AAV needed?

GTCA – Gene Therapy Center AustriaCovering all steps from vector to product Co-located in the Vienna area

GTCA is now part of TakedaGTCA is now part of Takeda

AAV is the Vehicle of ChoiceGlobal development & manufacturing capacities are limited.

GTCA Process DevelopmentExtensive & scalable process development capabilities.

LONG-STANDING EXPERIENCE in early & late stage process development along with profound commercializati on experti se. We have proven capabiliti es for diff erent AAV subtypes and off er extended process and assay development packages to characterize processes and products – which is reducing the need for additi onal clinical studies to demonstrate comparability.

Cell line development 15 mL – 200 L upstream & downstream purifi cati on platf orm

Proprietary full AAV enrichment by large scale ultracentrifugati on

Formulati on buff er development

Preclinical pilot scale (200 L) Seamless scale up & techtransfer to manufacturing

ProcessDevelopment

GTCA Analytics & Quality ControlBroad analytical portfolio with +50 assays for GTCA AAV platform.

CUSTOMIZED TO YOUR NEEDS. We have strong experti se in the development and robust performance of immunoassays, in vitro assays, sterility testi ng and diff erent PCR methods. The majority of our test methods is established in-house to de-risk product release. Our portf olio covers standard tests as well as more specialized assays for extended product characterizati on e.g. ddPCR, cryoTEM and AUC. Release testi ng is performed in highly regulated Quality Control labs (GMP certi fi ed, FDA approved).

Analyti cs

AAV parti cle characterizati onAAV vector quanti fi cati on Process related impuriti es testi ng

AAV vector characterizati onProduct related impuriti es/ safety testi ng

200 nm

5x10

0

0.25

0.5

0.75

11.25

1.5

1.75

2

2.25

2.5

2.75

3

3.253.5

3.75

4

4.25

4.5

4.75

5

5.25

5.55.75

6

6.25

6.5

6.75

7

Counts vs. Acquisition Time (min)3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8

In 2018, there are over 300 preclinical & clinical candidates under evaluati on, more than 1/3 build on AAV.1

SOURCES 1 Gene Therapy Market 2018-2030,

Root Analysis Report (2018).2 Smith, DC. (2017). AAV vector

manufacturing-Challenges & opportuniti es in the manufacturing of AAV vectors used in the delivery of gene therapy treatments. Drug Development and Delivery. 17.

3 Statement from FDA Commissioner Scott Gott lieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluati on and Research on new policies to advance development of safe and eff ecti ve cell and gene therapies. FDA Statement, 15 Jan. 2019. htt ps://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm629493.htm

4 Wechsler J. (Sep 2018). FDA Seeks to Enhance Manufacturing of Cell and Gene Therapies. BioPharm Internati onal, 01 Sept.

5 Wechsler J. (Nov 2018). Manufacturing Challenges Limit Gene Therapy Development. BioPharm Internati onal, 16 Nov.

6 Kolata, G. (2017). Gene Therapy Hits a Peculiar. Roadblock: A Virus Shortage, New York Times, 27 Nov.

“ … majority (74 %) of AAV-based therapeuti c products are in early to mid-phase clinical development …” 2

“ We anti cipate that by 2020 we will be receiving more than 200 INDs per year, building upon our total of more than 800 acti ve cell-based or directly administered gene therapy INDs currently on fi le with the FDA.” 3

“ … by 2025, we predict that the FDA will be approving 10 to 20 cell and gene therapy products a year …” 3

“ There remains a clear need for improved process producti viti es, and the need to develop manufacturing processes that can be applied to a wide number of AAV-based viral vector therapeuti c candidates.” 2

“ FDA further outlined in new guidance issued in July 2018 (…) how manufacturers should provide suffi cient CMC informati on to assure the safety, identi ty, quality, purity, and strength/potency of investi gati onal gene therapies.” 4

“ … FDA oft en is “very lenient” about companies meeti ng manufacturing standards for testi ng gene therapies in Phase I trials. But scaling up to larger producti on for further studies is diffi cult and can delay product development for years.” 5

“ Few gene-therapy companies have the factories or experti se to make the viruses for use in clinical trials, where standards are exacti ng and comprehensive. The fi rms that can do it are swamped with orders and requests.” 6

GTCA ManufacturingcGMP manufacturing for clinical & commercial supply.

LONG TRACK RECORD of being EMA & FDA compliant for global supply. We progress clinical development to commercial producti on without signifi cant process changes in one modular plant – which is de-risking and accelerati ng phase III supply and launch. A robust and mature quality management system with fl exibility to cover cGMP manufacturing from early clinical development up to commercial producti on is in place.

Drug ProductIsolator Drug Product

Inoculum Preparati on

Ultra-Diafi ltrati on

Upstream – 200 L SUB, 2 x 500 L SUB

Ultracentrifugati on

Harvest

Chromatography

Manufacturing

– Access control at each building entrance & personnel/material locks

– Inoculum area – Upstream area (Single-use bioreactors

2 x 50 L / 200 L / 2 x 500 L, cell disrupti on, harvest fi ltrati on, ultra-diafi ltrati on)

– 3 segregated downstream areas (ultra-diafi ltrati on, ultracentrifugati on, chromatography)

– Dedicated AHU for each area

FORMULATION, FILLING, FINISHING

– Asepti c area for clinical fi lling– Approved by major authoriti es like FDA

and EMA – Scale of up to 5 L per fi ll using semi-

automated method– Able to accommodate a variety of

container/closure systems – Stable liquid & lyophilized formulati ons for

a broad range of indicati ons– Highly experienced staff in asepti c

formulati on & fi lling for clinical and commercial products

Fully dedicated state-of-the-art AAV cGMP manufacturing plant: 22,000 ft2 effective area6,560 ft2 classifi ed area

GTCA The Partner of Choice for AAV

Choosing GTCA

GENE THERAPY CENTER AUSTRIATakedaUferstraße 15 | A-2304 Orth an der Donau | AustriaPlease contact: GTCA@takeda.com gtcaustria.com

ProcessDevelopment ManufacturingAnalytics

The team has 30+ years’ experience in late stage development as well as commercialization expertise in

the vaccines and recombinant biologics business and is your innovative partner for high-quality AAV solutions.

Our proprietary suspension-based platform process is applicable for all AAV subtypes. Extensive &

scalable AAV process development capabilities allow a tailored approach for your product.

From viral vector to cGMP manufacturing: All teams are co-located on the Gene

Therapy Campus near Vienna | Austria.

cGMP manufacturing for clinical and commercial supply at a scale of 200 L & 2 x 500 L. 40+ AAV cGMP lots have been

manufactured for global clinical supply.

Your partner for Ph III and commercial

supply

One-Stop-Shop

One platform All AAVs

Broad analytical in-house portfolio500 L cGMP

manufacturing scale

Established relationship with

FDA & EMA We have established a broad analytical portfolio for our AAV

platform (50+ methods) with the majority being performed

in-house.

A robust and mature quality management system with flexibility to cover cGMP

manufacturing from early clinical development up to commercial

production is in place and the plant has a long GMP inspection track

record including major authorities.