ProjeCt: robotIC teamwork - Optima

pharma 01 | 2013

The OPTIMA Magazine

CIP / SIP: Basic design points – a comparison with COP / SOP Flexibility from 0.03 to 1.000 ml, combined with process versatility

Project: Robotic teamwork Installing, Monitoring, Welding

COntent

EditOrial

New impetus

Faster, more flexible and more secure? In the famous words of Henry Ford: If I had asked the people what they wanted, they would have said “faster horses”. If today patients were asked what they want, the answer would be just as clear as it was then – to get healthy. The aim is simple but through the various processes of the health system, the prevalent circumstances make things much more complicated to achieve and are not so easy to achieve as in the case of a faster means of transport. This begins with the question, what in fact is considered to be “an illness” (definition) or is there an illness (diagnosis) here in this case? Which child is “just” a fidget, and which child has Attention Deficiency Syndrome? What is ADS? The next question could then be whether the child’s normal environment has caused a psychological disorder or whether the causes are genetic? And in which cases could treatment with pharmaceuticals be helpful? Research must be funded by more than just pharmaceutical com-

panies in order to find the answers. As a rule this happens indirectly via the pricing of pharmaceuticals. Taking into account the social aspects, however, financing of health issues is in most states also a political task. The top-heavy age pyramid is an additional modifier of health issues which are targeted for research. The result is that hard negotiations, often with state influence are major factors in setting the prices. It is essential that research continues within appropriate frameworks. Unfortunately this is where opinions differ as to how to define “appropriate”. Cost pressures increase but at the same time the integrity of the pharmaceutical industry must not be challenged. This is the experience of the specialists for filling and packaging

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technology. Although at this level the pharmaceutical process chain must be well considered in terms of profitability and viable implementation with supply and demand as the determining factors. Under these circumstances it is really quite remarkable that for pharmaceutical companies it is not only the machine price and not “only” the TCO which is the main consideration. The winner is always the best overall package. This remains unchanged in defining the safety of the patient as the first priority. Economic viability and safety remain the central themes around which this issue of o-com. It is a matter of the best way to achieve the aim. 

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Project: Robotic Teamwork

CIP / SIP:

Flexibility

Installing, Monitoring, Welding

Basic design points –

0.03 to 1.000 ml,

a comparison with COP / SOP

combined with process versatility



CompaCt



FoCus



4

News

6 –9

Sterile – yet rich in detail

20–21 Wide variety of processing options driven to the limit

5

Employee development

Spot

5

Definition: The leak rate



ShowrOOM

Panorama

14–15 No experiments 24–25 For improved skills



newcomer

16–19 Robotic teamwork



Zoom

26–27 Packaging Valley Germany heralds the start of Industry 4.0

10–13 System solution for syringes and vials

22–23 Freeze dried bacteria: assured safety in all phases



ORGAnIZER

25

Trade Shows

Quote:

“An investment in knowledge always pays the best interest.“ Benjamin Franklin (1706-90), US politician, writer and natural scientist, who in 1776 cosigned the American Declaration of Independence.

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Imprint o-com is the actual Communication service of the OPTIMA packaging group GmbH Address OPTIMA packaging group GmbH Steinbeisweg 20 74523 Schwaebisch Hall Germany

OPTIMA pharma GmbH Otto-Hahn-Straße 1 74523 Schwaebisch Hall Germany

OPTIMA pharma GmbH Vor dem langen Loh 8 35075 Gladenbach-Mornshausen Germany

Editor Felix Henning

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COmpact

COmpact

Code of conduct

Technological Diversity

Raffle Proceeds Go to a Good Cause

Employee Development 2013

Principles of cooperation

A round trip through Packaging Valley

Trainees Supports „Help! - Wir helfen!

Growth and growing responsibility Whatever applies to a company also applies to its employees: Tasks and requirements are constantly changing. Often advice from outside and professional knowledge transfer can be helpful.

Unfortunately many things which should be a matter of course all over the world are sometimes not. For this reason Optima has compiled a written code of conduct to which it has pledged. An excerpt: “As a mediumsized family company Optima tries to maintain its own values and principles, to do business on an ecologically sustainable basis, to look to the future and in doing so to protect the wellbeing of people and the environment in accordance with national and international regulations. In order to upkeep these ideals we expect our employees and our business partners to act under the framework of free competition, not to engage in competitive practice or offer or grant inappropriate advantage whether direct or indirect, of a private or business nature. We support the ten principles of Global Compact Initiative and reserve the right to work only with such companies which observe these fundamental principles …” Customers can read the complete code of conduct at any time on request. Further information is also available under www.unglobalcompact.org and www.globalcompact.de 

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Full production halls at Optima Pharma. The reason: Lots of people and a total of eight machine lines were presented to international visitors of Packaging Valley Days (April 10th and 11th, 2013). On the second day of this event the participants of the conference visited various companies on a round trip of Packaging Valley. Optima Pharma welcomed about 70 visitors. Eight production lines which were on the tour plan were, inter alia, two high performance syringe lines and four lines for diagnostic preparations, a line for infusion bottles, and one for special containers and eye drops. Packaging Valley member company ITEK demonstrated its syringe transport system. The diversity of leading technologies in the packaging sector, all convergent in one small area known as Packaging Valley, is unique in the world. Some of the visitors took the opportunity to acquire information beyond their own fields of application, by looking at new approaches and ideas from other branches. More information about the conference can be found on page 26. 

As in previous years Optima organized a raffle with items donated by business associates during for the 2012 Christmas party. The raffle was organized by several Optima trainees. The proceeds of Euro 1,500 were donated to the social service provider “Help – Wir helfen!” (Michelfeld, Germany). The mission of “Help! – Wir helfen!” is self-help. The registered association finances surgeries for people with cleft palates. In addition, the donations are used to buy prostheses and medical devices for hospitals. Most of the donations go to the Philippines where “Help! – Wir helfen!” has already sponsored approximately 500 surgeries. “Help! – Wir helfen!” was founded in 2008 and its memberships has grown steadily – to 250 volunteers. Several weeks after the raffle the trainees presented the check to members of “Help! – Wir helfen!”. 

In the Optima Group of Companies the Department “Employee Development” has been active since January 2012, combining external know-how and internal needs. The first most important task of the two-man team was to create a suitable structure. Seminars and workshops which have already taken place were evaluated by the participants and new requirements worked out with the department managers. One result of this is a Seminar and Workshop Catalogue for the year 2013 containing around 50 external professional development programs and which is continually updated to meet requirements. For example, there are office and technical training courses, business administration,

languages, self-management, stress management or also training in intercultural cooperation. Course levels extend all the way to a parallel work and study MBA degree. The quality of the training measures is continuously assessed and future offers are adjusted accordingly. After three months, at the latest, the question as to whether a certain measure brought the desired success is examined. As deemed appropriate, new training measures can then be implemented as required. These further training schemes are in practice at all the company locations in Germany. The international Optima locations primarily take part in locally offered courses. 

Knowledge. Success. Future. Seminars/Workshop 2013

Member of

Definition:

The leak rate (aka leakage rate) The leak rate (aka leakage rate) is a dimension for the volume or mass units escaping from a body. In vacuum technology the leak rate is defined as follows: The leak rate is the quotient of the pV value of a gas, which flows through a tube cross section for a period of time, and the unit of time. The pV value is the product of pressure and volume of a specified amount of a gas at the respective temperature. For an ideal gas at the given temperature the pV value is a dimension for the amount or mass of the gas. The leak rate depends on

the type of gas, the pressure difference and temperature. Very small leaks are frequently detected by means of helium leak detectors. This usually occurs under the following conditions: helium gas, pressure difference 1013 hPa, temperature 20 °C. These conditions are also known as “Helium Standard Conditions”.

From this estimate and from the size of viruses and bacteria the commonly used terms “bacteria-proof” and “virusproof” can be allocated to the respective limiting leak rates: Bacteria-proof: bacteria diameter approx. 0,5 µm  Q < 10-5 Pa·m3/s Virus-proof: diameter of small viruses approx. 10 nm  Q < 10-9 Pa·m3/s Modern helium leak detectors can detect leak rates of up to 5·10-13 Pa·m3/s. According to the above estimate this would correspond to a hole diameter the size of the radius of an atom.  Source: Wikipedia

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FOcus Changeover time for CIP/SIP

3,5

The design of CIP/SIP and a comparison with COP/SOP

Definitions

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Sterile – yet rich in detail CIP/SIP systems are frequently a constituent part of pharmaceutical filling and packaging systems. Their design depends less on the CIP/SIP units than on various external factors and overall conditions. Exactly what these are, and what needs to be taken into overall consideration in the design and configuration of CIP/ SIP systems is addressed in this contribution. In the second part we will go into further detail on advantages and disadvantages as compared to COP/SOP systems.

In order to understand the structure of an installation for inline cleaning and sterilization of a dosing system, and to be able to explain the associated questions, we should first present a typical cleaning and sterilization sequence and the associated technical facilities

2,5 2 1,5 1 0,5 0

CIP/SIP Rotary poston pumps

CIP/SIP TP dosing

Manual changeover rotary piston pump

Manual changeover time pressure

Batch-to-batch times with CIP / SIP and COP / SOP for rotary piston pumps and time-pressure systems

The CIP/SIP work flow (as a typical example for a time-pressure system) After the system has been run until it is completely empty of product, a switch is made from production mode into cleaning mode via the system controller. The filling needles are placed manually or automatically into a needle holder to prepare for cleaning (CIP). A leak test is performed before the first liquid cleaning medium is used in the system. This is done by applying sterile air or nitrogen at a defined pressure. The pressure drop that is the sum total of all possible system leaks is determined. This thus ensures that the system is closed and free of leaks before the cleaning and sterilization cycle continues. After the leak test has been completed successfully each path of the system is actively cleaned, path by path. The cleaning medium is either delivered directly via the product tank or via a CIP system or directly from the loop (usually WFI). The various cleaning media that are required are provided by the CIP system. As a rule, in the first step, all product residues are directly sent to the drain area, path by path. Next, the product filters are prepared for the sterilization process. It is recommended to have a bypass for product filter elements at this point so as to prevent a major overflowing of the filter element with steam during the heating-up phase. An excessively large pressure differential across the membranes can result in damage to the filter. If other types of needles would be re6

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quired for the new batch, the cleaned filling needles would be changed at this point.

condensate from forming in the dosing hoses and causing the hoses to cool down.

detected by automatic monitoring systems (fail-safe design).

The next step marks the beginning of the sterilization process. The entire system with all the piping is heated up to the sterilization temperature by means of saturated steam. The heating-up phase runs in a fixed sequence path by path so that the air is reliably driven out of the system and no enclosed air bubbles remain in the system as a potential cold spot. The heating-up phase is concluded when the sterilization temperature has been reached at the potential cold spots (= drain points located low down: aperture plate, condensate drain). Then, the actual sterilization phase begins.

After the sterilization cycle, the system is cooled down and dried with sterile air. At the same time an overpressure is produced in the system using the sterile air to maintain sterility until production mode is activated again. This thus prevents any contamination or penetration into the closed piping system.

When designing systems, attention must be given to the fact that parallel flow paths are not to be cleaned simultaneously. This can cause uncontrolled flow conditions – a “closed” valve would not be noticed.

A temperature of 121°C must be maintained for more than 20 minutes at all points for the sterilization process. Temperature sensors at the potential cold spots monitor the sterilization temperature continuously. Both the temperature and the pressure of the system are held constant during the sterilization process. This is, as a rule, done very simply by setting the sterilization pressure centrally by means of a spring-loaded membrane pressure regulator at the medium transfer interface for the sterile steam pressure. Due to the very small cross-sections of the pipes, and especially of the filling needle hoses, it is necessary to let the steam flow through the entire system and not to let it back up, thereby preventing

Basic points concerning the design of CIP/SIP systems In general, when setting up a CIP/ SIP system it is necessary to keep a clear and consistent concept giving consideration to the cleaning media being used (PW, WFI, alkali, acids), the parameters (preliminary pressure, temperature, concentration) and the acceptance criteria (conductivity value, TOC). In addition, the cleaning and sterilization limits are to be defined, together with the handling of the interfaces (overlapping cleaning / disinfection). In addition, a suitable design has to be selected for the piping cross-sections, the orientation of the pipe branches, the process connections for measuring devices and the use of T-valves and block valves. Above all, a CIP/SIP design must include safety features in the event of operating errors and the failure of individual components. Failures or errors must be

In the same way it is necessary to take into consideration in the design of the system that the relevant cleaning and sterilization media are reliably kept apart from one another. It is necessary to ensure when designing the interfaces, and especially the product piping, that all the valves are actively and thoroughly cleaned and sterilized up to their cleaning and sterilization limits. It is also necessary to monitor adjacent cleaning and sterilization processes so a possible defective valve membrane is detected by the automation system and the automated process is stopped. It is necessary to exclude any possibility of recontamination by the cleaning medium from an already cleaned and sterilized pipe. The implementation of inline sterilization must also be engineered with regard to certain basic principles that must be considered in the design and construction: Additional measures need to be taken for the simultaneous sterilization of parallel flow paths. The monitoring of

temperatures, the position indicators for the valves and the sequential heating up of the individual flow paths are examples of this. Each low point in the system requires a condensate drain or aperture plate (alternatively, a cycle valve) whose sterilization temperatures are monitored. If the sterilization is carried out as described above, without a preliminary vacuum, then it is necessary to ensure that the air is reliably removed from the system during the heating-up process. This is done via automated path by path switching of valves in the direction of the waste water / condensate during the heating-up phase whereby each path is heated up individually to the sterilization temperature. Similarly, a number of different aspects need to be taken into consideration in the drying process (DIP) as well. There should be no simultaneous drying of parallel flow paths. The most important question to be answered regarding the drying after the sterilization is always in which sequence systems that had already been cleaned and sterilized should be opened up to blow in sterile air for drying. Here too, a number of different systems and ideologies have developed (conventional air break, steam blocking, sterile condensate network etc.). Last but not least, the system must always have an overpressure with respect to the de-watering system during the drying process.

CIP = Cleaning in Place Cleaning in place is a cleaning process in which the cleaning and disinfection agents can be brought into the cleaning loop “online” without the need to dismantle the facilities and devices of the system. Cleaning systems of this type are frequently automated and are controlled by special programs. Cleaning and disinfectant solutions are circulated at high pressure by a pump so as to create a turbulent flow in the pipes, valves and small devices. Large tanks are cleaned at lower pressures, by applying the solutions with the assistance of spray heads or rotating nozzles. The CIP cleaning presupposes that the systems do not have any dead spaces.

SIP = Sterilization in Place A cleaning process that is carried out without disassembly [see CIP], using disinfectants or saturated steam in the aseptic area. Also called Steam in Place and Sanitize in Place.

DIP = Drying in Place Drying in place by means of sterile air.

COP = Cleaning out of Place Manual cleaning of the dismantled equipment.

SOP = Sterilization out of Place Done by means of equipment washing machines and steam autoclaves (steam sterilization). Also called Steam out of Place and Sanitize out of Place.

SOP = Standard Operating Procedure Instructions that specify how a particular process is to be carried out. o-com Magazine

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FOcus

CIP/SIP or COP/SOP: The advantages and disadvantages What exactly is to be understood by the above-mentioned fail-safe design being applied to CIP/SIP systems? The first prerequisite is that it must always involve automated and reproducible processes. In addition, all the cleaning- and sterilization-relevant parameters must be monitored continuously during the entire cleaning and sterilization process. All the values at quality-relevant measuring points must be continuously recorded. Errors and defects are detected and collected directly or indirectly. They lead to an alarm and are likewise recorded.

Various parameters (for example, the overlay pressure) must continue to be collected not only during but also after cleaning and sterilization. Additional measures need to be taken if it is not possible to avoid the simultaneous cleaning of flow paths that run in parallel. For example, the pressures of the lines and pipes must then be tested separately. With regard to the fail-safe design of the CIP/SIP units, the cleaning and sterilization limits also need to be monitored to be able to exclude the possibility of any unnoticed recontamination.

Automated system status management arises out of this monitoring. The relevant system status (cleaned / not cleaned / sterilized / not sterilized) is at the same time a release or lock-out signal for subsequent processes.

CIP systems: Two different types Procedures exist for systems with a CIP premix tank and a recirculating pipe as well as systems in which the media themselves are produced “inline” in the system and operate without CIP premix tanks. Both versions for the preparation of the cleaning media – inline or as a system with a CIP premix tank - can be used independently of the CIP unit (tanks, dosing system, etc.). There are no limitations since, in view of the very low flows, recirculation of the cleaning medium via the CIP unit dosing system is seldom done. In the case of CIP systems with a CIP premix tank the process to produce the CIP media is done ahead of time and to a certain extent independently, and hence whose timing is somewhat decoupled from the CIP process. A pump to convey the CIP medium to the respective CIP unit is always part of a recirculating system with a heater tank. In the case of CIP systems with fixed piping and a CIP premix tank, an intermediate rinsing with purified water or with WFI directly from the loop is performed during the use of the CIP premix medium for timing reasons. In the case of CIP systems that

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operate without a CIP premix tank, all the cleaning media are produced “online” and are monitored by fast measuring and regulating systems. This brings about a rapid availability of the CIP system; there are no waiting times for the production of the CIP medium. Recirculation of the CIP media is also possible via process tanks or freeze-drying chambers. The cleaning parameters need to be monitored constantly in both types of systems: temperature, concentration (conductivity) of the cleaning media, pressure (in connection with the flow rates), cleaning time.

What must be taken into consideration in the design of CIP/SIP systems? A great many questions need to be clarified: Fundamentally speaking, the number of cleaning cycles required per cleaning process and the number of CIP objects to be cleaned must be defined. This consequently raises the question as to whether the cleaning media will be run just once through the system or recirculated. It is also necessary to define which cleaning media are to be used in what working concentrations and at what temperatures. Furthermore, it is also crucial for the design of

the CIP system to decide in what containers the relevant CIP media are to be supplied. A further question is what cleaning and media infrastructure is already available at the customer’s site? What distances need to be bridged between the CIP system and the dosing system? Also, what is to be done with the waste water that is produced; is it conventional industrial waste water or does it contain highly active and/or toxic residues which need to be decontaminated and treated separately? Suitable points must be identified for placement of sensors to monitor the cleaning parameters such as the temperature and flow rate and/or pressure, as already stated above. In addition, it is necessary to agree upon how the CIP system is to be regulated. Is the CIP pump to be operated at system pressure (the flow rates to be set are a result of this) or is a new feed rate value to be set by the CIP pump, depending on the path switching? Is intermediate rinsing with purified water or WFI to be done or will the subsequent cleaning medium replace or displace the previous medium? Last of all, the criteria for the final rinse must be defined. Will the rinse be performed to a conductivity value, or will it be a function of time and quantity, etc.?

External offline cleaning and sterilization (COP/SOP) of product path parts (intermediate product tanks, filling hoses, filling needles, etc.) is done by specialized cleaning machines and steam autoclaves (steam sterilization). This raises the question as to why a system operator should select the one or the other procedure. As is almost universal in special machine construction, the choice of suitable cleaning and sterilization facilities for filling systems is at the same time an individual and a complex decision. Although it is possible to compare the systems on certain criteria, it is still not yet possible to make



a general recommendation solely on that basis. In addition there are often also laws, regulations or directives that must be followed. And, last but by no means least, the pharmaceutical companies themselves develop certain “philosophies,” convictions and internal guidelines within the specified scope, with the result that existing technical facilities can also have an influence on the decision. The decision matrix as to which type of cleaning and sterilization is to be used is nearly always characterized by the same factors:

The various cleaning and sterilization concepts need to be subjected to closer examination with these aspects in mind.



CIP/SIP

COP/SOP

The advantages are that…

 the cleaning and sterilization process is not subject to the influence of the operator. The automated process leads to reproducible results.  the product feed and sterile filtration together with the filling system are subjected to a single CIP/SIP process, with the advantage that the entire system can subsequently remain closed.  this also means that the product filter test (wetting, integrity test, drying) can be integrated and automated.   the entire documentation of the CIP/ SIP process for the filling system and the associated functions take place within a system.  no aseptic connections or manual actions are required. A manual setup would be difficult to carry out, especially in isolator applications.  the residues of H2O2 that occur in the hoses of isolator applications are eliminated by the SIP process.  the system does not require any intralogistical movements.

 the size and number of batches – the “total batch processing time”  the properties of the product (harmless vs. toxic) and the risk of cross-contamination  the training and level of knowledge of the machine operator(s)  the available infrastructure and capacities  the project budget and the time frame of the project  ability to validate

 no additional cleaning and sterilization facilities are required, such as washing machines or steam autoclaves.



The disadvantages are that…

 the filling lines are shut down longer and are unproductive (see the illustration on page 7) after a CIP/SIP cycle; in particular, the cooling down phase for rotary piston pumps after SIP is very time-intensive.   additional pipes and valves must be placed in the aseptic “core zone.”  the aseptic core zone can become contaminated in the event of damage to a hose.  the investment costs are higher.

The advantages are that…

 format change times are shorter (compared to CIP/SIP).  the offline cleaning and sterilization of the dosing systems runs independently of the production process.  no additional pipes are required in the aseptic core zone.  the investment costs are lower.



The disadvantages are that…

 the cleaning and sterilization process is subject to the influence of the operators (operator error)  aseptic connections and manual actions are required.  additional cleaning and sterilization facilities such as offline washing machines and autoclaves are required.  the cost of validation is greater, because all the processes that take place offline must be described and validated.  variable costs are higher.

o-com Magazine

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di nser t ion

ZoOm INOVA SV module: fully loaded!

System solution for syringes and vials

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Modular systems in pharmaceutical filling and packaging are gaining in importance. They have a great many advantages and come a long way towards meeting new requirements presented by biopharmaceutical products.

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Optima Pharma has, in the form of the INOVA SV, a well proven machine that had been re-engineered in recent years into a highly flexible modular system. This modular system is regarded as an important supplement in the construction of special machines – the quality is thus at the level of the high-performance systems. The INOVA SV covers a wide spectrum of application, all the way from testing up to small and medium-sized batches. Biopharmaceutical products hedge new requirements: Numerous product changes are typical. The INOVA SV modular system can therefore be equipped with comprehensive upstream and downstream equipment and barrier functions to ensure safe processing of various types and classes of pharmaceuticals.

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ZoOm

An INOVA SV machine can be set up either as a semi- or fully-automatic system. Versions with two, five or a maximum of ten filling points can attain an output of up to 18,000 containers an hour, depending on the properties of the product, the number of filling points and the method used to insert the stopper. The dosing range extends from 0.1 ml to 50 ml. Containers, filling systems and additional functions in all variations The keyword is flexibility: The INOVA SV allows the processing of nested ready to use syringes and of nested vials in one unit. The operator can set up the machine accordingly by himself within the scope of a form change. Customers make a quick change

within 30 minutes. The contact points of the system to the containers are reduced to an absolute minimum to allow for more gentle processing. In addition, there is no glass to glass contact of any kind during the processing. A further factor concerns the available filling systems. A number of variations are possible, all of which can be set up very quickly and easily as part of the format change work. Rotary piston pumps, peristaltic pumps, mass flow metering and time-pressure systems offer advantages and disadvantages relative to the various types of pharmaceuticals. A suitable choice can be made in each case with due regard to their specific properties.

Output of up to 18,000 containers/h

There are further options to choose from. If equipped with the appropriate modules, it is possible to fill under a vacuum or to pre- and post gasify the filled products with an inert gas. In addition, in-process control (IPC) takes place, by which the filling weights are recorded up to 100% and statistically evaluated. This system enables an especially high level of filling accuracy to be attained because it is possible to perform automatic trending control of the individual filling points. Buffer systems to temporarily store the product are likewise available. Nested syringes or vials are usually presterilized and placed in the machine. Several functions can be integrated into the upstream area of the INOVA SV to assist in the handling of the packaging materials.

Fully automatic, semi-automatic or also manual functions for bag opening (cutting open), for handing over to the transport system into the next higher room class, to pull off the sealed Tyvek foil from the nest and to remove the intermediate layer (e.g. TR robot or Tyvek Removal Box) are available as options which can be added to the INOVA SV machines. Secondary-processing and barrier systems Closing of the packaging component with a stopper or plunger under vacuum can be done in the downstream area. Syringes can be fitted with a plunger rod, backstop finger flanges and/or a safety device. Optical and sensory inspection

systems ensure pharmaceutical quality, labellers label the products and document the processing. Tack & Trace systems can likewise be implemented. Last but not least, barrier systems are a decisive criterion for deciding which classes of pharmaceuticals can be processed within a unit. The INOVA SV can be equipped both with isolators and laminar flow units that can be operated from the control panel. Higher clean room classes, operator protection and protection of the pharmaceuticals against contamination are added as required, including systems for processing toxic substances. The compact and narrow footprint of the INOVA SV makes effective use of barrier systems.

Advantage: can be scaled and modified The necessary investment is very flexible through the use of a modular system. The machine can be adapted at any time to suit changing market conditions or new requirements of the pharmaceuticals to be processed. It is possible to initially invest in a less comprehensive system and expand it later for increased output and functionality. Last but not least, a modular system has well-proven interfaces between the components and functions. This thus reduces the planning cost and, as a rule, the time to complete the project as well. Last but not least, a good modular system such as the INOVA SV is characterized by nothing less than this: It has a proven track record. 

Dosing Range from 0.1 to 50 ml

Model INOVA SV 125 12

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Format Change in

SpOt

15 to 20 min.

Maximum Output

Simple, compact and extremely flexible

3,600 Vials/h.

No experiments

Filling Accuracy

+/- 0.5 %

A system that is to be used for the development of pharmaceuticals and for small production runs must in the first instance be able to adapt to all conceivable requirements, and that, in an especially simple way. A leading pharmaceutical company is therefore making use of an INOVA VFVM 7000 from Optima Pharma. Simple and flexible work flows that also must be as secure as possible in a pharmaceutical environment are also necessary for the development of pharmaceutical products. The filling and closing area of the machine operates under an oRABS. In addition, the buffer and diverter area of the unit and the manual loading and unloading system is also under oRABS. The unit is intended for processing liquid and lyophilization products. Manual work was included in the system concept, which is possible in the RABS zone through strategically placed glove

ports. The stopper sorting equipment and the post-gasification unit including the sterile filter can be installed aseptically for format changes. In the same way, the installation of the rotary piston pump and the connection of the filling needles can be manually aseptically handled. The system flexibility is achieved among other ways with two filling systems, rotary piston and peristaltic pumps, both of which are installed in the machine. Different product recipes, including which pump system is to be used, can be selected at the system controller.

compact – good accessibility – large format range – high flexibility – short setup and changeover times – high filling precision Tests with high filling precision The transfer of the product is done via an LTP port (Liquid Transfer Port): The containers, vials, which had previously been autoclaved in stainless steel trays, are pushed by hand into the take-up point (under RABS), the cover is removed by gloved hand and the vials are drawn in manually by means of a slider valve onto the infeed turntable of the filling and closing machine. The stoppers or caps are inserted manually via an RTP port system. If liquids are to be processed without a subsequent freeze-drying process then the containers are transported to the first weighing station of the 100 % in-process control (IPC). This determines the tare weight. The first weighing and the associa-

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ted filling is followed by the second weighing station to determine and control the gross weight and hence the filled weight. The filling system is continuously adjusted through statistical evaluation, which results in very high precision of filling. After the cap or stopper has been put in place, the bottle passes through a transition zone to an existing crimping machine. Optima Pharma has taken all the required measures within the machine so that the customer can retrofit particle counting and install active and passive monitoring systems for viable and non-viable particles.

Quick format change Semi-automatic loading of the freeze-dryer Liquids that are intended for freeze-drying are given a lyophilization stopper which, as is usual, is not pushed in fully. These containers pass uncrimped to the buffer or diverter area into the semiautomatic frame loading and unloading system. The loading and unloading system is the interface to the existing freeze-drying system of the customer. The frames, which are cleaned and sterilized in the freezedryer, are removed manually plate per plate from the freeze-dryer and temporarily parked. A frame is placed in the lowering unit of the loading and unloading system. The vials are batched and the frames are

then lowered over the formatted vials at the press of a button. Now the frames with the vials in them can be manually pushed onto the plates of the freeze-dryer by the use of a gloved hand. Several frames can be positioned on each plate. During the freeze-drying process, the loading and unloading area is readied for unloading and the sprocket wheel replaced with a displacement plate. The frames with the vials are pushed out manually and the vials transported to a rotary turntable. After marshalling, further transport is done via the customer’s existing transport screw conveyor to the crimping machine. At the end of this process, the closed containers can be removed.

A change of format can be completed in 15 to 20 minutes, depending on the scope. The dosing system can also be changed within this time. The rotary piston pump and the peristaltic pump each attain a filling accuracy with +/- 0.5% deviation (as the median value of the set value) for volumes ranging from 1 ml to 500 ml. The machine is operated by one person. If the freeze-dryer is to be loaded, this can be done more quickly by using two persons.

Pharma for volume weights up to 250 ml. The maximum output is 3,600 vials an hour. The unit makes a convincing case through its compactness, good accessibility, its large format range, high flexibility and short setup and changeover times. 

The unit is set up for vial formats 2R to 50R (special vials) and can optionally be operated with vials of up to 250 ml (vial diameter = 66 mm). The 100% in-process control accommodates formats up to 50 ml, and can be optionally retrofitted by Optima

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NewcOmer The route for the components The debagger is on the other side of the line. Operating in parallel to the carpule processes, the line prepares the constituent parts of the devices for the assembly process. These are packed, pre-sterilized, in a tub that is bagged in foil packaging. The tubs that are fed in manually are freed of the foil semi-automatically in a cutting device. These then pass via a first air lock into an area that is protected by laminar flow. Here the TRR robot takes over and pulls the Tyvek paper from the tub fully automatically and places it in a waste container. The tub

is rotated by 90° before it passes through a further air lock into the area of the FSM assembly and welding machine. Each tub contains components for nine products. These are transported to a round indexing table. Once they have arrived, a plastic cover is taken off the tub by a gripper arm and is dropped into a container for waste that opens and closes automatically. The tub stops in this position. A total of six functions are handled at the round indexing table.

1: Placement of the transfer unit and cartridge holder into the round indexing table 2: Insertion of the carpule into the transfer Unit 3: Pressing the carpule into the final position and measuring it 4: Mounting of the cartridge holder 5: Welding of the transfer unit to the cartridge holder 6: Removal of rejects

Complex assembly with inspection and laser welding

Robotic teamwork A form of administering drugs that goes beyond anything known to date, so too the associated process in which several components are joined into one another and to some extent welded as well. The medication container, which resembles a carpule, only constitutes a product that is ready for use together with numerous other components. Two product streams converge on the line. On one side it involves the carpules that have already been filled with the medication. The components of a multi-part packing and application system are applied at another point. The carpules are inspected in several stages in the machine and only meet up with the packaging components at a round indexing table. Here they are put together to make up the final product

The functional units of the overall line: - Manual debagger DBM - Tyvek Lid and Liner Remover, TRR robot - Buffer system - Inspection machine - Assembly and welding machine FSM

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The process in detail: The path of the carpules begins at an upstream INOVA VKVM 3051 filling machine from the filling area via a paternoster and two sprocket wheels to a bottle lift. This allows the prevailing spatial restrictions which the line is installed to be overcome. A robot gripper arm takes the glass containers from the lift. The first process variation envisages a direct transfer to the inspection machine. The second variation allows a transfer to a buffer system as required, in which case robot “1” first inserts the carpules into trays. Filled trays are automatically placed in a tray system. Empty trays are made available. The loaded trays are then taken from the paternoster shelf system again at a later time and placed in the inspection machine area so the robot can resume processing.

The inspection process is performed over several steps. Three robot arms work “hand in hand” to monitor the product and its container. First of all, the carpules are put into a binary inspection cell by robot “1”. A rearward-placed robot “2” takes a carpule, passes it through two further process stations before it is inserted into the gripper of robot “3”, which transports and tips the container by 45° for a further visual inspection. The container is then finally passed on to a sprocket wheel in which it exits the inspection zone. The job of robot “4” is to initiate the subsequent processing route. This is a direct handover to the transfer unit for the assembly and welding machine or into a separate reject unit, which is separated into the removal of rejects and a path for quality control. The parameter for the number of samples to be ejected for quality control can be set by the operator. In addition, the operator can manually force the next good object to be conveyed as a quality sample into the QC magazine at the push of a button. The magazines (trays) can be removed by pushers. Inspection of the cartridges was performed with equipment supplied in collaboration with another company.

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NewcOmer

Merry-go-round The cycling round indexing table: Here a robot arm (# 5) always grips two components of the multi-part packaging and application system from the tub

Checked many times – the so-called transfer unit and the cartridge holder – and places them in a transport cup (work piece holder) in a gripping system of the round indexing table. After indexing to the second station the two “product streams” of the line are

finally joined with one another: the tested carpules and the packaging and application system. Here a robot arm (# 6) places the carpules into a transfer unit from above. In station 3 the carpules are pressed into the defined position with the application of a defined force. At the fourth station the cartridge holder is taken from its position and placed by means of swivelling movement onto the transfer unit with the cartridge and at the next station the cartridge holder and the transfer unit are welded together by a laser system. To do this, a jig is pressed onto the cartridge holder and the transfer unit is set into rotation via the work piece holder for the welding operation. Products that do not meet the specifications are rejected at the sixth station via a slide. The products that have passed the tests are next picked up by yet another robot arm (# 7) and placed back into a tub from which the components were initially removed. Components can still be taken out from one side of the tub while finished products are put down at the other side of the tub. In this way the line can function without the need for any additional temporary storage. Once a tub has been filled with nine completed packing and application systems it is transported out by means of a discharge conveyor belt and through a double air lock out of the clean room. The slight overpressure in the protected zone can be kept almost constant through the use of the air lock.

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The work flows in the entire system are checked and monitored by a large number of sensors; whether the specified machine movement positions have been complied with and also whether the products and components are actually present. The laser-welded seam is monitored by a pyrometer as well. The measured temperature values are evaluated by the pyrometer software and a test graph over time is produced. It is crucial for the individual and also temperature-sensitive product to know whether the values went above or below the relevant upper and lower limits during this welding operation. The product is rejected if that is the case. A further special point is the light barrier system over the extraction magazine. As soon as a magazine has been pulled out the light beam is broken and the magazine is “out-of-bounds” for the robot for the positioning of the carpules. Thereafter the carpules are laid down in a coordinate system of the next extraction magazine. The amount of particle contamination is also checked in the processing zones to ensure compliance with ISO class 5.

The laser welding process has been optimized so that the amount of particle contamination generated by the process is kept as low as possible. The transport device also avoids creation of particle by raising the tubs into the waiting position, away from the continuously moving belts, after a short time. This resolves any issues with particles created by friction.

need to be made can be done almost completely without tools. A format change is done in the first instance by the PLC. The line can process 600 units per hour. The extremely compact line was implemented within a period of 13 months. 

Carpules sized 5, 10 and 15 ml are processed by the line. The few mechanical adjustments that

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ShOwroom Numerous container and process variations for diagnostic products

Wide variety of processing options driven to the limit Optima Pharma has achieved a wide variety of processing options on the basis of a KUGLER Linoline monoblock machine for diagnostic products. The liquid and freezedried products are processed over a range from 0.03 to 1000 ml. The vials and bottles can be round or rectangular. The output rate is up to 7,200 products per hour.

Bottle Height up to

192 mm

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Format Change in

20 min.

 Dual dosing system: There are 4 ceramic rotating dosing pumps for small filling volumes and 4 peristaltic dosing pumps with an especially large format range. Each can be extended to a maximum of 6 filling points.  100 % in-process control with feedback to individual dosing points for high precision of filling (+/- 0.5 %)

 Scales in docking configuration for quick changes, for a wide processing range  Preparation for two-component filling; additional weighing cells can be retrofitted.  Aerosol extraction at each filling point, e.g. for volatile sulphuric acid.  Pre- and post screw cap tightening from 0.8 to 6 Nm with 100% torque monitoring

100 %

Torque Monitoring

 Further types of closures such as stoppers, crimp caps, dispenser pumps can be handled  Quick change of format (20 minutes), among other things, due to special format parts underneath the closure station 

Precision of Filling

+/- 0.5 Percent

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NewcOmer

Compact, single chamber freeze drying unit with integrated WFI production for CIP and decontamination

Freeze dried bacteria: assured safety in all phases When an independent decontamination station is economically not feasible due to low production demand, custom-tailored solutions, which are equally as safe, must be found. The to-date smallest Klee production unit will soon be used by a pharmaceutical company to freeze dry bacteria for the manufacture of vaccines. Despite the compact design, an autonomous decontamination system is included.

“Surface Area 0.2m², Loading up to 500 Ampoules, Format 0.2 ml” The surface area of the freeze dryer is only 0.2m2, large enough for loading up to 500 ampoules sized 0.2 ml. With the use of special format parts, batch sizes of 300 or 200 ampoules can also be processed. The actual vaccine will be later made in a batch tank using the freeze dried bacteria. The finished lyophilisate still contains enough water to allow the bacteria to survive, and allow a live vaccine to be manufactured from it at a later date. The compact, single chamber freeze drying unit comprises a shelf and a radiating plate for creating even temperature distribution. The special feature of the single chamber construction is that the chamber and the condensation unit are mounted in a single unit. An intermediate valve is not necessary. The fact that all other aggregates, such as the vacuum pump and coolant loop, are mounted on a skid, further contribute to the small size of the unit. The freeze dryer was installed in a Class-A cleanroom at negative pressure to the surrounding area.

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New solutions for waste water Particular emphasis in this project was placed on the entire CIP/SIP and decontamination process. The different bacterial agents to be freeze dried are classified as biosafety level (BSL) 3. Aside from the actual freeze drying, functions for Clean-inPlace and and Sterilize-in-Place (CIP/SIP), a decontamination cycle and a leak test are included. For cleaning of the unit (CIP), WFI water for cleaning generated by the freeze dryer itself, is used, since neither WFI nor purified water are available to the unit. WFI is generated by condensing the clean steam supplied to the unit. Sterilization is performed using conventional clean steam at up to 1.5 bar. Because it would have been economically unfeasible for the customer to supply a decontamination system in their building for this one single, small freeze drying unit, options and solutions were sought

after to decontaminate all condensate leaving the freeze dryer. This is unusual, however, as the industrial use of these types of bacterial products typically require a decontamination station. Particularly important is that the decontamination is performed as a redundant “overkill” process”. The freeze drying unit is capable today of containing and treating contaminated waste water in a closed system as required, before opening the system to draining. All media within the unit are heated to the prescribed temperatures, thus ensuring that bacteria within the media are destroyed. Thereafter, the waste water is passed to the on-site waste water treatment. Close cooperation between Optima Pharma and the customer during the course of the project was necessary to create the freeze drying unit which is best tailored to the special requirements posed by the product and process. Further processes were developed by OPTIMA pharma following a pre-FAT, to satisfy additional requirements 

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PanOrama

PanOrama calendar

Trade Shows

Instruction and Training for Customers

For improved skills A good combination: Optima Pharma has developed training programs which incorporate practical work on the production lines together with background theory. The aim of the first stage is competent routine operation. The term “Training” is intentional as, similar to practice in sports, the production line processes must also be practiced and learned. The training program is based on a four-stage concept whereby specialist elements can also be planned and carried out individually, entirely in accordance with the customer’s wishes.

Suggestions for customer training programs are always welcome! Visit www.optima-pharma.com and go to Service "Questionaire for training programs" to access a questionnaire with the help of which the most important and most interesting themes can be identified. For these topics, new or more advanced training course offers will be created. Please take part – thank you very much!

06-18-2013 – 06-21-2013 EXPO PACK México Mexico City, Mexico Booth 1924

06-25-2013 – 06-28-2013 Fispal Tecnologia Anhembi Pavilion São Paulo, Brazil Booth D136

09-23-2013 – 09-25-2013 PACK EXPO Las Vegas Nevada USA Las Vegas Convention Center

09-24-2013 – 09-26-2013 Fachpack Fairground Nuremberg Nueremberg, Germany

10-15-2013 – 10-17-2013 A3P Biarritz, France

Optima Pharma has developed a four-stage training program. This program unites the methodology and didactic knowledge of the two customer trainers, Ralf Horlacher and Alexander Herrmann, with the practiceoriented know-how of top machine fitters in Schwäbisch Hall: No-one knows the machines as well as the people who assemble them. The first stage of the program is the foundation course. After a machine has been installed and put into operation, there then follows instruction of first basic knowledge.

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Safety devices and operating functions are explained, format changes carried out, messages discussed and alarms acknowledged. The second and third stages involve training for the operators and technicians. Here, the aim is fault-free operation and ongoing maintenance of the machines. These training courses are mostly booked together as a package. They take place in part (approx. 30%) in the seminar room. On request, customer-specific training material can be prepared in digital form. This can include, for example, a virtual screen operation and visualized error correction, process reports, films,

animations and data sheets. The documents serve as reference material. At the same time, they also represent a useful tool for the introductory training of new employees. In the fourth stage Optima Pharma offers expert training. These training programs are developed and compiled individually on specific topics and in consultation with the customer. Typical issues dealt with here are, for example, automation, SOP, process technology, and also parameter training relating to time-pressure-dosing systems or cam control mechanisms.

At all training course levels there is a newly compiled guideline for the overall framework. This therefore guarantees the possibility to deal with important questions, objections and discussions as well as with all the important aspects scheduled for the training. Apart from the training schemes, the customer trainers also work out solutions in the service area for warehousing of spares and for preventive maintenance. Here too, there is a close cooperation between machine fitters and service technicians where key ideas

and instruction can be given. Customers benefit in the form of usable, practice-related documentation. 

10-29-2013 – 11-01-2013 Chinapharm Shanghai, China

11-05-2013 – 11-06-2013 PDA Universe of prefilled syringes Basle, Switzerland

11-05-2013 – 11-06-2013 ISPE Annual Meeting Washington D.C., USA

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The New Era in Packaging Technology

The Internet of all things – machines in the net

Packaging Valley Germany

When semantic product memories are fed with position and temperature information from sensors , optical or other sensors are an essential factor for the functioning of the so-called Smart-Factory. XML-based web servers the size of a sugar cube, with radio-control -technology and the replacement of the many different field bus systems by TCP protocols allow interaction between machines, the product and the packaging. Nowadays, as sensors are not costly, and are available with W3C (World Wide Web Consortium) standards. According to Prof. Wahlster, the way is open for the “Service-Oriented Cyber-Physical” production system. These are automated, interacting systems which function context dependent. The ambient machine, transport and robot park is therefore a “Service Offer” which is called up and utilized by the product. For example, should there be a hold-up in processing at a certain point, the product itself looks for a better alternative. Another example: especially low-energy production methods are chosen for ecological products.

heralds the start of Industry 4.0 “The importance of packaging and packaging systems technology in connection with Industry 4.0 is gaining ever more significance!”. At the 2nd Packaging Valley Days, Prof. Dr. Wolfgang Wahlster, leading expert in artificial intelligence, was convinced that Industry 4.0 is no longer just a vision. Those taking part from the packaging sector confirmed this. The congress of specialists in the Cluster Packaging Valley Germany e.V. in Schwaebisch Hall was attended on 10th and 11th April by around 250 visitors from 20 countries. Industry 4.0 is currently in the limelight of current media for the industrial world specializing in hi-tech, . The reason for this, of which Prof. Wahlster (German Research Center for Artificial Intelligence, Saarbrücken) is convinced, is that the current working environment is undergoing fundamental changes. Emerging products

or packaging in which processes information is recorded from the beginning right through to transport, has an enormous impact on the whole of the working environment. Machines are programmed for new tasks; the workforce goes to new, different factories.

Prof. Wahlster reports on the phenomenon of “Mass Customization”. The example of the automobile industry shows that today no two vehicles are identical; not only in appearance but also technically, improvements in components and software are being continually introduced. Today even mass wares such as training shoes, muesli or chocolate beans are available in production runs of a single unit. In the words of Prof. Wahlster, “Industry 4.0 offers the tools of implementation with practically no additional costs”. Individualization is becoming more and more the norm. Products which are customized to personal requirements will soon no longer be regarded as exclusive.

Prof. Wahlster went on to illustrate that the packaging also fulfills additional tasks. The scope of information contained in or on the packaging can be significantly

expanded, whereby the whole production chain becomes transparent. Also at home the packaging can be an observer and watchdog. If for example, light sensitive contents have been exposed to light for too long, an automatic warning can be sent to a Smartphone. In the subsequent discussion session, the subject of a filling and packaging line from Packaging Valley Germany which to a great extent already operates according to these principles came up. With this line perfumes are packaged at a high output rates for a run of one unit. Customers create a personalized perfume by selecting a mix of fragrances, and choose the flacon and the wording on it. The entire manufacturing and packaging process up to the declaration of the contents in conformity with the legal regulations of the country of receipt of the ordering party is automated. The representatives of the pharmaceutical industry who were present were a little more reserved towards the benefits of Industry 4.0 because of their complex certification procedures. At the same time, personalized medicine was acknowledged as a future scenario which could benefit enormously from the technical implementation of Industry 4.0.

Plasma, service and open doors Other interesting technologies presented were for example, surface treatment with plasma technology for sterilization through to improved adhesion. New requirements, technologies and potential in service in machine engineering were discussed. On the second day of the congress, the companies of Packaging Valley Germany opened their doors and demonstrated their latest machine concepts, from particlefree transport systems and Blow-Fill-Seal through to the tremendous precision of filler units in combination with flexible robot technologies. Several shuttle buses ferried the 250 visitors around Packaging Valley. The organizers summed up with satisfaction: “A visit to Packaging Valley demonstrates how inspirational both competition and close cooperation can be. In technological terms, everything is possible here. I believe that the event we organized has reflected this very well” reported Bernd Hansen as the Chairman of the cluster and owner of the Hansen Corporate Group. After the event, Kurt Engel (CEO of the Association) concluded “The positive feedback from the visitors and entrepreneurs will probably lead to a regular Packaging Valley Days event every three years”.

About Packaging Valley Approx. 8,000 people work in Packaging Valley in the packaging machine industry. The percentage of exports is often more than 80%. The USA and the whole of Europe are important markets and now the emerging markets in South America and Asia are being added. The established

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industrial structure with over 40 packaging machine manufacturers and supplier companies including numerous world market leaders led to the setting up of the association “Packaging Valley Germany e.V.” in 2007. One of the most important concerns for the Association is to draw attention to this

concentration of specialist competence unique in the world: in the Schwaebisch Hall district and adjoining regions, potential and existing customers get all the information they need on leading packaging solutions all within a small area.  www.packaging-valley.com

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“What drives me? My

goal to satisfy demanding customers. Worldwide.” Basem Gerges Bachelor of Science Electronics Engineer (Sales Manager)

We from Optima Pharma are convinced: A demanding customer should never have to settle for mediocre solutions and - above all - not when it comes to safety and hygiene. This is why we plan, develop and design filling lines that keep all the options open – regardless where your machine will produce.

OPTIMA pharma GmbH | Otto-Hahn-Straße 1 | 74523 Schwaebisch Hall Telefon +49 791 9495-0 | [email protected] | www.optima-pharma.com

Member of