Case Studies
Keeping Plasma Safe
Haematologic Technologies Inc. Implements Artel’s Liquid Handling Quality Assurance Systems to Ensure Consistent Results
Modern plasma protein research traces its roots back to the scientifically industrious era immediately after WWII. In the 1940s the U.S. Navy recruited the expertise of Harvard Medical School Professor Edwin J. Cohn to identify a transfusible substance that could be stockpiled in preparation for treating casualties of war. Within a few months, Cohn’s group of researchers developed a methodology to isolate plasma proteins, and not long thereafter utilized their process to successfully isolate the protein from human blood. The results were not only pure, but exhibited remarkable effects when administered to patients as an antidote to shock. The research group’s work represented a major advancement in understanding the biological framework for hematology—the study of the physiology of the blood.
When platelets, red blood cells, and white blood cells are removed from the blood, the clear and protein-rich fluid left behind is blood plasma. The aptly-named plasma proteins are the proteins found in the blood plasma and play a number of important roles and functions in the human body. Plasma proteins help to regulate the body's osmotic pressure, which keeps the body's systems working properly. They also transport various compounds needed by the body, in addition to playing a role in immune system function and blood clotting. An imbalance of plasma proteins can lead a patient to experience symptoms ranging from abnormally dilated blood vessels to a weakened immune system. All these factors explain the US Navy’s interest in hematology, and the studies which Dr. Cohn and his group at Harvard were pursuing.
A Vital Role in Medical Manufacturing and Research
In addition to being important to bodily function, plasma proteins are also valuable medical products which are used as components in manufacturing and in research. A number of pharmaceuticals can be manufactured from plasma proteins, with the proteins being extracted from donor plasma or synthesized in the laboratory. Research involving plasma proteins has resulted in drugs used in treating life-threatening diseases and serious medical conditions such as bleeding disorders, immune system deficiencies, alpha-1 antitrypsin deficiencies, burns and shock. Further, research focusing on clinical proteomics−utilizing plasma proteins−identifies proteins and develop assays for routine and reliable measurement that contribute to solutions for various clinical needs. A number of disease indicators, also referred to as biomarkers, based on single proteins have been FDA-approved and successfully implemented into clinical practice. In cancer research, these include tumor-associated antigen assays for diagnostic use, such as carcinoembryonic antigen (CEA) for colon cancer, prostate-specific antigen (PSA) for prostate cancer, or alpha-fetoprotein (AFP) for testicular and liver cancer.
Given the vital role plasma proteins are increasingly playing in medical and scientific research, suppliers like HTI have developed stringent quality assurance guidelines designed to surpass their customers’ own QA audit requirements. Given the critical role of pipettes in handling micro volumes, HTI focuses heavily on quality control for its liquid handling instrumentation.
Today, companies like Vermont-based Haematologic Technologies Inc. (HTI) are making high-quality plasma proteins and reagents readily available to the medical and scientific communities. “For our general manufacturing operations accurate volume delivery helps us ensure that we are delivering products to our customers with consistent quality, quantity, concentration and specific activity,” said Sara Ethier, HTI’s Quality Assurance Manager. “For our contract testing operations, the accuracy of our pipettes enables us to ensure the accuracy of data that is sent back to the customer.”
A 21st Century Hematologic Lab
HTI boasts a product line of over 150 highly purified and well-characterized proteins including zymogens, enzymes, cofactors, and inhibitors, and also works on stability and release testing—often running anti-drug antibody (ADA) ELISA assays for pharmaceutical companies. Realizing the impact its products have on its customers’ research, HTI (which is ISO 9001:2000-certified) tracks quality assurance in its facilities from basic training to regular equipment calibration. As in many labs, pipettes play an integral role in HTI’s day-to-day operations and Ethier’s department ensures they are not taken for granted, placing a strong emphasis on proper pipetting technique, as well as calibration.
“Our customers have come to expect consistent quality from our products,” said Ethier. “Quality is a crucial part of the work we do, enabling us to provide highly purified, functional and consistent products to our customers. Our equipment and skills are significant parts of this process—a calibrated pipette is not fully functional if it’s being mishandled and a miscalibrated pipette is of little use to the world’s best lab technician. We need to be able to stand behind the high quality of our products, behind the skills of our technicians, and behind the working order of our equipment.”
To help ensure the reliability of their lab processes, HTI turned to Artel, the Maine-based pioneers of liquid handling quality assurance. The company’s PCS® Pipette Calibration System automatically measures and documents the accuracy and precision of handheld pipettes using dual-dye ratiometric photometry. Because measurement results are traceable to the International System of Units (SI) through National Institute of Standards and Technology (NIST) reference standards, the PCS allows for direct comparison and measurement consistency between operators, methods and pipettes regardless of make, model, manufacturer or location. As well as being a global standard for liquid volume measurement, hence ensuring that a company’s pipettes in its Singapore lab perform the same as their pipettes in Indianapolis, the PCS is also used as a pipetting technique training tool by labs around the world, providing for consistent results, operator-to-operator, in any lab process involving manual pipetting.
“The pipette is a core fundamental piece of equipment in any lab,” said Bjoern Carle, PhD, Senior Applications Scientist. “In addition to helping ensure the reliability of a laboratory’s tests, the PCS can teach proper pipetting technique because it provides immediate feedback to the user.”
Partners in Lab Quality
To underscore the importance of proper pipetting technique, Artel developed a friendly competition that helps even the most experienced laboratory technicians assess their pipetting skills. The Artel Pipetting Olympics uses the PCS as a tool that goes beyond equipment calibration. At the AACC/Clinical Lab Expo, the Pipetting Olympics competition caught the attention of scientists from HTI, who saw the equipment as a cost- and time-effective solution that supported its stringent quality assurance needs.
HTI had installed a PCS in its laboratory, and began using it to ensure the quality of its pipettes and the pipetting technique skills of its technical staff. “Overall, the use of the Artel PCS helps us ensure the accuracy and reliability of the products that we send to our customers whether it be a coagulation factor from our manufacturing division or data from our contract testing division,” explained Ethier.
The company seeks to proactively meet regulations ranging from Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP) and ISO 9001. Constant operator training has played an integral role to this approach. Ethier goes on to remark, “We have always trained our laboratory technicians on the proper use of pipettes; it’s a generalized training that covers everything from what solutions you can and can’t use with pipettes, to when to use reverse pipetting. The PCS became an integral part of our training since it allows us to offer our technicians more in-depth training. Once they’ve gone through our general training they can use the PCS to test the skills they learned and identify problem areas. The instrument is always available for employees to practice on.”
And practice they do. During Artel’s 2011 Lab Week Pipetting Olympics, HTI’s lab technicians competed against teams nationwide and won the coveted first place award by scoring the lowest coefficient of variation, showcasing the strength of combining calibrated equipment with efficient pipetting skills.
Putting Training to Use
While proper training is a key element of quality assurance in the lab, it is most effective when paired with strict quality control guidelines. With more than 100 pipettes, HTI uses the PCS on a monthly basis to ensure the instruments are working properly. Using a weekly rotating schedule ensures that all HTI’s technicians have checked the performance of their pipettes at least once each month.
The traditional way to measure pipette volume is to follow the gravimetric approach, which involves weighing water on a balance and converting weight to volume. "When properly controlled gravimetry is fine for large volume measurement, but when making measurements in the small volume ranges its accuracy and precision fall off drastically,” said Dr. Carle. “Especially when working below 200 microliters, gravimetric methods often are plagued by evaporation and other environmental issues, which can affect the accuracy of the calibration. And, because measurements often are tracked manually, there is additional room for human error.”
“If you’re working with only a few single-channel pipettes and you’re not dealing in small volumes it’s not too time consuming to calibrate gravimetrically,” noted Ethier. “But when you have a significant number of single-channels pipettes from different manufacturers, are handling small volumes and you start pulling in a few multi-channels, you start looking at significant time consumption.” Ethier estimates that by integrating the PCS into HTI’s pipette calibration process, technicians have been able to shave off 5-10 minutes per pipette. That amounts to 8-16 hours saved per month—or 96-192 hours per year—which translates into valuable time and labor savings for HTI.
“Before investing in the Artel PCS, we used to send the pipettes back to the manufacturers every six months for calibration. If we thought something was really wrong with an instrument before it was due to be shipped off, we would resort to the balance,” added Ethier, noting the extra time and expense associated with shipping. “It’s an added step that adds up when you’re looking at it multiple calibration events per year.”
HTI’s results with the Artel PCS translated into enough benefits for the company to invest in a second Artel system—the MVS® Multichannel Verification System. Like the PCS, the MVS uses dual-dye ratiometric photometry to assess the precision and accuracy of each tip of almost any multichannel pipetting device at volumes as low as 0.01uL. Often used as a calibration tool for automated liquid handlers, the MVS is employed by HTI to calibrate handheld multi-channel pipettes.
“Before running any kind of critical ELISA assays, you want to make sure your pipettes are dispensing properly,” said Ethier. “We weren’t able to do this in the past, but now that we have the ability to do so in-house at a moment’s notice, we can more efficiently deliver on our promises of consistent high quality for our products.”
Life sciences companies stake their reputations on the reliability of their results and the quality of their products. For HTI, which provides the critical tools for cutting-edge medical and scientific research, the burden of quality is appropriately constant given the legacy it upholds. Plasma protein research began as a matter of national security and has evolved into a vital component of life-saving research. Through it all, it was the commitment to high quality standards from researchers companies like HTI and Artel that helped advance the legacy of Dr. Cohn’s discoveries.
About Artel
Artel is the worldwide leader in liquid handling quality assurance. Artel manufactures the most accurate, precise and easy-to-use systems for ensuring data integrity in any process requiring liquid volume measurement. Artel systems, based on proprietary Ratiometric Photometry, conform to ISO 8655-7 and provide measurements, which are traceable to the International System of Units (SI) through reference standards developed and maintained by NIST to ensure reproducible data and regulatory compliance Since 1982, Artel technology has been proven in daily use in thousands of laboratories including pharmaceutical, clinical, forensic, public health and environmental. Leading institutions such as Amgen, ARUP, Beckman Coulter, Bristol-Myers Squibb, Celgene, Centers for Disease Control, DuPont, Eli Lilly, FBI, Genentech, Genomic Health, GlaxoSmithKline, Mayo Clinic, Memorial Sloan-Kettering Cancer Center, Merck, Pfizer, Procter & Gamble, Tecan and U.S. FDA depend on Artel technology to help them meet their objectives for quality and productivity. For more information, contact Artel USA (Corporate Headquarters): 25 Bradley Drive, Westbrook, Maine 04092, USA; Tel: +1 207 854 0860; Fax +1 207 854 0867; Website: www.artel-usa.com.
About HTI
Haematologic Technologies, Inc. (HTI), an ISO 9001:2008 registered company, is a primary manufacturer that specializes in the isolation and characterization of high quality, plasma proteins which are intended for in vitro research use. HTI’s emphasis is focused on proteins involved in the coagulation cascade, as well as the regulation of bone metabolism. The mission of Haematologic Technologies, Inc. is to supply the international coagulation research community with the highest quality proteins and reagents attainable. We strive to make continuous advancements in our manufacturing and quality control processes to ensure the superiority of our products to those of our competitors. HTI also endeavors to be on the cutting edge of coagulation research through in-house efforts and the formation of strategic relationships with firms at the top of thrombosis and hemostasis research. For more information, contact HTI at +1 802-878-1777 or visit www.haemtech.com.