Chemical synthesis
Figure 1: Case I—unacceptable.
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The starting material should be removed from the finished product by multiple synthetic steps with intermediates isolated
and in-process controls specified. Salt interconversions, saponifications, esterifications, recrystallization steps, resolution
of racemates, and in-situ reactions with no intermediate isolated do not count as synthetic steps. In Case I (Figure 1), the starting material selection
is considered inappropriate because the synthesis is only one step removed from the finished product (salt interconversion
is not a valid synthetic step). Furthermore, all of the key structural elements found in the API are already included in the
proposed starting material.
Figure 2: Case II—unacceptable.
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For chiral molecules, how each stereocenter is introduced should be discussed in detail; proof of characterization using chiral
methodologies should be provided; and appropriate in-process controls should be highlighted. In Case II (Figure 2), the starting
material is inappropriate because all chiral centers A, B, and C are set in the proposed starting material with no indication
of how they were put in place or resolved.
Figure 3: Case III—unacceptable.
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In Case III (Figure 3), the racemate is purchased, resolved, and purified. There are no reaction steps or isolated intermediates,
and therefore, the racemate is not an acceptable starting material.
This also applies even in cases where the racemate is a drug substance in and of itself. For example, consider the case of
the API dexmethylphenidate. The racemate, methylphenidate, which is also an API, cannot be declared a starting material, as
there is only a resolution step involved in transforming it to dexmethylphenidate.
Figure 4: Case IV—unacceptable.
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Molecules that contain potential genotoxic (4, 5) structural elements in intermediates anywhere along the synthetic route
require extra care in managing impurity profiles and the corresponding risk associated with them. Designating a starting material
too late in a synthetic route with no information regarding impurity carryover and purification methods is not acceptable.
In Case IV (Figure 4), the DMF holder proposes the bis-anilino moiety as the starting material. A cyclization step and further
purification leads to the finished product. Aryl aniline functionalities are known carcinogens and are quite frequently derived
from aryl nitro groups, a well-known genotoxic functional group (4). From a risk-based point of view, controls of the impurities
at the nitration step are critical in this manufacturing scheme. The proposed bis-anilino starting material gives no indication
on how the nitration step was controlled or how subsequent impurities were removed. Furthermore, the proposed starting material
is only one step from the finished product with no intermediate isolated in between.
If a molecule is "well defined" in the literature, then the literature should be cited along with appropriate detailed comparative
structural analysis from the DMF holder against the literature values (e.g., published papers and patents). It is recommended
that data from multiple lots using the commercial process to demonstrate sameness be provided for review.
Commercially available starting materials need not be justified. In this context and per the draft ICH Q11, commercially available means "a chemical that is sold as a commodity in a pre-existing, non-pharmaceutical market" (2). In
contrast, chemicals for which a contract manufacturer custom synthesizes a predefined amount of material specifically for
the DMF holder are not considered "commercially available." Primary DMF holders submitting syntheses defining non-commercially
available starting materials will be asked a number of questions including the following:
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