Quality and safety

More than 500 participants gathered in Hyères, France for the 19th European GERPAC conference. Topics included syringes for ready-to-administer injections, advanced therapy medicinal products and lean preparation of cytotoxics

Christine Clark
Editor, HPE
Laurence A Goldberg
Editorial consultant, HPE

“How safe are syringes as the primary containers for ready-to-administer injections?” was the question posed in a workshop run by Irene Krämer (Director of Pharmacy, University Hospital Mainz, Germany) and Paul LeBrun (Head of Production, Central Hospital Pharmacy, The Hague, The Netherlands).

There are good published data to support the use of syringes as primary containers from the microbiological safety standpoint. However, there is little information about substances that might be leached from syringes and end up in the injection solution, said Professor Krämer.

Syringes can be two-piece or three-piece devices. In the two-piece syringe, both barrel and plunger are made of polypropylene. In the three-piece syringe the barrel and plunger are made of polypropylene but there is also a polyisoprene gasket and the inner side of the barrel is ‘siliconised’ to ensure that the plunger slides easily, explained Professor Krämer. In Europe, 50ml syringes are commonly used to administer drugs using a syringe pump, whereas small volume IV bags are more commonly used in the US.

When drugs are prepared in syringes, it is important to bear in mind the possibility that there could be sorption of the drug on to the container or leaching of substances into the drug solution. In addition, drugs that are susceptible to photo-degradation will need protection from light and the container must be tightly sealed to avoid microbial contamination. One publication has described leachable and extractable components in pharmaceutical containers and showed that complex analytical techniques were required to identify them.¹ If leachable substances are found, then a toxicological assessment is needed.

Leachable substances could be lubricants, anti-slip additives, anti-oxidants, stabilisers, metal ions and residues, for example, oligomers and unreacted monomers of the original plastic material. Leachables are usually reported as parts per million (ppm) and, although the concentrations may be low, they might influence stability or efficacy, said Professor Krämer.

Both dose volume and contact time with the container can influence leaching and consequently there is wide variation in the risk of leaching. The topic has attracted considerable attention in recent years and it is covered in a monograph of the United States Pharmacopeia. There is no comparable monograph in the European Pharmacopeia.

Dr LeBrun described a national study that was undertaken to examine the quality of 50ml syringes, which are widely used in intensive care in The Netherlands. The investigators found that the syringes (BD Plastipack) actually came from three different suppliers (in Ireland, Turkey and the US) and even underwent different sterilisation processes (ethylene oxide or gamma irradiation).

Syringes were filled with sodium chloride and glucose and after one month no changes were evident in appearance, pH, weight, or particulate contamination. The only change was an increase in the concentration of leachables. The significance of this finding was not known. Working with a specialist laboratory (Toxicum, Belgium), they attempted to identify the leachable components. Twelve products were found but only four could be identified from the reference database. The general conclusion was that there was no toxicity, but this is not entirely satisfactory because several products were not identified, said Dr LeBrun.

As a result of this study, the Dutch GMP guidance recommends investigation of every batch of syringes and a monograph has been compiled. “Alternatives to the single-use plastic syringe are necessary, said Dr LeBrun. One example is the ‘COC syringe’ in which both barrel and plunger are made from a cyclo-olefin copolymer (COC). COC syringes can be terminally sterilised after filling; potential drawbacks are that they are siliconised and are expensive. Another approach would be to use an alternative device, such as the Fleximed^® parenteral device, which is also sterilisable, added Professor Krämer.

Advanced therapy
Advanced therapy medicinal products (ATMPs) are a heterogeneous group of materials including gene therapy products and products for bone, cartilage and skin repair among others. They can be somatic cells, gene therapy products or tissue engineered products, explained Claude Bernard (Pitié Salpetrière Hospital, Paris).

The handling of ATMPs poses many practical challenges for pharmacists. For example, cellular products have always come from a donor and need to be appropriately labelled to avoid mix-ups. “Traceability from donor to recipient is critical”, said Dr Bernard. Another issue is that frozen graft material always requires 10% dimethyl sulphoxide (DMSO) to protect the membranes during the freezing process; it is stored at –130 to –180°C. In addition, liquid nitrogen used for freezing can itself be dangerous and so the tanks need to be fitted with appropriate monitor and alarms. Frozen products must be thawed immediately before administration but after thawing the DMSO must be removed by means of an appropriate ‘washing’ process, he explained.

Many other aspects of the handling of ATMPs are still to be developed and clarified, including microbiological security and mechanisms for follow up of undesirable effects – ‘biovigilance’.

During the discussion that followed, members of the audience raised a number of points:

ATMPs can now be used to treat some hitherto incurable diseases and so it is likely that their use will increase considerably.
About ten ATMPS have marketing authorisations at present but about 75 are currently under discussion by the European Medicines Agency. Although they are called ‘medicinal products’ they are unlike any previous medicinal products and pharmacists have not yet been trained to handle them.
The question of risks associated with the use of viral vectors was raised.

Manufacturers of gene therapy products should provide appropriate information about decontamination.

In addition, the products should be provided in such a form that they only need to be thawed and administered without further manipulation, said Dr Bernard.

Biopharmaceuticals of this type will be the norm in ten years’ time and pharmacy needs to build its capabilities to keep pace with developments, he concluded.

Lean chemo
Lean philosophy is a management approach based on the elimination of all steps in a process that do not add value, explained Laurent Carrez (University Hospital of Geneva, Switzerland). The centralised chemotherapy production unit at University Hospital of Geneva has seen a 31% increase in demand during the ten-year period 2006–2016. The current climate of cost containment does not allow for extra staffing, so a different approach was required, he added.

A team of frontline staff undertook the process of value stream mapping – identifying and timing all activities. They discovered that most prescriptions were written after 16.00 hours when the production unit was closed and that production equipment was in use for only 43% of the time. There was also wastage associated with doses prepared in advance, and much wasted movement of personnel because of the way the materials were stored.

Armed with this information, the team reorganised the work in such a way that doses are no longer prepared in advance but on the day required, and one member of staff prepares a dose from beginning to end. Every three hours, there are short meetings at which the ‘day coordinator’ makes prioritisation decisions to ensure a smooth workflow. The storage area has been reorganised to ensure that there is a logical, U-shaped ‘picking path’.

Operators also use a compartmentalised box for picking, which makes self-checking easy and is essentially foolproof, said Mr Carrez. This has reduced picking time and overall process time markedly, he added. This initiative smoothed out the workflow and made the work less stressful. The staff particularly liked having a day coordinator.

The lean chemotherapy production scheme is combined with dose-banding and robotic preparation of cytotoxic doses at the University Hospital of Geneva.

Reference

Larsson I et al. Leachable/extractable issues in a pharmacy setting. Hosp Pharm Eur 2015;77:39–41.

Quality and safety

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