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Recent guidance on quality assurance standards for hospital preparation could underpin the development of standardised intravenous injections and improve patient safety, according to experts at a B Braun satellite symposium
Christine Clark PhD FRPharmS
Editor, HPE
When vials and ampoules of parenteral drugs are supplied to clinical areas, the manipulations to prepare injectable doses are often unsupervised and unchecked – and yet this is a high-risk process, said Laurence Goldberg (Editorial Consultant, HPE), introducing the symposium. Healthcare professionals make errors in drug selection, diluent selection and the calculation of concentrations and volumes. The use of ready-to-use (RTU) or ready-to-administer (RTA) injections could offer a way to reduce the risks, he suggested.
Standard doses
The future of injectable medicines will entail two different approaches, according to Sylvie Crauste-Manciet (President, GERPAC and Paris Descartes University, Faculty of Pharmacy). On the one hand, there will be targeted therapy, where each patient is treated as a unique and complex individual and aspects such as pharmacogenetics are taken into account. On the other hand, there will be standardised therapy that can be prepared on a large scale for many patients.
This will have the advantage of minimising errors in ordering and preparation. Standardisation of doses is not a new idea; for example, solid and liquid oral medicines are almost all standardised doses. Furthermore, standardised doses are also used for intravenous drugs that have high therapeutic indices, such as antibiotics and some analgesics. Drugs with narrow therapeutic indices are more complex because many of them are high-risk products for which the use of standardised doses could reduce the risk of preparation errors.
A key step in introducing standardised doses is obtaining the agreement of prescribers. It is important to present a scientific argument and the first step is to carry out a risk analysis. This involves identifying high-risk medicines. In the UK, the National Patient Safety Agency published a Patient Safety Alert in 2007 that recommended the provision of RTU or RTA injectable products of standardised strengths to minimise risks during preparation and administration, noted Dr Crauste-Manciet.
A number of such lists have been compiled (for example, Medusa). Thus, it is possible to identify high-risk injections that are candidates for standardisation. This, in turn, allows the use commercially prepared products or, if these are not available, the use of standardised products that are prepared aseptically in pharmacy centralised intravenous additive (CIVA) units, in a RTU or RTA form.
International experiences of standardisation should also be discussed with prescribers. CIVA services have been developed in hospital pharmacies in several countries to prepare high-risk intravenous drugs, and dose-banding, which is a form of standardisation, was introduced in the UK in the 1990s for some cytotoxic drugs. The University Hospital in Geneva now routinely prepares a range of standardised injectable doses, including, phenylephrine, insulin and ketamine, she explained.
Dose-banding and flat-dosing
Two key questions that must be asked when dose-standardisation is discussed are: “Is the prescribed dose scientifically based?” and “Is the prescribed dose clinically important?” The dosing of many cytotoxic drugs is based on body surface area (BSA). However, this is an issue that is fraught with controversy because the original BSA calculation was based on retrospective toxicity studies and is not supported by pharmacokinetic or pharmacological studies. Regarding the second question, pharmacokinetic comparisons of dose-banded and individualised doses of 5-fluorouracil (5-FU) had shown that there were no differences in the plasma profiles. Furthermore, flat-fixed-dosing regimens have now been established for a number of cytotoxic agents, including capecitabine, cisplatin and docetaxel, added Dr Crauste-Manciet.
A survey in the UK had shown that oncologists were aware of the rationale for dose banding but concerns remained about the amount of variation from the prescribed dose that was acceptable and whether treatment given in this way would be safe and effective. However, it should not be forgotten that, even with individualised doses, there are numerous sources of variation, emphasised Dr Crauste-Manciet. These include, for example, genetics, co-morbidities, concurrent medication and factors such as smoking and alcohol intake.
The benefits of standardisation include reduction in the risk of preparation or administration errors, more timely administration of doses and reduced drug wastage. In addition, there is reduced exposure of nurses to cytotoxic drugs. There remains the theoretical risk of reduced efficacy or increased toxicity and the pharmaceutical industry should now take the lead in organising clinical trials with standardised doses to address these concerns, she recommended.
Once the standardisation route is adopted, there is a great deal of work to be done in terms of pharmaceutical preparation. The first step is to determine the list of drugs that will be prepared and the numbers of doses, concentrations and volumes that are required. Ideal candidates include high-risk drugs, parenteral nutrition solutions and cytotoxic drugs. One area of interest is the use of standardised concentrations of intravenous drugs for neonates. A standard concentration is provided and the dose is tailored by adjusting the volume administered, for example, by using a smart pump. The Institute for Safe Medication Practices (ISMP) has published a list of suggested drugs and standardised concentrations for neonatal use, she noted.
The physico-chemical and microbiological stability of the planned products need to be thoroughly investigated. Lastly, the technical aspects of preparation must be addressed. This could include consideration of whether to use automated compounding or filling devices, explained Dr Crauste-Manciet.
One example of standardised products was the use of neonatal parenteral nutrition. In 2004, treatment with three standardised preparations was introduced. A retrospective study was performed comparing the use of standard and individualised nutritional solutions in preterm infants of less than 32 weeks’ gestation. The results showed that the amino acid intake was higher and calcium and phosphate were better balanced in the group receiving standardised solutions. This was attributed to early feeding as a result of the readily available standardised solutions. In addition, there were considerable savings in pharmacy staffing costs when using the standardised products.
Once all the clinical and pharmaceutical issues have been worked out – it is time to start discussions with pharmaceutical industry about the provision of RTU or RTA versions, concluded Dr Crauste-Manciet.
Resolution impact
The publication in 2010 of The abridged survey report on quality and safety assurance standards for the preparation of medicinal products in pharmacies provided the foundations for the Council of Europe Resolution (CM/ResAP (2011)1) on the quality and safety of Intravenous injections, Vagn Handlos (Senior Scientist, Capital Region Pharmacy, Denmark) told the audience. The survey provided a good picture of the status of hospital preparation throughout Europe, he added.
One of the aims of the Council of Europe is to promote greater unity between its Members and this Resolution is intended to avoid or reduce quality and safety gaps between medicinal products prepared in pharmacies and those prepared on an industrial scale. The Council of Europe, which comprises 47 Member States, formally adopted the Resolution in January 2011. In doing so, Members undertook to adapt local regulations in accordance with the principles set out in the Resolution, explained Dr Handlos.
The Resolution applies to pharmacy preparations (also known as unlicensed pharmaceutical preparations), which are prepared by community and hospital pharmacies for the special needs of individual patients or small groups of patients. The survey covered 19 countries and was designed to investigate legal provisions and definitions, general safety and quality standards, the preparation and delivery (supply) between pharmacies and the quality and safety of pharmacy preparations. The results showed that a wide variety of legal frameworks and a considerable variability in quality standards and the levels of Good Manufacturing Practice (GMP) were applied. For example, in some countries the procedure for recall of faulty products was not always implemented and in some there was no differentiation in procedures for small and large batches.
The Resolution clearly recognises the need for pharmaceutical preparations that may be required to met the special needs of individual patients because of their medical condition or the unavailability of appropriate products.
There are a number of key recommendations or provisions in the Resolution. One of the first is the concept of ‘added value’ of a pharmaceutical preparation; healthcare professionals are asked to consider whether there is added value from a pharmaceutical preparation or whether a suitable equivalent product with a marketing authorisation already exists – in which case it should be used.
If a pharmaceutical product is to be prepared, then a risk assessment should be performed to determine the level of quality assurance that should be applied during the process. GMP standards are recommended for high-risk products and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) for low-risk products. It may be complicated in practice to operate according to two different systems and an alternative approach is to have a ‘special GMP’ for hospital preparation, said Dr Handlos. This has already been done in the UK and in The Netherlands, in collaboration with national authorities, he added. The Resolution contains a suggested risk assessment scheme that takes account of factors such as the amount prepared, the pharmacological effect, the therapeutic index and the complexity of the preparation process.
Another important point is compliance with pharmacopoeia requirements, for example, for the quality of the raw materials.
Correct labelling is essential for patient safety. The Resolution specifies the details that should appear on the label.
The recommendation for a product dossier will be new measure for many pharmacies. The dossier should demonstrate that the active pharmaceutical ingredients, excipients and containers meet relevant requirements, taking into account specific patient needs. It should also describe the preparation process and provide information about the correct use of the product for the patient and the prescriber.
Reconstitution
Turning to the matter of reconstitution, Dr Handlos said that reconstitution is defined as “manipulation to enable the use or application of a medicinal product with a marketing authorisation in accordance with the instructions given in the Summary of Product Characteristics (SPC) or the patient information leaflet”. Reconstitution is not considered to be pharmaceutical preparation. Nevertheless, reconstitution should preferably take place in a pharmacy, although low-risk products may be reconstituted onwards, provided that ward staff are suitably trained.
Dr Handlos recommended that hospital pharmacists should assess how well their own hospitals were performing by using the list of points from the Resolution as checklist.
NECC incident
A recent incident in the US underlined the importance of quality assurance in pharmacy compounding. The New England Compounding Center (NECC) had compounded injections of methyl prednisolone acetate and triamcinolone. The injections, which had been distributed to 75 medical facilities in 23 states between May and September 2012, turned out to be contaminated with fungal organisms. So far, 375 cases of fungal infection, including fungal meningitis, had been reported and there had been 44 deaths, said Dr Handlos. In October 2012, the Massachusetts Pharmacy Board shut down two more compounding pharmacies after they conducted surprise inspections because of concerns about sterility. An investigation of the NECC by the Food and Drug Administration (FDA) determined that four important factors had contributed to the poor quality of the pharmaceutical products. These were:
- Unknown microbiological quality of the active pharmaceutical ingredients
- The products were preservative-free
- The premises were contaminated and badly managed – there was a rubbish dump in the vicinity and the ventilation system was shut down at night
- There was no validation of the heat sterilisation process.
Many of the points on which the NECC failed were covered by the recommendations in the Resolution, emphasised Dr Handlos. Moreover, in Europe compounding centres must work to GMP (which was not the case at NECC).
Although the Resolution provides a strong framework for quality assurance, there will be challenges in future. Increasing demands from authorities for higher standards create the need for more investment that cannot always be funded. In addition, it can be difficult to recruit adequately trained staff and difficult to find suitable quality assurance and quality control services and Qualified Persons. Increasingly, the trend in Europe is to centralise facilities and standardise products in areas where patient needs are greatest and where safety is not compromised, concluded Dr Handlos.
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Ready-to-use or ready-to-administer?
The terms ‘ready-to-use’ or ‘ready-to-administer’ are often used interchangeably but they have different meanings.
RTU refers to an injection that contains the active drug in solution at the required concentration and volume in a vial. The total content of the vial is transferred to a syringe, bag or elastomeric device for administration.
RTA refers to an injection that contains the active drug in solution at the required concentration and volume, in the final container (for example, syringe, bag or elastomeric device) for administration. No further calculations or manipulations are required.
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The B.Braun satellite symposium, Safer IV therapy – a catalyst for change, was held on 13th March 2013, in Paris during the 18th EAHP Congress.
