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December 03 – 04, 2014

Pharma Days 2014Bünde, Germany

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Content

Preface 2

Summary of the presentations 3

Plant portrait Bünde 8

Customer newsletter | January 2014

This is the sixth time that we have held our most important event for customers, Gerres-heimer Pharma Days. And it met with vast interest. Over 80 participants from all over

Europe, the USA and Japan arrived in Bünde at the beginning of December to lis-ten to the presentations, take part in the workshops and network.

One of the highlights of the two-day event was a tour of the new, ultra-modern RTF®4 production line that was recently put into operation. Our guests took a great many interesting and lasting impressions back home with them and gave us some very positive feedback.

This motivates us to continue the tradition and organize another Pharma Days event for our customers soon. This issue of Up-date provides a summary of Pharma Days 2014, plus a number of insights into the event. We’re looking forward to seeing you again or for the first time at the next event!

All the best for a good start in the new year!

Preface

Jens KürtenDirector Corporate Communication & Marketing Gerresheimer AGj.kuerten@gerresheimer.com

Gerresheimer Pharma Days 2014

On the first day, which was conference day, Gerresheimer CEO Uwe Röhrhoff and Member of the Management Board Andre-as Schütte provided some very interesting presentations introducing participants to the Gerresheimer world. Professor Meinel of the University of Würzburg explained current developments in personalized medicine and pharmaceutical drug integrity from an aca-demic perspective, and provided suggestions on how pharmaceutical and packaging man-ufacturers can adapt to them. The presenta-tions were followed by workshops on the topics of “Prefillable High-Tech Syringes“, “Excellence and Innovation“ and “Quality“ during the afternoon.

Tour of the new RTF®4 production line

On the second day of the event the guests visited the Bünde plant to see its fourth and most modern production line for ready-to-

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fill syringes. Gerresheimer experts provided detailed explanations of the steps involved in the production of syringes and cartridges at seven stations.

Summaries of the presentations and work-shop reports, as well as numerous photos providing impressions of the two event days, are provided on the following pages.

On December 3 and 4, 2014 more than 80 international pharmaceutical

industry customers convened at Gerresheimer Bünde in Germany

to visit the new RTF®4 line and share experiences in a packed program

of events.

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Summary of the presentationsGerresheimer – Global Excellence for the Pharma and Healthcare Industry

Gerresheimer’s vision is to become the leading global partner providing solutions that im-prove health and well-being. Our comprehensive product portfolio includes both high quality medical technology devices and drug delivery systems as well as pharmaceutical primary packaging made of plastic and glass. We have a global network of more than 40 produc-tion plants manufacturing billions of standard products in addition to highly specialized solutions. Our aim is to continue extending our presence in developing markets such as Brazil, Mexico, India and China. The recently opened Technical Competence Center in China is proof of our intention to supplement our manufacturing operations there with develop-ment activities. We also believe that the continuous optimization of products and processes is essential, which is why we invest an average of 9–10 percent of our annual revenue in optimi-zation. Some of these investments are made in the development of innovative products such as Gx Multishell® vials or COP syringes for complex applications, and others in further improving the quality of our Gx RTF® syringes and in scratchproof, hardened glass vials with reduced delamination risk. However, we also believe it is equally important to invest in the extension of our production capacity, the global standardization of our processes and the implementation of innovative production, inspection and environmental technolo-gies. With our quality initiative, the Gerresheimer Management System (GMS), as the plat-form for our continuous improvement process and our key account management activities, we are putting standardized processes in place all over the world – delivering added value that our customers can depend on.

Uwe RöhrhoffGerresheimer AG, Chief Executive Officer

Conference Chairman:

Frédéric KahnGerresheimer AG

Our Global Competence in Customized Medical Systems

In developing nations, growth of specialist pharmaceutical products is higher than growth in basic pharmaceutical drugs. The continuously increasing market share of complex biotech drugs for the treatment of cancer, auto-immune diseases or HIV, for instance, poses a number of challenges relating to development, production, licensing, regulation and delivery. We are the number one in the European market with our Plastics and Devices Division, and we have now also gained a foothold in the emerging markets. The merger of Syringe Systems and Medical Plastic Systems into the Medical Systems Business Unit allows us to offer cus-tomers an integrated product portfolio that covers all market requirements of complex systems. Medical Systems has seven production plants and five development sites on three continents, which means it is excellently positioned to cater to a globalized market. This unusually comprehensive portfolio is possible as a result of services such as small produc-tion runs in Wackersdorf and a license for pharmaceutical filling operations. We offer our customers innovative processes such as the new RTF®4 production line and innovative products such as COP syringes, Gx MultiShell® vials and Duma® Twist-off closures. Over coming years we will be extending our portfolio to include RTF® syringes for specific applications, customized injection and drug delivery platforms and in-house developed closure and safety systems.

Andreas SchütteGerresheimer AG, Member of the Management Board with responsibility for Plastics & Devices

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Future Primary Packaging Requirements

The future challenges that the primary packaging industry will face are related to the chal-lenges that its customers, particularly those in the pharmaceutical industry, face today. Two aspects – personalized medicine and the increase in product piracy – were particularly focused on in this presentation. Personalized medicine involves segmentation with the help of bio-markers to achieve a more effectively characterized sub-population of a heterogeneous disease, in some cases segmentation down to patient level. There are also new and excit-ing pharmaceutical projects in the field of genetic diagnostics. For example rapid progress is being made in the prediction of phenotypes, which will enable preventative treatments supplementing today’s predominantly curative treatments. Pharmaceutical companies and packaging manufacturers will have to flexibilize medications in terms of individual dosage and possibly in terms of using the same medication for various dosages or even the capability of manufacturing many small batches. Recent technical advancements, such as the 3D print-ing of drugs, could lead to the flexibilization of pharmaceutical drug production, leading to a degree of individualization that is practically impossible to exploit with today’s diagnostic methods. Another challenge is product integrity. A new approach was presented for the manufacture of a tamper-evident primary packaging product involving the incorporation of metal organic frameworks (MOF). Integrity is guaranteed, firstly, by the MOF’s continuous loss of luminescence over time, and with sensor functions, e.g. for water, so that the sensor is irreversibly destroyed if the primary packaging is opened. A simple color change indicates to the user whether the packaging is intact or not.

Professor Dr. Dr. Lorenz MeinelUniversity of Würzburg

Improvements in the RTF® (Ready-to-Fill) syringe process

RTF®4 will take the production of ready-to-fill syringes into a new dimension. The new production machines for the RTF® process were developed in a cooperation between Ger-resheimer and Groninger (Crailsheim) and the packaging machines were developed in a cooperation with A+D (Weißensberg). Key process improvements include the avoidance of glass-glass and glass-metal contact through the use of pick-and-place and segment transport systems, optimized washing and siliconization processes and more effective, camera- based quality inspections. This gentle handling results in a lower syringe cosmetic defect rate. A state-of-the-art washing process guarantees compliance with both present-day and future regulatory requirements. The use of extended nozzles in spraying technology and in-line inspections in the siliconization process ensure consistent syringe function. A sequential assembly concept with two assembly units increases production capacity and makes it pos-sible to respond flexibly to customer requirements. Complete dimensional control ensures the syringes’ filling processability. Automated in-line controls of a considerably higher num-ber of inspected product features guarantees consistent quality. All production lines are operated under Class D clean room conditions, which further improves product hygiene and safety. Packaging technology has also been considerably simplified and a camera in-spection ensures the complete filling of the nests and that all syringe closures are in place.

Maren BöttcherMedical Systems

Excellence in tubular glass for ready-to-fill syringes

Gerresheimer focuses on a vertically integrated production strategy with its own produc-tion facilities for pharmaceutical primary packaging in high quality Type I tubular glass. In the next step, the tubular glass is processed into primary packaging such as syringes, am-poules, cartridges and vials. Two plants in Pisa (Italy) and Vineland (USA) ensure a contin-uous supply of tubular glass. Integrated tubular glass production is decisive for the quality of the end products because the first stage of the production process establishes the qual-ity standard for the finished products. Automated, state-of-the-art inspection technology guarantees that the product dimensions conform to the specification and have no cosmet-ic defects. Vertical integration also makes it possible to take the pharmaceutical customer’s requirements into account in a design process that extends along the entire value chain from glass tube to finished pharmaceutical product.

Silvia Baccetti, Michele SchinellaPrimary Packaging Glass

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Ready-to-Fill RTF® Syringes meet Present and Future Biotech Requirements

Ready-to-fill syringes have to meet a variety of requirements from different sides, such as cost, function and regulatory requirements. As a packaging, the syringe must be suitable for complex biotech and ophthalmic applications both today and in future. For example, minimizing silicone oil and tungsten residue is essential in ophthalmic syringes. ClearJectTM COP syringes are ideal for many complex biotech drugs. They are becoming increasingly popular and a broad knowledge base already exists. Another requirement of syringes is safe, low-pain and precise-dosage injections. The silicon coating inside the syringe barrel must deliver constant break loose forces and gliding properties even after lengthy periods of storage. Gerresheimer’s own closures and tip caps guarantee the safety of patients and medical personnel. With biotech drugs, which generally have a very small quantity of ac-tive ingredients, precise dosage is of ultimate importance. Special camera systems are used to check the position of markings and the end position of the plunger head on the syringe shoulder. Another future topic is the integration of syringes in autoinjectors, which in-volves the combination of glass and plastic systems with different dimensional tolerances. However, there is no standard solution for the complex challenges associated with innova-tive pharmaceutical drugs. Rather, the most suitable syringe for each application is devel-oped as a customized solution in close collaboration with the customer.

Bernd ZeissMedical Systems

Compliance Makes the Difference – How to Generate Added Value with Tablet Packaging

For decades, active ingredients were the most important factor of competition in the phar-maceutical sector. Expiring patents, increasingly small target groups and discerning con-sumers have now put the focus on primary packaging and drug delivery devices. Devices are one of the most important branding tools for products which are difficult to distinguish from one another on the basis of the active ingredient. Devices for chronic diseases can even assume lifestyle functions as objects of everyday use. However, the most important aspect is therapy compliance/adherence through use of the device. 40 percent of all phar-maceuticals are either not taken at all or administered incorrectly, and this is a cost burden that the healthcare sector cannot continue to bear. Devices that make it easier for the target group to take their medication as prescribed are one means of remedying the situa-tion. Key factors are designs that take disease or age-related limitations into account as well as behavior in stress situations. Electronic dispensers already exist for tablets; some with data functions for therapy monitoring. Gerresheimer item operates in this market with a range of designs for mechanical and electronic dispensers with reminder function.

Peter WallrabeMedical Systems

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Small world – micro-injection molding under the microscope

Manufacturing increasingly small parts is a challenging undertaking. If you reduce the length of a component by 50%, the other properties can, in some cases, change exponentially. The physics of injection molding are also taken to their limits. In small volume injection molding, screws with a normal diameter produce dwell times outside the admissible range, but it isn‘t possible to reduced the screw diameter due to granulate size and risk of break-age. Precision of dosage is also becoming increasingly significant due to the check valve on the screw head. These problems are solved by separating plasticization and injection. The screw is still responsible for plasticization, and the injection is performed by a valveless plunger with a diameter no larger than the granulate’s grain size. Gerresheimer uses a MicroPower machine by Battenfeld with a volume of 50 cm3 – 4 cm3 for micro injection molding. Alternatively, high-cavity molds can be used because their total cavity volume permits the use of conventional injection molding machines. A comparison of both tech-nologies shows that micro injection molding facilitates higher product quality. However, the use of molds with few cavities reduces throughput. To increase throughput, standard machines with high-cavity molds are the better option, even if cycle control is considerably more complex as a result.

Dr. Bernhard SchmittMedical Systems

Improving Production Excellence in Asia

The pharmaceutical markets in developing countries are growing at a much faster rate than those in advanced nations. Gerresheimer already generates one-quarter of its revenue in developing countries, and this will increase to one-third by 2017. It has a good foothold in the Asian market, with two production plants in India and four in China. At the Indian plant in Kundli a 300-strong workforce manufactures plastic primary packaging products. The second Indian plant is in Kosamba. The 570 staff there manufacture primary packaging products made of molded glass. Substantial investments have been made in Kosamba to prepare the plant for global accounts. The production capacity has been increased, energy efficiency has been improved and the quality management system now uses automated inspection equipment. A new plant for vial production is currently being built. The Chinese Zhenjiang plant has 370 employees and manufactures vials and ampoules from tubular glass. The Chinese plant in Danyang has two production facilities. Plant 1 has 400 employees and manufactures vials from tubular glass. Plant 2 has 320 employees and manufactures vials and cartridges. The attractiveness of these plants is confirmed by the fact that they have been audited by more than 200 customers in China and elsewhere. At the Chinese plant in Dongguan, 220 staff manufacture plastic disposables and devices such as inhalers and lancing devices. A Technical Competence Center was opened here in 2014 so that customers in Asia have access to local end-to-end product development and industrialization services.

Heinz-Wilhelm KlostermannPrimary Packaging Glass

The Gerresheimer Quality InitiativeEstablishing global standards in a challenging sector

The quality standards in the medical technology product market are continuously increas-ing. Both customer requirements of supplied product quality and our requirements of maxi-mum production efficiency demand a globally standardized zero-defect strategy. Gerres-heimer meets this challenge with a quality vision and strategy that is implemented at all sites around the world, defined, reviewed and driven forward by a Quality Council. Our quality strategy focuses on quality as an integral aspect of all products and processes and on our employees’ internalization of a value-based quality culture. The five aspects of Gerresheimer’s quality vision – high product quality, high service quality, well-maintained assets, consist-ent quality management and highly qualified employees – are systematically monitored on the basis of specific KPIs. Our Quality Initiative also applies the concept of continuous im-provement to quality. The quality culture and management at each site are reviewed annu-ally and quality will be a central element of management training in 2015. A monthly re-port on all quality specific KPIs will ensure that we achieve our goals for our quality culture and quality standards, and set global benchmarks.

Charlotte BorgensgaardPlastic Packaging

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Delamination – Science to Solutions

Even exceptionally inert Type I borosilicate glass is susceptible to attack by aggressive chemicals, causing it to spall. This phenomenon in primary packaging for parenteral prod-ucts, which is referred to as delamination, has increased since the introduction of innova-tive biopharmaceuticals, resulting in many product recall campaigns in the USA. In association with Alfred University (New York, USA), Gerresheimer AG therefore commissioned a three-year long-term study into the causes of delamination. More than 9,000 samples were test-ed for all potential factors of influence. Delamination only occurs in vials made of tubular glass, and it almost exclusively occurs in the stress ring near the bottom of the vial. The forming temperature of the vial bottom was identified as the main trigger for vial delami-nation. The study also revealed that treating the vials with ammonium sulfate increased the incidence of delamination. These findings make it possible to launch a new generation of vials on the market. In the production of ARMOR vials, SPC-aided process control in the proprietary THOR process increases the stability of the primary packaging production pro-cess and considerably reduces the delamination risk. This production process is comple-mented by the FLASH test that permits reliable forecasting of vial delamination behavior.

Carol Rea FlynnPrimary Packaging Glass

Quality by Design in the development of pharmaceutical primary packaging

Quality by Design (QbD) is a process by which quality is systematically built into a product. QbD represents a paradigm shift from conventional Quality by Inspection to a process in which all the critical production variables are understood and managed in such detail that product quality can be defined in advance. A design space is created in which the desired quality attributes can be precisely predicted. First of all, the critical product features are identified so that the production parameters which are critical for them can be defined. For example, in the production of an injection blow molded ophthalmological bottle, the in-side mouth diameter is critical to the bottle’s tightness and therefore contamination immu-nity. All parameters can potentially influence this dimension in the injection molding of the bottle blank. A Design of Experiment (DoE) makes it possible to identify the critical param-eters and understand their multivariate interactions. On this basis it is possible to optimize molds and define a process window in which there is a high probability that products can be manufactured which conform to the specification. Although Quality by Design makes the development phase more work-intensive, this disadvantage is more than offset by greater process stability and far lower expenditure of time, effort and costs on quality control.

Marek MiszczakPlastic Packaging

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Syringe production at Gerresheimer Bünde

The Bünde plant is Gerresheimer’s compe-tence center for innovative syringe systems made of glass which are marketed under the brand name of Gx RTF® and supplied to pharmaceutical customers in a ready-to-fill state. Bünde thus caters to the globally ex-panding market for drug delivery systems for vaccines, biologicals and thrombolytics.

Gerresheimer Bünde also markets ready-to-fill ClearJect® syringes in COP (Cylic Olefin Polymer) which are produced by Taisei Kako in Japan. Insulin cartridges that are built into pens for diabetes patients are also manu-factured at this site.

Bünde, in the German region of East Westphalia, is Gerresheimer’s syringe business hub. The tradition-steeped plant with its Technical Competence Center is today one of the most modern production facilities of its kind in the world.

Over the last three years, the Bünde facility has been substantially extended. It now has a new production hall with cleanrooms for its fourth ready-to-fill glass syringe produc-tion line. This fourth RTF production line has several new process features. For example, the syringes are conveyed individually to systematically prevent glass-glass contact, and the washing and siliconization process-es have been optimized. The upright trans-portation of the syringes (with the tip fac-ing up) also reduces particle load.

We manufacture our Gx RTF® syringes in a high-tech, quality assured production pro-

cess. The molding of the glass barrel, with syringe cone, cannula aperture and finger flange, takes place in a largely automated production environment, with additional state-of-the-art 100% inspections using camera systems. The cannulas are then bond-ed to the syringes in cleanroom conditions. Proven washing, siliconization and assembly processes, plus additional quality inspec-tions, ensure that only defect-free products leave the RTF lines. Most of the glass mold-ing, needle mounting and camera system machine park in Bünde was developed and built by the plant’s in-house experts.

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History The present-day Gerresheimer Bünde GmbH was established in 1947 as Bünder Glas GmbH by the Hennings and Zimmermann families. At that time, the company’s main product was glass tablet tubes. Later on, it added ampoules and dental cartridges to its production program. From time to time it also manufactured plastic products. At the beginning of the 1970s, Bünder Glas com-menced production of disposable ready-to-fill syringes, supplementing its successful portfolio of ampoules, cartridges and their plastic parts. The first cleanrooms were opened in 1978 at a time when few rivals were capable of offering similarly modern production facilities.

Gerresheimer took over Bünder Glas in 1987. Since then, it has gradually developed the plant into one of the world’s largest produc-tion facilities for sterile ready-to-fill syringes. Between 2002 and 2009 three Gx RTF® pro-duction lines were put into operation, and now the fourth and most modern RTF® line has opened.. Parallel to this, the experts in Bünde have developed innovative solutions such as baked-on siliconization and special closure systems for syringes. Some of them have even received awards. For example, the

Gx TERNS® product range won both the German Packaging Award and the World-Star award. An innovative, camera-based in-spection system that was developed in Bünde makes it possible to identify defects five times smaller in size than the smallest of defects that could previously be identified. It was recently put into operation in addi-tion to the regular inspection systems.

Approx. 800 employees

Products: Gx® RTF syringe systems, bulk syringes (unsterilized), pre-fillable syringe systems made of COP ClearJect™, Gx® insulin cartridges, Gx® syringe accessories

25,700 m2 production area, thereof 3,800 m2 cleanroom

Class 7 and 8 cleanroom technology

DIN EN ISO 9001, 13485, 15378, 50001, DMF (Drug Master File) for glass syringes and cartridges

Development of machines and camera inspection systems

Customers: Bayer, Baxter, GSK, Johnson & Johnson, Novo Nordisk, Roche, Sanofi Aventis, Teva, Vetter

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Imprint: © Design and editing Gerresheimer Corporate Communication & MarketingKlaus-Bungert-Straße 4 | 40468 Düsseldorf, Germany Jens Kürten | Phone: +49 211 6181-250 | Fax: +49 211 6181-241 | j.kuerten@gerresheimer.comDr. Cordula Niehuis | Phone: +49 211 6181-267 | Fax: +49 211 6181-28 267 | c.niehuis@gerresheimer.com

We wish you a healthy and successful New Year 2015