Interphex Manesty PAT Technology

Online Tablet Coating Thickness sensor for a Perforated Pan Coater

Dipankar Dey Head of Process and ValidationOYSTAR Manesty

Manesty PAT Technology | Dipankar Dey | 1105102

OYSTAR Manesty PAT Technology Development:Online coating thickness sensor

Developed in response to FDA PAT Initiative on Process Understanding

Collaboration funded by UK Government Technology Strategy Board

Partners: TeraView Ltd, University of Cambridge, University of Liverpool


OYSTAR Manesty PAT Technology Development

Motivation: Modified Release tablet manufacturing

Consortium Approach

Results

Applications

Project Offerings


Motivation: Issues in manufacture of Modified Release Tablets

Many new drugs have modified release characteristics

Modified Release product market size is growing 2007= $65 billion 2010=$100 billion Will grow further as existing product patents expire and

manufacturers introduce line extensions of existing products.

AVANDIA AVANDAMET AVANDARYL


Motivation: Issues in manufacture of Modified Release Tablets

Complex products manufacturing challenge High failure rates 10-25% manufactured batches wasted (industry sources)

Urgent need for non-destructive analysis of tablet coatings Multi-layer analysis Coat quality


Consortium approach: Use of THz Spectroscopy for online layer thickness measurement

THz imaging already proven offline for direct measurement of multilayer tablet coatings as found in Modified Release products

THz is the only spectroscopic method that gives statistical data on a large number of individual tablets during a run rather than anaverage value, giving important distribution data

The results from the terahertz coating analysis can be directly correlated to the drug release of the coated tablet*

* Ho et al., J. Contr. Rel. 127, 79-87 (2008)


Terahertz Pulsed Imaging (TPI) Single incidentTHz pulse

multiple return pulses Coated

tablet

Terahertz radiation (2 cm-1 120 cm-1) Penetrates through most pharmaceutical

excipients

Novel technique for non-destructive tablet coating quality analysis

THz Imaging

Pulse echo measure thickness of tablet layers.

Single tablet is held stationary in well defined orientation.

Layers determined by change in RI.


Comparison with NIR & OCT

TPI NIR OCT

Spectralrange 1000100microns 2.550.9microns 1.10.5microns

Penetrationdepth 1000smicrons 10smicrons 10smicrons

Depthresolution 40micronsorbetter 10microns Submicron

Depthprecision 2microns Afewmicrons Submicron

Measurementtime 20ms(abletoresolvetablettabletvariationwithinabatchinrealtime)

30secondswithacooledCCD(msifusinghighpowerlightsource)

40seconds(msifusinghighpowerlasersource)

Colorsensitive? No No(yes) Yes(no)

Directmethod? Yes,selfreference No(calibrationmodelrequired)

Yes,selfreference(processedsignal)


IMAGA 2000 Coating Thickness Measurements Offline using Robotic Analyser Data from whole surface: Hardness

Layer thickness Layer integrity Layer uniformity

Variation in a laboratory scale batch in ten sustained release products 10% variation


The Online Measurement Concept

Moving tablet bed

Emitter Receiver

THz

Challenge: to measure the coating thickness of large numbers of randomly moving tablets in a coating drum

Current techniques are extremely well controlled

Superficially tablets in random motion in a coater

Tablets actually arrayed against drum mesh


Tablet alignment with drum With larger numbers

there is a finite probability that a tablet will arrive with the correct position and orientation to be measured. Only those tablets will produce strong reflected signals

Align against a linear array of tablets

Apply strict selection criteria

A statistical approach

drum m

ovement


Sensor Head Design

Single body Electronics in Head (reduced losses) Hermetic Interchangeable optics CIP compatible Umbilical multi positional for flexibility


Patented Sensor Positioning

Sprung roller mount concept Enhanced hit rate

Rigid mounting position Enhanced stability Retrofit option


Principle of THz Online Measurement


The Key to the Technology

Waveform Selection Only tablets normal to the THz beam

Acceptance based upon Position Amplitude Shape

Self-referencing Reflections from drum surface Direct measurement


In line results-10mm tablets coated to 10% weight gain with an enteric coating


Tablet Coat Thickness Distribution with timeTime (H) No of

tabletsMean

Thickness (um)

SD

2 982 55 23

4 755 92 20

6 655 105 27


Histogram of tablet distribution-comparison with off line measurement


Tablet Distribution Implications

Wide range of tablet coat thickness

41 to 111 microns 623 tablets measured

Important to understand extremes of distribution

Online NIR only gives average with no details of this distribution

Off spec product?


Statistical distributions provided by THz SensorAverage thickness

Off spec FDA issues, wasted material, extra testing, failed dissolution = Cost

Batch 1Poor uniformity

Batch 2 improved uniformity

Num

ber o

f tab

lets

THz allows distribution information to ensure stable and In spec product Both batches have the same average NIR would report both as the same

Coating thickness


Applications: Early warning sensor for coating quality


Orange Peeling Picking


Identification of Coating Defects:

Sudden increase in Standard Deviation would indicate that the surface finish of the tablet is incorrect and that Orange Peeling is occurring

Unexpectedly low coating thickness readings would indicate that the coating is delaminating and that Picking is occurring


When and how would this technology add value?

Faster Product Design Helping to quickly measure properties that can then be

correlated to performance

Faster Process Development On-line monitoring allows the rapid optimisation of process

conditions to ensure the correct thickness and optimum distribution

Safer and Quicker Technology Transfer Direct measurement of quality critical properties at the sender

and receiver


When and how would this technology add value?

Cost Reduction Optimum amount of coatings Lower batch failures + quicker problem detection Avoid wastage from in process sampling

HSE Reduced in process sampling reduces operator exposure and

waste


Stepwise/ Project based approach

We can provide project services for the design and process optimisation of the tablet coating process

Off line we can study Coating uniformity Coating variability tablet to tablet How coating thickness varies with different time points How all of the above affect dissolution


Stepwise/ Project based approach

The Online system can monitor performance in real time and allows rapid optimisation of Manesty coater system. This can be done at Manesty or on site (subject to coater configuration).

Site installation of the Online system will be with full application support from Teraview and OYSTAR Manesty


Summary

Tablet coating in a pan will produce a tablet to tablet distribution of thickness

This distribution needs to be understood and controlled to ensure batch quality

THz Pulsed Imaging is the only online technique that can measure distribution

Alternative techniques only look at averages

This project has demonstrated at scale that we can monitor thickness and the distribution of thickness within a coating pan.


Summary

This technology can Speed Product Design Speed Process Development Enable efficient Technology Transfer Reduce material costs and product failures Improve HSE of operations

OYSTAR Manesty and TeraView can offer services, equipment and technical support to make this happen


The Complete Tableting Compression and Tablet Coating Solution

OYSTAR ManestyKitling Road Knowsley

Merseyside England L34 9JST +44 (0)151 547 8000 F +44 (0) 151 547 8001

[email protected] www.oystar.manesty.com


Validation of coating thickness distribution


In line resultsEnteric coating of 10mm tablets
Online Tablet Coating Thickness sensor for a Perforated Pan CoaterOYSTAR Manesty PAT Technology Development: Online coating thickness sensorOYSTAR Manesty PAT Technology DevelopmentMotivation: Issues in manufacture of Modified Release TabletsMotivation: Issues in manufacture of Modified Release TabletsConsortium approach: Use of THz Spectroscopy for online layer thickness measurementTerahertz Pulsed Imaging (TPI)Comparison with NIR & OCTIMAGA 2000 Coating Thickness Measurements Offline using Robotic AnalyserThe Online Measurement ConceptTablet alignment with drumSensor Head DesignPatented Sensor PositioningPrinciple of THz Online MeasurementThe Key to the TechnologyIn line results-10mm tablets coated to 10% weight gain with an enteric coatingTablet Coat Thickness Distribution with timeHistogram of tablet distribution- comparison with off line measurementTablet Distribution ImplicationsStatistical distributions provided by THz SensorApplications: Early warning sensor for coating qualityOrange PeelingPickingIdentification of Coating Defects: When and how would this technology add value?When and how would this technology add value?Stepwise/ Project based approachStepwise/ Project based approachSummarySummaryValidation of coating thickness distributionIn line resultsEnteric coating of 10mm tablets

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Interphex Manesty PAT Technology