected to meet quality specifications in more than 4000 monograph standards in USP-NF, including tests for impurities using 1,500 impurity Reference Standards available from USP.

In addition to official USP Pharmacopeial Reference Standards for impurities, we now offer a growing catalogue of impurities through our Pharmaceutical Analytical Impurities (PAI) product line.

The European Medicines Agency (EMA) has assessed the risk of nitrosamine formation or presence during the manufacture of human medicines and has provided guidance to marketing authorisation holders to avoid the presence of nitrosamine impurities.

EU regulators first became aware of nitrosamines in medicines in mid-2018 when nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were detected in blood pressure medicines known as 'sartans'.

EMA finalised a review under Article 5(3) of Regulation (EC) No 726/2004 in June 2020 to provide guidance to marketing authorisation holders on how to avoid the presence of nitrosamine impurities in human medicines.

EMA and national competent authorities will continue to monitor the presence of nitrosamine impurities in medicines, in co-operation with regulators from outside the European Union (EU), and will work with marketing authorisation holders to find rapid solutions to address any adverse findings.

Marketing authorisation holders should review their manufacturing processes for all products containing chemically synthesised or biological active substances to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities.

In June 2020, the European medicines regulatory network published the outcome of a lessons learned exercise on the presence of nitrosamines in sartan medicines (also known as angiotensin II receptor antagonists). This includes recommendations to help reduce the risk of impurities in medicines and ensure that regulators are better prepared to manage cases of unexpected impurities:

Such active substances contain vulnerable amine functional groups that can undergo a reaction called nitrosation (often a secondary amine). Nitrosamines are thought to form when the nitrosatable amine group in the active substances and trace nitrite impurities in the inactive ingredients (excipients) react.

Adeno-associated virus (AAV)-based vectors expressing therapeutic genes continue to demonstrate great promise for the treatment of a wide variety of diseases and together with other gene transfer vectors represent an emerging new therapeutic paradigm comparable in potential impact on human health to that achieved by recombinant proteins and vaccines. A challenge for the current pipeline of AAV-based investigational products as they advance through clinical development is the identification, characterization and lot-to-lot control of the process- and product-related impurities present in even highly purified preparations. Especially challenging are AAV vector product-related impurities that closely resemble the vector itself and are, in some cases, without clear precedent in established biotherapeutic products. The determination of acceptable levels of these impurities in vectors prepared for human clinical product development, with the goal of new product licensure, requires careful risk and feasibility assessment. This review focuses primarily on the AAV product-related impurities that have been described in vectors prepared for clinical development.

The workshop will include presentations on nitrosamines chemistry and toxicology and, on the finding of nitrosamines as impurities in drugs. The presentations will be followed by open discussion of questions prepared by the FDA and presented to expert panelists for deliberations over 2 days. Topics to be addressed include nitrosamines as chemicals present in the environment, in food and, more recently, detected as impurities in drugs, nitrosamine pharmacokinetics, carcinogenesis, mutagenesis, (Q)SAR, and health risk assessment and mitigation. In addition, the panelists will be asked to identify data gaps and research needs to address uncertainties in nitrosamine safety assessment and how to prevent or minimize their presence in drugs.

At its 174th session in November 2022, the European Pharmacopoeia (Ph. Eur.) Commission adopted the revised general monographs Substances for pharmaceutical use (2034) and Pharmaceutical preparations (2619), which now include a paragraph explaining the Ph. Eur. approach to N-nitrosamine impurities.

On 2 April 2019, the European Commission adopted a legally binding decision on nitrosamine impurities in medicines containing the five active substances initially concerned (valsartan, candesartan, irbesartan, losartan and olmesartan). In response, the Ph. Eur. Commission decided to revise the corresponding monographs (Valsartan, Losartan potassium, Irbesartan, Candesartan cilexetil and Olmesartan medoxomil). 041b061a72


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