Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	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 This potential was highlighted in FDA’s most recent draft guidance on this topic (1).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Quality Metrics program for pharmaceutical manufacturing is clearly a work in progress, and FDA’s November 2016 revised draft guidance, Submission of Quality Metrics Data, calls for a voluntary reporting phase through which “FDA expects to learn more about a limited set of quality metrics,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.

Submission of Quality Metrics Data, Draft Guidance for Industry

, 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," 

Articles

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

Industry experts weigh in on FDA’s Quality Metrics program

	The Baxter BioPharma Solutions (BPS) Oncology manufacturing expansion project at its Halle, Germany location was the winner of the Operational Excellence category of the 2016 International Society of Pharmaceutical Engineering (ISPE) Facility of the Year Awards (1). The company applied lean manufacturing principles in designing the expanded facility. The flexible design with adaptable equipment gave the company the ability to have rapid changeover to manufacture a wide variety of liquid formulations. Pharmaceutical Technology spoke with Frank Generotzky, plant manager for Baxter BioPharma Solutions’ Halle, Germany facility, about operational excellence at the site.

 How would you define manufacturing excellence or operational excellence for the pharma industry, and what are the keys to achieving it?
	

 The pursuit of operational excellence is an ongoing goal driving improvement. Operational excellence leads to continuous improvement to increase efficiency as well as capacity while maintaining high quality and client satisfaction. Some examples of methods include:

		An innovative facility layout optimized using a ‘form follows function’ concept, designed and planned utilizing visualization tools for processes and parameters

		Optimal equipment design defined by using simulation models for critical process steps (e.g., mock-ups, computational fluid dynamics, 3-D simulation models)

		An experienced project team that accompanies all phases from design and validation through routine operation.

 What programs have you found to be successful?
	

 It is important to implement programs where all employees are involved (from operator to manager) to enhance success. Creating an uplifting experience for the employees by implementing programs internally such as 5S and process visualization helps to pave the way for the implementation of more complex systems such as operational equipment effectiveness or SixSigma. At the end of the day, success is dependent on having the necessary tools (e.g., a value stream map being supported, for example, by failure mode and effects analyses, fishbone diagrams, and standard control charts). Additionally, statistical tools should be leveraged in order to determine variation signals early in the process so that countermeasures can be implemented in a timely manner.

 What aspects in particular of lean manufacturing have been most beneficial?
	

 Applying 5S in manufacturing areas and increasing the time that managers are on the floor (‘Gemba Time’) can help ensure a high degree of standardization and discipline. Continuous measurement of process parameters with standard control charts and statistical evaluation leads to continuous improvement of yield and reduction of process deviations.

 What is the importance of process standardization?
	

A high degree of standardization ensures low variability between batches, reduces stock and work in progress, and helps to enhance planning security. Standardization leads to stable and predictable processes, which are the basis for true efficiency enhancements.

 What is flexible design and how does this lead to operational excellence?
	

Today’s products have become more complex to manufacture (e.g., nanotech products) and smaller from a volume perspective, and additionally there is the demand to simplify the handling infrastructure to be as efficient as possible. In many cases, the same manufacturing rooms are used for different process set-ups. The result is that manufacturing departments need to change process design between manufacturing of batches quickly and efficiently. Standardized modular equipment and process design is important to minimize set-up and turnover times to manufacture efficiently and remain cost competitive. Therefore, we define flexible design as one important component in our operational excellence program.

		ISPE, 2017 Facility of the Year Awards Category Winner, www.facilityoftheyear.org/winners/2016-operational-excellence, accessed Feb. 8, 2017 


	Vol. 41, No. 3
	Page: 22, sidebar to J. Markarian, "Achieving Manufacturing Excellence," 

Pharmaceutical Technology spoke with Frank Generotzky, plant manager for Baxter BioPharma Solutions’ Halle, Germany facility, about operational excellence at the site.

Operational Excellence at Baxter BioPharma Solutions

	Process analytical technology (PAT) is becoming more widely used in solid-dosage drug manufacturing. PAT’s use is primarily in batch manufacturing, which still makes up the majority of processes, but also in continuous manufacturing. On-line near infrared (NIR) spectroscopy, for example, is being used to measure critical quality attributes (CQAs) such as blend uniformity and moisture content of tablets.

	With increased use, however, some of the limitations of current technology are becoming evident. “The industry is starting to take a serious look at where current PAT is reaching its limit and what the alternatives are,” notes Doug Hausner, Associate Director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), an academic–industry consortium based at Rutgers University. One of the challenges is that using PAT commercially, over a long time period, requires a significant amount of personnel hours for maintenance-checking equipment and keeping calibrations up to date, notes Hausner.

	One reason why existing calibration curves are a burden to maintain is that they lack robustness, says Hausner. “A solution is to build better calibration curves using more datapoints and using design of experiments to identify the edges of failure,” he explains. Hausner notes that continuous manufacturing allows process engineers to run experiments more quickly, with less material compared to batch, so that collecting more data is not as costly. Another benefit of continuous manufacturing is that, unlike batch processes where laboratory equipment is smaller than commercial equipment, the continuous manufacturing process is already at scale, so the data collected in development experiments are relevant to commercial manufacturing conditions.

	Another solution seeks to use “soft” (i.e., software or virtual) sensors, which use existing, direct process measurements (e.g., temperature, pressure, feed rate) to calculate the desired CQA or critical process parameter, instead of using on-line spectroscopic PAT. Measurements from these sensors do not need complex multivariate models that require developing, validating, and maintaining, explains Jim Holman, process development manager, APC Pharma Solids, at GEA UK. “The methods are robust to potential variation in incoming raw materials and scalable over throughput ranges.” 

	Another problem is that some PAT techniques may be too slow for some processes. For potent drugs, for example, the amount of API in the blend is typically low, so there can be a lot of “noise” in spectroscopy and a longer sample time is required. Light-induced fluorescence (LIF) spectroscopy is one of the solutions being considered to evaluate API concentrations that are too low to be measured with NIR or Raman spectroscopy, although it also has limitations.

	PAT enables real-time release and closed-loop control

	Real-time release (RTR) is often discussed as a goal for more efficient manufacturing that applies to both batch and CM processes. Regulators have not yet signalled acceptance of soft sensors for product release, and spectroscopic PAT would likely still be needed, notes Hausner.  RTR for drug tablets, for example, would need PAT to confirm the chemical identity of the API at the correct concentration in finished tablets exiting the tablet press, as well as to predict hardness and weight or thickness.

	Communication between PAT sensors and systems enables visibility of information about a reaction in real time and can eventually allow movement to automated, closed-loop control of a small or large-molecule reaction using PAT, says Ernie Hillier, principal systems manager at Waters Corporation. Hillier will discuss the lessons learned from ongoing industry collaborations in sampling and sensing in a presentation at the IFPAC conference (Feb. 28, 2017).  Waters’ PATROL ultraperformance liquid chromatography (UPLC) process analysis system allows nearly real-time chemical analysis so that scientists can know in greater detail what is happening in a reactor at a given point of time. Data from UPLC is used in R&D, process development, and manufacturing, notes Hillier.

	Eli Lilly and Company’s continuous direct compression process for oral solid dosage drug manufacturing won the International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards category award for Process Innovation, in part, for a control scheme anchored by advanced automation and PAT (1). The process uses soft sensors to estimate CQAs, and NIR integrated with a real-time residence distribution time model to allow real-time release. Spectroscopic PAT combined with automation logic can be used to reject portions of the batch suspected as being out of limits, explained the company (1).

	The upcoming IFPAC conference (Feb. 27–Mar. 2, 2017, Washington DC) is dedicated to advances in PAT, quality by design, and process control for the pharmaceutical, biotechnology, and other industries. Topics will include RTR and soft sensors in continuous manufacturing and advances in PAT technologies such as LIF.

		ISPE, “Category Winner for Process Innovation,” 

www.facilityoftheyear.org/winners/2017-process-innovation

Improved process analytical technology and new ways of thinking seek to enhance measurement and control for next-generation pharmaceutical manufacturing.

Overcoming Obstacles in Process Analytical Technology

	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

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

	In a biopharmaceutical process, pumps are needed to move fluids (e.g., buffer, media, and water for injection) through tubing and deliver them to the process equipment. Several types of positive displacement pumps are used, including peristaltic, diaphragm, rotary lobe, and gear pumps. In hygienic or sanitary uses such as in biopharm, pumps must prevent contamination and be able to be validated. Pumps may use single-use components or, if multi-use, be designed to be easily cleaned. Pumps must be designed to meet appropriate standards for biopharmaceutical processing, such as the American Society of Mechanical Engineers (ASME) Bioprocessing Equipment (BPE) standard (1). 

 spoke with experts at manufacturers of peristaltic and diaphragm metering pumps about some of the considerations for fluid handling in biopharmaceutical manufacturing.

	There are different types of diaphragm pumps. Air-operated double-diaphragm (AODD) pumps are used for transferring fluids from one place to another and for ultrafiltration or diafiltration, notes Gary Gaudet, technical leader of bioprocessing at LEWA-Nikkiso America. AODD pumps, however, do not have volumetric control. Diaphragm metering pumps, which have highly accurate volume control, are used in processes and for dosing. Applications include: chromatography, buffer inline dilution, homogenization, injection of fluids (e.g., liposomes) into extruders, coating operations, filling, caustic dilution, and aseptic transfer of proteins, cells, and other materials, says Gaudet.

	A diaphragm pump uses the reciprocating movement of a flexible diaphragm that decompresses to draw fluid into the pump chamber and then compresses the pump chamber to push fluid out. The diaphragm separates the pump drive from the product-wetted side. This separation means that mechanical seals are not needed, which ensures product safety, simplifies maintenance, and allows the pump to run dry (i.e., without fluid) without being damaged, says Andreas Frerix, product manager Quattroflow, at PSG, a Dover company.

	Multiple-use pumps have housings made from stainless steel that can be reused after cleaning in place. Multiple-use diaphragm pumps are still commonly used and are meeting customers’ needs, says Gaudet. Single-use diaphragm pumps have chambers made of plastic that have been designed for one process or batch. “After the process, they are replaced with a new chamber and the new process can begin. Single-use pump chambers save money and time by avoiding cleaning and associated cleaning validation and eliminating the risk of cross-contamination between batches or products. Single-use pumps are most valuable if products are changed frequently and fast product changeovers are needed,” says Frerix.

	In a peristaltic pump, the fluid is contained in a single-use tube that is compressed and decompressed by a moving rotor to move the fluid. Tubing is made from biocompatible materials that meet requirements for purity, and the single-use tubing is disposed of after each process to prevent cross-contamination. Because the fluid is completely contained within the tubing and connectors, process validation is simplified, notes Russell Merritt, marketing manager at Watson-Marlow Fluid Technology Group, “Once the pumps are within a cleanroom environment and remain there, no regular cleaning and little maintenance of the pump itself is required.”

	Although tubing could be treated as multi-use (i.e., cleaned and sterilized between batches), most tubing is treated as “single-use” because this ensures that no cross-contamination occurs and provides new performance for every batch, says Merritt. “The need to maintain fluid path sterility is a key consideration for handling/changing any component in the fluid path. Sterility is another advantage of single-use tubing.  The fluid path is provided assembled and sterile, which minimizes the number of connections which need to be made; each connection presents a risk of the introduction of contamination.”

	Peristaltic pumps are easy to install and set-up, says Gregg E. Johnson, global senior product manager for the Cole-Parmer peristaltic pump product lines. Because they don’t need to be primed, they are flexible in where they can be installed in the fluid path, explains Johnson.

	“Monitoring the tubing performance is probably the greatest concern,” says Johnson. “A catastrophic failure can cost the loss of an entire campaign, but it is easily prevented by monitoring the tube life, use of new long-life tubing materials, and a preventive maintenance program to replace or move the tubing to new position.”

	Biopharma fluids vary in how sensitive they are to shear forces due to flow. Peptides and small proteins, for example, are relatively insensitive to shear, but mammalian cells can be very sensitive. “Even if the product is not shear-sensitive, using a low-shear [diaphragm] pump also reduces the temperature increase of the fluid and thus reduces the need for cooling (e.g., for tangential flow filtration). If the product is shear sensitive, then using a larger-sized pump helps, because the pump can be run at low speed to achieve low velocities and thus minimum shear,” explains Frerix.

	Protecting fluids from damage is a complex issue that is affected by the pump as well as by the design of the entire fluid handling system, says Gaudet. For example, fluid damage can occur from squeezed flow (e.g., due to fluid exposed to crevices or dynamic seals) or from impact when flows come together as pipes join up. Shear is also created by cavitation at the gas/liquid interface. If the diameter of a pipe changes too quickly, for example, air can come out of the liquid and cause cavitation. “Gentle conveying means minimizing or avoiding these effects. The less resulting energy induced in the fluid, the better overall for the fluid. We design systems based on piping designs to ensure the operating conditions of the pump minimize shear and cavitation,” says Gaudet. “The absence of any dynamic seal in the pressure chamber of diaphragm pumps allows gentle conveying of process fluids. The only areas of possible damage are at the product valves during closing and possibly opening. One must note, however, the extremely short closing or opening times (around 1% of the total time), resulting in low integral damage potential. In comparison, the shearing effect at the plunger seal of a plunger pump or the impeller are present during the complete stroke cycle.” Gaudet adds, “Similar problems apply to other pump types (basically any rotating positive displacement, gear, rotary piston, peristaltic hose, or eccentric screw pumps).”

	Peristaltic pumps are inherently low shear, which means that they will circulate or pump cell suspensions without damage, says Johnson. “The acceptable shear level for a cellular suspension typically can be determined by measuring cell viability after passing through the fluid-path system,” explains Johnson. “Excessive shear is caused in a fluid path mostly by two surfaces that are moving against each other, which is particularly evident in centrifugal, gear, or other types of rotating pumps or mixers. Tubing occlusion can still cause cell death, but it can be mitigated by reducing the pump speed and increasing the tubing diameter.”

	“Peristaltic pumps ensure product cannot be damaged by high fluid velocities or contact with mechanical parts,” explains Merritt. “The achievable flow rate is determined by the bore size of the tube and the speed at which the pump is run. Fluid viscosity plays an important part in the speed at which the pump is run and the deliverable flow. Higher viscosity products require a large bore size tube, but a low running speed. In downstream processing, such as tangential flow filtration and high performance liquid chromatography, flow linearity with only trace pulsation and over a wide pressure range is the ultimate requirement. The acceptable level of shear is product dependent, and the suitability of any pump type can only be determined through specific testing. With peristaltic pumps, the pumping concept naturally provides low shear; through the correct sizing of the pump this can be kept to a minimum to maintain product integrity. General good practice to ensure low shear is to minimize fluid velocity. With peristaltic pumps, low shear is achieved through lowering the pumps operating speed and increasing the peristaltic tubing bore size.”

	The move to continuous processing is evolving and will affect the requirements for pumps and other process equipment, says Frerix. Gaudet agrees, adding that there is a trend to have more self-contained processes, such as combining buffer dilution, clean-in-place systems, and chromatography skids rather than having separate skids. Steam-in-place systems are also being requested more than in the past, he notes.

	Both multiple-use and single-use manufacturing systems are employed in biopharmaceutical manufacturing.  “Biopharm is naturally risk averse; innovations, therefore, rarely take hold overnight, and the advent of single-use continues to expand into different process areas due to the benefits offered,” says Merritt. “We will continue to see both single-use and hybrid (mixed single/multi use) processes being developed. Peristaltic technology is therefore well positioned to continue to meet customers’ requirements to provide a low-risk fluid handling solution through accurate pumping technology and high quality peristaltic tubing.”

	Another trend, says Johnson, is an increase in the need for companies to be able to monitor fluid-path processes from remote locations. “The ability to monitor a process remotely allows the process to be run unattended and to notify users when they are complete, so the next campaign can be set up, which helps maintain productivity and improves efficiency.”

www.asme.org/products/codes-standards/bpe-2016-bioprocessing-equipment

:
	When referring to this article, please cite it as J. Markarian, "Pumping Fluids in Biopharmaceutical Processing," 

Pump systems must be designed to meet the needs of specific processes, including preventing cross-contamination and damage due to shear forces.

Pumping Fluids in Biopharmaceutical Processing

	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.

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