Contract Manufacture

Contract Research

Drug Delivery

Tillotts was founded in the UK in 1963, originally as a distributor for herbal gastric ulcer treatments. Following the launch of Colpermin® capsules and Asacol® tablets in 1981 and 1986 respectively, Tillotts Pharma AG relocated to Switzerland and, in 1999 was the subject of a management buy-out.

In parallel to developing a Gastro-Intestinal (GI) franchise, Tillotts Services was established to provide development and manufacturing expertise specifically in liquid-fill encapsulation using two-piece, hard-shell capsules. In September 2009, Tillotts Pharma AG was acquired by Zeria Pharmaceutical Co., Ltd and is now part of a global and fully-integrated healthcare company.

Tillotts Services was re-launched in October 2010 with the addition of Contract Research Services to its already successful contract manufacturing business.

Capability Overview

Tillotts Services has over 26 years experience in the development and application of new formulation and drug delivery technologies. Our key capability is liquid-fill encapsulation using two-piece, hard-shell capsules and our Swiss-based development and production facility now manufactures over 150 million liquid-filled capsules per annum. So when it comes to choosing an integrated CRO and CMO partner with a strong technology and development capability, Tillotts Services are a safe and reliable choice.

From the largest to the smallest, our customers include many of the world’s leading pharmaceutical, biotechnology and virtual drug discovery companies. Our customers typically require us to solve the most difficult challenges in formulation design and manufacture; this has enabled us to develop a unique skill set and problem-solving approach.

Tillotts Pharma AG is a subsidiary of Zeria Pharmaceutical Co., Ltd, a leading Japanese pharmaceutical company. Being part of a Global and secure organisation is a key requirements for many of our customers when choosing a CRO/CMO partner.

Our History

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Our fully integrated formulation development, clinical supply services and commercial scale manufacturing capabilities (Figure 1) are supported by well equipped and well staffed Analytical Chemistry, QA and QC departments.

Our exclusive focus on liquid-fill encapsulation means that we are continuously building upon our 26 years expertise in this growing oral dosage form covering:

Excipient Screening and Formulation Development• – for poorly soluble API’s, drugs requiring specific release profiles and developing new intellectual property for life-cycle extension.Coating technologies and equipment• - for targeted delivery within the GI tract.Niche areas• – combination approaches, anti-counterfeit and anti-abuse applications.Challenging Applications• – biologicals, bacteria (e.g. probiotics), high potency molecules and API’s that are air or moisture sensitive.

Figure 1. Tillotts Services integrated CRO/CMO Capabilities

Contract Research

Contract Manufacturing

Packaging

ProcessDevelopment

Pre-formulationDevelopment

Logistics

ProcessValidation

ProjectManagement

FormulationDevelopment

Clinical Supply(Phase I to IV)

Analytical Chemistry,QC, QA, QP &

Regulatory Support

Having established ourselves as the global leaders in liquid-fill encapsulation, this capability is now supported with enabling technologies covering; pre-formulation and formulation development, enteric coating and drug delivery technologies.

Contract Research Services

Formulation Development

An increasing number of NCE’s coming through drug pipelines exhibit poor solubility and consequently show poor oral absorption and bioavailability (e.g. BSC Class II molecules). To help solve this challenge we offer customer two screening and development tools.

Our ExcipBaseTM and ExcipScreenTM innovations are pioneering developments in formulation screening and provide a quicker and cheaper route to a viable, first-in-man, or a commercial scale, formulation.

ExcipBaseTM is our proprietary in-house database that contains historical excipient-API formulation data compiled from our own in-house screening programmes. This information is complemented by the inclusion of academic and published data that is mapped for structural compound types. ExcipBaseTM allows us to quickly assess historical positive and negative data that facilitates the selection of the most suitable excipients for a more detailed formulation screen.

ExcipScreenTM is our new, excipient formulation screening service available to our customers that allows the rapid identification of a formulation prototype. Using similar technology and strategy to high throughput solubility screening, this innovation allows valuable time and costs to be saved through efficiencies in automation. We can offer customers a wide selection of known and novel excipients within such an excipient-API compatibility screen, as well as multiple excipient combinations with a subsequent secondary screen.

The integration of these resources, together with our formulation development and manufacturing capabilities, benefits our customers through reducing costs and development times.

As a “one-stop-shop” for API characterization, pre-formulation and formulation development, our integrated services business can supply drug product throughout clinical development to commercial manufacture and mature market supply.

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Our Phased Approach to formulation design and clinical supply

We have an established track record on working with a variety of customers within early clinical development on products which typically involves building a formulation strategy based on the available API data (Figure 2).

Through our co-operation with Solid Form Solutions Limited, we are able to help customers with respect to solid state characterisation (Figure 3). Our ExcipBaseTM and ExcipScreenTM innovations aid in the identification of prototype formulations from which we can construct phase diagrams and identify the most appropriate formulation. Subsequent characterisation and in vitro testing through the application of simulated GI environments can help us support our customers in more closely predicting the in vivo behaviour of the formulation.

As an integrated CRO and CMO, we recognise that our resources have to be aligned with the needs of our customers. Our client-centric project managers have all worked with the international pharmaceutical industry and provide a “single point of contact” for our customers.

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Figure 2. Tillotts Services Milestone-based approach to formulation development and scale-up

Figure 3. Tillotts Services & Solid Form Solutions Integrated CRO Capabilities

API Data

• Dose • Chem. structure • Solubility • Permeability • Log P/Log D • Crystallinity • Polymorphism • Oral Bioavailability • Metabolism • P-gp efflux • Stability • Storage conditions • Analytical data

Pre-formulation

• Excipient selection • API solubility in

excipients • Preliminary API

stability in excip

FormulationPerformance

• In vitro tests • Dilution • Lipolysis • “Absorption

(Papp, efflux, Caco-2)”

• In Vivo PK tests

Scale up andProduction

• Batches • Feasibility • Stability • Scale up • Clinical • Industrial

Formulation

• Select the best excipient(s) based on phase diagrams

• One Excipient • Binary Systems • Ternary Systems

• Select the best formulation(s)

Late Discovery Pre-clinical Clinical Commercialisation

Solid-State Optimisation& API Characterisation

Formulation Development& Clinical Supply

Commercial Drug Product Supply& Life-Cycle Extension Innovation

GMP Clinical Supply

Tillotts Services can supply customers with drug product from Phase I through to Phase IV clinical studies from our GMP development and production facility. We can tailor collaborative programmes to include ICH stability testing and any aspect of API or formulation characterisation and optimisation. We have a well resourced analytical chemistry department and QA and QC functions with “single point of contact” project management. The application of our technologies and expertise in drug delivery and clinical supply can help transform your NCE into a registered drug product.

Quality and Security

Quality and attention to detail are part of our Swiss culture. Our facilities are fully GMP compliant and we are routinely inspected by Swissmedic and audited by our customers.

Project Management

From experience, we know that our customers rely on us to meet development and production milestones on time. We operate a “single point of contact” project management system and assign experienced technical project managers to our development projects, while for commercial manufacturing these are managed within our logistics group.

Our customers routinely come on-site to monitor key experiments or production campaigns and we encourage a close working relationship with our project management, development and production staff. Effective planning and communication is built into our customer services approach.

Analytical Development and Quality Control

Our two dedicated analytical groups thrive on new challenges and our capabilities range from method development and validation to ICH stability and release testing. We have been successful in recruiting experienced staff from small and large CRO’s and pharmaceutical companies within the Basel region. Innovative thinking is combined with reliability and on-time delivery. Our client-centric approach involves open and prompt communication with our customers.

We have recently expanded our analytical development capabilities with new state-of-the-art facilities and recruiting more highly experienced staff, we add to our expertise through being continually challenged to solve the most difficult problems in formulation design and analytical development.

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Our analytical equipment includes;

• Agilent HPLC’s - 1200 series

• UHPLC 1290 infinity

• GC 7890A

• Büchi NIR

• Sotax and Erweka dissolution and disintegration testers

• Binder stability chambers

Contract Manufacturing Services

During the last 26 years, Tillotts Services has established itself as the world leader in liquid-fill encapsulation that is underpinned by the manufacture of global products including Colpermin®, Mebeverine, and other proprietary customer products. We have been instrumental in the development and application of liquid-fill encapsulation and now apply this expertise in combination with our contract research services offerings. We can now offer our customers a “one-stop shop” for all their liquid-fill formulation development and drug product supply needs.

Our GMP production facility, near Basel in Switzerland has two commercial-scale liquid-filling and sealing lines each with a capacity of 50,000 capsules/hour.

• Filling: Bosch GKF 1500L

• Sealing (banding): Shionogi S100

• >150 million liquid-filled capsules manufactured in 2011

• Capacity of >300 million capsules per annum

We also have a range of development scale equipment including a recently purchased FLUIDOCAP 1000 liquid and semi-solid filling machine from ACG Pam Pharma Technologies Pvt Ltd.

The key benefit of liquid-fill encapsulation is the ease at which commercial scale production can be effected from the development laboratory. Typically, when key parameters such as viscosity can be defined then the production of commercial volumes at a high filling speed (>30,000 capsules/h) is possible within days rather than weeks. Effort is then focused on in-process controls and further optimisation of filling speeds up to 50,000 capsules/h that can be achieved with many products.

We are able to fill a wide range of capsule sizes and volumes for both gelatine and HPMC capsules and from established suppliers such as Capsugel, Qualicaps or ACG. Capsule coating is also available for enteric or specific controlled release profiles. Tillotts Services has two automatic packing lines for blistering and packaging (including labelling). Our experienced logistics team is able to work with customers on complex supply requirements in order to achieve economies of scale and operate continuous product improvement cycles.

With over 26 years experience in commercial scale liquid-fill encapsulation we have built an unrivalled capability. Now with the introduction of contract research services and an expanded analytical chemistry group, we can now offer customers a “one-stop shop” for their liquid-fill needs.

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Liquid-fillencapsulation–Keybenefits

Liquid-fill encapsulation is becoming an increasingly used vehicle for oral drug delivery, especially for molecules that exhibit poor aqueous solubility or are highly potent. Tillotts Services has experience of filling a variety of different liquids and semi-solids into two-piece, hard-shell capsules. For liquids with a viscosity not lower than 15 mPa/s these can be filled into hard gelatine capsules which are then sealed within a few seconds. This prevents leaking and the visible band acts as a tamper-proof mechanism.

For paste (semi-liquid) formulations, there are two different approaches that we commonly use;

• Thixotropic formulation (in quiescent conditions the substance is solid and becomes a liquid when stirred); this can be achieved with a mixture of a liquid and thickening agent.

• Thermoplastic formulation (substance is liquid when heated and solidifies again at room temperature). Thermoresistent solid substances can be heated up to 75°C for liquid-filling and then cooled to room temperature.

Liquid-fill encapsulation using hard gelatine capsules has several benefits over soft gelatine capsules as summarised below:

Understanding the development needs and demanding timeframes of our customers has enabled us to build a responsive and customer-centric business. Tillotts Services can help transform your NCE into a registered drug product.

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Advantages of hard gelatine capsules over soft gelatine capsules

Require 4-5 times more gelatine than the hard gelatine capsules

Require addition of glycerin for softening purposes

Have to be sealed immediately after filling one substance (filling and sealing are one and the same process)

Filling temperature limited to about 35°C: filling of solid substances with higher melting points impossible

Tend to stick together and become gluey

Will disintegrate slower due to the thickness of its gelatine/glycerin wall

Glycerin acts as a plasticiser by disrupting the gelatine structure - consequently, higher diffusion into and through the walls

Dimensions vary according to filling weight and vary throughout a batch

Contain 4-5 times less gelatine than soft gelatine capsules

Require no other additives.Consists of water and gelatine only

Allow step-by-step filling of 2 differentformulations (i.e. 2-stage-release)

Heat resistant: allow filling of thermo-stable substances up to 75°C

Are stable in hot climates

Will disintegrate faster due to the capsule wall being five times thinner

than the walls of soft gelatine capsules

Less product migration into the shell, less diffusion of odours

Constant external dimensions(easier blistering/packaging)

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Copyright © Tillotts Pharma AG 2012

Tillotts Pharma AGTillotts ServicesHauptstrasse 274417 ZiefenSwitzerland

T: +41 61 935 28 28F: +41 61 935 28 29E: Services@tillotts.com

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