Key Considerations for API Source Change in Formulation

Changing the API source requires evaluating its impact on safety, efficacy, stability, and manufacturability. Below are the key factors to assess:

Physicochemical Properties

1. PSD: Check D10, D50, D90 for dissolution, bioavailability, and uniformity impact.
2. Polymorphism: Ensure the same polymorphic form to maintain solubility, stability, and bioavailability.
3. Morphology: Assess crystalline vs. amorphous nature, surface area, and compression impact.
4. Hygroscopicity: Evaluate moisture absorption and its effect on stability.
5. Thermal Behavior: Consider melting point for granulation and drying processes.
6. Solubility & pH Profile: Compare aqueous and pH-dependent solubility.
7. Excipient Compatibility: Conduct DSC & FTIR to check for interactions.

Dissolution & Bioavailability

1. Dissolution Profile: Compare dissolution in 0.1N HCl, phosphate buffer, etc.
2. BCS Class: If BCS II/IV, minor changes can impact absorption; BE studies may be required.
3. Intrinsic Dissolution Rate: Ensure rate-limiting steps remain unchanged.
4. Permeability & Absorption: Check for significant deviations in permeability.

Stability Considerations

1. Forced Degradation Studies: Assess stability under acid, base, oxidative, thermal, and photolytic stress.
2. API Stability Profile: Compare impurity levels to ensure no new degradation pathways.
3. Shelf-life & Packaging: Conduct accelerated stability testing and confirm packaging suitability.

Regulatory & Compliance

1. Pharmacopeial Compliance: Verify USP, BP, EP, IP, JP compliance.
2. Impurity Profile: Ensure limits meet ICH Q3A/B guidelines.
3. Genotoxic & Elemental Impurities: Check for new GTIs or heavy metals.
4. Regulatory Filing: Determine if a DMF update, ANDA variation, or CMC supplement is required.
5. Supplier GMP Compliance: Confirm GMP certification and review COA, DMF, stability data, and residual solvents.

Manufacturing & Process Impact

1. Flowability & Compressibility: Assess effects on granulation and blend uniformity.
2. Granulation Suitability: Check performance in wet/dry granulation and direct compression.
3. Bulk & Tapped Density: Ensure dose uniformity and consistency.
4. Blending & Scale-up: Confirm blend uniformity, yield, and batch reproducibility.

In-vivo Considerations

1. BE Studies: Conduct if dissolution profiles differ significantly.
2. Pharmacokinetics (PK): Assess absorption and metabolism impact.

Risk Assessment & Final Decision

1. Comparability Protocol: Summarize findings to justify equivalence with the old API.
2. ICH Q12 Compliance: Ensure regulatory alignment.
3. Implementation: If all parameters are met, proceed with regulatory filing and validation.

Conclusion

API source changes demand scientific, regulatory, and process evaluations to prevent any adverse impact on drug performance. A thorough risk assessment and compliance check is critical before implementation.

Read also:

• SUPAC Guidance on Qualitative Changes in Excipients
• Regulatory Strategies for Excipient Grade Changes Across Global Markets
• GMP Requirements for Supplier Qualification

Resource Person: Moinuddin syed. Ph.D, PMP