GSK’s Development of Novel Oral Delivery Technologies – Perspectives

Mark Wilson

Director, PTS, R&D

GlaxoSmithKline Pharmaceuticals

GSK Established a Technology Incubator To Develop Drug Delivery Systems and Manufacturing Technologies

GSK Required Reliable and Royalty-Free Delivery Systems, and Wanted To Have Access To “21st-Century Technologies”

GSK’s Initial Approach Was To Create a Few, Deep Partnerships

Company A

Partner A

Partner B

GSK Moved To a Networked Approach: Multiple External Technology Inputs Into GSK Lead to External Outputs Over Time

External

External

GSK: Internal

Developmennt

GSK: Scale-Up and

Commercialisation

GSK: Marketed

Products

External

ExternalExternal

External External

External

External

External

External

External

External

External

Multiple external interactions: GSK receives and provides technologies

GSK Developed a Novel Approach to Controlled-Release Formulation

DiffCORETM Is A Robust and Proven Controlled-Release Tablet Technology for Single Actives and Combination Products

DiffCORETM Delivers Drug from a Core through Apertures in a Functional Barrier Coating

A GSK proprietary modified release drug delivery technology

Several forms or ‘generations’ of DiffCORE™ provide a range of delivery mechanisms which can be tailored to meet desired product attributes

Marketed DiffCORE™ product - Lamictal XR

The Use of Enteric Coats and Bilayer Tablet Elements Provides a Wide Variety of Release Profiles

Insoluble Coat Enteric Coat

MR + IR BilayerTablet+ Enteric Coat

Further Variants

Patents Have Been Filed for Several Technology Variants

Aperture Diameter, Tablet Properties and Coat Type Determine Release Profile

Oral Dosage Form For Controlled ReleaseChi Li, Gino Martini, Vin Re & Helen WillyFiled Feb 12 2002, PCT/GB03/00594

DiffCORE™ Provides for Sustained Gastric and Enteric Delivery

DiffCORETM Has Been Commercialised and Tested Extensively Clinically

DiffCORE™ has been used in a number of clinical trials. GSK has one product commercialised using the platform, and has conducted trials on multiple late-phase development projects.

DiffCORETM Controls Release by Using a Precisely-Sized Aperture in the Tablet Coat

The Aperture Size Determines the Release Profile

DiffCORE’s Performance Characteristics - e.g. the Effect of Aperture Size - Have Been Clinically-Proven

The Platform Is Validated Clinically on Multiple Compounds

DiffCORETM Is Robust to Fed / Fasted Effects and Can Target Narrow Absorption Windows

Delivery of actives reproducibly in the fed and fasted state

Delivery of actives with a narrow window of absorption

Deliver a wide range of drug doses for titration demands

DiffCORETM Has Become the Standard In-House Approach to Controlled Release within GSK

DiffCORETM Offers Controlled-Release Formulation Flexibility

An IR or MR hypromellose matrix core which is surrounded by a film and enteric coat with one or more apertures

Enteric coat remains intact within the acidic environment of the stomach, but dissolves when exposed to higher intestinal pH

– Drug release is controlled via the apertures and tablet core within the stomach, and solely by the tablet core in the intestine

– The increase in exposed core surface area in less acidic pH increases drug availability in the intestine

Typically used for salts of weak bases and compounds with a low solubility at intestinal pH

DiffCORETM Pilot Units Replicate All Critical Full-Scale Processes

The DiffCORETM Aperture Formation Process Required Extensive Development

The aperture is critical to formulation performance

Many technologies were tested Vendor evaluation

– Multiple technologies evaluated

– Traditional pharmaceutical vendors and non-pharmaceutical companies

Drilling was found to be the most reliable approach

Small Scale Development Kit

The Manufacturing Process Has Been Scaled to Multiple 140,000 Tablets / Hour Production Units

Given the Criticality of Aperture Size, Extensive Testing Is Conducted on the Production Machine

For aperture control, there are four DiffCORE™-specific tablet quality attributes that have been defined:

– Aperture presence

– Aperture location

– Aperture size (i.e. aperture area)

– Aperture depth

A visual camera system and an in-line laser system have been used successfully as part of the control strategy to measure and thus control the size and depth of the apertures drilled into DiffCORETM

tablets.

DiffCORETTM Drilling Control Has Been Verified on Production for Over Several Years

The depth of the aperture is controlled mechanically by the position of the drill relative to the tablet and the set distance the drill bit can move.

An in-line laser inspection system on the drilling rig measures the depth of every aperture (both sides of the tablet) to check it meets specification.

Aperture depth = 0.3 mm +/- 0.1 mm; Ppk (Process Performance

Index) >2 (2.15); (sigma) level >6 (6.46).

A Visual Inspection System Checks Each Individual Drilled Tablet Face

Aperture presence and location is determined by an in-line camera visual inspection system that checks each and every tablet face which is drilled. The camera system checks that a full aperture is present and centrally located within a zone of acceptance as well as being of the correct size.

The DiffCORETM Technology Is Used To Manufacture Lamictal XR at GSK’s Zebulon Site in North Carolina

GSK Developed Several Technologies for In-House Use, Some of Which Can Be Combined with DiffCORETM

Liquid Dispensing Technology:

“Shirt- Sleeve Manufacturing” for Potent Drugs, with Extremely-High Accuracy

Liquid Dispensing Technology: “Shirt-Sleeve” Manufacturing

of Low-Dose and Potent Actives

Droplet Volume

Measurement

Drug Solution/ Suspension

+ Placebo Tablets

LiquidDispensing

On-LineImaging

On-line Coating& Printing

(Commercial

Only)

Drying

NIR Imaging ofDeposition Location

Liquid Dispensing Process Eliminates The Need for High-Capital Containment Facilities

Tablets are manufactured by dispensing a microlitre quantity of a liquid formulation, containing the drug substance & a polymer, onto the surface of an inert carrier tablet

Solvent evaporates leaving adherent polymer film

An opaque, pad-printed overcoat is applied over deposition

API & POLYMER LAYER

BICONCAVE

CARRIER TABLET

CORE

Overcoat AppliedBy Pad Tamping

API and Polymer Layer

Carrier TabletFilm Coat

BICONCAVE

CARRIER TABLET

CORE

Process

Process Provides Less Variation than Tablet Manufacturing: Much Better than “Six-Sigma”

Process Capability Report Drop Volume: Mean of 150 Drops

(Specification Limits +/- 3% of Overall Mean)

6.9

4E

6

6.9

6E

6

6.9

8E

6

7E

6 7.0

2E

6

7.0

4E

6

7.0

6E

6

7.0

8E

6

7.1

E6

7.1

2E

6

7.1

4E

6

7.1

6E

6

7.1

8E

6

7.2

E6

7.2

2E

6

7.2

4E

6

7.2

6E

6

7.2

8E

6

7.3

E6

7.3

2E

6

7.3

4E

6

7.3

6E

6

LSL -3.s +3.s USL

0

50

100

150

200

250

300

350

Fre

qu

en

cy

Process Data

LSL 6940000

Target

USL 7370000

Sample Mean 7154736.

Samples 605

Sample N 1

Total N 605

StDev(Within) 735.3406

StDev(Actual) 4384.394

Actual Capability

PPK 16.32577

Lower 95% CL 15.55283

PPL 16.32577

PPU 16.36594

PP 16.34586

Level 48.97731

Capability 49.03758

Potential Capability

CPK 97.34075

CPL 97.34075

CPU 97.58025

CP 97.4605

CPM

Observed Performance

PPM < LSL 0

PPM > USL 0

PPM Total 0

Exp. Within Performance

PPM < LSL 0

PPM > USL 0

PPM Total 0

Exp. Actual Performance

PPM < LSL 0

PPM > USL 0

PPM Total 0

LDT Droplet

N = 606

PpK =16

σ >>6

SixGraph X-bar and S Chart: Content

Uniformity

X-bar: 99.936 (99.936); Sigma: 3.3298 (3.3298); n: 10.

Y2145A67 Y2245A67 2345A67 2445A67 Y2555A6796

97

98

99

100

101

102

103

104

105

96.777

99.936

103.09

Normal Probability Plot

85 90 95 100 105 110 115-4

-3

-2

-1

0

1

2

3

4

0.010.050.150.300.500.700.850.950.99

Std.Dv.: 3.2387 (3.2387); Sigma: .77330 (.77330); n: 10.

Y2145A67 Y2245A67 2345A67 2445A67 Y2555A670.00.51.01.52.02.53.03.54.04.55.05.56.06.5

.91885

3.2387

5.5586

Capability Plot

80 85 90 95 100 105 110 115 120

Spec.Limits

Overall

Within

Individual Plot

Y2145A67 Y2245A67 2345A67 2445A67 Y2555A67828486889092949698

100102104106108110112114116118

LSL

-3.*S (89.4)

+3.*S (110..5)

USL

Capability Histogram

80 82 84 86 88 90 92 94 96 98 100 102104106108 110112 114 116 118

LSL -3.*S Nominal +3.*S USL

0

25

50

75

100

125

150

Within SD: 3.330; Cp: 1.502; Cpk: 1.495Overall SD: 3.519; Pp: 1.421; Ppk: 1.415LSL: 85.00; Nom.: 100.0; USL: 115.0

Conventional Tablet Data

N = 520

PpK =1.4

σ 4.2

115%85%

Droplet Volume Is Measured In Flight for Each Individual Dose Form

In-flight image6 drops/sec.

Dose Position Is Monitored by Near Infra-Red Analytics for Each Dose Form

Red color for illustration purposes only

Tracking and Archiving of Individual Tablet Data Is Possible through the Use of Tablet Transport Elements

Process Has Been Scaled to Phase III Supply / Commercial Launch Scale

• 40-80 K tablets/hour - 1 to 2 million tablets/day; designed for continuous, 3 shift operation

Conclusions

GSK Has Adopted DiffCORETM As a Flexible Delivery Platform

Provides flexibility for delivery across a very wide dose range

– From as low as 1 mg to as high as 2 grams

Provides a wide range of drug release profiles through system design

Allows for delivery combination products, alone or in conjunction with

liquid dispensing technology

– Permutations allow for delivery of 2-4 actives

Fed and fasted state performance is highly-consistent

Thank You