Risk of genotoxic impurities

Under current regulations, genotoxic substances have the potential to damage DNA at any level of intake, and this damage could lead to the development of tumors. Therefore, for genotoxic carcinogens, it cannot be said that "there is no clear threshold or that any level of ingestion is associated with a risk of carcinogenesis".

Acceptable Risk Intake

A TTC value of "1.5ug/day", equivalent to 1.5ug of genotoxic impurities daily, is considered an acceptable risk for most drugs (lifetime cancer risk is less than 100,000/1). Based on this threshold, an acceptable level of impurity in the active drug can be calculated based on the expected daily intake.

Guiding principles

ICH Q3A Impurities in New API

ICH Q3B Impurities in New Pharmaceutical Preparation

ICH M7 "Evaluation and control of DNA reactivity (mutagenic) impurities in drugs to limit potential carcinogenic risk"

China CDE: Technical Guiding Principles for the Standardization Process of the Establishment of Chemical Drug Quality Standards

Technical Guiding Principles for Validation of Analytical Methods for Chemical Drug Quality Control

Technical Guiding Principles for the Study of Chemical Drug Impurities,

"Chinese Pharmacopoeia" four general rules 0431, 0513

Impurity classification

Research strategy

According to the physical properties of genotoxic impurities, such as volatilization, molecular weight, ultraviolet absorption, boiling point, etc., different methods were used to quantify the impurities.

Business Development

Determination of NDMA in Metformin (LC-MS/MS, GC-MS/MS), N-nitroso amine in Sartans (LC-MS/MS, GC-MS/MS), Hydroxylamine in Sartans (Ion Chromatography-Electrochemical Method)

The warning structures of genotoxic impurity

Elemental impurity classification

Guiding principles

Formulate assessment and control strategies for elemental impurities, assess the elemental impurities in APIs and preparations based on ICH guidelines and relevant requirements of national pharmacopoeias, and provide scientific control strategies

Relevant guidelines and pharmacopoeia:ICH Q3D "Guidelines for Elemental Impurities", USP<232>"Guidelines for Elemental Impurities", USP<233 bbb="">Determination and Method Verification of Elemental Impurities ", "Chinese Pharmacopoeia" four general rules 0412

Research strategies

Based on the concept of QBD, relevant control thresholds were established according to dosage forms.Detection Method: Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

Business Development

Determination and methodological verification of Pb, Cd, Hg, As, Co, V, Ni in raw materials and oral preparations

Development and validation of elemental impurity analysis methods, development of more than a dozen elemental impurity analysis methods.

Guiding principles

ICH Q3D Guidelines for Elemental Impurities

USP<232>Guidelines for Elemental Impurities

USP<233>"Determination and verification of elemental impurities"

Chinese Pharmacopoeia four general rules 0412

Business Development

Testing and Certification Center Structure Verification team is dedicated to the identification and evaluation of relevant substances in the process of drug research. Under the guidance of cGMP system, the research team provides research services such as attribution analysis, structure verification (identification), quantitative nuclear magnetic evaluation (impurity COA) of relevant substances. Qualitative and quantitative analysis of starting materials, intermediates and API were carried out by using NMR, chromatography and mass spectrometry.

Main instrument testing items

Structure verification: IR, UV, NMR, XRD, MS, DSC and TGA, OR(elemental analysis) and structure analysis

Assay of drug quality research

5.Analyze the physicochemical and biological properties of the drug itself, investigate the factors of impurities and purity of various drugs, so as to  establish the characteristics of the drug, identification, inspection, assay and other inspection or determination items, storage conditions, etc.

API: focus on the physicochemical and biological properties, stability, impurity and purity control of the drug itself

Preparation: Based on API, it focuses on safety, availability, uniformity and stability

Drug stability study: Drug stability is the ability to keep physicochemical properties and biological properties unchanged. Investigate the change rule of drugs with time under the influence of temperature, humidity, light and other factors, which includes influence factor experiment, accelerated test, long-term test.

Quality control research includes

6.preparation technology research, structure confirmation research, formulation technology research, product quality research and quality standard formulation, and stability research, etc.

Guiding principles

ICH Q6A Quality Standards: Methods and Acceptable Standards for the Detection of New API and New Pharmaceutical Products

ICH Q6B Quality Standards: Methods and Acceptable Standards for the Detection of Biotechnology Products and Biological Products

ICH Q2(R1) Validation of Analytical Methods

CDE in China:

Technical Guiding Principles for the Standardization Process of the Establishment of Chemical Drug Quality Standards;

Technical Guiding Principles for Validation of Analytical Methods for Chemical Drug Quality Control

Technical Guiding Principles for the Study of Chemical Drug Impurities

"Chinese Pharmacopoeia" four general rules 9101

Business Development

7.Quality control of API;

Development and verification of analytical methods;

Establishment of quality standards for starting materials, intermediates and APIs, including development and verification of methods for studying and determining particle size of related substances, optical isomers, assay, residual solvents, genotoxic impurities, elemental impurities, and structural verification, physical and chemical testing;

Acquisition of central control data in synthesis process research.

Guiding principles

Guidelines for Safety Assessment of Fine Chemical Reactions (Trial)

Guiding Opinions of the State Administration of Work Safety on Strengthening Risk Assessment of Fine Chemical Reaction (Safety Supervisor No.3 [2017] No. 1)

Safety analysis of hazardous chemicals/reaction heat

Including: melting point of material, initial decomposition temperature, partial release heat;

Real-time temperature, pressure, stirring torque, volume and other changes of the reaction;

Heat accumulation and kinetic data of the reaction.

Optimization of chemical processes in pharmaceutical and fine chemical industries

Monitor the changes of parameters such as temperature, heat and pressure in the process of chemical reaction, physical mixing, distillation and crystallization, optimize the process conditions and improve the essential safety of production.

Instruments and equipment

Mettler Toledo DSC3 differential scanning calorimeter:

As a result of the modular design, from production, quality assurance to technical development and other processes are applicable. The instrument uses a robust and versatile DSC sensor with 56 pairs of thermocouples to ensure both excellent resolution and sensitivity. Equipped with automatic sampler,  all-weather efficient and reliable operation conditions can be provided.

The instrument is mainly used to measure the thermal stability of fine chemicals, the glass transition temperature Tg, melting temperature Tm, crystallization temperature Tc of polymer materials, and the energy absorbed or released. It is used to understand the crystallinity and purity of the substance, study the crystallization kinetics of the substance, and explore the substance.

Mettler Toledo RC1 automatic reaction calorimeter:

Mentler Toledo's fully automated reaction calorimeter, RC1MX, can be used to intuitively simulate and evaluate pilot-scale or larger reactions. The Icontrol software matching the first phase has the function of modular design, which can realize the full automation of most test reactions through simple modular design and programming with UCB comprehensive control box. The supporting ICSAFETY software can process and display the real-time signal data acquired by the sensor, and calculate the experimental parameters used for evaluation on this basis. In addition, the instrument is also equipped with safety brake facilities and voltage regulator power supply, which can maximize the safety of the instrument and the surrounding environment in the event of equipment failure or reaction out of control. The instrument has the characteristics of high accuracy, safe and reliable, accurate results, intuitive and simple operation, and powerful data processing function, which is an important hardware support for safety risk assessment.

- Main technical applications 

The instrument is mainly used to measure the heat release rate of the reaction process, the specific heat capacity of the reaction system (CP), the highest possible temperature of the uncontrolled system (MTSR), the total heat release of the reaction (Q) and the adiabatic temperature rise (△Tad).

-Services available 

① Chemical reaction safety risk assessment

In accordance with the national safety supervision bureau on strengthening fine chemical reaction risk assessment work guidance of "three (2017) no. 1 】 【 safety manager's requirements, to the catalogue of key regulatory dangerous chemical process full version (2013) contains 18 classes focus on regulation of dangerous chemical process and metal organic synthesis reaction for safety risk assessment.

② Safety analysis of hazardous chemicals/reaction heat Include: Measurement of various thermal data (e.g., heat of reaction), monitoring of reaction progress (reaction starting point, end point and kinetics), process safety assessment and amplification (△Tad, MTSR, Cp, U)

③ Optimization of chemical processes in pharmaceutical and fine chemical industries

Monitor the changes of parameters such as temperature, heat and pressure in the process of chemical reaction, physical mixing, distillation and crystallization, optimize the process conditions and improve the essential safety of production.