study medication time schedule résumé development of an improved tablet formulation long term...

Study Medication Study Medication Time scheduleTime schedule RésuméRésumé

Development of an improved tablet formulationDevelopment of an improved tablet formulation Long term stabilityLong term stability Reasonable production conditionsReasonable production conditions Focus on packaging materialFocus on packaging material

G&H Meeting Sep 29 - Oct 2, 2003G&H Meeting Sep 29 - Oct 2, 2003Munich, GermanyMunich, Germany

WP 7 Pharmaceutics (Lichtwer Pharma)WP 7 Pharmaceutics (Lichtwer Pharma)

Objectives…Objectives…

Time scheduleTime schedule

77thth-8-8thth Week Week Production Verum & PlaceboProduction Verum & Placebo77thth-8-8thth Week Week

77thth-8-8thth Week Week Writing & Authorisation production Writing & Authorisation production protocolprotocol99thth-10-10thth Week Week

99thth-10-10thth Week Week Writing Randomisation PlanWriting Randomisation Plan1212thth Week Week

99thth-10-10thth Week Week Quality Control Verum & PlaceboQuality Control Verum & Placebo1313thth Week Week

1010thth-11-11thth Week Week Writing & Writing & Authorisation(!)Authorisation(!) packaging/labellingpackaging/labelling1212thth Week Week

1212th th WeekWeek Packaging & LabellingPackaging & Labelling1616thth Week Week

1414th th WeekWeek Final Release & Delivery Final Release & Delivery 2222th th WeekWeek Final Release & Delivery (first part)Final Release & Delivery (first part)3333th th Week Week Final Release & Delivery (second partFinal Release & Delivery (second part))

Study Study MedicationMedication

Tabletting: Tabletting: Difficulties with the flowability Difficulties with the flowability and compressibility of the EU and compressibility of the EU garlic powdergarlic powder

Coating: Coating: Everything went fine…Everything went fine…

Sugar Coating: Sugar Coating: Everything went fine…Everything went fine…

Release: Release: Full compliance with Full compliance with specifications! specifications!

GCP: GCP: Minor deviationsMinor deviations

RésuméRésumé ……

Study Study MedicationMedication

Details on Stability StudiesDetails on Stability Studies

Organic film basedOrganic film based Full compliance to ICH-guidelinesFull compliance to ICH-guidelines Up to seven different packaging materialsUp to seven different packaging materials Two different dosage formsTwo different dosage forms

Aqueous film basedAqueous film based Reformulation of tablet coreReformulation of tablet core Formulation of coatingFormulation of coating Establishing aqueous coating procedureEstablishing aqueous coating procedure

Improved Tablet FormulationImproved Tablet Formulation

Commercial Products (Dragees)100mg and 300mg

0

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100

0 6 12 18 24 30 36Months

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Act

ivit

y (%

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100mg Tablets; Standard Polymer Blister; 25°/60%




Tolerance


Stability of Commercial Products (Dragees)Stability of Commercial Products (Dragees)

Comparison Powder vs Commercial Products (Dragees)

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100

0 6 12 18 24 30 36

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100mg Tablets; Standard Polymer Blister; 25°/60%300mg Tablets; Standard Polymer Blister; 25°/60%Powder 25°/60% (PE Bottles) non-lyoPowder 30°/70% (PE Bottles) non-lyoPowder 40°/75% (PE Bottles) non-lyo

Tolerance


Commercial Products (Dragees)Commercial Products (Dragees)

100 mg Tablets - 25°C / 60% Long Term Condition; Climatic Zone IV

40

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100

0 6 12 18 24 30 36Months

rel.

Act

ivit

y (%

)

PVDC 60 Polymer/Alu Blisterpure Alu/Alu Blister Alu/Alu Polymer Composite Blister PE Bottles Glass Bottles

Tolerance


OrganicOrganic Film Tablets (100 mg) Film Tablets (100 mg)

100 mg Tablets - 30°C / 70% Intermediate Condition - Climatic Zone IV

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100

0 6 12 18 24 30 36

Months

rel.

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ivit

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Tolerance



100 mg Tablets 40°C / 75 %Accelerate Condition

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60

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100

0 3 6 9 12 15Months

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Act

ivit

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Tolerance



300 mg Tablets 25°C / 60%Long Term Condition; Climatic Zone II

30

40

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100

110

0 6 12 18 24 30 36Months

rel.

Act

ivit

y (%

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Tolerance



300 mg Tablets 30°C / 70%Intermediate Condition; Climatic Zone IV

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100

0 6 12 18 24 30 36Months

rel.

Act

ivit

y (%

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Tolerance



300 mg Tablets 40°C / 75 %Accelerated Condition

0

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100

0 3 6 9 12 15Months

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Tolerance



Residual Humidity 25°C / 60%Long Term Condition

0,0

2,0

4,0

6,0

8,0

10,0

0 6 12 18 24Months

Res

idu

al H

um

idit

y (

%)

PVDC60 Blister (Standard)COC190 Blister ICOC190 Blister IITriplex BlisterHDPE BottlesAlu/Alu BlisterAlu/Alu Polymer Composite BlisterGlas Bottles



Residual Humidity 30°C / 70%Intermeditate Condition

0

1

2

3

4

5

6

7

8

0 6 12 18 24Months

Res

idu

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um

idit

y (%

)




Residual Humidity 40°C / 75%Accelerated Condition

0

2

4

6

8

10

0 3 6 9Months

res

idu

al H

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It is possible to prolong shelf life up to 4 times when…It is possible to prolong shelf life up to 4 times when…

1.1. the residual humidity of the tablets is limited to 3,5 – 4 %the residual humidity of the tablets is limited to 3,5 – 4 %

2.2. a strictly humidity controlled coating procedure is applieda strictly humidity controlled coating procedure is applied

3.3. a packaging material providing a 100% humidity barrier is a packaging material providing a 100% humidity barrier is usedused

It is possible to produce the improved tablets in an It is possible to produce the improved tablets in an economic way (e.g. no freeze drying necessary!)economic way (e.g. no freeze drying necessary!)

Concerning the high demands on the water barrier Concerning the high demands on the water barrier there is no sufficient polymer blister material availablethere is no sufficient polymer blister material available

Conclusion Organic Coated Film Tablet IConclusion Organic Coated Film Tablet I


Further optimisation is possible to solve…Further optimisation is possible to solve…

… … the the poor disintegrationpoor disintegration time of the 300 mg tablets time of the 300 mg tablets from up to 45 min to < 30 min from up to 45 min to < 30 min

… … poor robustnesspoor robustness of the formulation concerning high speed of the formulation concerning high speed tablettingtabletting

… … residual organic solventresidual organic solvent problem (film coating) problem (film coating)

Conclusion Organic Coated Film Tablet IIConclusion Organic Coated Film Tablet II


TransformingTransforming…


an organic film coated tablet into…an aqueous film coated tablet!

Why?Why?

a) More flexible production processb) No organic solvents necessaryc) Adaptable at Lichtwer’s Facilities

Three production scale batches according Three production scale batches according ICH-Guidelines have been manufactured ICH-Guidelines have been manufactured successfully in Aug 2003successfully in Aug 2003

The residual water content of the tablets are The residual water content of the tablets are 2.6 to 2.8% (limit: 3.5%)2.6 to 2.8% (limit: 3.5%)

The batches have been packed in PE bottles and The batches have been packed in PE bottles and COC300 Blister (Alu/Alu blister coming up next)COC300 Blister (Alu/Alu blister coming up next)

The batches are stored under 25°C/60%, 30°C/65%, The batches are stored under 25°C/60%, 30°C/65%, and 40°C/75% conditionsand 40°C/75% conditions

Overview Status Overview Status AqueousAqueous Coated Tablets Coated Tablets


Production SchemeProduction Scheme

1.1. Weighing and MixingWeighing and Mixing

2.2. TablettingTabletting

3.3. Coating suspensionCoating suspension

4.4. CoatingCoating

5.5. In-Process ControlsIn-Process Controls

6.6. PackagingPackaging

Weighting/Mixing

Weighting/Mixing

TablettingTabletting

Coating Suspension

Coating Suspension

CoatingCoating

In-Process Control

In-Process Control

Packaging (Blister)

Packaging (Blister)

The Team you can trust…The Team you can trust…

Wolfgang LüdekeWolfgang Lüdeke José Galan-SousaJosé Galan-SousaSilvia StrieglSilvia StrieglAnke Wermann

& Anja Müller

Anke Wermann &

Anja Müller

The Team you can trust… part The Team you can trust… part IIII

Bianca BeutkeStability

Coordination

Bianca BeutkeStability

Coordination

You can‘t get

enough stability!

You can‘t get

enough stability!

Thank you very Thank you very much for…much for…

!!!!!!

study medication time schedule résumé development of an improved tablet formulation long term...

Documents

improved tablets

tablet intoan aqueous

humidity barrier

coc300 blister alualu

applieda packaging material

study medicationtabletting

finesugar coating

nextthe batches