Clinical Testing System Demands Tight-Tolerance Reagent Packs

Tue, 05/22/2007 - 12:46pm
Blow-molded containers offer the right combination of precision and efficiency

Reagent packs blowmolded by Novapak to high dimensional specifications for Ortho-Clinical Diagnostics, Inc. The basic designs are shown here in white HDPE.
Blow molding is rarely approached as a high-precision process, and most blow-molded containers have relatively wide tolerances. But these comparatively easy-going ways are inappropriate when the container will be used in an automated system designed for medical or clinical use. After all, control is the word in automation - and emphatically, control is the word in medical manufacturing. For both, normal dimensional variability is likely to be unacceptable, so the tolerances of the small reagent packs for Ortho-Clinical Diagnostics' clinical testing system needed to push the limits of blow molding.

The dual-chamber blow molded packs contain MicroTip reagents or diluents that help the VITROS® 5,1 FS Chemistry System determine the concentration of more than 20 substances, or analytes, in tiny samples of body fluids. This new MicroTip technology complements the patented VITROS MicroSlide™ technology, allowing the system to run over 80 assays. When a clinic or doctor says, "We're sending these tests to the lab," more often than not analysis on systems like the VITROS 5,1 FS is what they mean.
Exceeding GMP requirements

The gray colorant helps protect light-sensitive reagents.
As these reagent packs moved from design to production, the blow molder, Novapak Corporation, and Ortho-Clinical Diagnostics worked closely to achieve the required tolerances. They also collaborated to establish manufacturing procedures that met or exceeded Ortho-Clinical Diagnostics' strict interpretation of US Food & Drug Administration (FDA) good manufacturing practices (GMP).

Thirty-six dual packs, with capacities up to 60 ml (~2 oz.), fit in a carousel on the VITROS 5,1 FS. The system selects the proper reagent for a given test by scanning bar-coded labels on the packs during carousel rotation. It then removes the cap from the pack to aspirate a predetermined amount of reagent, recapping the bottle to maintain reagent stability and reduce reagent-to-reagent contamination. The system dispenses the reagent into a disposable cuvette, a small, square vessel that holds test solutions, or analytes. A small amount of the body fluid is added, and if required, a second reagent is added. After an incubation period, the system measures the concentration of the analyte.

Basic blowmolded bottle forms include (left, in white) an arrow shape that minimizes exposure while the bottle is open, paired with a conventional cylindrical bottle. The conical bottoms on the arrow shape and (right, in gray) a variant cylindrical shape permit full evacuation of the reagent. This shape is important when a given reagent should be consumed as fully as possible.
The system can accommodate as many as 160 samples on board at one time, and as many as 125 reagent cartridges or packs. The VITROS 5,1 FS embodies high-precision electromechanical, chemical and software elements to accomplish tests for everything from alcohol and drugs to proteins and lipids, allowing for small amounts of sample and reagents to be precisely aspirated and dispensed. The system's patented Intellicheck® technology ensures the right amount of fluid is aspirated and dispensed every time.

"We considered a number of candidate designs for the reagent containers," said Scott Schwallie, Senior Product Development Engineer, Ortho-Clinical Diagnostics. "Virtually every assay requires two reagents, dictating the dual pack configuration. "The candidate designs were ranked against the pack requirements using a weighting prioritization matrix, and the blow molded dual reagent pack scored the highest in meeting our design and functional requirements".
Pack geometries

Detail of the Supply 3 component of the Ortho-Clinical Diagnostics VITROS 5,1 FS Chemistry System. The Supply 3 load cover (shown open) reveals a loading door that slides back to permit insertion of assay bottles. Operators simply place new blowmolded reagent packs into available carousel slots.
There are three basic dual-pack configurations. All feature full threads for caps designed for mechanical de-capping/capping. One configuration is a cylindrical bottle paired with a hollow wedge shape. A conical bottom to the cylinder enables extraction of the maximum amount of the reagent, which can be quite valuable. The hollow wedge shape contains the greatest volume of all the packs and is for reagents that are used more frequently.

The second configuration unites a conventional cylindrical bottle shape with a cylinder-plus-conical bottom form. The final pair is comprised of a straight cylindrical bottle with a low-volume, arrow-shaped bottle. The latter is intended for reagents that are used less frequently. These last two designs incorporate a vane that enforces loading of the packs in the carousel in the correct orientation.

Two high-density polyethylene (HDPE) formulations are used, one with a white colorant, the other with a dark, light-controlling colorant to help protect light-sensitive reagents. As with many resins used in medical production, both the white and the dark HDPE molding compounds contain no release agents or additives capable of leaching into the test solutions.
Meeting the tolerance challenge

Detail view, cover removed, of the carousel of the Ortho-Clinical Diagnostics VITROS 5,1 FS Chemistry System, shown with blowmolded containers in place. The carousel rotates to present the appropriate reagents to the arm at the back, which removes the cap, aspirates the correct amount of solution, then re-caps the blowmolded container.
"In evaluating the carousel slot tolerances specified by our mechanical design team, and knowing typical blow molding tolerances with the bottle dimensions I would need to hold," said Schwallie. "It was clear there would be some significant challenges."

Ortho-Clinical Diagnostics adheres strictly to FDA manufacturing guidelines and requires the same of its component and assembly suppliers. This includes tight calibration and control of production equipment, ensuring repeatable results.

The dual design offers the greatest production efficiency, permits the use of a single bar-coded label and provides system users with an easily handled, easily-loaded package. When the design was finalized, Schwallie called on Andy Elder, Novapak Technical Manager.

"The path to production was as intense as anything I've experienced," said Elder, who has been involved in bottle production for more than 35 years. "We measured, made changes and adjustments, and measured again. This cycle went on for quite a while, but the result is a product meeting OCD's capability requirements of Cpk ≥1.67 (index of process capability) on Critical to Quality dimensions."
Consistent performance at the highest level
Encountered most often in such high-performance manufacturing methodologies as 6 Sigma and statistical process control (SPC), Cpk is a value calculated on the statistical spread of product variation and is one of the most reliable indexes or expressions of production consistency. A Cpk ≥1.67 means that 999,767out of 1,000,000 parts fall within OCD's acceptable limits - and in blow molding, these are very tight limits. Novapak has consistently demonstrated they have met and or exceeded these capability requirements for the VITROS 5,1 FS Reagent Packs.
DOE helps finalize production
Design of experiments (DOEs) is a standard methodology used in Ortho-Clinical Diagnostics' design process. Schwallie explains, "A DOE, which uses a structured experimental approach, provides the most efficient method for determining the relationship between process factors and part features and/or attributes."

For example, a DOE project allows the multiple effects of each factor and the often complex interactions among factors to be studied in one experiment. Schwallie adds, "With what was learned from the DOE, we were able to set a process window wide enough to meet critical quality parameters while still ensuring our predetermined capability requirements could be met."

He adds: "We worked with Novapak to map each step of the manufacturing process, from the resin hopper to the parison extruder, to the blow molding stage. We identified the inputs for all process steps and weighted each - extrusion speed, metering temperatures, mold open/close times and more. These were all measured against the packs' Critical to Quality features (CTQs), identifying the most critical process inputs." These inputs were included in the DOE design as factors and evaluated against the pack CTQs and attributes responses."

Schwallie says, "This structured DOE approach and collaborative effort between Novapak and Ortho-Clinical Diagnostics allowed for a robust manufacturing process, ensuring a high quality product for use on the VITROS 5,1 FS Chemistry System."

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