Lean Manufacturing in a High Containment Environment

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Manufacturing

By Georg Bernhard A case study of how Pfizer’s Right First Time strategy helped overcome at Pfizer Global daunting capacity challenges at its new large-scale containment facility Manufacturing at Illertissen, Germany, while Six Sigma and Lean strategies enabled the site to achieve previously unknown levels of efficiency.

In late 2006, Pfizer launched its smoking cessation film-coated tablets. All of the process stages (granulation, product varenicline, known as Chantix® in the US tableting and coating) are controlled and monitored from and Champix® across Europe. According to IMS a separate control room so that employees do not come benchmarks, Champix® was the fastest product launch in into contact with dust that might be generated during the the European pharmaceutical industry, with marketing tablet production run. Transport is handled by automated, in 16 European countries in a five-month period. As well and entirely robotic, laser-guided vehicles. Operators as creating rapid and unprecedented consumer demand, monitor and control all containment room activities from the product launch also brought capacity challenges for a separate control room. Pfizer Inc’s small-scale IllertissenCONtainment (ICON) facility in Illertissen, Germany. The facility’s innovative IT systems integration enabled an extraordinary 85 per cent level of automation (LoA), A strategic site in Pfizer’s global manufacturing network, outstripping even the ICON facility’s extremely high 76 per Illertissen is focused on oral solid dosage forms and is a cent LoA. Thus, in NEWCON, all process sequences centre of excellence in containment production. Rapidly (dispensing through to coating) are triggered by an growing demand for Chantix®/Champix®, and meeting automation layer; as a function of the manufacturing future capacity for highly potent compounds led to a execution system (MES) layer, batch data is collected and decision by Pfizer Global Manufacturing (PGM) to expand archived automatically. existing ICON capacity by constructing a large scale facility – NEW CONtainment (NEWCON). COMPREHENSIVE IMPLEMENTATION OF PAT Following the PGM vision of an adaptive, automated The aim was to complete the facility in a very short time; quality control system, process analytical technology (PAT) this pressure intensified a few months after the start of techniques are used in all key production process areas, construction in 2006, when Chantix® was successfully enabling continuous online analysis and rapid discovery launched in the US. Despite these challenges, the and response should any irregularities occur. Near infrared NEWCON facility was completed in October 2007 – six spectroscopy (NIR), for example, is used to identify months earlier than originally planned. incoming active ingredient, check mixture homogeneity and confirm that the active substance is present in equal NEWCON DESIGN AND CONSTRUCTION doses in all tablets. PAT improvements include Like ICON, NEWCON is a single-floor, single- development of a device for measuring tablet potency containment module for the production of Varenicline, the online by automated collection and analysis of cores from active pharmaceutical ingredient in Chantix®/Champix®. the tablet press. In combination with process control All production equipment is located in a dedicated systems, PAT applications will in future significantly processing module that is mostly automated and highly contribute to increasing the quality, safety and efficiency of contained; isolator technology ensures that no dust can the manufacturing process. escape from the manufacturing area. Varenicline is manufactured under stringent containment standards. The EFFECTIVENESS FIRST maximum workplace (dust/particle) exposure for the Pfizer’s Right First Time (RFT) initiative aims to achieve product is set at 1-10µg per m3; the ICON and NEWCON maximised process robustness and reliability by use of facilities permit a maximum of just 0.1µg per m3. statistical Six Sigma tools. With the goal of quality optimisation, Pfizer’s RFT training on Six Sigma shows The NEWCON containment concept made possible, for PGM employees how to apply statistical/qualitative tools to the first time, dust-free and fully automated production of the task of increasing understanding of the processes that

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directly affect products. A process cannot be predicted PUTTING LEAN TO WORK unless it is understood, and only when a process is In continuous production from March 2007, the facility understood can mitigating/minimising strategies be devised was producing a daily total of four batches, seven days a and sustainable optimisation achieved. week – up from one batch per day, five days a week in January 2007; by April 2007, production had reached Implemented across the pharmaceutical industry – and a more than 5.3 batches per day. diverse range of other manufacturing sectors – the Six Sigma concept is designed to enable a near-perfect ‘Six Sigma level’ Production capacity increases like this do not occur in a quality standard: for every one million possible errors, only vacuum; what follows is an exploration of how Pfizer 3.4 errors actually occur. In practice, this translates into colleagues put Lean manufacturing to work to maximise working without error 99.9997 per cent of the time. capacity and – in parallel – maintained rarified Six Sigma quality levels. The RFT continuous improvement Pfizer’s ICON team achieved improvements by systematic programme is designed to give colleagues the tools to application of Six Sigma techniques to operate at rarified accurately assess manufacturing processes (internal and quality levels – that is, exceeding Six Sigma. These external), and ultimately to optimise those processes to statistical tools also promote better process understanding, realise increased efficiency for enhanced business gains. and thus ensure ongoing, data-driven process learning based on functional, mathematical correlations between Across Pfizer, the goals of Lean are reduced cycle time, input parameters and quality attributes. reduced inventory levels and improved process efficiency which leads to minimisation of working capital and The weakest link determines overall process robustness. reduced product cost. Pfizer designed its ‘Lean Toolbox’ to Consequently, ‘Black Belt’ and ‘Green Belt’ projects led by enable better management of complexity and improved Six Sigma certified colleagues have helped identify areas for efficiency. Based on value stream mapping (used to map improvement. For example, a tablet assay was improved by current and future process) Lean principles are applied to a modified test method and modification of a process create almost ‘continuous flow’. Semi-continuous, parameter at tablet press; the application of advanced synchronised flow was achieved via stepwise reduction of statistical tools, such as multivariate data analysis, yielded workload at each process step, concurrently monitoring the quality levels of above Six Sigma. overall balance of workload at station.

EFFICIENCY FOLLOWS Already in round-the-clock operation, Illertissen kicked off Another aim of the Right First Time initiative is to create its Lean initiative in February 2007, with the goal of value without waste. Minimising cost (working capital achieving more efficient processes to support continued and production cost), while achieving necessary output production of varenicline to meet market demand. to meet customer demand (Takt Time) ensures reliable, Production processes were closely examined to evaluate cost-efficient product supply. where and why micro losses occurred, as well as where and why things ran smoothly. Applying value stream mapping Being process robustness-based, Six Sigma methodology (VSM), ICON team members broke manufacturing is the mandatory foundation for any sustainable processes down into a series of discrete micro processes and efficiency gain achieved by Lean activity. Thus, Six Sigma evaluated their impact on overall processes. Bottlenecks and Lean are complementary approaches within the RFT were identified along the process path from active initiative used to drive improved overall performance. pharmaceutical substance to tablet and innovative improvement strategies were developed. Waste was cut by Pfizer’s RFT training on Lean shows PGM colleagues reducing transport times, wait times, and process times in how to optimise production; in the case of ICON, this granulation, tableting and coating. Set-up reduction, Single meant bringing production as close as possible to its Minute Exchange of Dies (SMED), spaghetti diagrams, maximum. In February 2006, pre-launch commercial standard work plans, and cycle-time diagrams were among production of varenicline was started at ICON with the the techniques that they used. goal of filling the entire supply chain. On the heels of the product’s simultaneous launch across US and European Applied to manufacturing and support processes like markets in late 2006, initial demand exceeded forecasts transport, and focused on minimising waste, Lean by a factor of five, and within six months, demand had principles enable sustainable efficiency gains to be outstripped even ICON’s capacity, while NEWCON was achieved. By applying Lean principles, the ICON team still under construction. achieved highly balanced, semi-continuous flow of three

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batches being processed in parallel at the three major other front-end decisions, enabling synchronised unit workstations (granulation, tableting and coating). operations to be achieved. Down-time between process stages has been virtually eliminated. Production stages CONTINUOUS IMPROVEMENT are linked so that as one batch is completed the next is Through its RFT, process analytical technology (PAT), brought in. Lean, and other continuous improvement initiatives, Pfizer works to instil a forward-thinking, solution-driven This gave colleagues a jump-start in the new facility – and highly proactive culture at every operational level, and rather than going through an extensive and repetitive encourages colleagues to take an active and participatory learning curve. As a result, the NEWCON team continuous improvement and learning process role. achieved semi-continuous flow at its best, translating in Combining RFT initiatives, the company strives to get the practice into achieving high levels of synchronicity very best out of its processes to advance the path forward between unit operations. Synchronised at all production and enhance business gains. stages, the plant can run efficiently and at capacity with very little down-time, and three batches (of the same Sometimes, however, more is needed. Leveraging product and dosage strength) can be run in parallel in a knowledge to gain new dimensions of performance is also semi-continuous sequence. a key element within the Pfizer RFT framework. The highly effective design approach of the ICON pilot plant is RESULTS COUNT one example. Despite the capacity challenge and urgency to At Illertissen, the overall result of Lean manufacturing is bring the NEWCON facility into operation, the Illertissen seen in more robust processes, increased process team strove to exceed ICON’s standards to realise the next understanding and greater efficiency levels. At the ICON level of innovation and performance. facility, loss of sales of US$200 million have been prevented, product availability has been ensured at all Adding value by implementing ‘lessons learned’ through time (99.5 per cent-plus service level, zero ‘stock out’ RFT was also a goal. Model simulation software, based on situations) – and no single launch was missed. For both actual process experience and knowledge gained at the ICON and NEWCON facilities, overall product cost ICON, was used to virtually mimic processes prior to was reduced by 52 per cent (as compared with 2007). transfer into NEWCON. This tool enabled the Illertissen Lead times and inventory levels have been kept at a low team to anticipate improvements based on virtual level (even with increased throughput). By implementing processing and to optimise process steps and optimal Lean manufacturing principles across the NEWCON design throughput by using Lean principles like line facility, the number of operators has been reduced by 66 balance at workstations. The resulting insight was used to per cent, for a corresponding efficiency gain of 300 per establish process goals, and decide priorities for action cent. Also noteworthy, PGM is currently filing the first before the first batch was produced at NEWCON. real time release for oral solids manufacturing using varenicline as a role model. Essential goals included minimising process downtime. An insignificant and easily replaced part is not so CONCLUSION insignificant when it’s holding up production. You can’t The quest for quality and efficiency is as old as fix a problem until you know it exists, and process manufacturing itself. With a substantial boost from Six mapping is an excellent tool for identifying where and Sigma and Lean, this age-old quest is playing out anew why process are breaking down. Another goal was across the modern pharmaceutical industry. At achieving line balance between the major unit Illertissen, PGM’s RFT strategy and framework enabled operations: compounding, core compression and film Pfizer colleagues to overcome daunting capacity coating. Process study findings guided equipment and challenges and accomplish their mission. Six Sigma and Lean strategies enabled the site to reach previously- Georg Bernhard has served Pfizer Global Manufacturing unknown performance levels of effectiveness and as Director, Right First Time, (RFT), at Pfizer’s Illertissen, efficiency, and to maintain the highest service level Germany site since 2003. At Illertissen, Bernhard has also (above 99.5 per cent) at competitive cost. The Lean served as Pharmaceutical Production Manager, and Validation initiative at Pfizer Illertissen is ongoing and shows no Manager/Team Leader. Before joining Pfizer, he worked as sign of losing steam. A truly collaborative effort Project Leader, Pharmaceutical Development, for Cyanamid. He holds a degree in Pharmacy from the University of Munich. between colleagues and departments, Lean applications Email: [email protected] continue to identify process waste and value-added strategic solutions.

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