Putting the Lid on Temperatures in Cryogenic Pharmaceutical Vials
By Robert Cretsinger, Romarc Corp.
Critical Decisions
Manufacturing Process
Advancing Field
Vials containing pharmaceutical or medical samples are often transported in cryogenic vacuum containers, which keep the substances at very low temperatures to prevent sample degradation. Containers use liquid nitrogen as a refrigerant, typically at a temperature of –320°F. To maintain low temperatures and allow access to the vials, foam plastic insulating closures—known as "neck plugs" or "neck corks"—must fit very precisely into the top of the containers.
Neck plugs, which represent a little-known technology perfected over the last 35 years, are used whenever pharmaceuticals (or medical vaccines, biopsy samples, and many other substances) are shipped in cryogenic vacuum containers. Demand for neck plugs is therefore strong in a market that continues to find new uses for low-temperature storage.
There are important reasons for this special closure technology. Without careful attention to plug dimensions and materials, substantial losses of nitrogen can occur, lessening the safe shipping time for pharmaceuticals. As an insulating medium resisting liquid nitrogen boil off, the plugs must be manufactured to tight tolerances, ensuring they fit exactly into the neck of the containers. Precise dimensions also ensure that plugs can be easily inserted and removed during vial handling.
An assortment of small diameter insulating closures, used by the pharmaceutical and medical industries to keep a tight seal on liquid nitrogen in cryogenic vacuum containers.
Another driving force for specialized closure systems is environmental regulations, which have drastically reduced acceptable losses of gas from cryogenic vessels. Regulations now require even closer tolerances on closures, plus consistent machining and high-quality testing meeting ISO 9000 standards.
Critical Decisions (Back to Top)
Partnerships between the plug manufacturer and pharmaceutical/medical customers are recommended to optimize plug performance for specific jobs. Manufacturers can help engineer and design a plug that meets end-user requirements, as well as furnish prototypes for testing.
Suppliers and customers must first decide which closure material is best for a particular application from the standpoint of tolerance control, thermal loss, and economics. The company can then draw up prints according to the recommendations from the supplier, who can then produce the prototype for first-piece inspection.
For optimal insulating capacity, plug materials are usually foam plastics, including polyvinylchloride (PVC), acrylics, polyurethane, expanded polystyrene, and lineal grade PVC.
Plug dimensions must be precisely engineered. Portable vacuum vessels for pharmaceuticals, for example, are generally not more than 3 ft. high and 2 ft. in diameter. Some containers are as small as 1 ft. high and 6 in. in diameter. Closures for these vessels may have a nominal diameter as small as 1.375 in., with tolerances of 0.0001 in. or less. The partnership must also engineer such features as precise grooves or other configurations to allow various metal and/or plastic tubes to be inserted into the liquid nitrogen. One end of the plug must be chamfered so that the plug can be easily inserted into the vial. The other end must be designed so that handle-type lids or anchors can be bonded into the foam at the top.
Manufacturing Process (Back to Top)
Materials are often not available in the correct thickness for manufacturing closures. They can be made thicker by laminating thinner sheets together. Laminates have previously not been widely used in cryogenics. Manufacturers instead preferred solids because they feared delamination. Lamination, however, allows the manufacture of many thousands of neck plugs for pharmaceutical and medical applications per day. Laminated plugs can be machined in an incredible variety of unusual shapes and parts. They are also stronger and more thermally efficient, allowing less nitrogen loss. The sheets are first glued together with an approved epoxy, and then vacuum laminated. This achieves the most consistent bond thickness and reduces entrained air, improving both the bond and thermal performance.
To ensure that the epoxy glue in the lamination can withstand shock, the finished parts are tested and rated at liquid nitrogen temperatures. Vacuum lamination has proven to be very accurate and cost-efficient. Cost savings with this approach range from 3% to 17%. The smaller the diameter of material, the faster the production rate. Plugs may cost as little as $7 each. The alternative—working from homogeneous single pieces 3 or 4 in. thick—would be prohibitively expensive.
Single pieces also conduct temperatures at a greater-than-acceptable rate. Vacuum lamination, on the other hand, is more thermally efficient. In machining to proper dimensions, the laminated pieces are cut into the required-size blanks, much as you do when turning stocks for large commercial lathes. For smaller plugs intended for pharmaceutical vials (generally less than 6 in. in diameter), circular cutting heads, much like dies, cut to extremely close tolerances of 0.005 in., create a very tight fit with very little loss of heat.
Romarc Corp. president Robert Cretsinger (center) thrashes out a cryogenics plug manufacturing problem with Joan Saalfrank, vice president and controller (left), and William Borresen, facility manager, during a production meeting at company headquarters in Plumsteadville, PA.
The blanks are then machined to correct diameter using continuous cutting or larger lathe-type machines and are either individually or "gang cut" with grooves or other configurations to allow tubes to be inserted.
The next steps generally involve cutting the plugs to the proper length, chamfering one end, and machining various head configurations. If they are required, final covers or handles for the plugs can also be provided, either separately or fully assembled. The covers are made either by injection molding or forming.
Plugs are shipped to container manufacturers in lots of 10, 20, 30, hundreds, or even thousands. The manufacturers, in turn, ship the plugs and containers to pharmaceutical and medical companies, who use the containers with plugs to ship their own products.
Advancing Field (Back to Top)
Producing insulated closures for cryogenic applications in the pharmaceutical and medical field has evolved into a very specialized technology that is constantly being improved. Thousands of sample vials, for instance, with plugs in a variety of materials and unusual shapes, are now being accessed by a computer-controlled robot in a cryogenic research effort.
Markets are also evolving as plugs are needed for everything from organ transplant tissues to samples for artificial insemination.
The state-of-the-art procedures which we have described involve an intricate trail of paperwork to assure proper billing, receipt of goods, payment, and distribution of parts to production. This accentuates the need for even better traceability of all parts.
Today, packaging is often designed for the number of parts most commonly used. There's also an almost universal requirement for even more efficient just-in-time procedures for receiving and employing closures in a timely fashion for most efficient production and cost control. We expect continual advances on all fronts. Working on a new plug application is always a unique challenge. Today, even a stopper on a container has its own science. Keeping on the leading edge is where the action is.
For more information: Robert Cretsinger, President, Romarc Corp., 32 Appletree Lane, P.O. Box 1350, Plumsteadville, PA 18949. Tel: 215-766-7740. Fax: 215-766-7606.