1. Different definitions:
The definitions of ICH Q7A are as follows:
Intermediate: Intermediate: A material produced in the process steps of the API that must undergo further molecular changes or refinement to become the API. Intermediates may or may not be isolated.
Pharmaceutical intermediates are actually some chemical raw materials or chemical products used in the pharmaceutical synthesis process. This kind of chemical product does not require a pharmaceutical production license and can be produced in ordinary chemical plants. As long as it reaches a certain level, it can be used for the synthesis of pharmaceuticals.
FDA summarizes the main intermediates into:
a. Hub intermediates: intermediates that can be synthesized by different methods;
b. Key intermediate: usually the intermediate where an important part of the molecule is formed for the first time. For example: a molecule with stereoisomerism is an intermediate in which chiral atoms are introduced 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 the synthesis of API.
Active Pharmaceutical Ingredient (API) (or Drug Substance) – Active Pharmaceutical Ingredient: Any substance or mixture of substances intended for use in the manufacture of pharmaceuticals and, when used in pharmaceuticals, becomes an active ingredient in pharmaceuticals Element. Such substances have pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, treatment or prevention of diseases, or can affect the functions and structures of the body.
It can be seen from the definition that intermediates are key products in the front-end process of making APIs and have different structures from APIs. In addition, there are testing methods for raw materials in the Pharmacopoeia, but not for intermediates.
2. Differences in certification:
Currently, FDA requires intermediates to be registered, but CEP does not. However, a detailed process description of the intermediate must be included in the CTD file. In China, there are no mandatory GMP requirements for intermediates.
Submitted by API companies, if the API synthesis route is very simple, such as only one step reaction, and FDA believes that risk control is insufficient, it is very likely to extend the inspection of intermediates. Intermediate management generally follows ISO or combined with Q7a, as long as there is a quality system management.
3. From the perspective of new drug development, a raw material drug is a compound that can be safely used in the human body for therapeutic and diagnostic purposes after sufficient pharmaceutical research; while an intermediate is a compound in the process of synthesizing a raw drug and may not necessarily have therapeutic effects or be toxic. . Note that what is said here is not necessarily the same. Some intermediates in the synthesis process of APIs are also APIs.
4. From the perspective of pharmaceutical management, raw materials must apply for registration with the drug regulatory authorities (in China, it is the State Food and Drug Administration, in the United States, it is FDA, and in Europe, it is EMA). After obtaining the approval number, it must comply with GMP It is synthesized in a factory; and intermediates are only intermediate products in the process of synthesizing APIs and do not need to obtain a registration number. It should be noted that compounds that are the same as APIs are not APIs if they have not obtained a registration number or are not produced in a GMP factory.
for example:
Amoxicillin capsules are called preparations, amoxicillin is called raw material, and 6-APA is called intermediate.
Ceftriaxone sodium powder for injection is called preparation, sterile ceftriaxone sodium is called raw material, and 7-ACA is called intermediate.
5. The relationship between the two:
1. The specific substances of the two are different.
Pharmaceutical intermediates are also called organic pharmaceutical intermediates, which refer to a semi-finished product and are a product in the production of certain products. The raw material drug refers to the active ingredient of the drug and is also the basic substance that constitutes the pharmacological effect of the drug. API is a pharmaceutical active substance prepared through chemical synthesis, plant extraction or biotechnology.
2. Making APIs must rely on intermediates
Pharmaceutical intermediates are a kind of chemical raw material or chemical product in the drug synthesis process. They are also intermediate products in the process of producing APIs. They are a product in the path of synthesizing APIs and are produced in the process steps of APIs. A substance that must undergo the next step of molecular change or refinement to become an API. The raw material drug can be directly used as a preparation, while the intermediate can only be used to synthesize the next step of the product, and the raw material drug can be manufactured through the intermediate.
3. Different production requirements
Pharmaceutical intermediates are intermediate products in the process of producing APIs, so pharmaceutical intermediates can be produced in ordinary chemical plants. If you want to produce APIs, you need to obtain a production license for APIs before you can produce them.
To sum up, reliable pharmaceutical intermediates and APIs are two completely different substances. The production threshold for pharmaceutical intermediates is relatively low, while the production of APIs requires higher production thresholds. If you want to make APIs, you must also have suitable pharmaceutical intermediates as raw materials.