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Medicilon Drug Impurity Analysis Service

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In the process of API process research, the research of impurities is one of the most important links, because the production and preparation of any API cannot avoid the existence and generation of impurities. More seriously, some substances in the impurities are toxic Or it can be carcinogenic. If it is mixed with drugs that are originally designed to cure and save people, it will cause immeasurable harm and damage. In the actual R&D and production process, the research and control of impurities is also a part that consumes time, energy and money. In the face of thousands of types of impurities with different properties, how should we effectively conduct research?

What are the impurities?

Any compound that is not part of the API in a batch of API samples is considered an impurity. Impurities may arise from reaction raw materials or reaction solvents, or may arise from chemical reactions. Impurities can be roughly divided into inorganic impurities and organic impurities. Among inorganic impurities, metal impurities account for the largest proportion, and they all originate from the reaction raw materials; organic impurities include solvent residues and impurities generated in some reaction steps, of which the most interesting ones are. Genotoxic impurities. Genetic impurities, or genotoxic impurities (GTI), refer to compounds that directly or indirectly damage cellular DNA, resulting in gene mutation or in vivo mutagenesis, with the possibility or tendency to cause cancer. Generally, when designing the reaction route, the CDMO organization should increase the ratio of API in the product to more than 70%, and try to avoid synthesizing genotoxic substances. This route is ideal.

In production practice, 100% impurity-free API products do not exist, and the pursuit of production is the highest possible API purity. Then, for the impurities in API products, the CDMO agency needs to conduct detailed analysis and data preparation to prepare for the declaration, and the ICH also clearly defines the content of impurities.

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How to evaluate the hazard of impurities?

When impurities exceeding the threshold are generated in the synthesized API product, the first thing we need to do is to determine what these impurities are, including their structure and corresponding physicochemical properties. After completing this puzzle, we need to determine whether this impurity is dangerous and can cause harm to the human body. The ICH guidelines Q3A, Q3B, Q3C, Q3D and M7 all provide more detailed guidance and references for the assessment of impurities. Here we take genotoxic impurities as an example to illustrate how to judge the safety of impurities.

The classification of genotoxic impurities provides a relatively convenient tool for determining whether an impurity is genotoxic. It acts like an index, building up a vast database of known carcinogens, mutagens, and warning structures that may be genotoxic. When an impurity of unknown genotoxicity occurs in the production process, the structure of the impurity can be compared with the structure in the classification to determine or guide the study of its mutagenicity. In order to further reduce the difficulty of judgment, ICH M7 recommends the use of two complementary, principled (quantitative) structure-activity relationship ((Q)SAR) methods for computer-simulated toxicity assessment—systems based on expert rules and Statistically based system to predict bacterial mutation assays. If both complementary (Q)SAR methods (expert rules and statistics) have no alert structure, it is sufficient to indicate that the impurity is not of mutagenic concern and further testing is not recommended. For potential carcinogenic or mutagenic substances and impurities with warning structures, the Ames test is generally used to test the mutagenic ability of the impurities.

How to control the danger of impurities?

So how can the level of impurities be recognized in the final drug product submitted? In principle, this substance is not present in the drug in sufficient doses to have a significant effect on human health or drug absorption. The maximum daily exposure (PDE) refers to the highest dose at which the frequency or severity of any reaction does not increase biologically significantly after a substance is exposed to humans or animals. The calculation of PDE can intuitively reflect the safety level of impurities. Provides references for feasible doses of toxic impurities.

 Medicilon Impurity Analysis Services

Impurities in APIs are as inseparable as shadows and cannot be eliminated. It is important to be able to tease out a clear process for analyzing and treating impurities, identifying-analysing-controlling or eliminating them. Shanghai Medicilon Biopharmaceutical Co., Ltd. has a powerful CDMO platform to solve impurity problems for you, so that impurities are no longer complicated and difficult, and help the success of API process research. The projects that the Medicilon CDMO platform can currently undertake include but are not limited to the design and screening of synthetic routes for innovative drugs, generic drugs, drug intermediates and other chemicals, process development and optimization, and quality and stability studies, as well as three batches of small trials. , pilot test, process validation and production of at least three batches of cGMP. Medicilon's process chemistry team has rich scientific management experience and rigorous scientific exploration spirit, and can provide customers with mature one-stop services from drug discovery and synthesis to process research.

The production of APIs often involves complex chemical and biological changes. As the production processes are based on chemical unit reactions and chemical unit operations, resulting in by-products, purification and refinement is quite necessary. Impurities such as API-related substances, residual organic solvents, and inorganic impurities, as well as their physical and chemical properties, the stability of APIs, and the possibility of contamination and cross-contamination are key considerations regarding the quality, safety and effectiveness of APIs.

Medicilon offers API related services including impurity identification and separation, as well as quality research and stability testing.

-Preparation (or purchase) and standardization of impurities/standard samples

-Preparation and standardization of API standard samples 

-Preparation and standardization of API and intermediate standard samples 

-Impurity standard samples (impurity preparation or purchase; structure identification and standardization if necessary, with impurity content of 10mg-500mg) 

-Impurity research and impurity profiling

Medicilon employs a number of methods to determine metal impurities in API processes including inductively coupled plasma mass spectrometry (ICP-MS), inductively coupled plasma optical emission spectrometry (ICP-OES), and graphite furnace atomic absorption spectrometry (GFAAS).

Medicilon’s analytical chemistry and purification separation team provides customers with high-quality analysis and purification separation services. Our experts are highly recognized by customers for their rich experience and proficient skills in problem solving. We mainly provide the following services:

Impurity analysis

Separation and supervision of impurities in starting materials, intermediates, APIs and pharmaceutical products using various techniques such as HPLC Collect complete 1D/2D NMR, LCMS, EA, HRMS, IR, UV and other data to identify the structure of the separated impurities Separation and structure identification of API forced oxidative degradation products Using quantitative NMR (QNMR) to quickly determine the content of crude materials, intermediates, API and synthetic impurities Prepare professional application materials

Method development and method validation

API method development and verification (according to Chinese Pharmacopoeia, American Pharmacopoeia, European Pharmacopoeia, ICH and other requirements and other special requirements of customers) Development and verification of residual solvent methods (in accordance with Chinese Pharmacopoeia, American Pharmacopoeia, European Pharmacopoeia, ICH, etc.)

Drug impurity analysis

Drug impurities have become one of the key concerns of domestic and foreign drug regulatory agencies due to their potential impact on drug quality, safety and effectiveness. With the expansion of the export scale of my country’s pharmaceutical products, understanding the requirements of drug impurity control in foreign regulatory markets and strengthening the analysis and control of drug impurities have become a topic of common concern for domestic pharmaceutical manufacturers.

Any substance that affects the purity of a drug is collectively called an impurity. The Registration Technology for Human Drugs requires the International Harmonization Council (ICH) to define an impurity as any component that exists in a drug and whose chemical structure is inconsistent with the drug. The impurities contained in the medicine will reduce the curative effect, affect the stability of the medicine, and some may even be harmful to human health or produce other toxic and side effects. Therefore, testing related substances and controlling purity are very important to ensure the safety and effectiveness of medication and to ensure the quality of medication.

Main types of drug impurities

1. Organic impurities
Raw materials or pharmaceutical preparations may produce impurities during production or storage. They may be known, unknown, volatile or non-volatile compounds, and their sources include starting materials, intermediates, by-products, and degradation products. They may also come from racemization or contamination between enantiomers. Impurities generated in all these situations may cause undesirable biological activity.

2. Inorganic (elemental) impurities
Inorganic impurities may come from raw materials, synthetic additives, auxiliary materials and production processes used in the production of pharmaceuticals. Several potentially toxic elements may be naturally present in these components, and these elements must be tested in all drugs. Other components may be added during the production process. Once added, the elemental impurities must be monitored. Sources of inorganic impurities include reagents in the production process (such as ligands, catalysts (such as platinum group element PEG)), metals introduced in other stages of the production process (such as production water and stainless steel reaction vessels), activated carbon and filter materials Elemental impurities.

3. remaining solvent
Residual solvents are volatile organic compounds used or generated during the production of drugs. Many organic reagents used in drug synthesis are toxic or harmful to the environment, and are difficult to remove completely. In addition, the final purification process of most pharmaceutical ingredients includes a crystallization step, which will retain a small amount of organic solvent, which may become harmful impurities or cause drug degradation. ICH, USP and EP all set limits for solvent residues.

Pharmaceutical impurity analysis method

1. Analysis method of organic impurities

The detection methods of organic impurities include chemical methods, spectroscopy, chromatography, etc., and different detection methods are used due to different drug structures and degradation products. Separation and detection of impurities with different structures through appropriate analysis techniques to achieve effective control of impurities. With the development and update of separation and detection technology, efficient and fast separation technology is combined with sensitive, stable, accurate and applicable detection methods, almost all organic impurities can be well separated and detected under suitable conditions . In the quality standards, the commonly used impurity detection methods are mainly high performance liquid chromatography (High Performance Liquid Chromatography; HPLC), thin layer chromatography (ThinLayerChromatography; TLC), gas chromatography (Gas Chromatography; GC) and capillary electrolysis
Swimming method (Capillary Electrophoresis; CE).

2. Analysis method of inorganic impurities

The production of inorganic impurities is mainly related to the production process. Since many inorganic impurities directly affect the stability of the drug and can reflect the status of the manufacturing process itself, understanding the status of the inorganic impurities in the drug is of great significance for evaluating the status of the drug manufacturing process. For inorganic impurities, the pharmacopoeias of various countries include classic, simple and effective detection methods. For imitation of mature production technology, quality inspection and control can be carried out by the method of pharmacopoeia according to the actual situation. For new drugs produced by new production processes, ion chromatography and inductively coupled plasma emission spectrometry-mass spectrometry (ICP-MS) and other analytical chemistry experiments are encouraged to qualitatively and quantitatively analyze various types of inorganic impurities that may exist in the product in order to The production process is evaluated reasonably and provides a basis for formulating reasonable quality standards.

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