Regulatory starting material (RSM) selection and justification can make or break your API CMC strategy. Regulatory authorities such as the FDA and EMA carefully scrutinize RSM designations, and inadequate justification is a frequent cause of information requests, delayed approvals, or even refusal to file.
Selecting the wrong starting material—or failing to justify it properly—can trigger extensive rework, additional GMP requirements, and even force changes to your overall API control strategy.
In this blog, we explore common pitfalls sponsors face when designating RSMs—and how to navigate this critical decision strategically.
What Is a Regulatory Starting Material (RSM)?
Per ICH Q11, RSMs are materials that are incorporated as significant structural fragments into the final API molecule. They serve as control points where GMP manufacturing begins, and their designation must be scientifically justified based on:
- The complexity of the structure
- The manufacturing process and impurity control
- The ability to ensure product quality without further characterization of earlier steps
RSMs represent the boundary between non-GMP and GMP operations—making their correct identification and justification crucial.
Common Pitfalls in RSM Justification
- Choosing an RSM that is too late in the synthetic sequence (too close to the API)
Problem: Selecting a late-stage intermediate as the RSM to minimize GMP effort may appear efficient—but regulators often reject this strategy if too much of the API’s structure is already present in the molecule.
Solution: RSMs should be selected early enough to capture meaningful structural complexity and allow for impurity control during GMP operations.
- Choosing an RSM too early without adequate controls
Problem: Designating a very early building block as the RSM without demonstrating control over impurities or variability can lead to regulatory pushback. This can also add additional manufacturing costs that will impact future commercial costs.
Solution: Ensure that material quality is well-characterized and that any impurities originating prior to the RSM are either removed or controlled through downstream processing.
- Inadequate scientific justification
Problem: Simply describing the RSM structure without linking it to process understanding is insufficient.
Solution: Provide a thorough, science-based justification including:
- Structural relevance
- Impurity purge studies
- Route complexity
- Analytical controls downstream
- Ignoring Genotoxic Impurity (GTI) Risks
Problem: RSMs that introduce potential GTIs must be carefully justified and controlled.
Solution: Conduct appropriate risk assessments per ICH M7 and demonstrate how GTI risks are mitigated post-RSM.
- Poor Alignment with regulatory trends
Problem: Agencies are increasingly scrutinizing starting material designations, particularly for synthetic peptides, oligonucleotides, and complex APIs.
Solution: Stay up-to-date with agency guidance, Q&A documents, and recent regulatory precedent when proposing RSMs. Realize that the what the FDA finds acceptable may not be acceptable in the EU.Best Practices for RSM Selection and Justification
- Perform a detailed process map early in development to identify candidate RSMs
- Conduct impurity mapping and purge studies for upstream steps
- Document rationale in alignment with ICH Q11 and regional expectations
- Engage regulatory CMC experts to review RSM strategy before submission
- Be prepared to defend the RSM selection during pre-IND, EOP2, or pre-NDA meetings
Tip: It’s easier to justify a conservative RSM selection up front than to rework your CMC strategy after regulatory rejection.
Key Takeaway:
Choosing and justifying the right RSM requires strategic foresight, scientific rigor, and regulatory expertise. Getting it right early protects your development timeline, minimizes regulatory questions, and ensures a smoother pathway to approval.
Need help selecting or justifying your API starting materials?
DSI provides expert support in RSM strategy development, impurity mapping, regulatory writing, and agency engagement. Our team helps ensure your API CMC package is scientifically sound and regulator-ready.
Contact us today or visit our Drug Substance Services page to learn more. rd. Let’s connect.
