The starting material for the manufacturing process does not comply with the Agency's current definition of an appropriate
regulatory starting material for an active pharmaceutical ingredient. Please declare appropriate starting material(s) from
an earlier point in the process and provide complete information on the entire process in this Drug Master File. Alternatively
you can provide the information shown below for the designated supplier:
A) The detailed synthetic route (including in-process controls, isolated intermediates, reagents/solvents, etc.) for the outsourced
starting material OR a DMF # from the outsourced vendor should be provided.
NOTE: If a secondary DMF is referenced within a primary DMF, the ANDA review time will be impacted.
B) The full name and address of the manufacturing site, related phone/FAX, contact person, and email address should be provided.
NOTE: It is possible that the Office of Compliance will inspect the site. If issues are found then neither DMF will be in
good standing with the FDA.
C) Extensive starting material specification requirements especially with regard to impurity carryover for both residual solvents
and related compounds may be requested.
D) Updated Certificate of Analysis (COA) from the vendor and in-house COA for the starting material will be requested.
E) A commitment to notify the FDA if the starting material vendor changes or the process is modified in any way, and to provide
again all the relevant information for any new vendor.
Fermentation-derived starting materials
For those manufacturers using starting materials resulting from a fermentation process, it is necessary to pay close attention
to the specifications for the well-characterized organic materials used in the fermentation (i.e., starch, glucose, lactose,
corn steep liquor, and soybean meal) (6). Inorganic starting materials should meet the same requirements as for chemical synthesis.
The microorganism cultured should be properly identified including morphological, cultural, and biochemical characteristics.
More details regarding fermentation processes can be found in the draft guidance on fermentation (6).
Plant- or animal-based starting materials
Starting materials from plant (e.g., thebaine) or animal (e.g., low molecular weight heparins ) sources should provide
source and location of plant or animal (i.e., species and organ tissue used), storage and transportation conditions, drying
conditions, and grinding conditions. Full disclosure of how the starting material is isolated, purified, and characterized
will be required. Pre-approval inspections of the source locations may be required on a case-by-case basis.
When choosing an API supplier, ANDA applicants must weigh the quality and commercial aspects judiciously. The choice will
have a direct impact on the review and approval times of submitted ANDAs. The choice of a high quality API is also integral
to building quality into a proposed drug product as part of a quality-by-design approach. API quality is essential to development
of a quality drug product, and API attributes should be considered as part of the QTPP (8). While the author has highlighted
a number of points with respect to API starting material designation and process controls, this is by no means an exhaustive
list of considerations when selecting a potential API supplier.