At the core of every successful drug development program lies a reliable, scalable Active Pharmaceutical Ingredient (API) manufacturing process. From early discovery chemistry to commercial supply, designing an API process that evolves efficiently through each phase is critical to meeting regulatory expectations, clinical timelines, and commercial goals.
Yet many programs stumble by either over-engineering early processes—or neglecting scalability until it’s too late. In this blog, we explore how strategic route selection and phase-appropriate process optimization can set your API program up for long-term success.
Why Early API Process Strategy Matters
Decisions made during preclinical and early clinical phases have ripple effects that can either streamline or derail future development. A poorly optimized or non-scalable synthetic route can result in:
- Low yields and high material costs
- Difficult or unsafe scale-up
- Excessive impurity generation and control issues
- Complex purification steps that delay timelines
- Regulatory challenges in justifying process consistency
Conversely, a thoughtfully designed process balances development speed, manufacturability, cost, safety, and regulatory readiness.
Key Steps to Building a Scalable API Process
- Strategic Route Selection
Early-stage route selection should focus on:
- Simplicity: Favor routes with fewer steps and readily available starting materials.
- Robustness: Select reactions and intermediates that are reproducible and tolerant of scale-up variability.
- Safety: Minimize hazardous reagents or conditions, especially those difficult to control at scale (e.g., exothermic reactions, pyrophoric reagents).
- Regulatory Acceptability: Consider how route design impacts impurity profiles, potential genotoxic impurities (GTIs), and regulatory starting material (RSM) selection.
Tip: Even if the “discovery route” works in the lab, a separate development route may be necessary for clinical and commercial supply.
- Phase-Appropriate Process Optimization
Process expectations evolve by development stage:
- Preclinical to Phase 1:
Focus on delivering material safely and quickly with basic reproducibility. Minor impurities may be tolerated if justified, but do not make the early toxicology lots “too clean”.
- Phase 2:
Optimize reaction conditions, crystallization, and impurity control. Begin identifying CPPs (Critical Process Parameters) and develop basic scale-up data.
- Phase 3 to Commercial:
Finalize process understanding, validate manufacturing processes, lock RSMs, and demonstrate consistency with formal process validation (PPQ).
Tip: Avoid locking into highly specialized or expensive processes early unless absolutely necessary.
- Scalable Purification and Isolation
Crystallization, filtration, and drying steps must be designed with commercial scalability in mind—not just purity at lab scale.
Key factors:
- Avoid excessive reliance on chromatography unless justified.
- Control polymorphs and hydrate forms early.
- Address particle size and flowability for downstream manufacturability.
- Regulatory Alignment
A scalable API process must support smooth regulatory filings. Consider:
- Justification of starting materials per ICH Q11
- Managing known and potential impurities
- Providing phase-appropriate process descriptions and validation summaries
- Building a control strategy that evolves logically with development
- Technology Transfer Planning
Even during early development, processes should be documented (development and campaign reports are a must) with future tech transfer in mind. Scalable processes transfer more smoothly to CDMOs for GMP manufacturing—and avoid costly rework.
Common Pitfalls to Avoid
- Over-optimizing purity at the expense of yield or process simplicity
- Ignoring impurity profiles until late-phase development
- Designing processes that are not reproducible across equipment scales
- Failing to engage regulatory experts early when selecting RSMs
- Rushing to lock commercial routes without adequate risk assessment
Key Takeaway:
Building a scalable API process isn’t just about chemistry—it’s about strategy. A well-designed, phase-appropriate process improves manufacturing robustness, reduces costs, and supports smoother regulatory approvals throughout the drug development lifecycle.
Need help designing your API process for success?
DSI specializes in strategic API process development—from early route selection to full commercial scale-up and regulatory submission. Our consultants combine hands-on process expertise with real-world regulatory experience to ensure your API program remains on track and compliant.
Contact us today or visit our Drug Substance Services page to learn more.
