Taking the team approach to development, Sigma Diagnostics of St. Louis has garnered Food and Drug Administration clearance for 11 coagulation products in just three years, including a fibrinogen kit, antithrombin kit and three levels of coag controls. Getting so many new products through the FDA in such a relatively short amount of time takes know-how and resources, and Sigma has them.
Sigma Aldrich is a $1 billion-plus life science and high technology company that develops, manufactures and distributes more than 200,000 products in the areas of biochemicals, organic chemicals, chromatography products and diagnostic reagents.
From start to finish, many eyes and hands help ensure the success of these products in the marketplace and the lab, said Mark Triscott, Ph.D., manager of research and development for Sigma Diagnostics, a division of Sigma Aldrich Corp.
In his five years at the company, Triscott has seen three improvements in the company’s design control and project management process. “I believe it’s because of the cross-functional team approach we use,” Triscott said. “Different departments take ownership of a product as it moves through its development cycle and their realm of responsibility.”
Once a new product idea is conceived, it moves into research and development, where it is studied to determine if it is going to fulfill a need. Using marketing information from Sigma sales people, and also focus groups at scientific meetings, the marketing department ties all that information together and puts it into a product description as early as possible in the life of the product.
Once the product is determined to be market worthy, the design is refined and it moves into feasibility, where having a giant parent company like Sigma-Aldrich helps immeasurably.
“It’s a company that’s been around 50 years. It specializes in producing raw materials from natural sources. For example, they make a large portion of the world’s bovine thrombin,” Triscott said. “With access to that kind of raw material, we can go back and test for various activities and functions. We have the advantage there with our vast array of raw materials.”
Sigma scientists create small-scale “feasibility batches,” he said, that allows them to do a correlation study and to get an idea of product precision and stability. Once that level is passed, (at every step in the process, rigorous in-house technical reviews are imposed before the product passes to the next step), team members from production, regulatory, marketing and quality control create documentation that gives a clear idea of what the product is meant to do and how it should be presented.
Once those departmental approvals are gained, “we go into design control mode, as required by the FDA and ISO 9000,” Triscott said. “We start by making a pilot lot. That involves a ‘transfer’ group that transfers [information] from R&D to production.”
The transfer group is key because it writes documentation that allows directions that can go right to production. “Rather than having to work through R&D notebooks, production can build product seamlessly.”
Scientists then produce another pilot lot, using transfer group documentation, verify it, ensuring the material made is the same as that which they designed at the beginning of the process.
“We take out verification testing from the first pilot and apply it to the second and third pilot lots,” he said. “The first pilot is usually a percentage of the amount you’re going to make each batch, a portion of your estimated annual usage. The second pilot lot is a higher percentage of that, and the third is 100 percent of final batch size.”
From the first pilot lot, Sigma puts together a package of data which serves as an internal verification that the project is on target and also as the basis for an FDA submission.
All this effort has added up to FDA clearance of 11 products since 1997 — a fibrinogen kit, an antithrombin (AT) kit, coagulation control levels I, II and III; Thrombomax (prothrombin time reagent); thrombin time; Alexin-LS; Alexin-HS; Accucolor high calibrator; and most recently a D-dimer assay.
“Part of our success is that we focus our R&D resources toward all parts of the coag market,” Triscott said. “We look at core products, such as controls and thrombin time, and we look at specialty markets, such as different PT and AT reagents. We also do more esoteric tests such as immunoassays. We build competency by having researchers who work in each of those areas.
“You’re building a base from which to run a system,” Triscott said. “You use core technologies to develop competency in a particular area.”
Sigma developers use state-of-the-art R&D tools such as Design of Experiments and Response Surface Optimization (REO), which allows them to monitor the effect of multiple components at the same time and to determine which formulations are going to be the most manufacturable and most robust.”
Having people from the various teams work together — R&D, product engineering, quality control, validation, regulatory, manufacturing, technical service and marketing — is a juggling act, but a necessary one, Triscott said.
“Keeping them all moving in the same direction is a challenge, but we do that by keeping people informed and giving them ownership over their part in the process.”
Sigma knows it’s on the right track with regard to FDA quality standards because its own general FDA site audit in spring 1999 turned up only a few minor issues. “And those were taken care of even before the FDA left,” Triscott said.
A large part of the reason Sigma has received FDA clearance on 11 coag products in three years, Triscott said, “is because our quality system is designed by people who really know the [coag diagnostics] industry. This has helped gel the fact that quality is something we strive for through the entire process, it’s not just tested at the end.”
