1. Helping the World Be Well through Innovative Manufacturing
Cost and Environmental Benefits from the Application of PAT to the API Precision Coating
K. Ganeshwar Prasad1, Jackeline Jerez Rozo2, Giovanni Cartagena, Shaira Davila1
Bruce Thompson3, Brandye Smith-Goettler3, Manoharan Ramasamy3
1 Pharmaceutical Commercialization Technology, MSD Intl GmbH (PR Branch), Las Piedras, PR
2 ACDS-Commercialization and Supply Analytical, MSD Intl GmbH (PR Branch), Las Piedras, PR
3 ACDS-PAT, Merck, West Point
Helping the World Be Well through Innovative Manufacturing

2. API Precision Coating in Merck
The drug product is a precision coated combination product of two API’s. The second API is precision coated on a tablet core of the first, to form a rapid release coat followed by an extended release core of the first API.
Control strategy for the precision coating unit operation is to monitor the amount of 2nd API applied to the core tablet.
A HPLC and a NIR method were developed as in-process testing method.
The NIR method provides a significant saving from cost of analysis, including consumables and analyst time, and cycle time.
Analysis time: NIR method 30 minutes Vs. HPLC 90 minutes
Turnaround time: NIR method 30 minutes Vs. 240 minutes results

3. API Precision Coating Control Strategy
Control strategy is to predict the time for 100% API coating from the linear regression of content assay (CA) estimates from prior time points.
Control strategy rationale
Mass measurement inaccurate due to moisture variability
HPLC and PAT CA is too slow for real time end point determination
% Assay of API 2 Coat
API 2 Coating Spray Volume 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100% 25 50 75
100
125
150
175
200
Projected
Volume for
100%LC
STOP
Control strategy assumptions
Coating gain linear process
No process upsets from last CA estimate to end point

4. Precision coating Monitoring Application
Granulation
API 1
API 2
API 2 Spray Coat
Release
Content Uniformity
Composite Assay
Elegance
Dissolution
API Blending
Compression
Film overcoat
Suspension
Stop the API 2 precision coating at right mass/volume to meet final tablet release assay specification

5. In-Process Test Methods: HPLC
Time taken to receive results from the lab: 240 minutes
Process area and laboratory area are separate
Turnaround time magnified by movement waste
Sample transported to Lab
Results printed in manufacturing area
Lab
Manufacturing Area
90 min

6. Load tablet wheel and measure
In-Process Test Methods: NIR
40 tablets (better estimate of mean)
30 minute cycle time
50% analyst time (currently IPT technicians)
50% machine time
Process and method at the floor
Obtain Sample
Triggered by HMI
Transport Sample
Co-located in Mfg area
Report Result(s)
Print in Mfg area
NIR Analysis
Load tablet wheel and measure
Outlier Diagnostics
Hotelling’s T2 (In space outlier)
Residual X-Variance (Out of space outlier)
Realtime alerts

7. Cost Benefit of PAT NIR Method
Savings by using PAT NIR versus HPLC
1 hour FTE savings per process sample for NIR Vs. HPLC analysis
HPLC analyses result in ~25% production downtime
Environmental Impact
1.4L of acetonitrile for HPLC extraction and analysis is saved per process sample
7L of acetonitrile chemical usage per and batch 3X volume of waste disposal per batch avoided by using the PAT NIR method

8. Conclusion
The PAT NIR in-process CA method for JANUMET XR provides tangible benefits to the company
Lower cost of analysis
Faster cycle time
Fewer hours of down time
Positive environmental impact from lower solvent usage and waste

9. Acknowledgements West Point Chuck Miller Pat Schilling …and others
Las Piedras
Ivelisse Hernandez
Luz Rodriguez
Guillermo Figueroa
Manuel Acosta
Maria Duarte
Ricardo Bermudez
Yovanni Brignoni
Astra Rodriguez
Ana Diaz
…and others
Las Piedras SLT
Patrick Breen
Humberto Diaz
Luis O. Garcia
Andrew Wirths
Arecibo
Luis Torres
…and others