In QbD, we often focus heavily on formulation and process variables. But a large part of product performance actually depends on the API itself. Understanding which API attributes are truly critical is essential for building a robust formulation, achieving BE, and ensuring long-term stability.
1. Start With QTPP and CQAs – Not With the API
Criticality always begins with the QTPP and CQAs of the drug product. An API attribute becomes a CMA only if its variability can impact a product CQA such as:
- Dissolution profile
- Content uniformity
- Impurities and degradants
- Assay
- Physical stability
This top-down thinking is essential for meaningful CMA identification.
2. Create a List of API Attributes
Before filtering, list down all attributes of the API, typically including:
Physical attributes
- Particle size distribution, particle shape, polymorphic form, crystallinity, density, flow properties, hygroscopicity, specific surface area.
Chemical attributes
- Assay, impurity profile, residual solvents, salt form, pKa, oxidative sensitivity, moisture interaction.
Biopharmaceutic attributes
- Solubility across pH, intrinsic dissolution rate, permeability,
Mechanical attributes (for tablets/capsules)
- Compressibility, plastic deformation.
This list becomes the starting universe of potential CMAs.
3. Connect Each API Attribute to the CQAs (Risk Assessment)
Using FMEA or a fishbone diagram, evaluate how each attribute may impact CQAs. For every attribute, assess:
- Severity – Can variation affect product quality or patient safety?
- Occurrence – How likely is this attribute to vary from lot to lot?
- Detectability – How easily can we identify variation during incoming control?
High-risk attributes become potential CMAs.
Examples:
- PSD of a BCS Class II API → significant impact on dissolution and BE.
- Polymorphic form with different solubility → high impact on release.
- Bulk density variation → usually lower severity.
4. Confirm Potential CMAs Through Experimental Data
QbD requires evidence. Once high-risk attributes are shortlisted, confirm them through:
- Screening DoE
- Targeted experiments varying only the API attributes while keeping formulation constant
- Dissolution, stability, CU, mechanical studies on resulting batches
A material attribute becomes a confirmed CMA only when variation within realistic ranges shows a measurable and meaningful impact on CQAs.
Examples:
- Fine API PSD improves dissolution but may cause CU issues — confirmed CMA.
- Changing API bulk density shows no impact on CQAs — not a CMA.
5. Establish Acceptable Ranges and Control Strategy
For each confirmed CMA:
- Define acceptable limits
- Integrate into API specifications and supplier CoA requirements.
- Strengthen incoming controls (e.g., in-house PSD testing, polymorph checks).
- Link CMA–CQA justification clearly
This ensures regulatory clarity and long-term product robustness.
Read also: API Particle Size Distribution (PSD) Matters in Generic Formulations
Resource Person: Moinuddin Syed. Ph.D, PMP®