CRED Getting the CMC Dossier Right 2024

28/08/2024

Starting Materials: Perspectives

Regulators: Risk to quality – impurities within process and cross-contamination from other processes

• Mutagenic impurities, Elemental Impurities (ICH M7 and ICH Q3D)

• Much more complex supply chains

Visibility of synthetic route – GMP + inspections for regulatory steps, no oversight for pre-SM steps

Lifecycle management: visibility of post approval changes; Responsibility, outsourcing

Industry:

Regulatory relief – fewer variations (Post approval global variations can take 4-6 years)

Risk to supplies and patient access- especially at launch

Economics - GMP and validation more expensive

Capability, complex processing, availability of facilities, new technologies, capacity, green chemistry

The Organisation for Professionals in Regulatory Affairs

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Starting Materials: ICH Q11 Principles

In general, changes that occur near the beginning of the manufacturing process have lower potential to impact the quality of the drug substance.

Enough of the drug substance manufacturing process should be described in the application to understand how impurities are formed in the process and why the proposed control strategy is suitable for the drug substance manufacturing process. This will typically include a description of multiple chemical transformation steps.

Manufacturing steps that impact the impurity profile of the drug substance should normally be included in Section 3.2.S.2.2 of the Common Technical Document (CTD).

Each branch of a convergent synthesis begins with one or more starting materials. GMP provisions described in ICH Q7 apply to each branch beginning with the first use of a starting material.

A starting material should be a substance of defined chemical properties and structure. These should usually be isolated compounds.

A starting material is incorporated as a significant structural fragment into the structure of the drug substance.

The Organisation for Professionals in Regulatory Affairs

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