RESEARCH & DEVELOPMENT

Beware New steroid test uses oil exploration technique

BD78/08
It’s a technique that has previously been used for oil exploration — now researchers at The University of Nottingham have developed a new, highly sensitive, anti-doping steroid test using hydropyrolysis.

The process — which uses high pressure environments to investigate the chemical structure and make-up of a sample — has been refined and developed at the University to develop highly accurate tests for detecting levels of illicit steroids in urine. The test procedure is already in the process of being commercialised and is expected to be ready for use in the 2012 Olympics.

Funding from the Research Council’s Ocean Margins LINK programme saw researchers take the hydropyrolysis technique and apply it to geochemical studies. This allowed the team to reconstruct the history of ocean basins to help assess whether it was worth drilling for oil. By taking core samples over geological time, the technique can detect the first ’charge’, or presence, of oil.

But the same process can be used to detect the presence of illicit steroids in the urine of athletes — and racehorses. High pressure hydrogen is used to bombard the sample at pressures of 150 atmospheres and temperatures of up to 500 degrees Celsius. This leaves sample molecules in a cleaner, less degraded state than other extraction techniques, allowing more accurate readings to be taken. Carbon isotopes are then measured, with the results showing the ratios of carbon 12 and carbon 13 in the sample — whether geochemical or biological.

John, Professor Morgan of Chemical Technology and Chemical Engineering at the University, said: “Steroids are produced naturally in the body, but they have a different carbon 13/carbon 12 ratios to those that have been introduced illicitly. By refining the measurements of these two isotopes we can produce a very accurate test for the presence of illegal steroids in athletes.

“We are currently working with specialist individuals to develop the technique for trial and have entered into partnership with Strata Technology, a London-based company with expertise in high pressure equipment, to commercialise the technique.”

The technique is also being used to refine current radio carbon dating processes, which use the carbon 14 isotope to measure the age of an archaeological sample.

“Most of these samples use charcoal,” Professor Morgan added. “But the stuff you are trying to accurately date is often mixed in with much later debris from the same site. Hydropyrolysis can remove this very rapidly and efficiently. We are hoping that this will become the accepted model for cleaning up radio carbon dating samples in the future — the fundamental research for this is taking place at the moment.”

Professor Morgan is an expert on hydropyrolysis — he’s been working on the technique, both in industry and academia, for the past 23 years. Over the coming year he hopes to refine the testing process, exploring optimum sample sizes and checking the sensitivity of the techniques.

The aseptic filling of injectable drugs has always been very challenging for the pharmaceutical industry. Contamination accidents, although rare, are still recorded among the 20 billion injections and infusions made every year in the world.  Authorities have taken a radical turn to strongly support the most advanced aseptic filling technologies, such as the use of isolators, whereas the use of classical processes in an Grade A/ISO 5  are increasingly challenged regarding risks due to the proximity of the operator to the open containers. The emphasis on the quality of aseptic filling has increased as well with the recent request from authorities to withdraw preservative agents whenever possible from injectables.

This article describes a new filling technology that has been initially developed to further increase the quality for the patient but also to simplify the filling process for the manufacturer compared to the classical glass vial. In addition, new features have been introduced to secure the supply chain, such as on-line coding by RFID or laser-coding.

THE CLOSED VIAL TECHNOLOGY

The closed vial technology is based on a vial that is provided clean and sterile with the stopper in place. Thanks to such container design, the most complex filling steps of classical open vials, such as vial washing, stopper washing, and hot air tunnel sterilization, are eliminated. The filling is done by means of a needle that pierces the stopper and dispenses the liquid. After needle withdrawal, the puncture trace is immediately resealed with a laser to restore closure integrity.

The Closed Vial

The closed vial is a container composed of 5 elements:

• The vial body: Cyclo-olefin copolymer (COC) is used for this part of the container. COC was selected because of its excellent barrier and transparency properties, making it one of the most reknown plastics for containers in the pharmaceutical industry. The vial bodies are produced by injection molding for the smaller vials or by injection blow molding for vials that exceed a 3-mL volume.
• The stopper: A thermoplastic elastomer with particular laser absorbance properties was selected to allow laser resealing. Under laser heating, melting is observed and the two sides of the puncture trace fuse to restore closure integrity.
• The top ring: This ring secures the closure integrity of the assembly of the vial body and the stopper with non-return, right angle snap fits.
• The bottom ring: This ring ensures very good stability of the vial and firm holding during piercing and needle withdrawal
• The cap: The polyethylene cap protects the piercing area by maintaining it as Class 100 until use by the health professional. This last feature, obtained by a circular rib that presses on the stopper surface, avoids the appearance of contamination of the stopper surface during vial storage.

The manufacturing of vials is also completely innovative as they are molded and stoppered by robots in Grade A/ISO 5 cleanrooms. The manufacturing of the vials is comprised of the following steps:

• The vial bodies and the stoppers are molded at the same time in two molds installed in Grade A/ISO 5 cleanrooms.
• Immediately after mold opening, two robot arms pick up the vial body and the stopper and bring them in front of each other. The assembly is performed by the simple pressure of the two elements.
• The vials, then closed, are transferred by one of the robot arms to an adjacent Grade C/ISO 8 cleanroom where the addition of both top and bottom rings are performed automatically.
• The vials are packed in corrugated polyethylene boxes.
• Six boxes are doubled wrapped in polyethylene foil.
• Finally, the vials are gamma-irradiated at a minimum of 25 kGray.

This process provides vials with extremely high quality in terms of sterility and both particle and endotoxin contamination. Therefore, any additional steps, such as washing and depyrogenation, are not necessary and the vials are provided ready-to-fill to the pharmaceutical manufacturer.

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