In development, especially within a QbD framework, there is frequent debate on whether non-critical excipients need detailed characterization of their CMAs. While critical excipients understandably require deep evaluation, we often overlook the assessment needed for excipients classified as “non-critical.”
The reality is:
- Non-critical excipients still require a evaluation—just not at the same intensity as critical ones.
Why Some Evaluation Is Still Necessary?
- ICH Q8(R2), Q9, and Q11 emphasize that material attributes must be assessed to understand their influence on quality. You cannot simply label an excipient “non-critical” without demonstrating why.
A right-sized assessment ensures that:
- You understand the excipient’s function and variability
- Your risk assessment is defensible.
- You justify why no extensive CMA studies are needed
- You avoid surprises at scale-up, PPQ.
- This aligns with the QbD principle: designing quality through scientific understanding, not assumptions.
- Minimum Required Assessment for All Excipients
Even for non-critical excipients, regulatory expectations include basic evaluation of:
- Functional role (filler, binder, lubricant, disintegrant, suspending agent, etc.)
- Grade or type (e.g., MCC PH102 vs PH200, lactose monohydrate vs anhydrous)
- Key CoA attributes: particle size, moisture, density, pH, purity
- Compatibility screening if risk exists
This ensures the excipient does not have a plausible impact on CQAs such as dissolution, assay, related substances, uniformity, or stability.
A deeper investigation may still be required if:
- The excipient constitutes a large percentage of the formulation
- There is a known variability between suppliers or grades
- Historical OOS or deviations were linked to it
- It affects processability (granulation, compression, coating)
- The excipient has reactive impurities (e.g., lactose, povidone)
- PSD variations could affect blend uniformity or dissolution
In such cases, characterization may extend to:
- Moisture-sensitivity studies
- Blend uniformity impact
- Preliminary dissolution impact checks
This does not imply running DOE unless risk persists—but it ensures scientific completeness.
What Is Not Required?
- A full-blown CMA study involving DOE, high/low variation testing, or extensive lab experimentation is not required for non-critical excipients—provided your risk assessment clearly shows low impact.
Recommended Language for Dossiers (3.2.P.2)
“Non-critical excipients were assessed to an extent appropriate for their functional role, inherent variability, and risk profile. Based on prior knowledge, supplier consistency, and structured risk assessment, no significant influence on CQAs was identified, and extensive CMA variation studies were not required.”
This statement is aligned with EMA, MHRA, and USFDA.
Read also: Lean Six Sigma and QbD
Resource Person: Moinuddin Syed. Ph.D, PMP®