The host, Optima Group Pharma, presented 14 renowned speakers from the international pharmaceutical industry covering a variety of significant topics of both importance and of concern with panel sessions and lively debate all set in a relaxed and atmospheric setting.

With his lecture on “Simultaneous Engineering“, Dr. Bernd Kühn (Sanofi Aventis, Frankfurt, Germany)  presented a comprehensive and innovative  approach to project implementation which he called, Simultaneous Engineering . The goal of this new and innovative method, is a shorter ‘time-to-market’ from product development to production and vending. As opposed to the traditional sequential organization, Simultaneous Engineering uses a multidisciplinary practice. The incorporation of experts from various fields into an interdisciplinary team early in the project is aimed at producing parallel work processes, and maximum process standardization frees capacities for creative and constructive tasks. In the speaker’s view, this is of considerable advantage for cost and quality factors.

Ryan Hawkins (Cook Pharmica, Bloomington IN, USA) spoke about the implementation of a large project which spanned two and a half years. The project included the installation of a filling and closing line for prefilled syringes featuring isolator and e-beam technology in addition to a filling and closing line with isolator and freeze dryer. The narrow time window was sufficient for developing new internal ‘standards’ for the infeed of liquid products. The new method uses disposable materials. Hawkins emphasized the significance of all-embracing and strict preparatory planning and consistent documentation to ensure efficiency and a satisfactory pace during actual implementation especially for projects with tight deadlines.

Another organizational technique to shorten implementation times is the so-called iFAT (integrated FAT), which – as a rule – is carried out at the facilities of the filling and packaging manufacturer, and not at the customer’s site. The speaker Cham Lam (Genentech Inc. South, San Francisco, CA, USA) argued that this approach allowed recognizing potential problems much earlier, and helped solve them with better staff resources. He reported how five suppliers came together in Germany for the iFAT of their project. Components requiring improvement were revised during machine dispatch (six to eight weeks). The higher costs for the iFAT were compensated by a calculated cost advantage of at least around 15% when compared non iFAT. Commissioning the line in the US later required almost no corrections.

Frank Generotzky (Baxter Oncology, Halle, Germany) introduced an ambitious project (not only with regard to implementation time) - “Six months from FAT until production“. A strictly limited time window of only three weeks was available for machine set-up at the customer’s site: Interruption of the production of another drug had to be avoided at all costs. The first ruling principle, therefore, was to leave as many critical process parameters unchanged as possible, i.e. clean room conditions (classes), materials in contact with products, batch sizes, staff etc. With these frame conditions, however, a barrier system was needed that would guarantee safe protection from toxic products. In the process, air flow directions needed special attention. To identify criticalities, the air flow was simulated by computer models within the risk management - most successfully, as it turned out later.

All speakers who spoke about project management agreed unanimously that extensive and intensive communication between stakeholders and early integration of the operating staff – in the design phase, if possible - is crucial for success.

Precision in technology and effective project management required

Gordon Ruane (Amgen Manufacturing, Juncos, PR, USA) confirmed the views regarding iFAT and early documentation, but went one step further and placed the focus on the complex topic of process flexibility and maximum product use. Both are relevant for biopharmaceutical ingredients – which are often processed in small batches of high financial value. The solution implemented at Amgen uses time-pressure filling systems, but also includes rotary piston pumps to be prepared for processing viscous products. The in-process control reduces potential product losses during machine start-up, clearing, and routine filling.

Wolfgang Epple (Cilag AG, Schaffhausen, Switzerland) discussed the high financial risks of expensive biotech-products that are processed in filling campaigns. Campaign filling is practiced for presterilized (SCF) and bulk syringes, which are filled and closed by using multiple isolator use. The isolator remains sterile during the entire process. This system is aimed at maximum exploitation of the lines’ capacity and saving costs by less frequent format changeovers and preparatory work. The methodology of the procedure: Examination of each campaign batch is based on ten parameters, among them bio burden testing, particle monitoring, microbiological surface control and a glove integrity test. (Operator and pressure testing are carried out at the end of each campaign batch). When SCF syringes are processed, the efficiency of the e-beam tunnel also undergoes testing. In addition, media fills are executed to ensure repeatability of the sterile conditions and microbiological product quality. The result: Savings per batch during bulk processing of max.10,000 CHF (less packaging and microbiological material and isolator gloves). This new approach to SCF syringe processing releases as many as four operators for other tasks. During bulk processing, free line capacity is augmented by another 41 percent, and by 47 percent when SCR syringes are processed. Epple conceded these advantages should not distract from the fact that potential financial damages caused by contaminated and unusable campaign batches could be significant. Consequently, he concluded, a precise analysis of risks and restrictions of a filling campaign already in the preparatory phase and with the greatest possible care was absolutely vital.

Justin Farell (Eli Lilly, Indianapolis, IN, USA) presented a project for new biodrugs that was to be implemented inside an existing building. At the time of the presentation, the project was not yet completed. The venture’s challenge consisted in making optimum use of the existing building technology and – simultaneously – generating maximum flexibility with regard to dosing systems and container types. A critical decision concerned the question if RABS or isolators should be used – or if VHP would affect the products. The solution includes a filling and closing machine that is able to process the required range of syringe types with the help of format parts, i.e. a machine that can flexibly carry out statistical IPCs from 0 to 100 percent, that can use rotary piston pumps as well as peristaltic pumps, but also masters vacuum filling and various vacuum closure types. A vial filling machine – also in RABS technology – will be installed additionally. The format range reaches from 2 to 50 ml. The two filling systems can be exchanged and process a variety of closure types, among them lyo plugs. Moreover, a connection to three lyophilization lines was established and an existing capper can be directly approached, if needed.   

As Farell, Dr. Christian Matz (Roche Diagnostics, Mannheim, Germany) presented an installation within a so-called modular building concept, which was implemented with the goal of optimizing the workflow. Compounding, filling and closing technologies are installed within class D and C clean room environments at ground level. Product tanks as well as ancillary materials, for example nitrogen, are stored on the floors below and above to allow supply from there. On these floors – in separate rooms - HVAC and EDP technologies were also installed. The space concept provides short paths, color orientation e.g. for the various clean room classes, generous integration of glass elements and is aimed at process optimization. Additional factors of efficiency: Peristaltic pumps mounted onto racks outside the isolator, a rapid transfer port for H2O2 and closed systems using alpha/beta ports for syringe plugs and disposable tubing are supportive elements that will be added in the near future.

Filling technologies and containers in detail

The conference’s agenda also included topics exclusively dealing with issues of pharmaceutical filling. A biopharmaceutical product had  also inspired the presentation of Leticia Fabiano (Genzyme Biosurgery, Ridgefield, NJ, USA), who outlined that temperature sensitivity, pressure sensitivity, homogenization and high product value (in this case: 1 million US$ per batch) are the typical challenges The specific case involved abnormal product viscosity, which initially had led to bubble formation inside the syringes during filling, resulting in potential hazards, as for example deficiencies in filling precision and high product loss. Above all, air within the syringes – if intravenously administered – impairs patient safety. The developed solution includes several elements: First, the filling needles were specifically adapted to the product’s properties. This measure, combined with filling and plugging under vacuum, finally produced the desired results. At the same time, a precise balance between insufficient and excessive vacuum suction forces had to be found to avoid suctioning excessive product quantities into the containers during filling, and to prevent product leakage at the side of the plugs during closing.   

Stability studies were the subject of the presentation of Jason Fernandez (Pfizer, Andover, MA, USA). He explained how changes under changing temperature conditions in various drugs - monoclonal antibodies and cytokines - in glass and plastic syringe drums were analyzed: Chromatography showed no differences, and nephelometry produced no irregularities. But micro flow imaging showed particle contamination in the glass syringe at a temperature of 40°C. Over a period of twelve weeks, higher values also developed in plastic containers. Nevertheless, the study confirmed that plastic material is particularly well suited for cytokines. Plastic containers also proved to be more suitable for biopharmaceuticals. Only oxygen penetration (oxidation) may cause certain problems.

Michael Mizenko (Sanofi Pasteur Inc., Swiftwater PA, USA) highlighted aspects of developing and implementing a project for filling and closing systems. A filling and closing machine had been ordered in the course of the development and/or the formulation of a new drug. During project implementation, some of the frame conditions changed, including the pharmaceutical substance itself. No information on the product was available throughout the project’s entire run time and the FAT/SAT were carried out utilizing water. In the following, this led to difficulties with product feed lines and with programming product parameters for the filling and closing line. Modifications with regard to integration of the equipment into the existing floor plan and logistic supply of the line, subsequently became necessary. In addition, the machine staff was familiarized with the line very late. The resulting difficulties clearly showed the importance of a close co-operation between customer and suppliers right from the start of a project, and the severity of consequential damages, if vital information– for whatever reason - is not available.

Lyophilization - another subject comprehensively covered by the Forum: Dominique Sierakowski (Octapharma, Lingolsheim, France) spoke about critical factors of the lyophilization process (temperature, pressure, time) and strategies for securing this complex procedure. The expert recommended to keep processes as simple as possible and to secure them by redundancies: By cooling system, sensors (pressure and temperatures), vacuum pumps, circulation pumps, PLC, data recording as well as backup power supply by generators – conceding that it was legitimate to question if this comprehensive backup could still be called simple. In addition, he continued, test programs had to be in place to discover potential faults at an early stage. Further requirements, in his view, are defined calibration programs, readily available spare parts, established SOPs and a qualified operating crew. In cases of emergency, only a few minutes remain to save a charge that may be worth millions of Euros. If several freeze dryers are operated in parallel, an alternative for a centralized cooling system should be considered. Such a system would simultaneously permit operation of a smaller conventional cooling system.

A competent specialist discussed the regulatory framework of pharmaceutical production: Analyzing the practical consequences of the revision of Annex 1 (2008) of the EU Directives, Dr. Daniel Müller (Regierungspräsidium Tübingen, Germany) emphasized that his statements expressed his personal views and no ‘official’ opinion. In addition to explanations regarding clean room classification, monitoring, media fills, bioburden monitoring, the presentation mainly treated vial filling. Müller postulated that vials with inserted plugs that are not entirely pressed-in had to be kept under class A clean room conditions. As crimping generates particle loads, crimping stations needed their own specific ventilation systems. Two variants were feasible for the capping process: Sterile plugs and sterile caps ought to be processed in an aseptic process, and the entire process had to take place in a class A clean room in a class B environment. The first step in a ‘sterile/clean’ process would be pressing in sterile plugs in a class A clean room. During capping, the laminar flow would have to be qualified as class A air to allow processing of non-sterile caps in a class C or D environment. According to the speaker, no definition for class A air existed so far.

Reduction of capital commitment of pharmaceutical companies by outsourcing measures was the topic of Dr. Werner Seiferlein. According to his theory, drug manufacturers will increase their outsourcing in the future to be able to focus on their core activities – i.e. developing and marketing pharmaceutical products.  According to Seiferlein, the share of infrastructural costs in the overall production costs could amount up to 27 percent. In an industrial park like the Industriepark Höchst (Frankfurt/M.) it is possible to generate synergy effects by bundling tasks e.g. with regard to energy efficiency, building technology including IT, logistics and waste management. By a specific example, the speaker demonstrated how one prime contractor could achieve a lead time of six months just by using synergies for approval, planning, construction and implementation for realizing a new pharmaceutical production site. The shortened time to market brought to a turnover increase by 150 million, which – in this case – was tantamount to the total building costs.

Insight into practice
During the Pharma Forum, Optima Group Pharma offered company tours through its assembly halls on both days of the event. The visitors had the occasion to inspect 17 ongoing machine projects for prefilled syringes, carpoules, vials and small bottles; a mock-up study, and a project ready for FAT with an output of 36,000 prefilled syringes per hour were also on display. Further interesting exhibits were flexible changeover systems for dosing modules, disposable systems for safety devices, one particularly compact line, an e-beam sterilization device and a pilot lyophilization line. The partner companies Lugaia STS and Metall + Plastic were also present. Lugaia showed equipment for the safe and efficient sterile transfer in and out of isolators (Stericon system), Metall + Plastic demonstrated isolators and e-beam systems.  

 
The visitors were more than satisfied with the event’s agenda and outcome.  Gordon Ruane, who closed the Pharma Forum with his presentation, summed up his impressions: ‘We have seen that we are all pretty much doing the same thing. To me, this shared experience and the resulting dialogue are an important confirmation, reassuring me in my work.”

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