If the first set of samples fails BU testing, follow these steps:
a. Investigate the Root Cause
Evaluate the Blend Process:
- Check for inadequate mixing time, speed, or sequence of material addition.
- Assess whether the blender design is appropriate for the formulation.
Assess Sampling Procedure:
- Verify whether the sampling technique introduced variability (e.g., sampling thief issues, segregation during sampling).
- Confirm that sample sizes and locations are appropriate.
Analyze the API and Excipients:
- Check particle size distribution (PSD), density, and flow properties of the API and excipients.
- Look for segregation or static charge issues.
b. Retest (Second Set of Samples)
- Collect a new set of samples from different blender locations.
- Increase the number of samples if needed (minimum 10 for a robust analysis).
- Reanalyze blend uniformity to confirm whether the issue was an anomaly or systemic.
c. Perform Additional Tests
- Content Uniformity (CU) Testing: Evaluate content uniformity on finished product units (e.g., tablets, capsules) as a secondary check.
- Stratified Sampling: Use stratified sampling to understand the variability across the batch.
Criteria for Blend Uniformity Acceptance
- Beta Gamma Criteria
- This statistical method is used to assess blend uniformity and content uniformity.
Key Parameters:
- Beta Value (β): Measures variability between sample means.
- Gamma Value (γ): Measures variability within individual samples.
Acceptance Criteria:
1. Blend Uniformity:
- Individual sample results: Within 90%-110% of the label claim.
- Relative standard deviation (RSD): ≤ 5% (unless justified for high-dose or low-dose products).
2. Content Uniformity (CU) for Finished Product:
- Follows USP <905> criteria:
- 85%-115% of the label claim for individual units.
- RSD ≤ 6.0%.
FDA Approach (2003):
- If the first 10 blend samples fail, analyze the next 10 samples.
- Results must demonstrate uniformity across the batch and comply with the predefined specification.
ICH Approach (Q8 and Q9):
- Risk-based evaluation of blend uniformity, focusing on process control parameters and material attributes.
3. Corrective Actions After Failure
If a systemic issue is identified, take the following corrective steps:
a. Adjust Process Parameters
- Increase or decrease mixing time or speed.
- Modify blender fill levels or mixing sequence.
b. Improve Sampling Techniques
- Use validated sampling devices to prevent segregation or disturbance.
- Ensure samples are collected consistently from critical locations.
d. Implement Process Analytical Technology (PAT)
- Utilize tools like near-infrared (NIR) spectroscopy for real-time blend uniformity monitoring.
Conclusion
When a first set of BU samples fails, the priority is to investigate the root cause systematically, collect additional data, and take corrective actions to address variability.
Read also:
- Blend Uniformity Analysis
- Differences Among Blend Uniformity, Content Uniformity and Weight Variation
