Is a Bioequivalence (BE) Study Needed When Replacing Crospovidone with Croscarmellose?

A BE study may or may not be required, depending on several factors. Here’s a structured approach to determine whether regulatory agencies like the FDA or EMA would require a BE study for this type of qualitative formulation change:

Regulatory Perspective on Excipients in Bioequivalence

Regulatory agencies consider excipients when evaluating bioequivalence, especially when they affect drug release, absorption, or solubility.

Key points for consideration:

• Crospovidone and Croscarmellose Sodium are both super-disintegrants, but they have different properties:
• Crospovidone (PVPP): Works via capillary action and swelling, but does not form a gel.
• Croscarmellose Sodium (CCS): Swells significantly and forms a gel-like structure, which can affect dissolution.
• The switch may alter disintegration time, dissolution rate, and ultimately bioavailability.

When a BE Study is NOT Required?

Regulatory agencies may waive a BE study if:

• The dissolution profile remains similar (f2 similarity factor ≥ 50).
• The change does not impact drug solubility or permeability (important for BCS Class I & III drugs).
• The drug is a Biopharmaceutics Classification System (BCS) Class I drug (high solubility, high permeability).
• There are no changes in drug release mechanism (e.g., switching from IR to ER would require a study).
• The formulation meets the SUPAC (Scale-Up and Post-Approval Changes) guidelines for Level 1 or Level 2 changes (for the US FDA).

When a BE Study is Required?

A BE study is likely needed if:

• The drug is BCS Class II or IV (low solubility, permeability concerns).
• The dissolution test shows significant differences between the old and new formulation.
• The change significantly affects the disintegration or dissolution rate, impacting bioavailability.
• The regulatory authority specifically requires a BE study due to past precedent or case-by-case evaluation.

Subsequent Steps for Conducting Comparative Dissolution Testing:

• Perform dissolution studies in at least three media (pH 1.2, 4.5, 6.8).
• Calculate the f2 similarity factor (if f2 ≥ 50, dissolution profiles are similar).

Evaluate BCS Class & Drug Release Mechanism:

• If the drug is BCS Class I or III, a waiver may be possible.
• If Class II or IV, regulators will likely require BE data.

Refer to SUPAC (FDA) or Variation Guidelines (EMA):

• For the FDA, this would be a SUPAC-IR Level 2 or 3 change, where dissolution testing may suffice.
• For EMA, check the variation classification (Type IA, IB, or II).

Conclusion

• If dissolution is similar, a waiver is possible (especially for BCS Class I & III drugs).
• If dissolution differs, a BE study is likely required.
• For BCS Class II or IV drugs, be prepared for BE requirements.
• Check regulatory guidelines (FDA SUPAC or EMA variations) for country-specific decisions.

Read also:

• Steady-State Bioequivalence (BE) Studies
• Factors Affecting Bioequivalence (BE) Results
• Paragraph IV (Para IV) Filing | Overview & Strategies

Resource Person: Moinuddin syed. Ph.D, PMP®