Regulatory Starting Materials
Common Deficiencies, Agency Perspectives & Case StudiesAuthors:
Dr Leticia Monjas-Gómez
Consultant
Dr Asha Kattige
Technical Head (UK) & Principal Consultant
Introduction
A regulatory starting material is a chemical compound that marks the point in the synthesis of an active pharmaceutical ingredient (API) where current Good Manufacturing Practices (cGMP) begin. It is formally designated in regulatory submissions and must be scientifically justified based on its impact on the quality and safety of the final drug product.
An “API starting material” is defined in ICH Q7 as a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API.
The rationale for the point at which production of the API begins should be designated and documented. For synthetic processes, this is known as the point at which “API starting materials” are entered into the process. For other processes (e.g., fermentation, extraction, purification, etc), this rationale should be established on a case-by-case basis. Appropriate GMP (as defined in ICH Q7) should be applied to the manufacturing steps immediately after “API starting materials” are entered into the process.
Selection of Regulatory Starting Materials for Synthetic Drug Substances
The ICH Q11 guideline, released in 2012, establishes key principles for selecting and justifying starting materials in drug substance development. Following its implementation, global experience with applying these recommendations has led to calls for further clarification, particularly around the criteria for starting material designation. In response, EU regulators issued a reflection paper in 2014 (EMA/448443/2014) to elaborate on regulatory expectations. This was later supplemented by an ICH Questions and Answers document published in 2017.
ICH Q11 outlines overarching principles to guide the determination of where the drug substance manufacturing process should commence. These principles should be evaluated collectively when selecting regulatory starting materials, rather than being applied individually or in isolation. These principles are described below.
In general, changes to material attributes or operating conditions that occur early in the manufacturing process pose a lower risk to the final drug substance quality…