9th June 2011

APS Biopharmaceutics Focus Group Meeting.

To be held at the Merck Sharp & Dome Innovation Centre, Hoddesdon, UK.

For more information please visit:www.apsgb.co.uk/Events/20110609

31st August – 2nd September 2011

The Science of Medicines

To be held at the East Midlands Conference Centre, University Park, Nottingham, UK.

For further details and online registration please visit:www.ukpharmsci.org

25th – 27th October 2011

Chemical and Pharmaceutical Intermediates (CPhI) exhibition.

To be held at the Messe, Frankfurt, Germany.

For more information please visit:www.cphi.com/home

www.tillotts.com

We were delighted with the response to our first Tillotts Services quarterly newsletter. In this second issue we report on our continued expansion, conference attendance and an informative “Focus on Technology” article.

In May we completed the refurbishment of our Ziefen liquid-fill development and manufacturing site with a new reception area and the addition of new branding livery to the exterior of our main building. Our new reception now provides a more comfortable area for our visitors with additional access to an office and WiFi. We continue to invest in the expansion of our development and manufacturing facilities in order to accommodate the needs of our customers and the increasing trend in outsourcing R&D to specialist companies such as Tillotts Services.

Production Facility ExpansionAs part of our continued expansion, we have recently increased the footprint within our production area with minimal disruption by attaching a new building for material storage and material lock from our current warehouse ramp. Our new material lock now has a capacity of 12 pallets per locking cycle. In addition, an intermediate storage space for 15 pallets is available for incoming and outgoing goods and so increasing our efficiency. Both rooms are qualified as clean rooms with an independent air ventilation system. Locking duration is now optimised to around 20 minutes and has been operational for the last 6 weeks.

Issue 2

Ziefen Site Refurbishment

NEWSLETTER

Acknowledgements: Design by David Anthony, AK Design (Scotland) Ltd.

For more information, please contact us at:

Q: So Thomas, please tell us a little about you?

A: I grew up in Basel and live now in Bubendorf (next village to Ziefen). I am married and we have 3 children. In my free time I spend a lot of time in my lovely garden, hike, participate on sailing regattas and make handicraft work in my small workshop. In winter I go skiing.

Q: When did you join Tillotts and what is your role?

A: I joined the company in 1985 and I am responsible for the Engineering department. We maintain all of the technical installations at our facility in Ziefen and also in our new Pharma R&D facilities in Rheinfelden. Our key focus is to avoid any technical breakdown so we keep a very close eye on everything. In line with our expansion, we also procure new machines and equipment, plan the construction of new buildings and/or modifications which is very exciting!

Q: What was the biggest challenge for you at Tillotts?

A: My continuous challenge is to ensure that we meet our deadlines within all the projects in which we are involved and we have been successful in this respect.

Q: Of which project are you most proud?

A: The expansion of the Ziefen product development and manufacturing facility was a very proud moment. I am sure there will be more to come as we continue our expansion!

Q: What will be your next bigger challenge at Tillotts?

A: We are currently undertaking the procurement of an automatic bottle filling line for enema production that will come on stream at the beginning of 2012. Also, the implementation of our plans for the new high potent suite for the handling of highly active compounds is a new and exciting challenge.

In the first issue of our Newsletter we interviewed Kanda Nägelin: “Who is behind our new brand”. For this issue Claudio Scialdone interviews Thomas Kaiser who is managing our Engineering Department.

ww

w.tillotts.com T: +41 61 935 28 28

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

Tillotts Pharma AGTillotts ServicesHauptstrasse 274417 ZiefenSwitzerland

Tillotts Services will be represented at the following events during 2011. We would be delighted to meet with you.

Let’s Have Coffee..

Going to CPhI (Messe, Frankfurt) in October? Registration is free

(http://www.cphi.com/visitors) and Frankfurt is an excellent venue for what is a mammoth show with previous visitors from over 125 countries.Tillotts Services will be located at Exhibition Stand 41F67 in Hall 4.1

so please come and visit us.

Out and about

Copyright © Tillotts Pharma AG 2011 www.tillotts.com

During the last quarter we have attended several drug delivery and formulation development conferences and had the opportunity to meet many representatives from the pharmaceutical and biotechnology industries.

Focus on TechnologyWithin this section we aim to profile a technology area related to our business.

In this section we focus on the application of Dynamic Light Scattering (DLS) which Tillotts Services uses in their formulation development programs for the characterization of lipid-based self dispersing formulations. We routinely apply lipid-based Self Micro- and Nano- Emulsifying Drug Delivery Systems (SMEDDS and SNEDDS) in order to improve aqueous drug solubility and therefore the oral bioavailability of poorly soluble molecules.

Typically, after the dilution of a self dispersing formulation in the gastrointestinal tract (i.e. in-vivo) this leads to the formation of small lipid droplets where the active molecule is dissolved, resulting in improved oral bioavailability. The particle size of the resulting micro- and/ or nano-emulsions is often in the range between 10 to 200 nm and should remain thermodynamically stable independently of the extent of aqueous dilution investigated. In this range, the state of the mixture and the particle size of the small droplets should not change after high aqueous dilutions of the formulation. Generally, the evaluation of these self dispersing systems is commonly conducted by visual observations of the resulting formulations after sequential aqueous dilutions. However, at Tillotts Services we also investigate the actual particle size of the small lipid droplets using the DLS technology.

DLS or photon correlation spectroscopy (PCS) is a spectroscopic method that allows determining the distribution of particle size of aggregates in

solution and/ or colloidal systems in the submicron range. The range of measurement covered by this technology is generally between 1 to 6000 nm. Therefore, it can be applied for the characterization of micro and nano emulsion formulations. DLS correlates the distribution of particle size of colloidal formulations with the frequency changes in intensity of backscattered light produced by the particles (small oily droplets). The concept of this method is that the small droplets are randomly moving in solution (Brownian motion) and the distance between them is constantly varying. Shining a monochromatic light beam, such as a laser, onto a solution with spherical particles in Brownian motion causes a Doppler Shift when the light hits the moving particle, changing the wavelength of the incoming light. This change is related to the size of the particle. By knowing the incident light frequency and measuring the scattered light frequency in function of the time it is possible via the Stoke Einstein equation to calculate the particle size distribution and their diameter [I].

In May we attended and presented a paper at the Delivering a Potent and High Potent Manufacturing Strategy conference in Munich, organized by NextLevel Pharma.

The Conference provided an excellent forum in terms of discussing current issues in high potent API and secondary drug manufacture. A key presentation from Dr. Walter Spieler, Head of Occupational Hygiene at F. Hoffmann-La Roche Ltd, Basel, Switzerland focused on the challenges in determining Occupational Exposure Limits (OELs) for pre-clinical development candidates in addition to highlighting key developments in occupational hygiene, safety and process control.

Dr. Spieler highlighted the various and conflicting systems that are currently used to categorise highly potent molecules and the audience debated the need for harmonisation of these systems which would ensure more consistency.

Within Roche, a compound with an OEL of < 10 mcgr/m3 or 10 mcgr/m3 with additional carcinogenic or mutagenic properties is classified as a highly active substance (HAS). Being an experienced

occupational hygienist, Dr. Spieler cited dose as being the key consideration as opposed to the class of molecule (i.e. cytotoxic versus hormone). It was clear from this presentation that Roche have invested considerable resources into developing a safe working environment for their employees and use state of the art containment equipment within newly designed high containment facilities. The new versatile laminar flow isolators offered by SafeTech were presented along with disposable systems.

Dr David Elder from GSK’s Pre-Clinical Development gave an informative presentation entitled, “Eliminating Problems before they Exist: Using screening to Impact on Formulation Development: A Holistic Perspective“. David highlighted the issues with Biopharmaceutical Classification System (BCS) Class II drugs:

>40% of newly discovered drugs have little or no water solubility

If the NCE is not available in solution at the site of action, it is not a viable development candidate.

>90% of drugs approved since 1995 have poor solubility, poor permeability, or both. Approximately 16% have less than optimal performance due to poor aqueous solubility.

GSK’s approach to address these challenges involves early formulation testing in which they utilise an in-silico approach and predictability modelling.

In April we attended the Global Pre-formulation and Formulation Summit in Amsterdam that was organised by IQPC Ltd. Several excellent presentations highlighted some of the key challenges faced in early development and provided the basis for debate during the panel discussions. We highlight one of the presentations from this event;

This is complemented by early formulation screening using a 96-well plate system in which scarce API can be better managed and provides some key benefits:

David also addressed the current debate concerning forced degradation in relation to the ICH requirement Q1A(R2); Method validation, intrinsic stability and presented GSK’s “decision tree” for managing this aspect of drug development. In conclusion, David summarised that in-silico approaches to formulation design, excipient compatibility and degradation assessment can facilitate rapid and cost effective early development. However this predictive tool must not be over-interpreted and backed up by real/accelerated data.

This approach allows rapid identification of excipient, excipient mixtures and loading levels which generate the highest and most stable kinetic solubility on dilution (issue of in vitro/in vivo precipitation).

Good correlation between maximum solubility and equilibrium solubility.

I Constantinides P., Hiv S.H. Particle size determination of phase-inverted water-in-oil microemulsions under different dilution and storage conditions. International Journal of Pharmaceutics. 1995; 115: 225-234.II http://www.lab.hii.horiba.com/page/php?id=674 (25.06.2007)

Figure 1 represents the basic principle for the determination of particle size using DLS.

This method has some key advantages: A short experiment duration Automation allows for routine measurements and cost savings Extensive experience is not required in terms of operation

Fig. 1 General configuration of a DLS apparatus for the determination of particle size [II]

Out and about

Copyright © Tillotts Pharma AG 2011 www.tillotts.com

During the last quarter we have attended several drug delivery and formulation development conferences and had the opportunity to meet many representatives from the pharmaceutical and biotechnology industries.

Focus on TechnologyWithin this section we aim to profile a technology area related to our business.

In this section we focus on the application of Dynamic Light Scattering (DLS) which Tillotts Services uses in their formulation development programs for the characterization of lipid-based self dispersing formulations. We routinely apply lipid-based Self Micro- and Nano- Emulsifying Drug Delivery Systems (SMEDDS and SNEDDS) in order to improve aqueous drug solubility and therefore the oral bioavailability of poorly soluble molecules.

Typically, after the dilution of a self dispersing formulation in the gastrointestinal tract (i.e. in-vivo) this leads to the formation of small lipid droplets where the active molecule is dissolved, resulting in improved oral bioavailability. The particle size of the resulting micro- and/ or nano-emulsions is often in the range between 10 to 200 nm and should remain thermodynamically stable independently of the extent of aqueous dilution investigated. In this range, the state of the mixture and the particle size of the small droplets should not change after high aqueous dilutions of the formulation. Generally, the evaluation of these self dispersing systems is commonly conducted by visual observations of the resulting formulations after sequential aqueous dilutions. However, at Tillotts Services we also investigate the actual particle size of the small lipid droplets using the DLS technology.

DLS or photon correlation spectroscopy (PCS) is a spectroscopic method that allows determining the distribution of particle size of aggregates in

solution and/ or colloidal systems in the submicron range. The range of measurement covered by this technology is generally between 1 to 6000 nm. Therefore, it can be applied for the characterization of micro and nano emulsion formulations. DLS correlates the distribution of particle size of colloidal formulations with the frequency changes in intensity of backscattered light produced by the particles (small oily droplets). The concept of this method is that the small droplets are randomly moving in solution (Brownian motion) and the distance between them is constantly varying. Shining a monochromatic light beam, such as a laser, onto a solution with spherical particles in Brownian motion causes a Doppler Shift when the light hits the moving particle, changing the wavelength of the incoming light. This change is related to the size of the particle. By knowing the incident light frequency and measuring the scattered light frequency in function of the time it is possible via the Stoke Einstein equation to calculate the particle size distribution and their diameter [I].

In May we attended and presented a paper at the Delivering a Potent and High Potent Manufacturing Strategy conference in Munich, organized by NextLevel Pharma.

The Conference provided an excellent forum in terms of discussing current issues in high potent API and secondary drug manufacture. A key presentation from Dr. Walter Spieler, Head of Occupational Hygiene at F. Hoffmann-La Roche Ltd, Basel, Switzerland focused on the challenges in determining Occupational Exposure Limits (OELs) for pre-clinical development candidates in addition to highlighting key developments in occupational hygiene, safety and process control.

Dr. Spieler highlighted the various and conflicting systems that are currently used to categorise highly potent molecules and the audience debated the need for harmonisation of these systems which would ensure more consistency.

Within Roche, a compound with an OEL of < 10 mcgr/m3 or 10 mcgr/m3 with additional carcinogenic or mutagenic properties is classified as a highly active substance (HAS). Being an experienced

occupational hygienist, Dr. Spieler cited dose as being the key consideration as opposed to the class of molecule (i.e. cytotoxic versus hormone). It was clear from this presentation that Roche have invested considerable resources into developing a safe working environment for their employees and use state of the art containment equipment within newly designed high containment facilities. The new versatile laminar flow isolators offered by SafeTech were presented along with disposable systems.

Dr David Elder from GSK’s Pre-Clinical Development gave an informative presentation entitled, “Eliminating Problems before they Exist: Using screening to Impact on Formulation Development: A Holistic Perspective“. David highlighted the issues with Biopharmaceutical Classification System (BCS) Class II drugs:

>40% of newly discovered drugs have little or no water solubility

If the NCE is not available in solution at the site of action, it is not a viable development candidate.

>90% of drugs approved since 1995 have poor solubility, poor permeability, or both. Approximately 16% have less than optimal performance due to poor aqueous solubility.

GSK’s approach to address these challenges involves early formulation testing in which they utilise an in-silico approach and predictability modelling.

In April we attended the Global Pre-formulation and Formulation Summit in Amsterdam that was organised by IQPC Ltd. Several excellent presentations highlighted some of the key challenges faced in early development and provided the basis for debate during the panel discussions. We highlight one of the presentations from this event;

This is complemented by early formulation screening using a 96-well plate system in which scarce API can be better managed and provides some key benefits:

David also addressed the current debate concerning forced degradation in relation to the ICH requirement Q1A(R2); Method validation, intrinsic stability and presented GSK’s “decision tree” for managing this aspect of drug development. In conclusion, David summarised that in-silico approaches to formulation design, excipient compatibility and degradation assessment can facilitate rapid and cost effective early development. However this predictive tool must not be over-interpreted and backed up by real/accelerated data.

This approach allows rapid identification of excipient, excipient mixtures and loading levels which generate the highest and most stable kinetic solubility on dilution (issue of in vitro/in vivo precipitation).

Good correlation between maximum solubility and equilibrium solubility.

I Constantinides P., Hiv S.H. Particle size determination of phase-inverted water-in-oil microemulsions under different dilution and storage conditions. International Journal of Pharmaceutics. 1995; 115: 225-234.II http://www.lab.hii.horiba.com/page/php?id=674 (25.06.2007)

Figure 1 represents the basic principle for the determination of particle size using DLS.

This method has some key advantages: A short experiment duration Automation allows for routine measurements and cost savings Extensive experience is not required in terms of operation

Fig. 1 General configuration of a DLS apparatus for the determination of particle size [II]

9th June 2011

APS Biopharmaceutics Focus Group Meeting.

To be held at the Merck Sharp & Dome Innovation Centre, Hoddesdon, UK.

For more information please visit:www.apsgb.co.uk/Events/20110609

31st August – 2nd September 2011

The Science of Medicines

To be held at the East Midlands Conference Centre, University Park, Nottingham, UK.

For further details and online registration please visit:www.ukpharmsci.org

25th – 27th October 2011

Chemical and Pharmaceutical Intermediates (CPhI) exhibition.

To be held at the Messe, Frankfurt, Germany.

For more information please visit:www.cphi.com/home

www.tillotts.com

We were delighted with the response to our first Tillotts Services quarterly newsletter. In this second issue we report on our continued expansion, conference attendance and an informative “Focus on Technology” article.

In May we completed the refurbishment of our Ziefen liquid-fill development and manufacturing site with a new reception area and the addition of new branding livery to the exterior of our main building. Our new reception now provides a more comfortable area for our visitors with additional access to an office and WiFi. We continue to invest in the expansion of our development and manufacturing facilities in order to accommodate the needs of our customers and the increasing trend in outsourcing R&D to specialist companies such as Tillotts Services.

Production Facility ExpansionAs part of our continued expansion, we have recently increased the footprint within our production area with minimal disruption by attaching a new building for material storage and material lock from our current warehouse ramp. Our new material lock now has a capacity of 12 pallets per locking cycle. In addition, an intermediate storage space for 15 pallets is available for incoming and outgoing goods and so increasing our efficiency. Both rooms are qualified as clean rooms with an independent air ventilation system. Locking duration is now optimised to around 20 minutes and has been operational for the last 6 weeks.

Issue 2

Ziefen Site Refurbishment

NEWSLETTER

Acknowledgements: Design by David Anthony, AK Design (Scotland) Ltd.

For more information, please contact us at:

Q: So Thomas, please tell us a little about you?

A: I grew up in Basel and live now in Bubendorf (next village to Ziefen). I am married and we have 3 children. In my free time I spend a lot of time in my lovely garden, hike, participate on sailing regattas and make handicraft work in my small workshop. In winter I go skiing.

Q: When did you join Tillotts and what is your role?

A: I joined the company in 1985 and I am responsible for the Engineering department. We maintain all of the technical installations at our facility in Ziefen and also in our new Pharma R&D facilities in Rheinfelden. Our key focus is to avoid any technical breakdown so we keep a very close eye on everything. In line with our expansion, we also procure new machines and equipment, plan the construction of new buildings and/or modifications which is very exciting!

Q: What was the biggest challenge for you at Tillotts?

A: My continuous challenge is to ensure that we meet our deadlines within all the projects in which we are involved and we have been successful in this respect.

Q: Of which project are you most proud?

A: The expansion of the Ziefen product development and manufacturing facility was a very proud moment. I am sure there will be more to come as we continue our expansion!

Q: What will be your next bigger challenge at Tillotts?

A: We are currently undertaking the procurement of an automatic bottle filling line for enema production that will come on stream at the beginning of 2012. Also, the implementation of our plans for the new high potent suite for the handling of highly active compounds is a new and exciting challenge.

In the first issue of our Newsletter we interviewed Kanda Nägelin: “Who is behind our new brand”. For this issue Claudio Scialdone interviews Thomas Kaiser who is managing our Engineering Department.

ww

w.tillotts.com T: +41 61 935 28 28

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

Tillotts Pharma AGTillotts ServicesHauptstrasse 274417 ZiefenSwitzerland

Tillotts Services will be represented at the following events during 2011. We would be delighted to meet with you.

Let’s Have Coffee..

Going to CPhI (Messe, Frankfurt) in October? Registration is free

(http://www.cphi.com/visitors) and Frankfurt is an excellent venue for what is a mammoth show with previous visitors from over 125 countries.Tillotts Services will be located at Exhibition Stand 41F67 in Hall 4.1

so please come and visit us.