Practice And Improvement On Starting Material Selection For The Manufacturing Process Of Synthetic Drug Substance In Drug Registration

As proposed by ICH countries in Europe,the United States and Japan,an active pharmaceutical integrant(API)starting material is the starting point of API synthesis.The ICH Q11 defines the general principles of the definition and selection of starting materials,from both technology and good manufacturing practices(GMP).The China Food and Drug Administration(CFDA)has issued the general principles about starting material in 2005,which provides the guidance to pharmaceutical development and data collection required for regulatory submission.Nevertheless,this guidance apparently has not yet clearly defined the criteria of selecting starting materials and not clearly set a standard of defining the starting point,that could cause some confusion in development and negatively affecting the quality of submission.First of all,this paper investigates the ICH requirements and studies cases study of starting material selection.Then combining with the starting material selection applied in the practice of the drug application,this paper compares different requirements for starting materials based on regulations in China and ICH,analyzes the model and problems occurred from drug substance development and registration for Chinese enterprises.Finally,aiming to the problems existed in the domestic regulations,this paper discusses how to improve the starting material selection&definition and drug substance development focus,also suggests completing domestic relevant guidelines to match the international registration requirement,and introduce ICH reference in regulatory submission.In conclusion,from the ICH Q11 general principles,this paper investigates the practice of current starting material selection for synthetic drug substance based on the regulatory submission for China and overseas,deficiencies cited from the reviewers and responses are also reviewed.This paper applies the QbD concept and risk assessment theory and preliminarily establishes a risk assessment strategy to evaluate the suitability of starting material selection,and proposes suggestions of compliance with the international standards.The research results could raise the level of API production process development research in China,and provide reference to improve the technical requirements of regulatory submission and review.This paper helps drug enterprises and managers better understand the research content and technical requirements for the starting material in drug substance manufacturing.It is beneficial to register drugs in domestic and overseas market synchronically according to the ICH concept of drug substance development and starting material selection,improve product lifecycle management and the overall quality of the pharmaceutical research in China.