QualitybyDesign – Thinkdifferently Files...Jun 20, 2012 · QualitybyDesign – Thinkdifferently Name of presenter 2012-06-20 Barcelona, Spain Quality by Design in In-process Curing

Quality by Design –

Think differently

Name of presenter

2012-06-20 Barcelona, Spain

Quality by Design in In-process

Curing of EUDRAGIT® NM 30 D

Dr. Min Yang

Principal Scientist

Pharma Polymers, NAFTA

1. Introduction of Evonik and the Health Care Business Line

2. Introduction to EUDRAGIT® Polymers

3. Applications of EUDRAGIT® Polymers: Taste Masking and Moisture Protection, GI Targeting, Sustained Release and Bioavailability Enhancement

4. DOE Case Study - In-process Curing of EUDRAGIT® NM 30 D

14 June, 2012 | Quality by Design in In-process Curing of EUDRAGIT®

NM 30 D

Page 3

Where we stand

Evonik is the

creative industrial group

from Germany.


NM 30 D

Page 4

An attractive company

• One of the global

leaders in specialty

chemicals

• Financial

Investments in the

energy and real

estate sectors

• Ownership structure:

RAG-Stiftung

(74.99%) and CVC

Capital Partners

(25.01%)


NM 30 D

Page 5

A worldwide presence

Piscataway 2002

Key strengths

• GI targeting

• Solubility

enhancement

• Controlled release


NM 30 D

Page 6

A modern structure reflects those

trends

Services

Inorganic

MaterialsAdvanced

Intermediates

Consumer

SpecialtiesHealth &

Nutrition

Performance

Polymers

Coatings &

Additives

Site

Services

Evonik

Business

Services

Financial investments

Real Estate

Energy

Business

Units

Evonik

Executive Board

Consumer,

Health & NutritionResource Efficiency Specialty Materials


NM 30 D

Page 7

From APIs to drug delivery solutions

Rexim® Amino Acids

Amino-Acids for

parenteral

nutrition, as APIs

or as versatile

building blocks for

chiral pharma

syntheses

Formulation Services

• Assist customers

with formulation

development

Pharma Polymers for

Oral Dosage Forms

Exclusive Synthesis

Proprietary advanced

intermediates and APIs, from

the clinical stage all the way

to commercialization.

Pharma Polymers for Depot &

Medical Devices Applications

Commercial APIs

& intermediates

Portfolio of generic actives

with global supply options

PRODUCT LINE PHARMA POLYMERSBL Health Care

RESOMER® &

LAKESHORE

BIOMATERIALSTM

PLGA based polymers

for controlled release

depot injections and

medical device

applications

EUDRAGIT®

Acrylic Drug Delivery

excipients for oral solid

dosage forms


NM 30 D

Page 8


NM 30 D

Page 9

Oral drug delivery by EUDRAGIT®

Protective formulations:

Moisture protection

Taste and odour masking

Light protection

EUDRAGIT® E-series

Delayed Release formulations:

pH-triggered GI targeting

Colonic delivery

Protection of acid sensitive APIs

Protection of stomach against irritant

APIs

EUDRAGIT® L, L-55, FS and S-series

Time or pH

ReleasedAPI (%)

Sustained Release formulations:

Time controlled drug release by

diffusion barriers

Inert matrix tablets

EUDRAGIT® RL, RS, NE, NM-series


NM 30 D

Page 10

Commercial examples of drugs formulated

with Metacrylic based excipients





Slide 12

How do you say…

EUDRAGIT®

“Eu” (good)

+

“Dragee” (coated tablet)

+

GIT (gastro-intestinal tract)

(Oi´ dră gĭt) n.,

Slide 13

Radical Polymerization StepsChain Growth Reaction with Different Monomers

1. Reaction Start

2. Chain Growth

I · + H2C = C

|

|

CH3

C = O|

R

I - CH2 - C ·

|

|

CH3

C = O|

R

H2C = C

|

|

CH3

C = O|

R

I - CH2 - C ·

|

|

CH3

C = O|

R

+exothermic

I - CH2 - C

|

|

CH3

C = O|

R

- CH2 - C ·

|

|

CH3

C = O|

R

Lit.: H.-G. Elias, Makromoleküle, Grundlagen, 5. Ed., S.441ff, Hüthig und Wepf Verlag, Heidelberg 1990

J.M.G. Cowie, Chemie und Physik der Polymeren, S.49ff, Verlag Chemie, Weinheim 1976

Slide 14

Products Via Emulsion

Polymerization

EMULSION

POLYMERIZATION

SOLUTION

SPRAY

DRYING

EUDRAGIT® S 12,5

EUDRAGIT® L 12,5

EUDRAGIT® S 100

EUDRAGIT® L 100

EUDRAGIT® L 100-55

EUDRAGIT® NE 30 D

EUDRAGIT® NM 30 D

EUDRAGIT® L 30 D-55

EUDRAGIT® FS 30 D

MONOMERS

+ ADDITIVES

+ WATER

MIXING

Slide 15

Products Via Bulk Polymerization

MILL

SOLUTION

DISPERSION

BULK

POLYMERIZATION

Granules

EUDRAGIT® E 12,5

EUDRAGIT® RS 12,5

EUDRAGIT® RL 12,5

EUDRAGIT® E PO

EUDRAGIT® RS PO

EUDRAGIT® RL PO

EUDRAGIT® E 100

EUDRAGIT® RS 100

EUDRAGIT® RL 100

EUDRAGIT® RS 30 D

EUDRAGIT® RL 30 D

Slide 16

Trade Name Codes

• 100 = Solid: EUDRAGIT® L/S 100;

L 100-55; RL / RS 100;

E 100

• PO = Powder: EUDRAGIT® RL PO

RS PO; E PO

• 30 D = Aqueous Dispersion: EUDRAGIT® L 30 D-55;

RL / RS 30 D; NE 30D

NM 30 D

• 12,5 = org. solution: EUDRAGIT® L / S 12,5;

RL / RS 12,5; E 12,5

Slide 17

Dosage Forms

� Tablets

� Capsules

� Powders

� Granules

� Crystals

� Solid Dispersions

� Transdermals

Type of Action

� Protective

� Moisture Protection

� Taste Masking

� Enteric Delivery

� Colonic Delivery

� Sustained Release

Applied Technology

� Film coating

� Granulation (e.g., matrix)

� Tableting

� Spray drying

� Hot Melt Processing

Overview of Applications





Slide 19

Why taste masking?

Bad taste Patient compliance

Coating

Bad odor Pediatric use

Slide 20

Why moisture protection/isolation?

Degradation Stability

Coating

Interaction Isolation

Slide 21

Fluid bed approach

Powder

Blend

Roto-Granulation

with tangential

spraying

EUDRAGIT®

coated Drug

granules

ExcipientsDrug

granules

E PO coating ODT

Slide 22

Example Acetaminophen:

particle coating

Substrate: Acetaminophen „Special Granular“ (Mallinckrodt)

Particle size: 99.5% 150 - 420µm

Coating: 30% EUDRAGIT® E PO (aqueous)

Process: Fluid bed with Top Spray (standard parameters)

Drying: Trays, 2h, 40°C

Dissolution: USP Methode II – Paddle

Slide 23

40 - 70°C

Tablet bed

25 - 35 °C

Compressed air

>3 bar operating air

1 - 2 bar atomizing

Exhaust air

25 - 35°C

Spray rate

~ 1 – 3 g /

min / kg Product

Drying air capacity

0.3 – 0.5 m³/min/kg tablets

Distance nozzle to

tablet bed

10 - 25 cm

Pan speed

Adjusted, depending on

pan size, baffles design and

mechanical stability of tablets

Coating Conditions:

Side Vented Pans

Slide 24

Gastro intestinal targeting with

EUDRAGIT®

0

20

40

60

80

100

4 5 6 7 8pH

drug release (%)

Polymer

coating

Core

with drug

increasing

pHDrug release

Drugs are released at a specific site of

the GI tract:

• Conventional aqueous coating

processes

• Tablets, pellets, crystals

• Flexible coatings for disintegrating

• tablets

Enteric or colonic

drug release, triggered

by polymer dissolution

1 mm

Slide 25

Influence of Product Temperature on

Film Formation

product temp. < MFT

No coalescence, but single latex particlesproduct. temp. > MFT

Coalescence, film formation

Recommendation: Product Temp. ≥≥≥≥ MFT + 10 K

Slide 26

Test method for enteric-coated

dosage forms

0

10

20

30

40

50

60

70

80

90

100

0 30 60 90 120 150 180

time [min]

drug release [%]

pH = 1.2

pH = 6.8

(7.2 or 7.4)

Requirements2 hours pH 1.2 (0.1 N HCl)

< 10% drug released

45 minutes at pH 6.8

> 75 / 80 % drug released

ExampleBisacodyl pellets, 1 mm

25% EUDRAGIT® L 30 D-55

approximately 6 mg/cm2

According to current USP, paddle apparatus

Slide 27

Why Sustained Release?

� Reduction in dosing frequency, more convenient regimen

(e.g., taking one 75-mg tablet/day vs. three 25-mg tablets/day)

� Therapeutic Advantage

� Better maintenance of therapeutic window

� Reduced side effects

� Increased Patient Compliance

� Product Line Extensions

Slide 28

0

20

40

60

80

100

0 50 100 150 200 250 300 350 400 450 500

Time [min]

Drug released [%]

After spraying

5 min drying

10 min fluidization

20 min fluidization

30 min fluidization

24 h tray drying

After 30 min in-process curing stable profile as after 24h tray drying

Parameters

Process time 30 min

Product temp. 45 – 50 °C

Drying air

capacity 1.2 – 1.4 m³/min/kg

Exhaust air humidity 10 – 15% r.h.USP, paddle app. 2, 150 rpm

2h 0.1N HCl, then buffer pH 6.8

In-process-curing EUDRAGIT®

RL/RS 30 D

Slide 29

Bioavailability and Solubility

Enhancement

Melt Extrusion Spray Drying

Slide 30

5 10 15 20 25 30 35

2θ (deg.)

impulse (relative)

carbamazepine PM Ex SD

Influence of preparation method –

spray drying vs. melt extrusion

0

20

40

60

80

100

0 20 40 60 80 100 120

time (min)

% dissolved

Spray dried sample Extrudate Carbamazepine

Dissolution in pH 1.2

Case: Carbamazepine






NM 30 D

Page 32

Quality Target Product

Profile


NM 30 D

Page 33

Quality Target Product Profile

Modified release pellets

Degradation products

Content uniformity

Assay

Twice a day80 mg propranololDosage strength

Dissolution over 12hSustained releaseDrug release

Dissolution testingDrug release unchangedStorage stability

Pharmacopeial

methods

Meeting compendial or

other applicable quality

standards

Identity

Coated pellets

Oral modified release

pellets

Dosage form and route

of administration

ImplicationsTargetProduct attribute


NM 30 D

Page 34

Scientific Background


NM 30 D

Page 35

Model of film formation

Aqueous polymer dispersionAqueous polymer dispersion

III. Fragmentation and segregation

of hydrophilic shells

III. Fragmentation and segregation

of hydrophilic shells

I. Evaporation of water and densification of latex particles

I. Evaporation of water and densification of latex particles

Densest sphere packing

II. Deformation of latex particlesII. Deformation of latex particles T > MFTT > MFT

Deformed particles

IV. Interdiffusion IV. Interdiffusion T > TgT > Tg

Homogeneous polymer film


NM 30 D

Page 36

Properties:

• Nonionic (Neutral Ester)

• permeable, not soluble

• pH-independent release

• Tg: 9°C (DSC)

• MFT: 5°C

Available as:

• EUDRAGIT® NM 30 D

• 30% aqueous

dispersion

CH2C

C=O

H

OC2H5

CH2C

C=O

CH3

OCH3

Highly flexible

No plasticizer needed

Chemical structure EUDRAGIT® NM


NM 30 D

Page 37

Interdiffusion of polymer out of latex

particles

• Temperature has to be above glass transition

temperature (Tg)

• Stabilisation (steric or electrostatic) of the dispersion

not needed

• Latex particles lose their identity

• Continuous & mechanical stable film

• Interdiffusion characterized by:

• Diffusion coefficient

• Penetration of particles

• Elongation at break

• Entanglement of polymer chains

• Described by Ficks law of diffusion

Not detectableby:

spectroscopicalmethod(IR, Raman, NMR)

dielectrical analysison coatedpellets


NM 30 D

Page 38

0

20

40

60

80

100

0 50 100 150 200 250 300 350 400 450 500

Time [min]

Drug released [%]

After spraying

5 min drying

10 min fluidization

20 min fluidization

30 min fluidization

24 h tray drying

With progressing

storage time the release

profile drops down.

Distances get smaller.

How curing can look like in storage


NM 30 D

Page 39

Setup of Trials


NM 30 D

Page 40

Basic Setup

Bosch Unilab

100% on d.s. polymerTalc

10% on d.s. polymerHPMC (E5)

10% on d.s. polymerPolysorbate 80

EUDRAGIT® NM 30 D

Coating formulation

25 kgPilot scale batch

3 kgLab scale batch

Batch sizes

propranolol HCl pelletsAPI

Bosch Pilotlab


NM 30 D

Page 41

Determination of the coating level

0

10

20

30

40

50

60

70

80

90

100

0 120 240 360 480 600 720 840 960

time [min]

drug dissolved [%]

12% Polymer 14% Polymer 16% Polymer 18% Polymer

USP Dissolution

Apparatus II (Paddle)

Media:

2h 0.1N HCl +

6h phosphate buffer pH 6.8

Stirrer speed:

150 rpm

Sampling time:

0, 60, 120, 150, 180, 210, 240,

270, 300, 360, 420, 480, 540, 570,

600, 660, 720, 780, 840

Coating level defined to 15% polymer weight gain (>80% after 12h)


NM 30 D

Page 42

Implementation of QbD


NM 30 D

Page 43

Ishikawa Chart for Pellet Coating

by ICH Q8 Annex I


NM 30 D

Page 44

Process Chart - Process

optimization

Preparation of

coating suspension

Preheating of pellets

Coating

In-process curing

Drying

Preheating

Sampling

Sampling


NM 30 D

Page 45

20

25

30

35

40

45

50

55

60

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Specific Humidity ( mg water / kg air )

Temperature [°C]

Curing Conditions in Mollier Chart

Impossible in

fluid bed

ovenCirculating

air cabin

IPC

Curing Field

100%

90%

80%

70%

60%

50%

40%

30%25%20%15%10%

IPCKnown

“sweet spot”

for in-process

curing

oven


NM 30 D

Page 46

Risk Analysis


NM 30 D

Page 47

Process Visualisation leads to Risk

Analysis

S: Severity (how serious the consequences of the failures are)

O: Occurence (how frequently failures occur)

none0000n/an/an/anoneDrying

Time10010110noneCuring time too

short

Instable release profile

over time

Incomplete

coalescence

Spray rate for water20010210Exhaust air humidity

sensor

Process humidity

too low


over time

Incomplete

coalescence

Inlet air / product

temperature

10010110Product

temperature sensor

Inlet air temperature

too low


over time

Incomplete

coalescence

Curing

Change filter to rougher

type

0110Pressure differenceFilter cloggingInterruption of batchFilter cloggingPreheating

Product temperature set

to 20-23°C4114Product

temperature sensor

Spray drying due to

too high inlet air

temperature

No coatingProduction of fine

parts

Stirring of coating

suspension to avoid

sedimentation of talc

54916Spraying

suspension weight

control

Nozzles blockedNo coatingNo spraying

Inlet air volume set to

exhaust air humidity of

max. 60%

54239Humidity sensorProcess humidity

too high

Drug release out of spec; if

pellets stick together

surface area will change

and therefore, release rate

Pellets sticking

Product temperature set

to 20-23°C54239Product

temperature sensor

Inlet air temperature

too high

Drug release out of spec; if

pellets stick together

surface area will change

and therefore, release rate

Pellets stickingCoating

Inlet air volume set to x

m³/h

8118noneInlet air volume too

high

Drug release out of spec

due to incorporation of

drug particles in SR

coating

Abrasion of pellets

Preheat coater without

pellets

Preheating time set to 2

min

8118NonePreheating time too

long

Drug release out of spec

due to incorporation of

drug particles in SR

coating

Abrasion of pelletsPreheating

ActionsRPNDOSControlsCauses of failure

mode

Failure effectsFailure ModeProcess

step

D: Detectability (how easily failures can be detected)

RPN: Risk priority number (scale running from 1 to 10 with 10 being the worst)


NM 30 D

Page 48

Factors and Responses

Factors

• Humidity

• Temperature

Cheap Factor

• Curing Time

Responses

• Dissolution at 180, 360, 600 min


NM 30 D

Page 49

Design & Design Space


NM 30 D

Page 50

Constraints based on theory


NM 30 D

Page 51

Classical Design vs. D-optimal

design

-1,0

-0,5

0,0

0,5

1,0

-1,0 -0,5 0,0 0,5 1,0

B

A

Investigation: Demo CCF

1 2

3 4

5 6

7

8

91011

MODDE 9.1 - 2011-10-12 15:23:35 (UTC+1)

30

35

40

45

50

55

15 20 25 30 35 40 45 50 55 60Temp

Humidity

Investigation: D-opt_ Evonik_whole theoretical area

Worksheet Scatter Plot with Experiment Name labels

N1 N2

N3

N4

N5

N6

N7

N8N9N10N11 SweetSpot

MODDE 9.1 - 2011-10-13 09:36:54 (UTC+1)


NM 30 D

Page 52

35

40

45

50

55

28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

Temperature

Humidity

Investigation: Evonik_curing_long Worksheet Scatter Plot with Experiment Number labels

1

2

3

4

5

67

8

9

10

11

12

13

14

15

16

17

1819

20

21

22

23

24

MODDE 9.1 - 2012-04-04 15:44:26 (UTC+1)

52UMETRICS CONFIDENTIAL

Performed experiments / Potential

Design Space


NM 30 D

Page 53

Model and Contur Plots


NM 30 D

Page 5454UMETRICS CONFIDENTIAL

Model quality

0,0

0,2

0,4

0,6

0,8

1,0

Diss 180 Diss 360 Diss 600

Investigation: Evonik_curing_long (MLR)Summary of Fit

N=24

R2

Q2

Model Validity

Reproducibility

MODDE 9.1 - 2012-04-04 15:48:37 (UTC+1)


NM 30 D

Page 55

Influence of Parameters

180 min 360 min 600 min


NM 30 D

Page 56

Design Space Plot

The design space

is calculated with a risk

of 10000 DPMO

(1 % risk).


NM 30 D

Page 57

Summary

Any aqueous dispersion shows aging, if T>Tg

In-process curing has the power to accelerate/prevent

aging.

Visualization of processes can help to identify critical

attributes.

Risk analysis is to be conducted thoroughly.

Common PAT-Technologies can are no alternative

because of interference and curvature.

….

….

….


NM 30 D

Page 58

Acknowledgements

Mr. Thomas Dassinger

Ms. Ilaria Forlizzi

Dr. Jessica Albers

QualitybyDesign – Thinkdifferently Files...Jun 20, 2012 · QualitybyDesign – Thinkdifferently Name of presenter 2012-06-20 Barcelona, Spain Quality by Design in In-process Curing

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