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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

Helping the World Be Well through Innovative Manufacturing

1 Pharmaceutical Commercialization Technology, MSD Intl GmbH (PR Branch), Las Piedras, PR2 ACDS-Commercialization and Supply Analytical, MSD Intl GmbH (PR Branch), Las Piedras, PR3 ACDS-PAT, Merck, West Point

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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 minutesTurnaround time: NIR method 30 minutes Vs. 240 minutes results

API Precision Coating in Merck

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API Precision Coating Control StrategyControl 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 rationale1. Mass measurement

inaccurate due to moisture variability

2. HPLC and PAT CA is too slow for real time end point determination

Control strategy assumptions 1. Coating gain linear process2. No process upsets from last

CA estimate to end point

% A

ssa

y o

f A

PI

2 C

oat

API 2 Coating Spray Volume

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 25 50 75 100 125 150 175 200

Projected Volume for 100%LC

STOP

Precision coating Monitoring Application

Stop the API 2 precision coating at right mass/volume to meet final tablet release assay specification

Granulation API 1

API 1

API 2

API 2 Spray Coat

Release

Content UniformityComposite AssayEleganceDissolution

API BlendingCompression

Film overcoat

Suspension

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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

LabManufacturing Area

90 min

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In-Process Test Methods: NIR

Obtain Sample

Triggered by HMI

Transport Sample

Co-located in Mfg area

Report Result(s)

Print in Mfg area

NIR AnalysisLoad tablet wheel

and measure

• 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

• Outlier Diagnostics– Hotelling’s T2 (In space outlier)– Residual X-Variance (Out of space outlier)– Realtime alerts

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• 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

Cost Benefit of PAT NIR Method

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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

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AcknowledgementsWest PointChuck MillerPat Schilling…and others

AreciboLuis Torres …and others

Las PiedrasIvelisse HernandezLuz RodriguezGuillermo FigueroaManuel AcostaMaria DuarteRicardo BermudezYovanni BrignoniAstra RodriguezAna Diaz…and others

Las Piedras SLTPatrick BreenHumberto DiazLuis O. GarciaAndrew Wirths