Differences between Intermediates and APIs

Differences between intermediates and APIs

1. Different definitions:
ICH Q7A is defined as follows:
Intermediate: a material produced in the process steps of API, which must undergo further molecular changes or refining to become API. The intermediate can be separated or not.

Pharmaceutical Intermediates are actually some chemical raw materials or chemical products used in the pharmaceutical synthesis process. This chemical product can be produced in ordinary chemical plants without a drug production license. As long as it reaches some levels, it can be used for drug synthesis.

FDA classifies the Main Intermediates into:
a. Hub intermediates: intermediates that can be synthesized by different methods;

b. Key intermediate: usually the intermediate formed for the first time in an important part of a molecule. For example, the intermediate with stereoisomeric molecules introduced chiral atoms for the first time. It can be understood as the main part of drug synthesis.

c. Final intermediate: the step before the final reaction of API synthesis.

Drug substance: Active Pharmaceutical Ingredient (API) (or Drug Substance) – Active pharmaceutical ingredient: any substance or mixture of substances intended for use in drug manufacturing, and when used in pharmacy, it becomes an active ingredient of drugs. This substance has pharmacological activity or other direct effects in disease diagnosis, treatment, symptom relief, treatment or disease prevention, or can affect the function and structure of the body.
It can be seen from the definition that intermediates are the key products of the previous process for the preparation of APIs, and are different from APIs in structure. In addition, the pharmacopoeia contains the detection methods for APIs, but there is no intermediate.

2. Differences in certification:
At present, FDA requires that intermediates must be registered, while CEP does not. However, detailed process description of intermediates must be included in the CTD document. In China, there is no mandatory GMP requirement for intermediates.

If the API synthesis route submitted by API enterprises is very simple, such as only one step reaction, FDA thinks that risk control is insufficient, it is very likely to extend the inspection of intermediates. Intermediates are generally managed in accordance with ISO or Q7a, with quality system management.

3. From the perspective of new drug development, API is a compound that can be safely used in human body for treatment and diagnosis after full pharmaceutical research; Intermediates are compounds in the process of synthesizing APIs, which do not necessarily have therapeutic effects or toxicity. Note that what is said here is not necessarily. Some intermediates in the synthesis of APIs are also APIs.

4. From the perspective of pharmaceutical administration, APIs should apply to the drug regulatory authorities (the State Food and Drug Administration in China, the FDA in the United States, and the EMA in Europe) for registration according to law, and be synthesized in the factory meeting GMP after obtaining the approval number; Intermediates are only intermediate products in the process of synthesizing APIs, and no document number is required. It should be noted that the same compound as the API is not a API if it has no document number or is not produced in the GMP plant.

Example:
Amoxicillin capsules are called preparations, amoxicillin is called APIs, and 6-APA is called intermediates.

Ceftriaxone sodium powder injection is called preparation, sterile Ceftriaxone sodium is called API, and 7-ACA is called intermediate.