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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
3
Intra-vaginal Rings - Designs
4
Intra-vaginal Rings - Designs
5
Intra-vaginal Rings – Drug Release Profiles
In vitro In vivo
6
HIV - Global Prevalence in Adults
7
HIV/AIDs and Microbicides
8
The Driving Force
ARV-loaded IVRs could protect women from infection from HIV+ partners
9
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)
11
( q 2)
Injection mold crumb to form IVRs
In-vitro Drug-release from Experimental Combination ARV IVRs
12
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
13
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
15
1 1
Developing IVR Manufacturing Processes
Blend Drugs + excipients
16
Developing IVR Manufacturing Processes
EVA 3 kg/h, 1.3% Dapivirine, 5.6% Maraviroc
Blend Drugs + excipients
Feed APIs and Polymer to Mixer
17
Developing IVR Manufacturing Processes
EVA 3 kg/h, 1.3% Dapivirine, 5.6% Maraviroc
Blend Drugs + excipients
Feed APIs and Polymer to Mixer
18
Developing IVR Manufacturing Processes
Blend Drugs + excipients
Feed APIs and Polymer to Mixer
MiMix Polymer + drug blend
19
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
21
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
22
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
23
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
25
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
26
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
27
Acknowledgements
PSIJason McConnellOnajite OkohJigar PatelMatthew BigertChristopher Morgan
LeistritzK-TronScheck-Accurate
28
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