GSK s Development of Novel Oral Delivery Technologies Perspectives

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1 GSK s Development of Novel Oral Delivery Technologies Perspectives Mark Wilson Director, PTS, R&D GlaxoSmithKline Pharmaceuticals

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

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

4 GSK s Initial Approach Was To Create a Few, Deep Partnerships Partner A Company A Partner B

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

5 GSK Moved To a Networked Approach: Multiple External Technology Inputs Into GSK Lead to External Outputs Over Time External External External External External External External GSK: Internal Developmennt GSK: Scale-Up and Commercialisation GSK: Marketed Products External External External External External External Multiple external interactions: GSK receives and provides technologies External

6 GSK Developed a Novel Approach to Controlled- Release Formulation

7 DiffCORE TM Is A Robust and Proven Controlled-Release Tablet Technology for Single Actives and Combination Products

DiffCORE TM Delivers Drug from a Core through Apertures in a Functional Barrier Coating A GSK proprietary modified release drug delivery technology Several forms

8 DiffCORE TM 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

9 The Use of Enteric Coats and Bilayer Tablet Elements Provides a Wide Variety of Release Profiles Insoluble Coat Enteric Coat MR + IR Bilayer Tablet + Enteric Coat Further Variants Patents Have Been Filed for Several Technology Variants

Enteric Delivery Oral Dosage Form For Controlled Release Chi

10 Aperture Diameter, Tablet Properties and Coat Type Determine Release Profile DiffCORE Provides for Sustained Gastric and Enteric Delivery Oral Dosage Form For Controlled Release Chi Li, Gino Martini, Vin Re & Helen Willy Filed Feb , PCT/GB03/00594

11 DiffCORE TM 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.

12 DiffCORE TM Controls Release by Using a Precisely- Sized Aperture in the Tablet Coat The Aperture Size Determines the Release Profile

13 DiffCORE s Performance Characteristics - e.g. the Effect of Aperture Size - Have Been Clinically-Proven The Platform Is Validated Clinically on Multiple Compounds

14 DiffCORE TM 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

15 DiffCORE TM Has Become the Standard In-House Approach to Controlled Release within GSK

DiffCORE TM 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

16 DiffCORE TM 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

17 DiffCORE TM Pilot Units Replicate All Critical Full-Scale Processes

The DiffCORE TM Aperture Formation Process Required Extensive Development The aperture is critical to formulation performance Many technologies were tested Vendor evaluation

18 The DiffCORE TM 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

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

20 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 DiffCORE TM tablets.

DiffCORET TM 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

21 DiffCORET TM 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).

22 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.

23 The DiffCORE TM Technology Is Used To Manufacture Lamictal XR at GSK s Zebulon Site in North Carolina

24 GSK Developed Several Technologies for In-House Use, Some of Which Can Be Combined with DiffCORE TM Liquid Dispensing Technology: Shirt- Sleeve Manufacturing for Potent Drugs, with Extremely-High Accuracy

25 Liquid Dispensing Technology: Shirt-Sleeve Manufacturing of Low-Dose and Potent Actives Drug Solution/ Suspension + Placebo Tablets Liquid Dispensing Drying On-Line Imaging On-line Coating & Printing (Commercial Only) Droplet Volume Measurement NIR Imaging of Deposition 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

26 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 & and POLYMER Polymer LAYER Layer Overcoat Applied By Pad Tamping Process Carrier Tablet Film Coat BICONCAVE CARRIER TABLET CORE

27 Frequency 7.3E6 7.2E6 7.1E6 7E6 7.36E6 7.34E6 7.32E6 7.28E6 7.26E6 7.24E6 7.22E6 7.18E6 7.16E6 7.14E6 7.12E6 7.08E6 7.06E6 7.04E6 7.02E6 6.98E6 6.96E6 6.94E6 Overall Spec. Limits Process Provides Less Variation than Tablet Manufacturing: Much Better than Six-Sigma Capability Histogram.5) LSL -3.*S Nominal +3.*S USL Conventional Tablet Data N = 520 PpK =1.4 σ % Process Capability Report Drop Volume: Mean of 150 Drops (Specification Limits +/- 3% of Overall Mean) LSL -3.s +3.s USL 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 0 115% Process Data LSL Target USL Sample Mean Samples 605 Sample N 1 Total N 605 StDev(Within) StDev(Actual) Actual Capability PPK Lower 95% CL PPL PPU PP Level Capability Potential Capability CPK CPL CPU CP CPM LDT Droplet N = 606 PpK =16 σ >>6

28 Droplet Volume Is Measured In Flight for Each Individual Dose Form In-flight image 6 drops/sec.

29 Dose Position Is Monitored by Near Infra-Red Analytics for Each Dose Form Red color for illustration purposes only

30 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

31 Process Has Been Scaled to Phase III Supply / Commercial Launch Scale K tablets/hour - 1 to 2 million tablets/day; designed for continuous, 3 shift operation

32 Conclusions

GSK Has Adopted DiffCORE TM 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

33 GSK Has Adopted DiffCORE TM 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

34 Thank You

Association. Innovation in Medicines PDA: A Global. and Manufacturing. David Tainsh, GSK Keith Pugh, MHRA

Association. Innovation in Medicines PDA: A Global. and Manufacturing. David Tainsh, GSK Keith Pugh, MHRA Innovation in Medicines PDA: A Global and Manufacturing Association David Tainsh, GSK Keith Pugh, MHRA Joint Regulators/Industry QbD Workshop 28-29 January 2014 London, UK Introduction Current State We