14 - 16 May 2013 BioTrinity Newbury, UK http://www.biotrinity.com

22 - 24 October 2013 CPhI/ICSE Frankfurt, Germany http://www.cphi.com/event-calendar

www.tillotts.com

NEW LAYOUT OF THE NEWSLETTER Dear Reader, As a regular reader you will notice that we have modified the layout of our newsletter slightly. We hope you like the new style and enjoy reading this new issue of the Tillotts Services Newsletter.

All the best, Your Tillotts Services Team

IN THIS ISSUEFocus On Technology : measuring the viscosity and elasticity of liquid and semi-solid drug products using the Rheometer.

Bottle Filling at Tillotts : installing and implementing our semi-automatic bottle filling production line

Interview : Sonja Dubach-Schneider, Logistics Specialist

Qualicaps is an international manufacturer and supplier of high-quality empty pharmaceutical capsules and pharmaceutical processing equipment, with manufacturing sites in the U.S., Canada, Spain, Romania and Japan. With more than 100 years of experience, Qualicaps is a leader in innovation in both gelatin and Quali-V® (cellulose) capsules, and offers a proprietary product line of pharmaceutical equipment, including capsule filling and sealing machinery.

“Qualicaps is looking forward to working in partnership with Tillotts Services to be able to offer our customers a robust program for liquid fill encapsulation”, states Angie Roberson of Qualicaps. “Tillotts Services brings significant expertise in the development of liquid filled capsule products and when combined with Qualicaps history of two-piece capsule and capsule processing experience, we can present customers with a more complete development program”.

Since more than 25 years, Tillotts Pharma AG has built up its expertise in liquid filling of hard shell capsules with a variety of own and contract manufacturing products of high quality. With the input from the development experts within Tillotts and Qualicaps®, numerous difficult formulations could be filled into gelatin and cellulose capsules. We are fortunate to be located near Basel, the heart of Europe’s pharmaceutical industry and have attracted talented and experienced staff from our larger pharmaceutical and biotechnology neighbours. Hansueli Schaub from Tillotts Services states, that this partnership will ensure a great benefit for our customers in the field of liquid filled encapsulation as the expertise of both companies are available at once. A kick-off meeting was held at the beginning February in Basel where the official start of this collaboration was announced (see picture).

In this edition Miriam Adler interviews Sonja Dubach-Schneider, Logistics Specialist

ww

w.tillotts.com

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

For more information, please contact us at:

Tillotts Pharma AGTillotts Services, Hauptstrasse 274417 Ziefen, Switzerland

Collaboration between Tillotts Pharma AG and Qualicaps

Follow us on LinkedIn:Please join our LinkedIn Group “Tillotts Services” on LinkedIn.

We will inform you about several forthcoming events as well as the latest news within Tillotts Services.

At the kick-off meeting in Basel, From Left:Dr. Leo Stevens (President, Global Sales & Marketing – Qualicaps), Hans Christian Moxter (Vice-President, Sales & Marketing Capsules - Qualicaps), Hansueli Schaub (Head of Tillotts Services) and Claudio Scialdone (Senior Manager Contract Services & Business Development, - Tillotts Services)

See us on YouTube:If you are interested in the Liquid Fill Encapsulation Technology as well as in the manufacturing process of Tillotts Services you now have the opportunity to follow us on YouTube.

Tillotts Pharma AG has entered into a collaboration with Qualicaps with the aim to provide their customers with the extensive experience and know-how both companies have built up over the last decades in the field of liquid filled encapsulation. We are pleased to publish a short announcement written by Angie Roberson, Marketing Director of Qualicaps and Miriam Adler, Commercial Operations Assistant of Tillotts Pharma AG.

NEWSLETTER

INT

ER

VIE

W

Issue 8

Let’s Have Coffee..

Sonja please tell us a little about yourself?

I live in Ziefen with my family (two boys, 9 and 5). At home we have a big farm where I also work in my spare time (bookkeeping, working in the barn and on the fields). I like to spend time outdoors with my kids,walking, skiing, cooking, listening to music, going to concerts, etc.

When did you join Tillotts?

I joined Tillotts on 02.05.2000 working 100% and reduced to 50% in Autumn of 2003 (after the birth of my first child).

What is your role within Tillotts?

I’m responsible for production planning and packaging changes forcontract manufacturing.

Which projects are you most proud of?

Soon after my start at Tillotts I took over packaging changes. Due to alot of new customers and the launch of the Asacol 800 mg tablet it was a huge amount of work.

What will be your next bigger challenge at Tillotts?

To understand ERP and work with it!

What was the biggest challenge for you at Tillotts?

To prove that it is possible to do the planning job working 50% even if some people were sceptical.

Tillotts Services will be represented at the following events during 2013. We would be delighted to meet with you there.

For more information about Qualicaps, call 1-800-CAPSULE or visit www.qualicaps.com

For more information about Tillotts Services visit www.tillotts.com/tillotts-services

For more information please visit:

For more information please visit:

Copyright © Tillotts Pharma AG 2013 www.tillotts.com

Focus on Technology Focus on Technology / Continued

Within this section we aim to profile a technology area related to our business.

One of the most important parameters in the development of liquid and semi-solid drug products is the viscosity. The viscosity describes the amount of force (also called “shear force”), which is necessary to move a sample across a certain path in a defined time. The resulting dimensions are therefore N×s×m-2 or Pa×s; 1Pa×s = 1000mPas which is used in this article. Also there is the shear force [1/s] and frequency when oscillating [Hz].

A good example to describe “ideal viscosity” is water. Water has a viscosity or flow behaviour that is called “Newtonian” meaning that its viscous stress and the shear rate are directly proportional or linear.

The HAAKE RheoStress®1 (Figure 1) is due its air-beared motor (Figure 2), able to be operated in rotational and in oscillatory mode. There are two different geometries available; plate-plate and cone-plate (Figure 3). The temperature is peltier-controlled within a range of –40 to +180°C on a high accuracy. The peltier also allows for rapid heating or cooling of the sample.

Typical products that show thermosoftening behaviour include margarine, chocolate or suppositories which exhibit a lower viscosity at an increased temperature. The most prominent example for a thixotropic product is yoghurt, it appears solid when not moved, but once it is shaken or stirred it becomes almost liquid.

The advantages of having a capsule filling mass with a high apparent viscosity are mainly the potential to prevent a dispersed drug substance from segregation for a robust stability during shelf life. Also, by having a filling mass which only shows a strong pseudoplastic or thixotropic rheological behavior without any thermosoftening effect it is feasible to fill at ambient temperature. This can be used for protection of temperature-sensitive API’s and for making the blending and filling process a little bit more cost effective by savings in energy for heating and cooling.

A liquid or semi-solid fill-mass needs to be adequately processable. This means that several parameters need to be within a suitable range, most of them can be measured with the Rheometer. During manufacturing, it is key for cost-effectiveness that the API can be homogeneously dispersed or dissolved in the fill-mass without much effort. For achieving this, the fill-mass needs to have either a very low viscosity, or a shear-thinning behaviour. The fill-mass also needs to prevent the API from sedimentation when in the hopper, but needs to be fillable into hard-shell capsules without splashing or tearing at the same time. Also the viscosity of the fill mass at elevated temperature still needs to be high enough to prevent sedimentation of a dispersed API in order to enable appropriate shelf life stability.

There are basically two approaches to achieve all of the aforementioned conditions and both can be controlled by measuring and understanding the viscosity profile.

The first and classical approach is to formulate a fill-mass having a low viscosity at increased temperature and a semi-solid or solid behaviour at room temperature. Such fill-masses are called “Thermosoftening” or “Thermoresponsive”.

The second approach is to formule a fill-mass that shows a high apparent viscosity at rest, mostly independent of the temperature, and a low viscosity under shear (e.g. while stirring or mixing). These fill-masses are then described as “Pseudoplastic”, “Thixotropic” or simply “Shear-Thinning”. Both approaches can also be combined, if desired.

Typical measurements look as follows:

The blue curve, obtained from a commercial thermosoftening capsule fill mass, only shows little decrease in viscosity at increased shear forces in rotational mode (Figure 4). The red and green (a newly formulated product containing the same API as the commercial product) show a strong decrease when increasing shear forces which correlates with the level of shear-thinning behavior. At a shear force of about 350 1/s, which corresponds to the force as applied by the filling piston of a capsule liquid filling machine, both new formulations exhibit an lower viscosity value than the commercial, which is intended, for achieving increased filling speeds.

When measured in rotational mode, a viscosity curve needs to be recorded at any temperature in the range of interest to see a difference.

In oscillatory mode (Figure 5), this can be performed directly since the plate or cone is oscillating at a defined frequency of e.g. 1Hz while a defined shear force in the linear-viscoelastic region is applied. Then a lot of time can be saved, only an amplitude (or stress) sweep needs to be previously performed in order to find the linear visco-elastic region, in other words, finding the shear force leading to a loss of elastic properties.This means that the sample is continuously oscillated in a way that the viscosity stays constant at the same temperature. If in parallel the temperature is varied and changes in viscosity can be detected, then the product is thermoresponsive.

For many years a bottle filled product has been produced and packaged at the Tillotts Pharma AG factory in Ziefen. In the past it was a mainly manual process and a lot of staff was necessary in our manufacturing.

In 2012 we produced more than 1 million bottles in the whole year. In the Budget 2011 and 2012 we planned the installation of a semi-automatic filling line for our enema bottles. The aim was to double the daily output of bottles and to reduce the necessary workload by one third.

The aim was to fulfill the following conditions:

In order to achieve this, the following equipment was installed:

Figure 2:Air-beared motor

Our current article focuses on another fine piece of equipment, used to measure the viscosity and elasticity of nearly all liquid and semi-solid drug products, the Rheometer.

Conclusions

The rheological properties of a liquid fill-mass and any other liquid and semi-solid drug product are among the key parameters for their stability and processability With the described Rheometer all necessary rheological parameters can be evaluated either in rotational or, if suitable in oscillatory mode as well

Measurements in oscillatory mode are ideally suited for investigation of thermorheological effects and are time-saving, once the necessary preliminary measurements were performed

References [Mark] Podzcek F., Jones B.E., (2004). Pharmaceutical capsules. Pharmaceutical Press

Holding tank for the storing of 500 kg filling suspension.

Bottle feeder: Bulk bottles are put into the bottle feeder and the machine feeds the bottles in the correct position to the bottle filler.

Filling machine: The bottles are purged with nitrogen, filled with the necessary amount of suspension by means of a peristaltic pump, purged again with nitrogen and closed with a cap.

Check weigher: The weight of all bottles is checked, and off-limit bottles are ejected.

Labeling: Batch details are printed online on the labels and the printing is checked by a camera. The labels are then put on the bottles.

Packaging: The bottles arrive on a rotating table where the staff does the manual packaging into the final pack, together with a leaflet and a cannula. As we have packs of one and of seven bottles, automation of this step would be quite expensive.

Printing the final pack with batch details: This printing too is checked by a camera and badly printed packs are ejected.

Packaging of the final packs into the shipping boxes is again done manually.

- Daily capacity of 10’000 bottles.- Operating the line with 4 People.

Figure 1:ThermoHAAKE RheoStress®1

Figure 3: (a) Plate-plate and (b) Cone-plate

Figure 4: Measurement at 25°C, Rotational

(a) (b)

For our Enema we are using a soft plastic bottle and a plastic cap. There was no standard equipment on the market which guaranteed success. Zellwag AG, a Swiss company from Frauenfeld offered equipment which fulfils our requirements. Some companies told us that the project was very difficult and were not able to supply equipment within the budget available to us.

During the project some people at Zellwag and also at Tillotts probably had their hair go grey because it was very hard and time-consuming to construct the prototype equipment and to adjust all the settings until everything was running smoothly. Such a project can only be realised if all parties involved work together very closely. The different suppliers of the equipment, Zellwag as main supplier, our engineering team and also our production and packaging staff had to monitor and discuss each step of the process. The right measures had to be taken to improve each step.

After more than one year’s project time, we started a normal filling cycle on January 7th , 2013. Every day we were able to fill two batches of 5’000 bottles which corresponds to the specifications. The staff has been trained and is familiar with the new equipment.

Bottle Filling at Tillotts Pharma AG

Figure 5: Thermorheogram 20-40°C, Oscillatory

Copyright © Tillotts Pharma AG 2013 www.tillotts.com

Focus on Technology Focus on Technology / Continued

Within this section we aim to profile a technology area related to our business.

One of the most important parameters in the development of liquid and semi-solid drug products is the viscosity. The viscosity describes the amount of force (also called “shear force”), which is necessary to move a sample across a certain path in a defined time. The resulting dimensions are therefore N×s×m-2 or Pa×s; 1Pa×s = 1000mPas which is used in this article. Also there is the shear force [1/s] and frequency when oscillating [Hz].

A good example to describe “ideal viscosity” is water. Water has a viscosity or flow behaviour that is called “Newtonian” meaning that its viscous stress and the shear rate are directly proportional or linear.

The HAAKE RheoStress®1 (Figure 1) is due its air-beared motor (Figure 2), able to be operated in rotational and in oscillatory mode. There are two different geometries available; plate-plate and cone-plate (Figure 3). The temperature is peltier-controlled within a range of –40 to +180°C on a high accuracy. The peltier also allows for rapid heating or cooling of the sample.

Typical products that show thermosoftening behaviour include margarine, chocolate or suppositories which exhibit a lower viscosity at an increased temperature. The most prominent example for a thixotropic product is yoghurt, it appears solid when not moved, but once it is shaken or stirred it becomes almost liquid.

The advantages of having a capsule filling mass with a high apparent viscosity are mainly the potential to prevent a dispersed drug substance from segregation for a robust stability during shelf life. Also, by having a filling mass which only shows a strong pseudoplastic or thixotropic rheological behavior without any thermosoftening effect it is feasible to fill at ambient temperature. This can be used for protection of temperature-sensitive API’s and for making the blending and filling process a little bit more cost effective by savings in energy for heating and cooling.

A liquid or semi-solid fill-mass needs to be adequately processable. This means that several parameters need to be within a suitable range, most of them can be measured with the Rheometer. During manufacturing, it is key for cost-effectiveness that the API can be homogeneously dispersed or dissolved in the fill-mass without much effort. For achieving this, the fill-mass needs to have either a very low viscosity, or a shear-thinning behaviour. The fill-mass also needs to prevent the API from sedimentation when in the hopper, but needs to be fillable into hard-shell capsules without splashing or tearing at the same time. Also the viscosity of the fill mass at elevated temperature still needs to be high enough to prevent sedimentation of a dispersed API in order to enable appropriate shelf life stability.

There are basically two approaches to achieve all of the aforementioned conditions and both can be controlled by measuring and understanding the viscosity profile.

The first and classical approach is to formulate a fill-mass having a low viscosity at increased temperature and a semi-solid or solid behaviour at room temperature. Such fill-masses are called “Thermosoftening” or “Thermoresponsive”.

The second approach is to formule a fill-mass that shows a high apparent viscosity at rest, mostly independent of the temperature, and a low viscosity under shear (e.g. while stirring or mixing). These fill-masses are then described as “Pseudoplastic”, “Thixotropic” or simply “Shear-Thinning”. Both approaches can also be combined, if desired.

Typical measurements look as follows:

The blue curve, obtained from a commercial thermosoftening capsule fill mass, only shows little decrease in viscosity at increased shear forces in rotational mode (Figure 4). The red and green (a newly formulated product containing the same API as the commercial product) show a strong decrease when increasing shear forces which correlates with the level of shear-thinning behavior. At a shear force of about 350 1/s, which corresponds to the force as applied by the filling piston of a capsule liquid filling machine, both new formulations exhibit an lower viscosity value than the commercial, which is intended, for achieving increased filling speeds.

When measured in rotational mode, a viscosity curve needs to be recorded at any temperature in the range of interest to see a difference.

In oscillatory mode (Figure 5), this can be performed directly since the plate or cone is oscillating at a defined frequency of e.g. 1Hz while a defined shear force in the linear-viscoelastic region is applied. Then a lot of time can be saved, only an amplitude (or stress) sweep needs to be previously performed in order to find the linear visco-elastic region, in other words, finding the shear force leading to a loss of elastic properties.This means that the sample is continuously oscillated in a way that the viscosity stays constant at the same temperature. If in parallel the temperature is varied and changes in viscosity can be detected, then the product is thermoresponsive.

For many years a bottle filled product has been produced and packaged at the Tillotts Pharma AG factory in Ziefen. In the past it was a mainly manual process and a lot of staff was necessary in our manufacturing.

In 2012 we produced more than 1 million bottles in the whole year. In the Budget 2011 and 2012 we planned the installation of a semi-automatic filling line for our enema bottles. The aim was to double the daily output of bottles and to reduce the necessary workload by one third.

The aim was to fulfill the following conditions:

In order to achieve this, the following equipment was installed:

Figure 2:Air-beared motor

Our current article focuses on another fine piece of equipment, used to measure the viscosity and elasticity of nearly all liquid and semi-solid drug products, the Rheometer.

Conclusions

The rheological properties of a liquid fill-mass and any other liquid and semi-solid drug product are among the key parameters for their stability and processability With the described Rheometer all necessary rheological parameters can be evaluated either in rotational or, if suitable in oscillatory mode as well

Measurements in oscillatory mode are ideally suited for investigation of thermorheological effects and are time-saving, once the necessary preliminary measurements were performed

References [Mark] Podzcek F., Jones B.E., (2004). Pharmaceutical capsules. Pharmaceutical Press

Holding tank for the storing of 500 kg filling suspension.

Bottle feeder: Bulk bottles are put into the bottle feeder and the machine feeds the bottles in the correct position to the bottle filler.

Filling machine: The bottles are purged with nitrogen, filled with the necessary amount of suspension by means of a peristaltic pump, purged again with nitrogen and closed with a cap.

Check weigher: The weight of all bottles is checked, and off-limit bottles are ejected.

Labeling: Batch details are printed online on the labels and the printing is checked by a camera. The labels are then put on the bottles.

Packaging: The bottles arrive on a rotating table where the staff does the manual packaging into the final pack, together with a leaflet and a cannula. As we have packs of one and of seven bottles, automation of this step would be quite expensive.

Printing the final pack with batch details: This printing too is checked by a camera and badly printed packs are ejected.

Packaging of the final packs into the shipping boxes is again done manually.

- Daily capacity of 10’000 bottles.- Operating the line with 4 People.

Figure 1:ThermoHAAKE RheoStress®1

Figure 3: (a) Plate-plate and (b) Cone-plate

Figure 4: Measurement at 25°C, Rotational

(a) (b)

For our Enema we are using a soft plastic bottle and a plastic cap. There was no standard equipment on the market which guaranteed success. Zellwag AG, a Swiss company from Frauenfeld offered equipment which fulfils our requirements. Some companies told us that the project was very difficult and were not able to supply equipment within the budget available to us.

During the project some people at Zellwag and also at Tillotts probably had their hair go grey because it was very hard and time-consuming to construct the prototype equipment and to adjust all the settings until everything was running smoothly. Such a project can only be realised if all parties involved work together very closely. The different suppliers of the equipment, Zellwag as main supplier, our engineering team and also our production and packaging staff had to monitor and discuss each step of the process. The right measures had to be taken to improve each step.

After more than one year’s project time, we started a normal filling cycle on January 7th , 2013. Every day we were able to fill two batches of 5’000 bottles which corresponds to the specifications. The staff has been trained and is familiar with the new equipment.

Bottle Filling at Tillotts Pharma AG

Figure 5: Thermorheogram 20-40°C, Oscillatory

14 - 16 May 2013 BioTrinity Newbury, UK http://www.biotrinity.com

22 - 24 October 2013 CPhI/ICSE Frankfurt, Germany http://www.cphi.com/event-calendar

www.tillotts.com

NEW LAYOUT OF THE NEWSLETTER Dear Reader, As a regular reader you will notice that we have modified the layout of our newsletter slightly. We hope you like the new style and enjoy reading this new issue of the Tillotts Services Newsletter.

All the best, Your Tillotts Services Team

IN THIS ISSUEFocus On Technology : measuring the viscosity and elasticity of liquid and semi-solid drug products using the Rheometer.

Bottle Filling at Tillotts : installing and implementing our semi-automatic bottle filling production line

Interview : Sonja Dubach-Schneider, Logistics Specialist

Qualicaps is an international manufacturer and supplier of high-quality empty pharmaceutical capsules and pharmaceutical processing equipment, with manufacturing sites in the U.S., Canada, Spain, Romania and Japan. With more than 100 years of experience, Qualicaps is a leader in innovation in both gelatin and Quali-V® (cellulose) capsules, and offers a proprietary product line of pharmaceutical equipment, including capsule filling and sealing machinery.

“Qualicaps is looking forward to working in partnership with Tillotts Services to be able to offer our customers a robust program for liquid fill encapsulation”, states Angie Roberson of Qualicaps. “Tillotts Services brings significant expertise in the development of liquid filled capsule products and when combined with Qualicaps history of two-piece capsule and capsule processing experience, we can present customers with a more complete development program”.

Since more than 25 years, Tillotts Pharma AG has built up its expertise in liquid filling of hard shell capsules with a variety of own and contract manufacturing products of high quality. With the input from the development experts within Tillotts and Qualicaps®, numerous difficult formulations could be filled into gelatin and cellulose capsules. We are fortunate to be located near Basel, the heart of Europe’s pharmaceutical industry and have attracted talented and experienced staff from our larger pharmaceutical and biotechnology neighbours. Hansueli Schaub from Tillotts Services states, that this partnership will ensure a great benefit for our customers in the field of liquid filled encapsulation as the expertise of both companies are available at once. A kick-off meeting was held at the beginning February in Basel where the official start of this collaboration was announced (see picture).

In this edition Miriam Adler interviews Sonja Dubach-Schneider, Logistics Specialist

ww

w.tillotts.com

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

For more information, please contact us at:

Tillotts Pharma AGTillotts Services, Hauptstrasse 274417 Ziefen, Switzerland

Collaboration between Tillotts Pharma AG and Qualicaps

Follow us on LinkedIn:Please join our LinkedIn Group “Tillotts Services” on LinkedIn.

We will inform you about several forthcoming events as well as the latest news within Tillotts Services.

At the kick-off meeting in Basel, From Left:Dr. Leo Stevens (President, Global Sales & Marketing – Qualicaps), Hans Christian Moxter (Vice-President, Sales & Marketing Capsules - Qualicaps), Hansueli Schaub (Head of Tillotts Services) and Claudio Scialdone (Senior Manager Contract Services & Business Development, - Tillotts Services)

See us on YouTube:If you are interested in the Liquid Fill Encapsulation Technology as well as in the manufacturing process of Tillotts Services you now have the opportunity to follow us on YouTube.

Tillotts Pharma AG has entered into a collaboration with Qualicaps with the aim to provide their customers with the extensive experience and know-how both companies have built up over the last decades in the field of liquid filled encapsulation. We are pleased to publish a short announcement written by Angie Roberson, Marketing Director of Qualicaps and Miriam Adler, Commercial Operations Assistant of Tillotts Pharma AG.

NEWSLETTER

INT

ER

VIE

W

Issue 8

Let’s Have Coffee..

Sonja please tell us a little about yourself?

I live in Ziefen with my family (two boys, 9 and 5). At home we have a big farm where I also work in my spare time (bookkeeping, working in the barn and on the fields). I like to spend time outdoors with my kids,walking, skiing, cooking, listening to music, going to concerts, etc.

When did you join Tillotts?

I joined Tillotts on 02.05.2000 working 100% and reduced to 50% in Autumn of 2003 (after the birth of my first child).

What is your role within Tillotts?

I’m responsible for production planning and packaging changes forcontract manufacturing.

Which projects are you most proud of?

Soon after my start at Tillotts I took over packaging changes. Due to alot of new customers and the launch of the Asacol 800 mg tablet it was a huge amount of work.

What will be your next bigger challenge at Tillotts?

To understand ERP and work with it!

What was the biggest challenge for you at Tillotts?

To prove that it is possible to do the planning job working 50% even if some people were sceptical.

Tillotts Services will be represented at the following events during 2013. We would be delighted to meet with you there.

For more information about Qualicaps, call 1-800-CAPSULE or visit www.qualicaps.com

For more information about Tillotts Services visit www.tillotts.com/tillotts-services

For more information please visit:

For more information please visit: