We typically work with small molecules of synthetic origin, but occasionally are retained to work with products that have active ingredients from botanical (plant) sources. Lynn Gold, our VP of CMC provides the following discussion on how to define the starting material for the Active Pharmaceutical Ingredient (API).
The definition of the starting material for any API is a negotiation process with the agency. This begins with your pre-IND meeting discussions and will continue as the program progresses through development. It is helpful in this negotiation process to provide as much information to the agency as you can. Clearly map your thoughts and key points for the agency to follow.
There is a guidance that can be helpful when beginning this process. The “ICH Q7A Good Manufacturing Practice for Active Pharmaceutical Ingredients” defines raw material, intermediate and API.
When dealing with an API extracted from plant origin there are two important points; the starting material is always the plant source and the API starting material can be different as shown in Table 1 from the ICH Q7A guidance.
Table 1: Application of this Guidance to API Manufacturing (Ref. ICH Q7A)
Type of Manufacturing
Application of this guidance to steps (shown in gray) used in this type of manufacturing
|Chemical Manufacturing||Production of the API starting material||Introduction of the API starting material into process||Production of Intermediate(s)||Isolation and purification||Physical processing, and packaging|
|API derived from animal sources||Collection of organ, fluid, or tissue||Cutting, mixing, and/or initial processing||Introduction of the API starting material into process||Isolation and purification||Physical processing, and packaging|
|API extracted from plant sources||Collection of plant||Cutting and initial extraction(s)||Introduction of the API starting material into process||Isolation and purification||Physical processing, and packaging|
|Herbal extracts used as API||Collection of plants||Cutting and initial extraction||Further extraction||Physical processing, and packaging|
|API consisting of comminuted or powdered herbs||Collection of plants and/or cultivation and harvesting||Cutting/ comminuting||Physical processing, and packaging|
|Biotechnology:fermentation/cell culture||Establishment of master cell bank and working cell bank||Maintenance of working cell bank||Cell culture and/or fermentation||Isolation and purification||Physical processing, and packaging|
|“Classical” Fermentation to produce an API||Establishment of cell bank||Maintenance of the cell bank||Introduction of the cells into fermentation||Isolation and purification||Physical processing, and packaging|
The botanical starting material, the plant being harvested, should be documented and should be subject to change control procedures. Multiple sources can be identified with the proper documentation.
The API starting material as defined in Table 1, is the material obtained from the first extractions. From this point in the process forward, GMP documentation and procedures should be in place. The in-process controls and testing should be well defined and documented. The components incorporated from this point forward should be clearly defined and received under GMP’s, tested per internal SOP’s and released prior to use in the manufacturing process.