Hot Melt Extrusion in the Production of Intra-vaginal RingsProduction of Intra vaginal Rings

Containing Antiretroviral Drugs

May 18th 2010Andrew LoxleyAndrew Loxley

1

Introduction to Particle Sciences

2

Intra-vaginal Rings

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Intra-vaginal Rings - Designs

4

Intra-vaginal Rings - Designs

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Intra-vaginal Rings – Drug Release Profiles

In vitro In vivo

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HIV - Global Prevalence in Adults

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HIV/AIDs and Microbicides

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The Driving Force

ARV-loaded IVRs could protect women from infection from HIV+ partners

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Ethylene Vinyl Acetate (EVA)

1000

ethylene Vinyl acetate 100

1000

(g)

1

10

Mel

t ind

ex (

~ 7 – 40 wt%0.1

1

0 10 20 30 40 500 10 20 30 40 50

% vinyl acetate

10

Lab Scale Preparation of Dapivirine / Maraviroc IVRs

Micronize drug powder(s)

Melt EVA in a Banbury batch mixer

Mi

Add API in one shot

Mix Polymer + drug

Cool

Grind (liquid N2)

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( q 2)

Injection mold crumb to form IVRs

In-vitro Drug-release from Experimental Combination ARV IVRs

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Potential Issues at the Lab-scale

API degradation

SampleProcess

Temp (°C)Average Degradants

(% based on API)API

Sample Temp ( C) (% based on API)

API - 0.6

API + EVA 155 32.6

API + EVA 141 3.7

API + EVA + 50ppm BHEB 164 1 7

API

S ll # f IVR b t h t dil l bl

API + EVA + 50ppm BHEB 164 1.7

API + EVA + 75ppm BHEB 159 1.9

API + EVA + 100ppm BHEB 161 1.2

Small # of IVRs per batch – not readily scalable

Not sure if performance (especially drug release) will be the same as commercial scale IVRscommercial scale IVRs

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Manufacturing Dapivirine / Maraviroc IVRs

Micronize drug powder(s)

Blend Drugs + excipients

Hot Melt Compounding/Extrusion

Mi

Hot Melt Compounding/ExtrusionFeed APIs and Polymer to Mixer

Mix Polymer + drug blend

Extrude drug-loaded polymer

Pelletize extrudate

Cut extrudate and glue ends to form IVRs

14Injection mold pellets to form IVRs

Developing IVR Manufacturing Processes

Blend Drugs + excipients

100 0102.0104.0106.0108.0110.0

Assay

90.092.094.096.098.0

100.0

p e m p e m p e m p e m

30 m

in, t

op

30 m

in, m

iddl

e

30 m

in, b

otto

m

60 m

in, t

op

60 m

in, m

iddl

e

60 m

in, b

otto

m

90 m

in, t

op

90 m

in, m

iddl

e

90 m

in, b

otto

m

120

min

, top

120

min

, mid

dle

120

min

, bot

tom

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1 1

Developing IVR Manufacturing Processes

Blend Drugs + excipients

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Developing IVR Manufacturing Processes

EVA 3 kg/h, 1.3% Dapivirine, 5.6% Maraviroc

Blend Drugs + excipients

Feed APIs and Polymer to Mixer

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Developing IVR Manufacturing Processes

EVA 3 kg/h, 1.3% Dapivirine, 5.6% Maraviroc

Blend Drugs + excipients

Feed APIs and Polymer to Mixer

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Developing IVR Manufacturing Processes

Blend Drugs + excipients

Feed APIs and Polymer to Mixer

MiMix Polymer + drug blend

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Developing IVR Manufacturing Processes

Powder / Polymer Mixing

Considerations:Considerations:* thermal stability of API* thermal stability of polymer* residence time

Blend Drugs + excipients

* residence time* mixing efficiency and homogeneity / API solubility in polymer (DSC?)

Feed APIs and Polymer to Mixer

MiMix Polymer + drug blend

20

Developing IVR Manufacturing Processes

Benefits of HME over Batch Processes

Lower Processing Temperature andLower Processing Temperature and shorter residence time

Reduced API degradationReduced Polymer degradation

Blend Drugs + excipients

Reduced Polymer degradationFeed APIs and Polymer to Mixer

Mi

BatchBatch + 50ppm BHEBHMEMix

Polymer + drug blendHME

Continuous processEasy conversion to pelletsHigher throughput

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Higher throughputProduct uniformity

Developing IVR Manufacturing Processes

Die optionsDie optionssingle orificedouble orificediameter

Blend Drugs + excipients

diameter

Choice of conveyor belt

Feed APIs and Polymer to Mixer

MiChoice of cooling (water, air…)

Mix Polymer + drug blend

Extrude drug-loaded polymer

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Developing IVR Manufacturing Processes

Pellets required to feed Injection MolderPellets required to feed Injection Molder

Choice of pelletizer

Blend Drugs + excipients

Effect of speed etc on pellet size and uniformity

Feed APIs and Polymer to Mixer

MiCollection of pellets

Assay pellets

Mix Polymer + drug blend

Assay pellets

Pelletize extrudate

Extrude drug-loaded polymer

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Developing IVR Manufacturing Processes

Process Developmenttimetemperatureinjection rateinjection ratecooling

Mold designgatesprue removalpush pins

24Injection mold pellets to form IVRs

In-vitro Drug Release Results

Compare Banbury batch IVRs with ZSE18Nissei IVRs for release of Dapi and DS006

Dapivirine Release from 4mm Combination Rings EVA2803

L di 25 / i10000

Maraviroc Release from 4mm Combination Rings EVA2803

L di 300 / i100000Loading: 25 mg/ring

100

1000

10000

ease

/ μg

Loading: 300 mg/ring

1000

10000

100000

ease

/ μg

10

100

Dai

ly R

ele

Banbury batch IVR

ZSE18-Nissei IVR

10

100

Dai

ly R

ele

Banbury batch IVR

ZSE18-Nissei IVR

10 5 10 15 20 25 30

Time / d

10 5 10 15 20 25 30

Time / d

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Regulatory Considerations

For human clinical trialscGMP

raw materials purchasing qualification storageraw materials purchasing, qualification, storage, handlingpersonnel qualificationsqualified equipment (IQ OQ PQ)qualified equipment (IQ, OQ, PQ)validated analytical methodsvalidated production processesMOC not additive reactive nor absorptiveMOC not additive, reactive nor absorptivevalidated cleaning procedures requiredQBD development approach (design space)QA oversight of productionQA oversight of productionBatch recordStability study following ICH guidelines

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Conclusions

Batch-wise compounding is suitable for small scale formulation development

There are issues associated with small scale processing that may not be observed at production scale

Hot Melt Extrusionrequires upstream process development (powder blending, powder feeding)p g)May reduce degradation of key materials Yields uniform, high quality compound Is readily scaled to commercial volumesyIs the process of choice for EVA matrix IVRs

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Acknowledgements

PSIJason McConnellOnajite OkohJigar PatelMatthew BigertChristopher Morgan

LeistritzK-TronScheck-Accurate

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