Quality control ensures safety of chemotherapeutic infusions

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  • Published: Nov 14, 2016
  • Author: Ryan De Vooght-Johnson
  • Channels: HPLC
thumbnail image: Quality control ensures safety of chemotherapeutic infusions

Preparing the payload

Illuminated under a cold, white glare, disinfectant and bleach stinging their nostrils, scientists working in the cancer ward are entrusted with a very important job. Their arms feeling into an aseptic isolator via a rubber sealant worn like a hand-puppet, they must handle their molecular payload with the utmost attentiveness and care: the chemotherapeutic cocktail they prepare will soon be heading into a patient’s bloodstream, hopefully, to quell the uprising of the rogue cancer cells inside.

Mustering all the dexterity afforded through a second skin, the pharmacists must ensure that the cocktails they prepare are dispensed at the correct dose, that they remain microbe-free, and are not inadvertently administered to themselves. Further still, there can be absolutely no cross-contamination.

Aseptic isolators are ideal for this, explains Guillaume Brachet of the University of Tours in France. ‘In our hospital, we have opted to prepare cytotoxics [chemotherapeutic drugs] in the Isocyt Freja®, an aseptic isolator manufacturer by Getinge,’ he writes.

A slight snag with this model, however, is that two pharmacists, potentially preparing very different cocktails, sit side-by-side. ‘This leads to a risk of cross-contamination of anti-cancer compounds during preparation due to spillage; switching of syringes, needles or vials between operators; or, to a lesser extent, aerosolization,’ warns Brachet.

Safety all-round

Brachet estimates that he and his colleagues at the University Hospital prepare 30,000 cocktails each year. Each is made up of the numerous permutations of 90 distinct cytotoxic agents, ranging from monoclonal antibodies to anthracyclines and vinca-alkaloids. As you can imagine, numerous checks and quality controls are necessary.

For this, each drug vial and infusion bag must be inspected manually, the drugs and diluents are then ID’d by their UV or infrared emissions, and their doses are assayed in real-time with a MultiSpec UV-Fourier transform infrared spectroscopy analyser. Though seemingly thorough, these checks Brachet argues, cannot ‘assess cross-contamination between two or more products’ that could arise from pharmacists working on top of one another.

If proven correct—if cross-contamination does indeed happen within these two-man isolators—it could have huge consequences. And yet with no suitable test, we cannot tell for sure.

Leaving nothing to chance, Brachet and colleagues write in Drug Testing and Analysis on how they went about developing a method sensitive enough to detect trace levels of seven commonly used chemotherapeutic drugs: 5-Fluorouracil. Cytarabine, Gemcitabine, Irinotecan, Doxorubicin, Epirubicin, and Daunorubicin. This test could then be added to the battery of existing quality controls to ensure patient safety.

Using standards of each drug suspended in buffer, Brachet loaded the chemical cocktail onto a C12 column and separated these over a 30-minute reverse-phase gradient by HPLC. To enhance the separation of their seven drugs, the French researchers exploited the presence of protonatable nitrogen atoms within four of the seven drugs by lacing buffer A with perfluorinated carboxylic acid, which would provide a pool of transferable protons. Next, the unique spectral emissions of each drug were detected having been excited by UV light.


The chromatogram published with their paper shows how the drugs were more or less resolved within 26 minutes, except for Doxorubicin and Epirubicin.

Having fashioned a straightforward analytical test, they then validated it in accordance with reputable guidelines. For this, they measured seven standards of either low, medium or high dose in triplicate over the same or three consecutive days. This experiment proved above all that their HPLC-UV assay was both precise (<5.4% RSDs) and quantitation was made within 95–108% of their fortified dose.

Limits of detection, meanwhile, ranged from 0.12 to 0.58 μg/mL. These levels, the authors reason, would translate to less than 1.3% of the dose contained in a 500-mL infusion bag—suitably sensitive for most cases.

Wrapping up their study, Brachet and colleagues sought to detect cross-contamination in 47 cocktails prepared either at the same bench or within the same cabinet. Assuringly, no cross-contamination within these infusions was found, which authors claim ‘validated the safety of the local standard operating procedures for the preparation of cytotoxic infusions in an aseptic isolator’.

Where next? ‘This strategy is the first step towards a global programme of quality control in preparation units, which will increase safety levels not only for patients but also technicians,’ the authors envision.

Related Links

Drug Testing & Analysis, 2016, 8, 985–990. Brachet et al. An ion-pairing, reversed-phase liquid chromatography method to assess the cross-contamination of cancer chemotherapy infusions prepared in a dual-operator aseptic isolator.

University of Maryland, Preparing Chemotherapy

Article by Ryan De Vooght-Johnson

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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