Regulatory review of the starting material selection commences with the filing of the initial investigational new drug application
(IND) or investigational medicinal product dossier (IMPD) to support clinical trials. In the US, agreement on starting materials
is usually sought at the IND end-of-Phase II meeting, although final approval always awaits NDA approval. FDA encourages dialogue
with the sponsors on starting material selection throughout synthesis development. In Europe and Japan, consultation is less
common, and usually starting materials are agreed during MAA/NDA review.
In demonstrating process control of the registered process, the sponsor must determine whether the proposed starting material
is made by means of custom synthesis or it is a commodity reagent.
Commodity reagent starting materials are likely to have been made by well-characterized synthetic techniques in large scale
and are commercially available for several industrial applications (e.g., food or speciality chemicals). As a consequence,
they are unlikely to present an unexpected risk to a patient. Very limited process information is submitted to regulatory
authorities in these cases because it is often very difficult to obtain proprietary information from suppliers unfamiliar
with the demands of the pharmaceutical industry.
Custom-synthesis starting materials are likely to be made by custom manufacturers and in varying scales throughout the drug's
development. The sponsor must demonstrate the process has been fully developed and that further scale up will not present
a risk to a patient.
Data that would confirm a process is under control would include:
- Disclosure of sufficient synthetic stages must explain how the important structural elements are assembled into the complex
- Identification of the final intermediate in the submitted documentation not only helps the selection of the starting materials,
it also clarifies significantly differing filing requirements for postapproval change in the US (changes to an approved NDA
or ANDA, CANA) (8).
- Detailed discussion of the fate of impurities, including potential genotoxic impurities, present in the starting material
and those generated during the registered process should be addressed. Discussion of the process design space and how variation
in the process affects the removal of impurities in the starting material should be included.
- Complex chemistry stages (e.g., chiral synthesis, novel chemistry) should be discussed.
- Risks from TSE must be assessed and controlled.
- Provision of supporting chemical literature (e.g., CAS numbers, patents, journal articles) should be included.
At the heart of a strong justification for a starting material is the demonstration of adequate analytical control of the
registered process. This will include data about:
- The initial characterization of the starting material, including an overview of stability of the isolated starting material
- Starting material batch data from various suppliers used during development
- An assessment of how process changes could affect impurity profiles
- Demonstration of the selectivity of an analytical method for known and potential impurities.
Quality control points are used at appropriate points in the synthetic process to confirm the level of impurities at a particular
stage and to ensure patient safety. At minimum, a sponsor is likely to provide robust specifications for the starting material,
final intermediate, and drug substance to demonstrate that quality is built into the drug substance synthesis. Robust specifications
for key intermediates may also be proposed. Other intermediates may not require detailed specifications to ensure drug substance
Specifications for starting materials are likely to include identity, assay, and organic impurities (limits for specified,
unspecified, genotoxic, and total). In some cases, these specifications are supplemented with those for residual solvents,
heavy metals or catalysts, and chirality.
The specifications will follow guidance from ICH Q3A R2 Impurities in New Drug Substances, Q3C Impurities: Guidelines for Residual Solvents, and Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (14–16). The control of unspecified impurities in the starting material to a level of 0.1 or 0.2% should be considered an
argument for robust process control. For genotoxic impurities, consideration should be given to the threshold of toxicological
concern based on short or long-term exposure (17–20). Greater analytical control could be a used to justify fewer synthetic
stages subject to regulatory oversight.