Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	Single-use tubing can be used for the length of a biopharmaceutical product campaign and changed when a new product is to be manufactured. To prevent failure during lengthy use, tube life should be monitored and a preventive maintenance program enacted. 

 spoke with Gregg E. Johnson, global senior product manager for the Cole-Parmer peristaltic pump product lines, about these concerns.

 How long does single-use tubing typically last?

The lifespan for tubing is dependent upon pumping conditions- speed, pressure, fluid, and fluid temperature. Some new biopharm formulations of silicone tubing can last 200 to more than 1000 hours. For the Pharmed materials (made from a thermoplastic elastomer), life expectancy can be several thousands of hours.

 How does a company go about monitoring the tube life?

 In our testing lab, we monitor the tube life by recording the hours between failure. Once we have a pattern, we can set up preventative maintenance based on the specific installation. Each one is different due to different fluid, piping systems, and other devices in the fluid path.

 What are some rules of thumb for performing preventive maintenance?

 Preventative maintenance (PM) and the frequency at which it is performed is determined by the pump operator. A simple recommendation is to review the tube-life data provided by the pump manufacturer. A good place to start may be at 75 to 80% of the manufacturer’s data until a reliable pattern is defined. Each installation is different. Once this pattern is established, and longer PM cycles are desired, the operator can elect to extend the cycles to fit needs.

 How can tube life be extended by moving the tubing to a new position?

 If an operator is performing a long-term campaign and is concerned about tube life, he or she can extend the run and prevent the possibility of tubing failure by moving the tubing to a new position. This is accomplished by setting the system up with excess tubing on the discharge (outlet) of the pump. Once the campaign is running, the operator can, on a periodic basis-once a week or once a month-pause the pump rotation, open the pump head, and slide a section of unused tubing (from the excess at the start of the campaign) and move the used section from the pump head to the suction (inlet) side. The pump is then closed and restarted.

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To prevent failure during lengthy use, tube life should be monitored and a preventive maintenance program enacted.

Preventive Maintenance of Single-Use Tubing for Peristaltic Pumps

	Process analytical technology (PAT) is helping process engineers to better understand and control their processes by measuring the critical process parameters (CPPs) that affect critical quality attributes (CQAs) of the product. PAT is particularly important for implementing continuous solid-dosage manufacturing, in which material must be measured and tracked as it continuously flows through connected equipment. Spectroscopic PAT is useful, but has some limitations (1). Industry experts say that PAT can be more than spectroscopy; PAT can also include “soft” (i.e., software or virtual) sensors that correlate easily measured process conditions (e.g., temperature, feedrate) to CPPs using first-principle models. 

 spoke with Dr. Jim Holman, process development manager, APC Pharma Solids, GEA UK, about the role of PAT in solid-dosage manufacturing and in the GEA ConsiGma continuous manufacturing platform, for which the company won the “Best manufacturing technology and equipment” award at the 2016 CPhI Pharma Awards (2). The ConsiGma platform can produce blends, granules, or coated tablets continuously using either wet granulation or direct compression. 

	PAT in continuous solid-dosage manufacturing

What role does PAT play in continuous solid-dosage manufacturing?

 PAT plays a crucial part in continuous dose manufacture and is already successfully utilized on a number of GEA continuous solid oral dose manufacturing platforms. The mistake that is often made is to automatically assume that PAT refers only to spectroscopy or other added instruments, such as laser diffraction. In theory, a displacement sensor could be called PAT if after data analysis, it allows one to analyze and control the process, and therefore product quality, through the (indirect) measurement of a CQA.

	However it’s defined, the real benefit of any PAT system is that it can enable real-time monitoring of the drug product quality attributes that would normally be measured by other methods, usually off-line laboratory testing.  PAT often also ensures that a far higher percentage of the material is measured, thereby increasing the ‘data points per kg’ in comparison to traditional off-line or at-line methods.

	Blend uniformity prior to compression, particle size 

 laser diffraction, moisture content post drying, tablet assay, and tablet coating film thickness are all examples of measurements that have been successfully enabled on GEA continuous lines in the past. The use of PAT enables the rapid development of the process design space without the need for extensive off-line testing, and it allows the development cycle to fully utilize structured scientific methods to assess products in a much shorter timeframe. 

	For example, on a GEA ConSigma granulation, drying, blending, and compression line, 105 separate design of experiment points have been conducted in one eight-hour working day. By comparison, the feedback from the project industrial partners at the time was that 3–5 points would be managed, at best, using traditional manufacturing methods. PAT enabled the real-time measurement of granule loss on drying and blend particle size distribution (PSD), while at-line PAT enabled the measurement of tablet assay and other key properties. This testing would have taken weeks to yield the same level of data using off-line systems. 

	Spectroscopy, however, is not a golden bullet that will solve this matter for all cases. Not all products can be tracked using near infrared (NIR) spectroscopy.  Secondly, if there is significant change to raw materials/API lots, then models built and verified for one supply may no longer be valid for another. Changes to the process can also cause the model to be invalidated, for example ramping the throughput of a line from 10 kg/hr to 50 kg/hr.  NIR models will be required to cover specific API concentrations, so for multi-dose strength formulations, a number of PAT models will need to be built and maintained.

	The key to PAT is consistent sample presentation, and while continuous processing makes it easier to control this, the shifts naturally seen in development programs as the design space is explored can cause issues with some PAT applications.

What are some examples of what is measured by online spectroscopy for continuous tablet production?

 Currently spectroscopy based-PAT is employed in a number of locations on GEA continuous platforms:

  NIR spectroscopy focusing on the specific water wavelengths has been integrated into the GEA continuous tableting line for some time now, and is routinely used to give a real-time prediction of the loss on drying of exiting granules. These data can be fed back into the control system of the fluid bed dryer, altering the release criteria and actively controlling the drying process to ensure the correct product quality of the dried granules.

Particle Size Distribution (Laser diffraction):

 Instruments aimed at measuring the PSD of the milled granules has been proven on ConSigma granulation lines.

  By locating a NIR system on the powder inlet to the tablet press, the blend uniformity of a system can be measured in real time just prior to tablet compression. This system is employed on both the continuous direct compression system and the continuous wet granulation line. The measurement of blend uniformity is used for two key purposes:

		For APIs where an accurate and precise NIR model can be validated, the system can be used to track the actual blend concentration in real time in place of off-line high-performance liquid chromatography (HPLC) testing. 

		If models can only be used to give indications of the API percentage, NIR can still be a powerful tool in assessing the process design and operating space. Measuring the residence time distribution (RTD) of systems enables the direct modeling of systems using fundamental understand of the process. GEA continuous blending and compression systems have been accurately modelled using RTDs to the point that the blend potency can be predicted using the measured input feed variability and the system RTD, which can be fully aligned with measured blend potency from the online NIR system.

 On the GEA continuous coater, the thickness of coating layers can be measured as the layer is applied in real time. The measurement is performed by monitoring the drop in the API signal as the tablet is coated and the inherent rise in the coating material signal.

How can ‘soft’ sensors be used as PAT tools and what information can they provide?

 Some of the most powerful tools often overlooked as PAT on any continuous solids line start in the basic process data taken from current unit operations, specifically loss-in-weight feeders and the tablet compression systems. The development of virtual (soft) sensors that use robust direct measurements (e.g., temperature, pressure, displacement, force) and turn these data into product quality information is of significant interest at this time and has already been shown to give insight that can potentially replace the function of some spectroscopy-based PAT. 

	Data generated from the unique, air-compensated compression stations in a GEA tablet press are shown to track RTD disturbances through the system (to the actual point of compression as opposed to close to point of compression as with NIR). In one case study, a valid NIR model could not be built, so this alternate PAT method was used to quantify the mixing capability of the entire GEA CDC-50 direct compression system. The design space was mapped using the GEA RTD model of continuous blending built on the data from the tablet press only. This method eliminated the need for NIR and allowed for the development to continue without the need for time-intensive HPLC testing.

	The advantage of such an analysis is that unlike NIR, the measurement signals from displacement sensors do not need complex multivariate models that required developing, validating, and maintaining. The methods are robust to potential variation in incoming raw materials and scalable over throughput ranges. 

	Previous studies have shown that by tracking changes in the filling of individual dies in the tablet press, changes in granule properties out of the granulation and drying system can be directly tracked by comparing the apparent powder bulk density in the press. This method has been shown to have a greater accuracy than continuous PSD measurements via laser diffraction. 

	Changes in powder characteristics (e.g., lot-to-lot density or flowability changes) can be directly measured going into a continuous process using the data from the GEA compact feeder, potentially opening the possibility of feed-forward quality control where systems are prepared for product changes.  

What do you foresee as trends in the use of PAT in continuous solid-dosage manufacturing as this type of process begins to be more widely used?

 The benefits of spectroscopic PAT instruments are well known, as are the limitations. The technology is shown to yield significant benefits into the development system of a product, enabling faster analysis of products. The exponential growth area, however, will be in other virtual sensors that can be considered PAT. Continuous systems generate a significant amount of data, and at this time only basic data are routinely used. Using soft sensors to analysis these data, yielding more insight into the actual product quality, will generate significant interest in the coming years.

	We are already seeing a trend of using spectroscopy-based PAT during development to verify fundamental models such as RTD models, but this spectroscopic PAT is excluded for commercial production platforms in favor of soft sensors and mathematical models that are more robust.

		J. Markarian, “Overcoming Obstacles in Process Analytical Technology,” Equipment & Processing Report, Feb. 15, 2017.	

		PharmTech, “Manufacturing Technology and Equipment Prize Goes to GEA Group,” (Oct. 5, 2016), 

www.pharmtech.com/manufacturing-technology-and-equipment-prize-goes-gea-group

olid Dosage Drug Development and Manufacturing
	

	When referring to this article, please cite it as J. Markarian, "Solid Dosage Drug Development/Manufacturing 2017," 

olid Dosage Drug Development and Manufacturing

Soft sensors are powerful tools that can be used along with spectroscopic instruments in on-line measurement.

Using Spectroscopic and Virtual Sensor PAT in Continuous Solid-Dosage Manufacturing

	Continuous manufacturing of pharmaceuticals could reduce the inefficiencies found in batch manufacturing. It creates an opportunity to implement more modernized manufacturing processes, which lead to better quality end products. This technology could also help prevent drug shortages through faster and more responsive supply chains. Continuous technologies offer the potential to replace the outdated "quality by testing" regime currently employed by the industry with a more robust "quality by design" system, which is possible because of the improved process understanding and  robust control strategies gained through continuous processing, said Bayan Takizawa, co-founder and chief business officer at CONTINUUS Pharmaceuticals, at a conference session on continuous manufacturing at INTERPHEX on March 21, 2017.

	Industry, academia, and regulators have spent significant time and money over the past decade to develop pharmaceutical continuous manufacturing, and commercial approvals have been the fruit of this labor. Many other companies have developed the required technical capabilities and are poised to implement them, but seem to be in a “wait and see” mode, commented Doug Hausner, associate director at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), at the INTERPHEX session. Most of the technical barriers have been overcome by the industry as a whole, he noted, but having the right people, knowledge, and equipment at an individual company can be a challenge. A “big picture” mindset, rather than evaluating the advantage of the new technology on a product-by-product basis, is needed to promote high-level support for capital expenditures, said Hausner. The perception of regulatory uncertainty, particularly in large, important markets, such as Europe, is another limiting factor.  


	FDA has been quite clear on its support of continuous manufacturing over the past several years. FDA’s message has been consistent that it sees no regulatory hurdles for implementing continuous manufacturing, it supports the implementation of continuous manufacturing using a science- and risk-based approach, and it sees continuous manufacturing as consistent with FDA’s quality initiatives (1,2).

	Other regulatory bodies have perhaps not been as vocal in their support of continuous manufacturing as FDA has been, but the European Medicines Agency (EMA) has begun to express support and recently clarified its position, providing further technical specificity. At the 3

 FDA/PQRI Conference on Advancing Product Quality (March 22­–24, 2017), EMA’s Dolores Hernan noted that the current regulatory framework allows continuous manufacturing, and although specific guidelines are not available, the existing ones are supportive of this approach (3).

	Both FDA and EMA recommend communicating with the agencies early in development (2,3). “The toolbox is out there, and EMA and FDA want you to come talk with them to show them you understand these new tools as you go to use them,” notes Hausner.


	Several conferences in 2016, such as the International Society for Pharmaceutical Engineering (ISPE)’s 

, the FDA-American Institute of Chemical Engineers (AIChE) 

Workshop on Adopting Continuous Manufacturing

 International Symposium on Continuous Manufacturing of Pharmaceuticals

 organized by the Massachusetts Institute of Technology (MIT) and the Continuous Manufacturing and Crystallization Consortium (CMAC), have worked to increase understanding and to promote adoption of continuous manufacturing.

	In May 2017, the global International Institute for Advanced Pharmaceutical Manufacturing (I2APM) is hosting the 

Emerging Pharmaceutical Manufacturing Summit

, May 8–9, 2017 in Malta, to bring together first- and second-wave technology adopters, regulators, and academics. C-SOPS, one of the founding groups of I2APM and one of the event organizers, hopes that European regulators, in particular, will benefit from seeing the examples of commercially approved implementations of continuous manufacturing.

	The United States Pharmacopeial Convention (USP), in collaboration with C-SOPS, hosted a workshop in the US in 2016 on continuous manufacturing, one of the outcomes of which was a new expert panel that is now working to standardize terms and characterize materials specific to what it is calling PCM [pharmaceutical continuous manufacturing]. USP and C-SOPS signed a memorandum of understanding in February 2017 as part of their commitment to collaborate and work to make PCM more widely available (4). USP is hosting a 

on May 16–17, 2017 to introduce PCM to Indian pharma companies, particularly generic drug companies.

FDA Perspective on Continuous Manufacturing

,” Presentation at IFPAC Annual Meeting (Baltimore, Jan. 2012).

Continuous manufacturing: Challenges and opportunities. EMA perspective

 FDA 3rd FDA/PQRI Conference on Advancing Product Quality 22-24 March 2017. 	

		USP, “Exploring Continuous Manufacturing Technology and Applications in the Pharmaceutical Industry,” (March 13, 2017), 

http://qualitymatters.usp.org/exploring-continuous-manufacturing-technology-and-applications-pharmaceutical-industry

” Presentation at MIT-CMAC ISCMP (Cambridge, MA, May 20, 2014). 

Conferences focused on continuous solid-dosage manufacturing aim to spread the word about technical capabilities and alleviate perceptions of regulatory uncertainty.

Mindset Change Needed to Drive Continuous Manufacturing Adoption

 are sponsoring a Keynote Series that will be held on the INTERPHEX Innovation Stage. The presentations On Tuesday, March 21, the morning session will feature experts in 

, and the afternoon session will look at 

continuous manufacturing of solid-dosage drugs

. On Wednesday, March 22, the morning session will introduce an 

, and the afternoon session will address the challenges of 

	With the November 2017 US Drug Supply Chain Security Act (DSCA) implementation deadline just months away, companies need to put compliance plans in place if they haven’t already. At the 

, Vivek Nadadur, Program Director for End-to-End Traceability at J&J Supply Chain will discuss best practices for connecting with distributors, and Graham Clark from TraceLink will share insights into gauging CMO partners’ readiness for serialization. Experts from Ropack and Systech International will discuss the quick compliance initiatives they recently launched and how they can help companies and their supply chain partners meet DSCSA requirements by the deadline. At the end of the session, Robert Celeste, Founder, Center for Supply Chain Studies, and Darryl Glover, chief clinical officer, i-Solve, will examine BlockChain, used for secure online transactions, and how it might be used in the pharma industry. 

					To learn more about these topics, read these recent articles and others on 

Continuous manufacturing of solid-dosage drugs

	Continuous manufacturing of solid-dosage drugs has moved from the laboratory to commercial-GMP production, but there are different approaches that can be taken. Bayan Takizawa, MD, MBA, Co-Founder & Chief Business Officer, CONTINUUS Pharmaceuticals, Inc., will describe some of these approaches. Pamela (Bruen) Docherty, Life Sciences Industry Manager for Siemens in the US, will explain the mechanisms of implementing an integrated automation approach and process analytical technology in continuous manufacturing. Doug Hausner, associate director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers University, will present some of the newest innovations for faster development of products using less material, along with programmatic activities aimed at easing the regulatory pathway for continuous manufacturing.     

					To learn more about these topics, read these recent articles and others on 

	The American Society for Testing and Materials (ASTM) is finalizing the “Standard Guide for Science and Risk-based Cleaning Process Development and Validation.” Andrew Walsh, President of the Center for Pharmaceutical Cleaning Innovation; Mariann Neverovitch, research scientist at Bristol-Meyers-Squibb; and Igor Gorsky, consultant, Valsource, will discuss various aspects of the new standard in presentations on Wednesday, March 22 (10:30–12:30).

	The Parenteral Drug Association (PDA) formed a task force to address the concern that the complexity of post-approval changes is hindering modernization of facilities. Maik Jornitz, G-Con LLC, and member of the PDA Innovation for Availability of Medicines (PAC iAM) Task Force will discuss findings from the task force’s activities.

	Kashappa Goud Desai, PhD, Biopharmaceutical Product Sciences, GlaxoSmithKline, will describe bracketing strategies for filing drug applications for the Japanese market. Different strategies can show whether pre-approval for implementation of a post-approval change is required or not. These two presentations will take place on Wednesday, March 22 (1:30–3:00). 

The Innovation Stage, open to all exhibit hall attendees, is located on the far left side of the exhibit hall, towards the back, in front of the meeting rooms  (#1170).

A Keynote Series includes presentations by experts in serialization and traceability, continuous solid-dosage manufacturing, cleaning validation, and post-approval changes.

Industry Trends on Stage at INTERPHEX

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:

		Understand and characterize its raw materials, manufacturing processes, and products

		Be fully engaged in identifying, monitoring, and controlling variation

		Have systems and processes in place that ensure flawless execution during manufacturing

		Deliver products in a robust and reliable supply chain.

	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.

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, 

:
	When referring to this article, please cite it as J. Markarian, "Achieving Manufacturing Excellence," 

Moving to the next level of productive, reliable performance in bio/pharmaceutical manufacturing requires a willingness to make changes and create a quality culture.

Achieving Manufacturing Excellence

	As FDA has noted, the same quality metrics used by the bio/pharmaceutical industry to evaluate manufacturing and fuel continuous improvement efforts “can also be useful to FDA: to help develop compliance and inspection policies and practices, such as risk-based inspection scheduling of drug manufacturers; to improve the Agency’s ability to predict, and therefore, possibly mitigate, future drug shortages; and to encourage the pharmaceutical industry to implement state-of-the-art, innovative quality management systems for pharmaceutical manufacturing.” This potential was highlighted in FDA’s most recent draft guidance on this topic (1).  

	FDA’s Quality Metrics program for pharmaceutical manufacturing is clearly a work in progress, and FDA’s November 2016 revised draft guidance, Submission of Quality Metrics Data, calls for a voluntary reporting phase through which “FDA expects to learn more about a limited set of quality metrics, associated analytics, and improve the FDA quality metrics reporting program” (2).

	Operational excellence programs at many manufacturing facilities already measure, review, and implement metrics, and “developing synergistic quality metrics that will have wide-ranging acceptance by the industry makes tremendous sense,” wrote Thomas Friedli, professor of management at the University of St. Gallen’s Institute of Technology Management, and consultant Prabir Basu in the 2016 CPhI Annual Industry Report (3). Friedli, Basu, and Nuala Calan of the Dublin Institute of Technology are working on an FDA-funded quality metrics research project that was awarded to the University of St. Gallen in July 2016. 

	The research involves using the group’s database as a scientific basis to propose potential quality metrics, explains Friedli. The three initial metrics to be collected by FDA do not adequately reflect a company’s internal processes, and other key indicators are needed, said Basu in an interview with Pharmaceutical Technology published in January 2017 (4).

	“Companies need to review and analyze the information the FDA is asking for, as well as other metrics they are collecting, and identify potential problem signals so that they can solve issues and self-correct before regulatory inspections,” adds Sue Schniepp, distinguished fellow at Regulatory Compliance Associates.
	The metrics that FDA will collect are not primarily intended to help individual companies achieve manufacturing excellence, but are a limited, standardized set of a metrics to help FDA identify companies that may have problems that affect the supply chain. Manufacturers shouldn’t have a goal of simply meeting these minimum requirements. “If we are not careful, the temptation may be to manage to the metrics. And in the end, managing quality to minimal regulatory expectations is never a good idea,” cautions Hal Baseman, COO at ValSource LLC.

	Such metrics can be a starting point, however. Proactive companies might use this initiative to give new momentum to their own quality and excellence programs, suggests Friedli.

	“One way to encourage firms to develop and improve their quality culture and product quality is to establish an effective use of publicly available quality metrics, leading to product, plant, and company grading. I believe that quality metrics combined with a grading system will revolutionize the approach to quality within our industry, significantly improving product quality,” says Martin Van Trieste, chairman of the board at the Parenteral Drug Association, who has developed such a grading system and a scorecard for pharma quality (5). “However, it will not be easy to develop or implement a quality metrics program. If it is to succeed, the right metrics must be chosen, industry skepticism must be overcome, and there must be checks and balances within the system,” he says.

		FDA, “Quality Metrics for Drug Manufacturing,” 

, www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm526869.htm, accessed Feb. 3, 2016.

, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM455957.pdf	

		T. Friedli and P. Basu, “Measurement of Pharmaceutical Quality in an Operational Excellence Environment,” in CPhI Annual Industry Report, 2016, p. 15.	

Pharm. Tech. Quality Throughout the Supply Chain eBook


	Vol. 41, No. 3
	Page: 20, sidebar to J. Markarian, "Achieving Manufacturing Excellence," 

Quality metrics are used by FDA and by bio/pharma companies to evaluate manufacturing and fuel continuous improvement efforts.