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Moving to the next level of productive, reliable performance in bio/pharmaceutical manufacturing requires a willingness to make changes and create a quality culture.
In any industry, manufacturing or operational excellence can be thought of as efficiency, productivity, and reliability, with minimized downtime and few product failures. But excellence is an ever-moving target. “Manufacturing excellence is not just the best way to do it today, but continually improving to the next level,” suggests Hal Baseman, chief operating officer at ValSource LLC.
In the pharmaceutical industry, manufacturing excellence also encompasses the need to serve patients by providing safe and effective medicines without an interruption in supply. Regulatory quality requirements-current good manufacturing practices (cGMPs) and product testing, for example-are designed to ensure safety and efficacy, but opinions vary as to whether compliance necessarily leads to excellence. “Compliance is important, but it is not where a firm should focus the majority of its resources and efforts. The bio, pharmaceutical, and medical device industries must transform to embrace quality beyond compliance,” advises Martin Van Trieste, chairman of the board at the Parenteral Drug Association (PDA).
Some have the misconception that profitability and quality are mutually exclusive; compliance is costly, and quality is just too costly. In reality, “quality processes are more profitable. They are more reliable and error free. Yields are higher, rejects and defects lower,” says Baseman. Proponents of operational excellence in pharma hope that the industry will move from a compliance to a quality culture.
What is needed to achieve manufacturing excellence? To perform at six sigma quality levels, says Van Trieste, a manufacturer must:
Robust process design, highly qualified personnel, a reliable supply chain with second sources identified for critical components, and well maintained, reliable equipment, are all crucial, adds Sue Schniepp, distinguished fellow at Regulatory Compliance Associates. “In addition, there must be a functioning quality system underlying the entire process that is proactive in identifying issues and risks to the supply chain by using metrics and information that inform the company of potential problems,” she says. The three metrics proposed in FDA’s November 2016 guidance (lot acceptance rate, product quality complaint rate, and invalidated out-of-specification rate) (1) are three basic measures, but companies also need to develop and use their own metrics beyond FDA’s program (see “Industry experts weigh in on FDA’s Quality Metrics program”).
Traditional quality measures in pharma focus on product measures or end results, but “smart” devices and equipment provide more data about the equipment during the process that can be analyzed. “Automation, data collection, and data handling are part of the informatics movement that is one of the fastest growing areas in manufacturing. Compared to other industries, pharma is well behind the curve in this respect and it represents a huge improvement opportunity for the entire industry,” suggests Marc Bonner, senior director of operations at Mayne Pharma USA.
Automation and process analytical technology (PAT) help to reduce human error and support data-based decision making, adds Frank Generotzky, plant manager for Baxter BioPharma Solutions’ Halle, Germany facility. “These are helpful tools to handle and statistically evaluate data to identify process variations in a timely manner. Quick decisions for optimization can be made based on technical/scientific data leading to an environment of continuous improvement.”
Achieving manufacturing excellence requires process understanding, risk-based thinking and decision making, science, and common sense, adds Baseman. “The bio/pharma industry tends to focus too much on what we think regulators want to see, rather than what we actually need to do to improve the process.”
One of the first steps in moving toward excellence is the willingness to look for areas that need improvement and the courage to make changes, whether that means better use of existing technologies or using new technologies or systems that can bring a process’ performance to the next level.
Often operators and staff have many ideas for what could be improved. Leaders must prioritize where to start. “My advice is to start with a project that is creating the most pain for operators in manufacturing and make significant improvements quickly,” recommends Van Trieste, who points out that this action is a good way to gain needed support from the plant floor. “Success breeds success. Only take on new projects that can be accomplished with the existing resources, and only start another project after one has successfully completed,” he suggests.
Continuous manufacturing and PAT, for instance, create opportunities for improving process efficiency and productivity. The focus on improved process understanding that comes with implementing these technologies is likely a significant driver for process improvements, says Thomas Friedli, professor of management at the University of St. Gallen’s Institute of Technology Management, who has been studying pharmaceutical manufacturing practices since 2004. Data indicate that the most successful companies “have a higher focus on true root cause analysis and also have more PAT implementation,” he says.
“Embracing new technology often requires new and different ways of thinking,” notes Baseman. “For example, continuous manufacturing is a great way to increase process efficiency, but existing strategies for batch control, validation, and testing don’t always align well with it. People have to get past the concerns over batch definitions and traditional means to test and monitor processes.” A tendency to focus and rely on testing and monitoring rather than process improvement can hinder change. “The pharma industry is good at collecting data, testing, and monitoring, but needs to be better at listening to what that data tells them,” says Baseman.
The regulatory burden of post-approval changes for existing processes is a real concern, but this barrier must be overcome to achieve excellence. While PDA’s new Post Approval Change Innovation for Access to Medicines (PAC iAM) taskforce is working to create awareness and find broader industry solutions to this challenge (2), companies are finding ways to improve their facilities where the benefits outweigh the costs and risks (3). Modernizing aging manufacturing facilities requires long-term benefit analysis. “It is often a matter of progressive process improvement. One step may result in only a 10% increase in productivity by modernizing, but that step will set you up for another 10% improvement when you make the next change, and so on,” suggests Baseman.
Reluctance to upgrade manufacturing equipment and facilities is a barrier to excellence. “Older equipment can be unreliable and hard to maintain, resulting in unforeseen downtime,” notes Schniepp. Another problem is older products that are not up to today’s standards. “Many of these products were developed with different standards than those required for new products. The transitioning to today’s standards can be a time-consuming process and could potentially result in supply chain interruptions. If the industry can work with regulatory authorities in determining a path forward to updating these products, then this obstacle could be overcome,” she suggests.
Various methods are available to help manufacturers improve quality and set up continuous improvement programs, including Six Sigma, Kaizen, lean manufacturing, and operational equipment effectiveness (OEE), and many companies use pieces of these depending on the problems that need to be solved. “I see more companies using an internally branded, blended approach to solving problems and implementing effective change that sticks,” adds Jerry Rosenthal, director of continuous improvement for US Pharma Commercial Operations at GlaxoSmithKline (GSK). “A balanced combination of project management, change management, and continuous improvement (Lean and Six Sigma) seems to be on the way to becoming the most common way for pharma manufacturing to achieve their goals.”
“There is no one-size-fits-all program. Every approach should start with an analysis of the company’s current status,” says Friedli, who advises that teams tackle any underlying equipment or process instability issues before trying to reach other objectives, such as taking out waste and driving down inventories. The University of St. Gallen’s Operational Excellence (OPEX) Benchmarking program aims to help analyze a company’s starting point on a scientific basis. For the past three years, Friedli’s team has also been moderating an industrial OPEX exchange group to facilitate conversation about best practices and experiences.
Japanese quality gurus such as those who developed the Toyota Production System describe the need for senior management to be in touch with people actually doing the work, in the “Gemba,” Japanese for the place where truth will be found. Gemba walks--getting onto the plant floor to see problems first-hand, and try to get suggestions from workers to help solve them directly--have the advantage of allowing managers to take action to solve the problem at its source, rather than just measure and monitor, notes Baseman. At the same time, improvement programs should have measurable, objective metrics. “Understanding the performance of process and equipment is the first step to improvement. One cannot improve without objective methods to assess and evaluate manufacturing,” says Baseman.
OEE is used by many to improve productivity. “We measure and review OEE daily to understand what is affecting our equipment availability, performance, and quality and put action plans in place, following the Deming cycle ‘Plan, Do, Check, and Act’ to track our performance improvement,” notes Catherine Kay, Operations director at Aesica. “We are also looking to implement measures for ‘Mean Time to Repair (MTTR)’, which is the average time that it takes to repair equipment after a failure.”
Programs used at Vetter include OEE, Six Sigma, lean manufacturing, and the internal “Vetter Optimization System,” which includes a Production Excellence (PRODEX) initiative. PRODEX is designed to track all aspects of production, including people, material, machines, customers, and processes, explains Gerald Buerkle, vice-president Pharmaceutical Production, Vetter-Pharma-Fertigung. The program has helped improve quality and yield, increase flexibility and capacity, and improve personnel management, among other benefits.
The main benefit to any of these programs is having a structured approach to determining what needs to be done to improve operations, and a viable course of action to implement the improvements, says Schniepp.
“We’ve found that a structured process makes it easier to train personnel and provides tools and techniques to solve problems,” says Bonner. “It also provides consistency and continuity to the problem-solving process, which helps streamline rapidly solved or similar problems and improves persistence and perseverance to systematically address larger or more complex issues.” Whatever approaches are used must fit in a company’s culture.
“Culture” might seem an ambiguous term, but experts say it is crucial for achieving excellence in anything, including manufacturing. “Manufacturing excellence is an entire philosophy, and, to become sustainable, it must be deeply ingrained in the structure and the culture of the company,” says Friedli. He notes that “one-dimensional efforts only aimed at cost cutting, short-term initiatives, and no visible top management commitment,” among other problems, are signs that initiatives will not be sustainable.
“All levels of the organization must be involved and invested, from the line operator and maintenance personnel to the general manager,” adds Schniepp. “Having a consistent culture can be particularly challenging when multiple sites or companies are involved, such as CMOs. The CMOs need to have a manufacturing excellence culture, as well as their clients.”
People tend to resist change, notes Van Trieste, but “an effective leader must create the case for change, tie the case for change to the mission of the organization, and be specific about what has to change and who it will impact.” Leaders must also overcome the fact that organizations in pharma still tend to work in silos (e.g., R&D, Quality Control, or Operations), rather than crossfunctionally. They must gain and maintain alignment of goals and priorities across the silos in their organization so that all the stakeholders are engaged, says Van Trieste.
Quality and continuous improvement must be more than the names of departments in the company--they must become what everyone is trying to achieve. Ideally, if the concepts and tools of continuous improvement were to truly become “part of the way things get done, part of the first step, and not the last consideration, then I believe that manufacturing excellence would be something that more pharma organizations could achieve with ease,” predicts Rosenthal.
1. FDA, Submission of Quality Metrics Data, Draft Guidance for Industry (Nov. 29, 2016).
2. PDA, “PDA’s PAC iAM Task Force Releases Work Plan to Reduce Manufacturing Change Barriers,” Press Release, Sept. 19, 2016.
3. D. Marks, Pharm. Tech. 41 (3) 70-73 (2017).
Vol. 41, No. 3
When referring to this article, please cite it as J. Markarian, "Achieving Manufacturing Excellence," Pharmaceutical Technology 41 (3) 2017.