The DMF in CTD format consists of 7 sections. In this video we will talk about section 3.2.S.2.
This is where we will find information about the manufacture of the API, first about its manufacturer and the site where it is produced, and then about the manufacturing process.
This section is divided in applicant part - which is shared with clients and regulatory agencies - and restricted part - which is usually shared only with regulatory agencies, since it may include more sensitive information about the API manufacture.
In the manufacturer sub section, the address where the API is produced must be clear and include all sites involved from the introduction of the starting material. Is the site responsible for the initial stages the same as the one involved in the final stages? Is any intermediate manufactured at a different site?
If the API is micronized, in which address it this step done?
Also, is the quality control performed in the same address where the analytical validations were done?
Then, we will see a diagram of the route of synthesis, whether it is a chemical synthesis, fermentation, or another. All structures must be part of the diagram displayed in the applicant part, and we also need to see a description of the manufacturing process, and a flow chart with the unit operations which are performed.
In the applicant part this description and flow chart are simplified, but all materials which are introduced need to be described, so that the drug product manufacturer can evaluate all potential impurities. In the restricted part more detailed information will be described, including the conditions that are used, such as temperature, pressure, operation time, in-process controls.
In case reprocess or recovery of materials can be applied, these procedures also need to be clear in the DMF.
After that, we will see information about the starting material. The starting material must be chosen and justified based on the principles of ICH Q11. To know more about definition of starting materials, we have a specific video about that.
In the restricted part we will also find out if there is more than one manufacturer for the starting material, who they are, and their addresses. What is the route of synthesis of this starting material, for each manufacturer?
And what about its quality control specification? Does the specification make sense considering the different routes? One of the most critical aspects to understand if the starting material is appropriate are the controls which are performed. Are all impurities originated from the starting material controlled or with their elimination justified? Do the controls consider all impurities from the different manufacturers?
This information about the starting material is part of the section control of materials. In the applicant part we should also see a list of all materials, while the restricted part will include the specifications and methods for all these materials which are introduced in the process.
Finally, the remaining sections are mainly present in the restricted part: the control of critical steps and intermediates, which will describe the specifications and methods of the isolated intermediates of the route, as well as how the critical steps of the process are controlled;
A section about the process validation;
And a section about the development of the process, which will be mainly applicable if the API is a new chemical entity, but it can also include information about process optimizations and changes in the route of synthesis which were done throughout the years.
Section 3.2.S.2 is one of the most critical of the DMF, because it's the basis to understand the potential impurities that may be present, which will need to have their control described in the section that follows.
In the next video we will talk about this next section, 3.2.S.3 - which describes the characterization and the impurities section. Stay tuned!
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