28-30 March 2023
The ICH Q11 Guideline describes approaches to developing and understanding the manufacturing process of drug substances. It was finalised in May 2012 and since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experiences during implementation of these principles within this 4 years period have shown that there is need for clarification in particular with regard to the selection and justification of starting materials.
On 30 November 2016 the ICH published a Questions and Answers document "Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)" which was developed by the Q11 Implementation Working Group. This document aims at addressing the most important ambiguities with respect to starting materials and at promoting a harmonised approach for their selection and justification as well as the information that should be provided in marketing authorisation applications and/or Drug Master Files.
In the following some examples of questions and answers from this document:
ICH Q11 states that “A starting material is incorporated as a significant structural fragment into the structure of the drug substance.” Why then are intermediates used late in the synthesis, which clearly contain significant structural fragments, often not acceptable as starting materials?
The selection principle about “significant structural fragment” has frequently been misinterpreted as meaning that the proposed starting material should be structurally similar to the drug substance. However, as stated in ICH Q11, the principle is intended to help distinguish between reagents, catalysts, solvents, or other raw materials (which do not contribute a “significant structural fragment” to the molecular structure of the drug substance) from materials that do. ... The presence of a “significant structural fragment” should not be the sole basis for of starting material selection. Starting materials justified solely on the basis that they are a “significant structural fragment” probably will not be accepted as starting materials by regulatory authorities, as the other principles for the appropriate selection of a proposed starting material also require consideration.
Do the ICH Q11 general principles for selection of starting materials apply to processes where multiple chemical transformations are run without isolation of intermediates?
Yes. The ICH Q11 general principles apply to processes where multiple chemical transformations are run without isolation of intermediates. In the absence of such isolations (e.g., crystallization, precipitations), other unit operations (e.g., extraction, distillation, the use of scavenging agents) should be in place to adequately control impurities and be described in the application. The drug substance synthetic process should include appropriate unit operations that purge impurities.
The ICH Q11 general principles also apply for sequential chemical transformations run continuously. Non isolated intermediates are generally not considered appropriate starting materials.
Is a “starting material” as described in ICH Q11 the same as an “API starting material” as described in ICH Q7?
Yes. ICH Q11 states that the Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to each branch of the drug substance manufacturing process beginning with the first use of a “starting material”. ICH Q7 states that appropriate GMP (as defined in that guidance) should be applied to the manufacturing steps immediately after “API starting materials” are entered into the process ... . Because ICH Q11 sets the applicability of ICH Q7 as beginning with the “starting material”, and ICH Q7 sets the applicability of ICH Q7 as beginning with the “API starting material”, these two terms are intended to refer to the same material.
ICH Q7 states that an “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API. ICH Q7 provides guidance regarding good manufacturing practices for the drug substance; however, it does not provide specific guidance on the selection and justification of starting materials. When a chemical, including one that is also a drug substance, is proposed to be a starting material, all ICH Q11 general principles still need to be considered.
With the recent publication of this draft Q&A Document with the complete title "Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers (regarding the selection and justification of starting materials)" on the ICH website it reached Step 2b of the ICH Process and now enters the consultation period. Comments may be provided by e-mailing to the ICH Secretariat at firstname.lastname@example.org.