The Establishment And Practice Of A Standard Toxicopathological Platform In Drug Safety Evaluation

The preclinical safety evaluation, which directly affects the capability and quality of new drug research and development (R&D), constitutes an important part and procedure in the process of new drug R&D. Toxicological pathology is one of the most important parts and basic components in the field of drug safety evaluation and research, which is involved in the acute toxicity study, long term toxicity study, carcinogenicity study and teratogenicity study in the drug safety evaluation and research. Therefore, the ability and level of toxicological pathology will not only directly affect and restrict the development of preclinical safety evaluation and reaserch, but also indirectly affect and restrict the development of new drug R&D.Compared to the US, European Union, Japan and other developed countries and regions, there is a large gap in China with regard to the ability and level of drug safety evaluation and toxicological pathology which has restricted the development and progress for new drug research in China. Specific performance in hardware, the low level of automation in experimental facilities and equiptments can not keep up with the development of toxicological pathology wich will increase the possibility of uncertain errors in experimental system. And the personnels in toxicological pathology lack of strong GLP concept and executive force. There is no comprehensive training and certification management system in respect of software for any specific work.Based on the status of toxicological pathology in drug safety evaluation and research in China, this research aims to establish a set of standard platform with good compliance to international standards in advanced countries and regions, such as the guidelines of the United States Food and Drug Administration (US FDA) and the American Society of toxicological pathology (STP), which were widely recognized by toxicopathologists in the world. And we guide the toxicological pathology test by the established practices in the following drug safety evaluation and research study. We hope our study achievments could offer a Chinese characteristcs and good compliance to international standards, which can promote the rapid develoment of standardization in toxicological pathology in China, and narrow the gap between China and developed countries in this field. At the same time, we hope this study might help to the rapid development of the pharmaceutical industry and drug preclinical safety evaluation and research in China.This study focused on three important aspects in toxicological pathology at GLP laboratories:1) hardware construction, including purchase, management and operation of advanced automatic equipments related to toxicological pathology;2) Software construction, covering SOP compiling and personnel training at every step of the pathological exam process, such as animal anatomy, organ weighing, tissue trimming, tissue fixation, tissue dehydration, tissue embedding, tissue sectioning, tissue staining, histopathological examination, peer review, pathology reporting, standardization of diagnostic nomenclature and diagnostic criteria, and establishment of the database of organ weights and coefficients and spontaneous diseases in the commonly used laboratory animals; and3) The construction of training and qualification system for the personnels of toxicological pathology. We look forword to make achievements at the above mentioned aspects in toxicological pathology.In the past three years we got the following results in this study:1. Hardware standardizationWe investigated and purchaseed the required equiptments in toxicological pathology, including ThermoScientific PrintMateTM and SlideMateTM, Sakura Tissue-Tek VIP5Jr., Sakura Tissue-Tek TECTM5, Sakura-TekTM DRS-2000, and Hamamatsu NanoZoomer Digital Pathology station with remote consultating devices. A managing system for all of the equiptments, including SOPs compiling, qualification, use and maintenance, has been set up. And we obtained very good results from the running of the above mentioned equiptments.2. Software standardizationWe compiled the SOPs for every step of the pathological exam process, including animal anatomy, organ weighing, sample trimming, tissue fixation, dehydration, embedding, sectioning, staining and mounting, which had good compliance to the international standards. We established and validated Lab Information Management System-EasyGLP. We standardized the processes and format of histopathological examination, peer review, and pathology report. Following the guidelines and best practices by STP, we standardized the diagnostic nomenclature and criteria for histopathological examination, and established the database of organ weights and coefficients, and spontaneous diseases in the commonly used laboratory animals;3Establishment of training and qualification system for the personnels of toxicological pathologyWe formulate rules and regulations to describe the requirements for the toxicological pathology personnels at different levels, including education background and qualification examination. All of pathologists in our lab obtained the qualification certifications by the Chinese College of Veterinary Pathologists (CCVP). We established training and examination system for the new staff, with the details of training content, training time, training methods, lecturer, and examination questions and operations.This study established a set of standardized platform for toxicological pathology based on the current status in China. The platform involves the standard operating procedures and processes for regulatory toxicology study with good compliance to regulations of China. For all of the equiptments, requirements for the purchsae, manegement, qualification, performance, maintaince and repairment were established. A remote consultation system for toxicological pathology was also established. All of the hardware devices and systems run well by the guidance of the SOPs, which offered the necessary hardware support for the standardization construction of toxicological pathology.The software construction in this platform systematically described the operating process, method, details and key points of animal anatomy, organ weighing, sample trimming, tissue fixation, dehydration, embedding, sectioning, staining, histopathological examination, peer review and final pathology report. We established and validated the toxicological pathology module of Lab Information Management System (LIMS)-EasyGLP. And we established toxicological pathology standardized diagnostic nomenclature and diagnostic criteria system, established background databases of the toxicological pathology laboratory animal organ weight, organ coefficient, the spontaneous disease and common spontaneous tumor pathology image database. Among them, toxicological pathology diagnostic nomenclature and diagnostic criteria is of significance to the standardized diagnosis (?)ologicai pathology.This platform described the requirement and method for different personnels in education background and qualification requirements in toxicological pathology of drug safety evaluation and research, established personnel training and examination system. Among them, it is the first time that the toxicological pathologist is required to get the the qualification certification by the Chinese College of Veterinary Pathologists (CCVP).The standard practice of preclinical safety evaluation and research in toxicological pathology in this study described standardized method and content of toxicological pathology from "material"(hardware construction),"method"(software construction) and "staff"(personnel construction), which established standard toxicological pathology in multi-level and three-dimensional way under the condition of GLP. Among them, a lot of contents and viewpoints are presented for the first time in China, which might throw light on other toxicological pathology practitioners, GLP managers and drug trial supervision departments.