The goal is to identify the optimal moisture level and ensure batch-to-batch granule consistency by integrating real-time PAT tools into process control decisions.

2. Scope

This SOP is applicable to all wet granulation processes performed within the manufacturing development and analytical labs where NIR is employed as a Process Analytical Technology (PAT) tool to monitor and determine granulation end point in real-time.

3. Responsibilities

• Process Analyst: Prepares and calibrates NIR instrument, collects spectra, and analyzes granulation profile.
• Formulation Scientist: Coordinates granulation run and provides granule samples for model calibration.
• QA Representative: Ensures calibration model validation and maintains data integrity.
• Instrumentation Engineer: Maintains NIR hardware/software and resolves integration issues.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring all granulation end point determination using NIR is validated, repeatable, and documented as per ICH Q8/Q9 and GMP guidelines.

5. Procedure

5.1 NIR Instrument Calibration

1. Ensure NIR spectrometer is qualified and installed as per IQ/OQ/PQ protocols.
2. Calibrate wavelength accuracy using certified polystyrene film standard.
3. Perform photometric and baseline checks using internal diagnostics.

5.2 Reference Method and Sampling

1. Use loss on drying (LOD) or Karl Fischer method to generate reference moisture values of granules during development runs.
2. Collect granule samples at 2–3 minute intervals during granulation from different process batches.
3. Immediately scan each sample using NIR and record the spectra.

5.3 Calibration Model Development

1. Import NIR spectra and corresponding moisture content into chemometric software (e.g., SIMCA, Unscrambler, or TQ Analyst).
2. Use Partial Least Squares Regression (PLSR) or Principal Component Regression (PCR) for model generation.
3. Evaluate model with:
   • Correlation Coefficient (R² > 0.98)
   • Root Mean Square Error of Calibration (RMSEC)
   • Residual Predictive Deviation (RPD > 2.5)
4. Validate model with independent dataset (RMSEP ≤ 1%).

5.4 Real-Time Granulation Monitoring

1. Position fiber-optic probe in granulator at standardized sampling position.
2. Start granulation and initiate real-time spectral acquisition (1 scan every 30 seconds).
3. Monitor spectral peak shifts and scores plot against calibration model in real-time.
4. Determine end point when:
   • Moisture content reaches pre-defined threshold (e.g., 1.5% – 2.5%)
   • No further significant changes in absorbance spectra for three consecutive scans

5.5 Data Interpretation and Reporting

1. Generate granulation moisture trend graph and overlay batch spectra.
2. Document end point decision time, total granulation duration, and final moisture value in Annexure-2.
3. Submit report to QA for verification and process record archival.

5.6 Deviation Management

1. If end point not achieved or batch exceeds moisture limit, escalate to deviation log.
2. Document deviation root cause, corrective measures, and impacted batch disposition.

6. Abbreviations

• NIR: Near Infrared Spectroscopy
• PLSR: Partial Least Squares Regression
• PAT: Process Analytical Technology
• RMSEC: Root Mean Square Error of Calibration
• RMSEP: Root Mean Square Error of Prediction

7. Documents

1. Calibration Model Summary – Annexure-1
2. Granulation Run Report – Annexure-2
3. Deviation Investigation Form – Annexure-3

8. References

• ICH Q8 (R2): Pharmaceutical Development
• ICH Q9: Quality Risk Management
• FDA PAT Guidance: Process Analytical Technology
• 21 CFR Part 11 – Electronic Records and Signatures

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name	Ashok Rao	Neha Bhatia	Dr. Harshita Goyal
Designation	NIR Analyst	QA Reviewer	Head – AMD
Department	Analytical Method Development	Quality Assurance	Analytical Method Development

11. Annexures

Annexure-1: Calibration Model Summary

Model ID	Method	R²	RMSEC	RMSEP	Status
NIR-GR-01	PLSR Moisture	0.987	0.42	0.48	Approved

Annexure-2: Granulation Run Report

Batch No.	Start Time	End Point Time	Moisture (%)	Duration (min)
GR-B2301	10:00 AM	10:18 AM	2.2%	18

Annexure-3: Deviation Investigation Form

Deviation ID	Description	Root Cause	CAPA	Status
DEV-307-01	End point missed, excess moisture	Probe misalignment	Calibrate probe and retrain operator	Closed

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
01/06/2025	2.0	Expanded NIR probe placement and chemometric model criteria	Annual Review	Dr. Harshita Goyal
20/05/2022	1.0	Initial Release	New SOP	QA Head