CMC Expectations During Drug Substance Transfer from Ex-US Manufacturers

Regulatory Drivers for US-based API Manufacturers

Recent shifts in US tariff policies have introduced new pressure points in the global pharmaceutical supply chain, particularly for manufacturers sourcing drug substances and active pharmaceutical ingredients (APIs) from overseas—most notably from China. In response, many firms are now evaluating the feasibility of transferring manufacturing operations to US facilities.

While advantageous for supply chain security and regulatory alignment, transferring API manufacturing is a complex process that presents significant CMC and regulatory challenges. Explore the critical expectations and steps needed to ensure a compliant and efficient transfer of drug substance manufacturing from ex-US sites to US-based facilities.

Step 1: Site Selection and Technology Due Diligence

The first step to any successful transfer is to identify a qualified manufacturing site in the US that can make the API, the intermediates, or both. The focus should be on technical capabilities at the US receiving site and on their current compliance status with the FDA. A technical visit, gap analysis, and a quality assurance audit of the CMO are recommended.

Key evaluation criteria include:

• Technical capability assessments – Confirm that the new site has the right infrastructure, equipment, and technical expertise to replicate or improve upon the legacy process.
• Regulatory history – Examine the CMO's FDA inspection record, compliance status, and history with similar product types.
• Due diligence audits – Conduct an in-depth gap analysis and on-site audit to assess quality systems, data integrity practices, and alignment with current Good Manufacturing Practices (cGMP).

Engaging cross-functional internal teams (including QA, manufacturing science, and regulatory) during this early phase is critical to establishing a shared understanding of expectations and potential challenges.

Step 2: Review Existing CMC Information

Next, the existing CMC information in the dossier as well as from the current supplier should be reviewed.

Specifically, all the information required to manufacture the API should be current and provide clear instructions on how to manufacture the target compound. Information should include:

1. Synthetic route and reaction scheme – Ensure the chemistry is well-defined and reproducible.
2. Reagent and solvent specifications – Include concentration ranges, grades, and allowable variability.
3. Key starting materials (KSMs) – Document commercial availability or synthesis methods, including origin, traceability, and specifications.
4. Process parameters – Identify critical process parameters (CPPs) and acceptable ranges.
5. Impurity profile – Characterize known and unknown impurities, including genotoxic impurities, nitrosamines, elemental impurities, and residual solvents per ICH Q3A/B guidelines.
6. Critical quality attributes (CQAs) – Define attributes essential to safety and efficacy, supported by process knowledge and risk assessment.
7. Specifications and test methods – Confirm method suitability, validation status, and historical control data.
8. Stability data – Evaluate existing data under long-term and accelerated conditions to set storage and re-test intervals.
9. Process development history – Collect and interpret data from previous scale-ups, changes, and validation exercises.

This data must serve as the baseline for any subsequent comparability or bridging strategy.

Step 3: Process Development and Technology Transfer

The NDA holder should devise a development plan working with the new CMO, using the information above to develop a suitable process at the new site. Equipment differences and changes to the reaction conditions should be clearly identified. Engineering batches should be made and analyzed to detect any differences between the intermediates and API. For a synthetic chemical API, differences to examine include changes in solubility, particle size distribution and morphology, differences in impurities or related substances, yields, and other critical quality attributes.

Core activities include:

• Technology transfer documentation – Develop a comprehensive transfer package including batch records, SOPs, equipment specifications, and control strategies.
• Process adaptation – Adjust for differences in equipment, site-specific utilities, raw material sources, and operator expertise.
• Engineering batches – Manufacture pilot-scale batches to assess process robustness, impurity profiles, yield consistency, and reproducibility.
• Comparability assessments – Characterize differences in particle size, morphology, solubility, and impurity levels between the original and U.S.-produced API.

Any deviations from the legacy process must be scientifically justified and documented for regulatory submission.

Step 4: Exhibit Batch Production and Analytical Bridging

Upon completion of the development work, exhibit (registration) batches will need to be produced under conditions that simulate commercial manufacturing.

Three Consecutive Batches

Three consecutive batches are typically expected to establish reproducibility. If less batches are desired due to cost, timing, or other factors, the NDA holder is strongly encouraged to interface with the FDA prior to execution to gain agreement on the transfer plan.

Analytical Comparability

A comparability plan and protocol should be defined for the exhibit batches. Side-by-side comparative analysis with legacy analytical data should confirm that the API is highly similar or equivalent to the previously manufactured material. The exhibit batches should be placed on long-term and accelerated stability to demonstrate that the new API degrades in an equivalent manner to the original API.

Stability Testing

Place batches under both long-term and accelerated conditions. Ensure protocols meet ICH Q1A(R2) requirements.

If budget or timing constraints require fewer batches, early communication with FDA via a Type C meeting or Q-Submission is advised to align expectations.

Step 5: Process Validation at the New Site

Assuming that the API is for an approved commercial drug product, the API process must be validated at the new CMO site prior to its commercial use. In certain cases, the exhibit batches could be used as the validation batches, provided that the validation protocol is in place prior to the execution of the manufacturing process.

• Concurrent or prospective validation – Either approach may be used but must be justified
• Use of exhibit batches – If these will serve dual roles as validation batches, the validation protocol must be approved prior to synthesis

Validation should confirm process control, reproducibility, and compliance with approved specifications and critical quality attributes.

Step 6: Drug Product Bridging and Stability

API exhibit batch materials must then be used to manufacture three drug product batches that are also placed on accelerated and long-term stability. Typically, six months of data should be collected for the API and the drug product prior to submission.

The key to the successful transfer of API into the US is comprehensive knowledge of the API manufacturing process, the critical process parameters, key starting materials, and the critical quality attributes of the critical intermediates and the API. When done correctly, this will result in a complete and comprehensive set of CMC information that is supportive of the manufacturing site transfer.

• Use validated API batches to manufacture three drug product lots under representative conditions.
• Conduct full characterization of drug product attributes (e.g., dissolution, content uniformity, degradation profiles).
• Place these batches on accelerated and long-term stability to demonstrate compatibility with the new API.

Regulatory note: As this is considered a major change major change, submission of a Prior Approval Supplement (PAS) to the NDA is required.

Best Practices for Regulatory Strategy and Risk Mitigation

To support regulatory success and avoid costly delays:

• Engage early with FDA to discuss the transfer plan, comparability strategy, and any deviations from standard expectations.
• Develop a formal comparability protocol that outlines the scientific rationale, testing approach, and equivalency criteria.
• Implement strong project management across internal and external stakeholders to ensure timelines, documentation, and quality standards are maintained.
• Leverage lifecycle knowledge of the product to anticipate risks tied to scale, equipment, and raw material variability.

A CMC-Driven Approach to Successful Technology Transfers

The transfer of API manufacturing to the US is a critical opportunity to strengthen supply chain resilience and regulatory alignment. However, it is also a high-stakes process that requires CMC and regulatory teams to lead with technical rigor, cross-functional coordination, and strategic foresight.

When executed properly, an API site transfer can be more than a relocation—it can be a chance to enhance product quality, optimize process control, and deepen regulatory confidence.