Professional and technical dry goods: a brief discussion on the selection of starting materials for chemical synthesis APIs

01 Definition of the starting item

Definition of starting material in the GMP guidelines for the production of ICH Q7 APIs:

1. A raw material, intermediate or API used to produce a certain API and become an important structural component of the API structure. 2. API starting materials can be listed commodities, products purchased from one or more suppliers by contract or commercial agreement, or substances produced by the enterprise itself. 3. API starting materials usually have clear chemical properties and structure.

02 Requirements for starting materials in registration regulations

According to the relevant provisions of the requirements for the declaration data of the new registration classification of chemical drugs (No. 80 trial implementation in 2016), the selection basis of the starting material should be provided in the registration data, and the key steps that have a significant impact on the quality of the final product should be included in the production process of this product. According to the requirements of controlling the quality of drugs from the source, the appropriate starting materials should be selected, and the selection of starting materials should meet the relevant technical requirements of ICH Q11 and the European Union.

03 ICH Q11 EU and CDE related technical requirements

1. ICH Q11 requirements:

Based on the coordination of the basic principles of starting material selection by the United States, Japan and Europe, ICH issued ICH Q11 guidelines in 2012 based on scientific and risk assessment, formulated the basic principles for the selection of starting materials for chemical synthetic APIs, and clearly stated that the selection of starting materials should consider all the following principles, rather than strictly following a single principle. (1) Generally, changes in material properties or operating conditions that occur near the beginning of the production process have little potential impact on the quality of the API. The relationship between risk and the number of steps to complete the manufacturing process is the result of two factors, one related to the physical properties of the drug substance and the other related to the formation, destination and removal of impurities. The physical properties of the drug substance depend on the final crystallization step and subsequent operations (e.g., grinding, micronization), which occur at the end of the production process. Impurities introduced or produced earlier in the manufacturing process usually have more chance of being removed by the refining operation (e.g., washing, crystallization of separated intermediates) than impurities generated later in the manufacturing process, and are therefore less likely to be brought into the API. However, sometimes (e.g., synthesis of peptides or polynucleotides with solid carriers) the relationship between risk and the number of steps to complete the production process is very limited. (2) The regulatory authorities assess whether the control of APIs and API production processes has been fully considered, including whether impurities have been appropriately controlled. In order to carry out this assessment, the manufacturing process of the API should be fully described in the declaration so that the regulatory authorities can understand how impurities are formed during the process, how process changes will affect the formation, destination and removal of impurities, and why the proposed control strategy is suitable for the production process of the API. This will typically include a description of multiple chemical transformation steps. (3) The description of the production process in part 3.2.S.2.2 of the declaration material should usually include the production steps that have an impact on the impurity profile of the API. (4) Each branch of the polymerization API production process begins with one or more starting materials. The Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to each branch and are applied from the first use of the starting material. The production steps carried out under GMP conditions combined with appropriate control strategies can provide assurance of the quality of the API. (5) The starting material should be a substance with clear chemical properties and structure. Unseparated intermediates are usually not considered as suitable starting materials. (6) The starting material is incorporated into the structure of the API as an important structural fragment. The term "important structural fragments" here distinguishes starting materials from reagents, solvents, and other raw materials. Common chemicals used to prepare salts, esters, or other simple derivatives should be considered reagents. Based on the selection of starting materials in synthetic APIs, the applicant shall confirm the reasonableness of each proposed starting material on the general rules listed in the selection of starting materials. It can contain the following information: (1) The ability of the analytical method to detect impurities in the starting material. (2) In the subsequent process steps, the whereabouts and removal of impurities and their derivatives. (3) How the proposed quality standards for each starting material will contribute to the control strategy. As part of the reasonableness argument, the applicant should provide a flow chart of the synthesis route of the current API production, which should clearly mark the proposed starting material. Changes in starting material quality standards, as well as changes in the synthetic route from starting material to final API, must meet local requirements for approval before making changes. Regional requirements that involve starting material suppliers may also apply. If commercially available chemicals are used as starting materials, the applicant usually does not need to justify their rationalization. Commercially available chemicals generally refer to commodities that are marketed as pre-existing non-pharmaceutical markets, in addition to those intended for use as starting materials. Chemicals prepared by custom synthesis are not commercially available. If custom-synthesized chemicals are used as starting materials, their rationality needs to be justified in accordance with the general rules outlined in the Starting Material Selection Principles section. In some cases, API manufacturers need to add a refinement step to the starting material to ensure the consistency of the quality of the starting material from commercially available sources. In this case, the additional refining steps should be described as part of the API manufacturing process. Quality standards for purchased and refined starting materials are often required.

2. EU requirements: The main principles of EMA and EDQM for chemical synthesis of API starting materials are summarized as follows: (1) The starting material is introduced into the API structure as an important structural fragment, but its structure should usually not be very close to the API, including relative size and complexity (depending on the number of reaction steps from the starting material to the API). (2) The characteristics of the starting material should be fully identified. (3) There should be multiple synthesis steps involving covalent bond formation or breaking between the starting material and the API. Only in special cases, such as the structure of the API is very simple, or the proposed starting material has obtained the CEP certificate, etc., a shorter synthesis route containing only 1~2 synthesis steps may be accepted. (4) A detailed API process description should cover all synthesis steps that have a critical impact on safety (impurities) and/or effectiveness, such as steps for the use or generation of genotoxic substances, steps that affect the overall stereochemistry of the API, or biocatalytic transformation steps.

3. CDE requirements: In 2005, CDE issued the "Guidelines for the Preparation and Structural Confirmation Research of Chemical Drug Raw Materials", which stipulates that the starting materials should be of stable and controllable quality, and there should be inspection reports of sources, standards and suppliers, and if necessary, internal control standards should be established according to the requirements of the preparation process. For impurities and isomers introduced by starting materials, relevant research should be carried out and quality control methods should be provided if necessary; For chiral starting materials, the limits of enantiomers or enantiomers as impurities should be formulated, and a certain understanding of the impurities that may be introduced during the preparation of the starting material should be obtained. The basic principles of starting material selection mentioned in the 2015 CDE training are: (1) It should be an important structural component fragment of the API, and the reaction reagent and solvent are not starting materials. (2) The API manufacturer should have a comprehensive and accurate understanding of the impurities of the starting material (including toxic impurities such as residual solvents and heavy metals), control it by appropriate analysis methods on this basis, and formulate reasonable limit requirements according to the impact of each impurity on subsequent reactions and final product quality. (3) The starting materials should have a stable commercial source that can meet the large-scale production of APIs. (4) Starting material suppliers should have a sound production and quality control system, and have a good communication and cooperation relationship with API manufacturers to ensure that they can always produce starting materials that meet the requirements in accordance with unified requirements.

04 Editor's Share

ICH is a guiding principle based on scientific and risk assessment based on the basic principles of coordination between the United States, Japan and Europe on the selection of starting materials. CFDA's policies and regulations are also based on this. It is recommended that the work should be guided by ICH Q11 and ICH Q11 questions and answers