The Selection and Quality Control of the Starting Materials of API

Pharmaceutical preparations are composed of three major elements: qualified raw materials, appropriate amounts of excipients, and scientific production technology. Among them, the quality of raw materials is the first element that affects pharmaceutical preparations. Pharmaceutical outsourcing process institutions can provide outsourcing process R&D and production of intermediates, bulk drugs, preparations, etc. Starting materials are an important part of determining the quality of APIs. Improving the selection criteria of starting materials and strict requirements for starting materials control will help standardize the production of APIs and improve the quality of APIs.

The selection and quality control of starting materials are an important part of the development of APIs. The supervision of a drug usually starts with the starting materials. For example, in the registration and application materials of APIs, the details of the API production process should be started from the starting materials. Description: In the commercial production of APIs, the implementation of GMP requirements is also based on the introduction of the starting materials into the reaction process as the starting point; generally speaking, the regulatory agency focuses on the changes after the starting materials, including the source of starting materials and quality control requirements For the production of starting materials and their changes, the attention of the regulatory agencies is much lower. Therefore, starting materials are also an important node for change management. Contract processing outsourcing service organizations can accept the entrustment of pharmaceutical companies to provide customized production services. The business covered includes drug outsourcing process, formulation development, clinical trial drugs, chemical or biosynthetic API production, intermediate manufacturing, preparation production (such as Powder, injection) and packaging services.

For the impurity control of APIs, the impurities contained in the starting materials and the conversion products of these impurities in the subsequent reactions may be brought into the APIs, and some quality attributes of the starting materials may also affect the subsequent reactions. . Medicilon’s chemical process research services provide customers with chemical process services such as chemical process research, drug synthesis process optimization, pharmaceutical process research and development, and chemical project research and development outsourcing. It is a comprehensive biomedical research and development service company.

All of the above can see the importance of starting materials. In 2012, the Center for Drug Evaluation issued “Answers to Common Questions of Chemical Drugs-Pharmacy”, which provided supplementary explanations on the selection principles and quality control requirements of starting materials.

The basic requirements of starting material selection and quality control in our country:

(1) The starting material should be an important structural component of the API. ICH Q7A US defines “important structural fragment” as the part of the molecular structure that contributes to the pharmacological activity of API molecules or has important significance. “Important structural fragments” are suitable for materials that contribute to the final molecular structure of APIs, as opposed to reagents, catalysts or solvents.

(2) The API manufacturer should have a comprehensive and accurate understanding of the impurities of the starting materials (including residual solvents and heavy metals and other toxic impurities), and on this basis, adopt appropriate analytical methods to control, and perform follow-up reactions and analysis based on each impurity. The impact on the quality of the final product sets reasonable limit requirements.

(3) The starting materials should have a stable commercial source that can meet the large-scale production of APIs. In contrast, the FDA also stipulates that the chemical substance to be used as a starting material has been sold and widely used in other non-pharmaceutical fields, and there is no need to demonstrate the rationality of the chemical substance as a starting material; otherwise, it needs to be based on the selection principle. Demonstrate the rationality of its use as a starting material.

(4) The starting material supplier should have a complete production and quality control system, and have a good communication and collaboration relationship with the API manufacturer to ensure that it can always produce the starting material that meets the requirements in accordance with the unified requirements, such as its process or If there is a change in process control, the API manufacturer shall be notified in time so that necessary changes can be studied and reported in time.

(5) In addition, the API manufacturer needs to conduct a strict supplier audit on the starting material supplier.

As the front-end material of the preparation, the API has a direct impact on the quality of the final product. Therefore, for pharmaceutical companies, ensuring the stability and reliability of the quality system of the API supplier is directly related to the economic interests of the pharmaceutical company and the company. Image. As far as pharmaceutical companies are concerned, they should strictly follow the requirements of drug GMP, improve the drug quality assurance system, audit and audit material suppliers, and incorporate them into the scope of production quality management, as a subsystem for effective management, and pass quality system audits to ensure Material supplier reliability.

Impurity control of starting materials

The impurity control of the starting material is very important because:

First, the starting material is an important part of the API. If it contains impurities, during the production of the API, the impurities or impurity conversions may also enter the subsequent reactions and affect the API’s performance. Production quality

Second, some quality attributes of the starting materials are affected by impurities and change, which ultimately affects the quality of the API.

FDA regulations: The name, chemical structure, chemical and physical characteristics and properties of the starting material, and impurity spectrum are detailed in the chemical literature. The chemical substances to be used as starting materials should be separated and purified substances, and the impurities contained in them should not be the source of the main impurities in the API, that is, the starting materials, the impurities contained in the starting materials, and the impurities in the subsequent processes The content of the resulting conversion product in the bulk drug is not more than 0.10%.