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Published on 24 May 2016

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Quality and security

More than 450 pharmacists shared their experiences of compounding problems, risk assessment, environmental contamination and new developments at the recent GERPAC conference

 

 

More than 450 pharmacists shared their experiences of compounding problems, risk assessment, environmental contamination and new developments at the recent GERPAC conference

 

 

Laurence A Goldberg
Editorial Consultant, HPE
Christine Clark
Editor, HPE
A series of events at a hospital in England led to a five-fold glucose concentration error and consequent injury to the patient. Richard Bateman (Quality Assurance Specialist Pharmacist, East and South East England) described how an old automatic compounding device was in use and the order in which data were entered into the machine was different from the order in which the ingredients appeared on the paper worksheet.
On this occasion, dextrose 50% and water were transposed. The finished product was checked by weight. However, as the administration sets were attached in the pharmacy it was difficult to position the tubing on the scale pan and obtain an accurate reading. The staff routinely reweighed products until they got the ‘right’ weight, and on this occasion failed to register that the product was unusually heavy.
In another incident, the design of software led to a serious ‘near-miss’. During the data entry process a drop-down menu offered sodium chloride 30% and 0.9%. The 0.9% solution was selected in error and a large volume was calculated. When assembling the ingredients, the operator selected 30% sodium chloride (as usual) and therefore a large volume of highly concentrated solution could have been prepared. This error could be engineered out simply by removing the choice from the drop-down menu, noted Mr Bateman.
In many cases, errors only come to light when a product is administered, but it can be difficult to recognise isolated events. Microbiological contamination is a cause of concern – and finding the source can be very challenging. Contaminated facilities are easy to identify but faulty procedures, staff techniques or contaminated materials are more difficult to track down.
New standards
In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) issues standards for ‘Specials’ (MS) license holders. Essentially this is an interpretation of EU GMP MS license holders (hospitals and specials manufacturers) and it is undertaken to ensure consistency of standards, explained Alison Beaney (Regional Quality Assurance Specialist, North East England).
The key provisions include a requirement that there should be a check that the correct starting materials are connected to the correct lines of automatic compounders, volume delivery checks and reconciliation of starting solutions at the end of the session for both manual and automated systems. Barcoding is now considered to be an integral part of the risk reduction strategy and, if available, it must be used. In addition there should be no splitting of ampoules over more than one product.
Vials are preferred over ampoules because they are closed systems. Pooling operations (into bulk containers) should be minimised and only undertaken if it reduces risk of errors in compounding. If it is done, it should be treated as a batch operation and be validated by a media fill test. Any such bulk container should be given a maximum shelf life of four hours and should not be transferred between workstations.
A new sanitisation process has been introduced to deal with bacterial spores, said Dr Beaney. As 70% alcohol will not kill spores, when items are transferred from an unclassified zone to a Grade A zone two sanitisation steps are required; there should be a spray and wipe at both stages and a sporicidal agent must be used at the first stage.
Risk matrix 
A hospital can be using more than 500 different injectable products but few are available in a ready-to-use form and so it is important to have a logical way to decide which of them should be centrally prepared, Anna Maria Martin de Rosales and Carmen Lopez de Cabezas (Spanish Pharmaceutical Compounding Group) explained. The Council of Europe Resolution (CM/resAP (2011)1) had called for risk assessment of all injections and had proposed a model. In Spain, a risk assessment matrix had been designed and validated.
The Spanish model is based on a failure mode and effects analysis of six aspects:
  • The preparation process
  • The route of administration
  • The safety profile of the active ingredient
  • The number of units prepared
  • The distribution of the preparation
  • The susceptibility to microbial contamination.
A numerical scoring system proved to be problematic and so an alphabetic (A-D) scoring scheme was developed. Thus, each product gets a score that comprises six letters. If there is one or more Ds, the product is high risk; one C or three or more Bs is intermediate and fewer than three Bs is low risk. An example would be a batch of 12 fentanyl and bupivacaine 120ml injections for epidural administration. This scored CCBBAA and is therefore classified as ‘intermediate risk’. Only low-risk reconstitution should be undertaken on hospital wards. A further development of the matrix has related the risk categories to beyond-use dating at room temperature, under refrigeration and when frozen.
Patient-related factors and risks associated with the personnel responsible for compounding are two dimensions of risk that are not covered by the matrix, the presenters noted.
The risk matrix was checked for validity and reliability. Both inter-rater reliability and reproducibility were high. The presenters concluded that the risk matrix was well-adapted to day-to-day use and could be used to decide which products should be centrally prepared, and for assignment of beyond use dates. It should increase patient safety and make possible better use of resources. They also pointed out that an English version of the risk matrix is available.
Robot validation
Media fill simulation tests used to validate the microbiological integrity of the Apoteca Chemo compounding robot showed that it performed as well as manual compounding in vertical laminar flow cabinets, Irene Krämer (Director of Pharmacy, University Medical Centre, Mainz, Germany) told the audience. Double strength tryptic soy broth was diluted with water for injections and packed in 50ml syringes.
The syringes made in the robot were capped manually in the loading area of the robot. A total of 500 units was made by each method. They were incubated for 28 days at 22°C and positive controls were inoculated with Staphylocoocus epidermidis after 14 days. The results showed that no turbidity was seen in any of the syringes either at 14 days or 28 days and this confirmed that the aseptic procedure in the Apoteca Chemo robot is well-controlled.
Professor Krämer acknowledged that turbidity is not seen until bacterial counts exceed 105–106 per ml. An alternative would be to filter the end product and culture the filter, but such a procedure would risk contamination and misleading results.
Surface contamination
Surface cleaning to remove traces of cytostatic drugs in pharmacy preparation areas could be improved, according to Paul Sessink (Exposure Control, Sweden) and Sylvie Crauste-Manciet (Bordeaux University Hospital, France).
A multi-centre study including hospitals in France Belgium and Switzerland, had analysed wipe samples from five locations – the counter for prepared drugs, the telephone, the fridge handle, the door exit handle and the computer keyboard. Standard wipe sampling kits were provided to participants at the GERPAC conference in 2014. Each hospital was asked to sample one of the five locations.
In total, 81 samples were received from 78 hospitals. Just over 50% of hospitals were preparing more than 10,000 cytotoxic doses per year and about half had implemented containment measures such as closed system transfer devices. The results showed that 12% of samples were contaminated with one or two drugs and the most frequently contaminated locations were the counter top (seven of 35 samples) and the computer keyboard (three of 19 samples). The authors recommended that disposable protection sheets should be used on counter tops and disposable plastic films should be used over computer keyboards.
Reproductive toxicity
Alternative duties for pregnant workers to avoid exposure to hazardous drugs is a topic that is now being actively considered by the National Institute for Occupational Safety and Health (NIOSH) in the USA, said Thomas Connor (NIOSH, Cincinnati, Ohio, USA). Exposure to hazardous drugs can cause effects on fertility, spontaneous abortions, congenital abnormalities and low birth weight.
In the US, about half of all pregnancies are unplanned and so there is a risk that the foetus can be exposed to hazardous drugs before the woman realises that she is pregnant. Many low-molecular weight drugs, including cyclophosphamide, cisplatin and doxorubicin, can enter the breast milk. This is of concern because metabolic and elimination pathways in infants are not fully developed until at least six months of age and so infants can be more sensitive to the toxic effects of the drugs. A new, simplified FDA labelling scheme is to be introduced (after June 2015) for drugs with reproductive toxicity. There will be three categories namely, ‘pregnancy’, ‘lactation’ and ‘females and males of reproductive potential’.
A 2012 study of nurses who worked with hazardous drugs during the first trimester of pregnancy showed that the rate of spontaneous abortion was 10%, a twofold increase over the normal rate. There was a 3.5-fold increase when it was the first pregnancy. A systematic review of studies of reproductive risk with occupational exposure to antineoplastic drugs noted that many of the studies had small numbers of subjects. The findings included increases in spontaneous abortions and congenital abnormalities. There were also indications of subfertility and menstrual problems.
In Europe, guidance for protection of pregnant workers is provided by Directive 92/85/HC – pregnant workers. In the UK there is additional guidance for new and expectant mothers from the Health and Safety Executive (www.hse.gov.uk/mothers/).
Drugs in waste water
No fewer than 33 kilograms of pharmaceuticals, 20 kilograms of which are paracetamol, enter one water treatment plant in Bordeaux each day, according to Damien Granger (Project Leader, SUEZ, Bordeaux). Earlier studies had shown that the river Jalle (a tributary of the Garonne) contained a wide range of pharmaceuticals including relatively high levels of gabapentin, sotalol and hydroxyibuprofen. These findings prompted water engineers to investigate further to see whether the local hospital was the main source of the pharmaceuticals.
Analyses showed that there was a wide range of micropollutants in the waste water. Pesticides were the most common, followed by pharmaceuticals. They calculated that the hospital was the source for a maximum of 10% of the pharmaceuticals in the waste water. However, three of these – gabapentin, propranolol and diclofenac – were classified as high-risk substances. Environmental authorities throughout Europe are now monitoring diclofenac and its use may have to be prohibited, said Mr Granger. The local hospital uses 1500 kilograms of paracetamol per year, he noted.
Asked why there were no oestrogens listed as micropollutants, Mr Granger said the laboratory does not routinely monitor oestrogens or antibiotics, although large quantities of antibiotics are known to be in waste water.
In brief
Short communications covered a diverse array of topics. Some of the highlights were:
  • A technique for preparation of frozen stool suspensions enables faecal microbiota transplantation (FMT) to be carried out in a timely manner. FMT is a recognised alternative to antibiotic treatment for Clostridium difficile infection but its use is limited due to availability of donor material (University Hospitals Paris – Hotel Dieu, France)
  • Teicoplanin cannot be stored syringes because it interacts with the silicone lubricant but it can be stored for 28 days, in a fridge, in polypropylene infusion bags and Baxter Intermate® SV200ml/hr infusion pumps (Stepping Hill Hospital, Stockport, England)
  • Frozen azacitidine is stable for one month and this means that advance-preparation of 25mg/ml syringes would be possible. In aqueous solution azacitidine degrades irreversibly in a time and temperature dependent manner (University Hospitals Paris – Hotel Dieu, France)
  • A new device (Pharmacolog, Uppsala, Sweden) for rapid identification and quantification of antineoplastic drugs by UV spectrometry was validated in a cytotoxic compounding unit. Some 80–90% of cytotoxic drugs have absorption spectra below 225nm and could therefore be identified with this device. (University of Lille, France and University Hospital Geneva, Switzerland)
  • The DrugCam® device provides a reliable way of checking small volumes in paediatric syringes. Using a video camera in this way avoids the need for double-checking and therefore saves time (Institute Poali Calmettes, Marseille, France)
The 13th European GERPAC conference took place in Hyères, France, 7–9 October 2015. GERPAC stands for Groupe d’Evaluation et de Recherche sur la Protection en Atmosphère Controllée.


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