laser diffraction and other appropriate techniques in Analytical Method Development (AMD).

2. Scope

This procedure applies to all particle size analysis method development, optimization, and preliminary validation studies conducted within the AMD department for pharmaceutical solids and suspensions.

3. Responsibilities

• Analytical Scientist: Designs and executes method development experiments, interprets PSD data, and maintains logs.
• Instrument Operator: Performs equipment calibration, sample loading, and ensures measurement accuracy.
• QA Officer: Verifies documentation, calibration records, and procedural adherence.
• Head – AMD: Approves final method protocol and ensures regulatory compliance.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring that all particle size analysis methods are scientifically justified, adequately documented, and aligned with regulatory requirements.

5. Procedure

5.1 Instrument Selection

1. Select appropriate technique based on material type and size range:
   • Laser Diffraction (0.1 – 3000 µm)
   • Dynamic Light Scattering (10 nm – 10 µm)
   • Optical Microscopy (≥ 1 µm)
   • Sieve Analysis (≥ 38 µm)
2. Record instrument details and software version in Annexure-1: Instrument Selection Log.

5.2 Sample Preparation

1. Weigh ~20–50 mg of sample for dry analysis or disperse in ~10–20 mL of diluent (for wet method).
2. Use sonication or surfactants (e.g., 0.1% Tween 80) if necessary to prevent agglomeration.
3. Filter large particles or foreign matter if required without affecting PSD.
4. Document preparation steps in Annexure-2: Sample Preparation Log.

5.3 Dispersion Medium Selection

1. Select a dispersion medium based on:
   • Chemical compatibility
   • Refractive index difference
   • Low viscosity and volatility
2. Common media: Water, Isopropanol, Acetone (with appropriate safety precautions).
3. Log medium selection in Annexure-3: Dispersion Medium Assessment.

5.4 Method Development and Optimization

1. Define measurement parameters:
   • Obscuration (10–20% for laser diffraction)
   • Pump/stirring speed (as per equipment guidelines)
   • Refractive index (of sample and dispersant)
2. Conduct replicate trials (n=3–5) to assess method precision and reproducibility.
3. Evaluate PSD results for:
   • D10, D50, and D90 values
   • Span = (D90 – D10) / D50
   • Distribution pattern (mono-modal, bi-modal)
4. Document in Annexure-4: Optimization and Result Summary.

5.5 Method Robustness and Preliminary Validation

1. Alter variables such as sonication time, dispersion media, or stirring rate to assess method sensitivity.
2. Check for stability of dispersion over time (e.g., PSD consistency after 5, 10, 30 minutes).
3. Perform day-to-day variability studies using same and different analysts.
4. Log all robustness findings in Annexure-5: Robustness and Validation Sheet.

5.6 Safety Precautions

1. Wear appropriate PPE when handling solvents or volatile materials.
2. Ensure proper waste disposal of dispersants in accordance with MSDS and environmental regulations.
3. Document safety checks in Annexure-6: Safety Compliance Log.

6. Abbreviations

• PSD: Particle Size Distribution
• DLS: Dynamic Light Scattering
• D50: Median Particle Diameter
• PPE: Personal Protective Equipment
• SOP: Standard Operating Procedure

7. Documents

1. Instrument Selection Log – Annexure-1
2. Sample Preparation Log – Annexure-2
3. Dispersion Medium Assessment – Annexure-3
4. Optimization and Result Summary – Annexure-4
5. Robustness and Validation Sheet – Annexure-5
6. Safety Compliance Log – Annexure-6

8. References

• USP <429> – Particle Size Analysis
• ICH Q6A – Specifications: Test Procedures and Acceptance Criteria
• Instrument manufacturer’s method development guide

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Instrument Selection Log

Instrument Type	Make	Model	Software	Selected For
Laser Diffraction	Malvern	Mastersizer 3000	v3.80	API-B

Annexure-2: Sample Preparation Log

Sample ID	Weight	Medium	Sonication Time	Prepared By
PSD-115-A	25 mg	Water + 0.1% Tween 80	5 min	Sunita Reddy

Annexure-3: Dispersion Medium Assessment

Water was chosen over isopropanol due to better dispersibility, lower viscosity, and absence of peak distortion.

Annexure-4: Optimization and Result Summary

D10 (µm)	D50 (µm)	D90 (µm)	Span	Distribution Type
2.3	6.8	15.5	1.94	Mono-modal

Annexure-5: Robustness and Validation Sheet

Parameter Changed	Condition	D50 (µm)	RSD (%)
Sonication Time	3 vs 5 min	6.8 / 6.7	1.5

Annexure-6: Safety Compliance Log

Date	Solvent Used	PPE Worn	Disposal Method	Verified By
18/05/2025	IPA	Gloves, goggles	Hazardous waste bin	Rajesh Kumar

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Expanded to include robustness and safety annexures	Annual Update