Applying lean manufacturing to the pharmaceutical fill-finish facility

Applying lean manufacturing techniques to the fill-finish facility

February 27, 2017 - Blog, Pharma Industry

By: Eric Petz
Senior Marketing Manager
Vanrx Pharmasystems

In 2014, I walked an electronics production line in Shenzhen, China. The factory made high-reliability power electronics. As we toured the facility, the production leader outlined how lean manufacturing principles enabled the company to produce according to demand, flexibly produce many different products, and eliminate waste.

Here’s a video, so you can see the production line at work.

Pharma companies are facing scrutiny over drug prices and manufacturing-related drug shortages. Implementing lean manufacturing principles can be part of a solution. Lean applies an operating discipline that can positively impact the company’s financial health.

Matching production to demand

The production manager in Shenzhen said the inability to produce according to market demand—either under- or over-production—was the greatest threat to profitability and cost of production.

Pharma CEOs know this pain well. Shortages harm patient outcomes and reduce revenue. Excess inventories tie up billions in working capital.

In the mid-2000s, Merck implemented lean to make its manufacturing processes demand-driven and reduce costs. One of the crucial inputs for Merck was demand signals from the customer. When demand signals were known, a “continuous, just-in-time production flow” would support an appropriate amount of production. Their efforts reduced production-related inventory costs by up to 30% and overall operating expenses at the plant level by up to 20%. Merck cited the reduction of downtime as crucial to these successes.

In a separate example, Petrides et. al explores how production scheduling can support lean fill-finish operations. Their emphasis is on how plant capacity is matched to demand through scheduling, including the effective use of downtime. Removing bottlenecks from production is an activity undertaken in lean systems by cross-functional teams (CFTs). CFTs will look at limitations in equipment, labor, utilities and materials to remove bottlenecks as part of continuous improvement programs.

In Shenzhen, unscheduled downtime was the greatest danger to meeting production quotas. Downtime could occur from multiple sources, with the most common being machine failure or component quality. Scheduled preventative maintenance avoided the failures, while incoming QC checks looked at component quality to ensure parts met specifications.

In the fill-finish context, matching supply with demand will be an increasingly important performance metric. The consulting firm Bain & Co. found that drug companies are launching many more drugs for smaller patient populations and that competition for market share is more intense than in the past. In their analysis, 50% of all launches in the peak sales range did not meet expectations and half of those missed by more than 50%.

When front line conditions can change so rapidly, it becomes more important for the pharmaceutical manufacturer react to changing demand (and to perform better forecasting). Production systems that are more flexible, with faster cycle times and less downtime must be adopted.

Flexible manufacturing capacity

The Shenzhen factory was already accustomed to the need for flexibility. That company had hundreds of SKUs with variations in cabling or software making up most of the differences. Production systems supported flexibility with short changeover times and clear work instructions. Cross-training of employees supported agile production.

Robotic automation was a critical part of that flexibility. When humans could not perform a task quickly or reliably, robots would be introduced to the line. Robots are designed for extremely high reliability and repeatability. Robotic operation means that flexibility is built into software, not hardware, making robots a superior option for companies whose long-term production requirements are not yet known.

At a recent pharmaceutical trade show, we had a long conversation with the production leader of a major pharmaceutical company. He admitted that his organization was not prepared for the diversity and uncertainty of the products in their pipeline. The key difference was that all of their existing commercial products had big volumes, and all of their pipeline candidates had smaller targeted patient populations. They were struggling to find time on their existing lines to produce clinical batches. Changeover times made format and product changes unfeasible. He said they would likely choose CMOs for those batches, even when they preferred to keep new drug products in-house.

The production leader was describing the need to introduce lean principles into the pharmaceutical industry.

Lean manufacturing facilities for pharmaceutical fill-finish enable greater production flexibility into different containers, with higher quality, and lower costs / resources committed to production.

The elimination of non-value added activities

For the CFTs at the Shenzhen plant, there was a continuous evaluation occurring of where value (defined as value to the customer—the aspects of the product that made it saleable) was created in the manufacturing process. Non value-added activities were eliminated.

As an example, certain electronic components would arrive in bulk. They would have to be repacked in smaller trays to be taken to the assembly line. Working with the component supplier, the CFT asked that the parts be provided in custom trays, in quantities that matched the flow of the production line and allowed easy restocking. The parts could arrive just-in-time and ready to use, reducing inventory costs and rework that could cause the line to go down.

This story has a direct parallel in fill-finish. Washing and depyrogenating containers and closures prior to filling is necessary, but does not add value when done by the filling facility.

The lean solution is pre-sterilized, ready-to-use (RTU) containers and closures within plastic nests. These products have additional benefits including that the containers and closures can move immediately from the warehouse into production, and the product risks of singulated component handling are removed by treating a nest of containers as a single unit.

Combining nested containers with nested closures also allows a fresh look at the lyophilization process, says Gregor Deutschle, Business Development Manager for SCHOTT: “Up to 100 vials are held in a nest and can be moved at once, hence loading and unloading the freeze dryer becomes much faster – up to three times, to be precise. And: a separate stoppering and an additional crimping step are no longer needed. Stoppers are already integrated in the nested plastic closures which are placed on the vials. When the shelves of the freeze dryer press down, the closures thousands of vials are fully sealed at a time.”

SCHOTT ready-to-use vials, syringes and cartridges.

Pre-sterilized, nested vials, syringes and cartridges support two key areas of lean manufacturing: flexibility and focus on value-added work.

Fill-finish has another significant non-value added activity: the number of operators observing the process. Other industries would not have highly-trained people standing ready to intervene in an “automated” process. In a lean facility, the machine would perform all of the work, while a single operator observed. In a lean operation, glove ports are undesirable because they introduce waste in the form of excess labor and manual interventions that cause bottlenecks.

Finally, another lean principle can come into effect: flexible manufacturing. Gregor Deutschle explains: “Let’s say we want to fill product A, B, and C in different containers on the same line, and changing the setup in between would take about a day. We would be filling each product for two weeks, and including the two changeover days it would take 30 days until product A could be manufactured again. Within those 30 days, however, the market demand might change. If all container formats are processed in the same standardized nest, we can bring changeover time down to several hours. And if necessary, a pharma company would be able to manufacture A, B, and C on the same day. As batch sizes continue to decrease and drug treatment targets ever smaller patient populations, such flexibility will be decisive.”

Where to start?

This post provides the reader with some basic thinking about how lean principles from other industries can influence pharmaceutical fill-finish manufacturing.

Vanrx embraces many of the key components of lean manufacturing and is championing them in the pharmaceutical industry. The company’s Aseptic Filling Workcell supports flexible production, making it easier to align demand and production. Vials, syringes and cartridges can be filled with minimal (<1 hour) changeover times. The Workcell approach is highly scalable, based on a standardized machine design with built-in flexibility. Standardized machines with predictable maintenance schedules are preferred by lean practitioners.

The Workcell reconfigures aseptic filling around robotics, gloveless isolator and nested container and closure technologies. These new approaches to filling machine design eliminate non-value added labor and container / closure preparation. The Matrix Alliance, a collaboration between leading pharmaceutical packaging companies, is working to assure the compatibility and performance of nested packaging components. All of these design choices contribute to a lean approach that reduces the cost of manufacturing sterile injectables.

Talk to Vanrx

Contact us to find out how our Aseptic Filling Workcells can cut production costs, reduce downtime and bring drug products to market faster.

Links for further reading

The U.S. Food and Drug Administration’s Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base

Benson, R. and Kulkarni, N.S. Understanding Operational Waste From a Lean Biopharmaceutical Perspective. Pharmaceutical Engineering. November/December 2011, Vol. 31, No. 6.

Cunningham, A. “Just in Time. An Approach for a cGMP Fill-Finish Facility.” Pharmaceutical Engineering. March / April 2010. www.flad.com/content/epubs/hff_just_in_time.pdf

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