Les sources de contamination (flacons & le produit fini)
Chimie ParisTech ; Sorbonne Paris Cité ; Chemical, Genetic and Imaging Pharmacology Laboratory, F-75006 Paris, France
CHI Poissy Saint Germain-en-Laye, Pharmacy department, 20 rue Armagis. 78105 Saint Germain-en-Laye, France
External surface contamination of manufactured vials with cytotoxics was widely published for many years (Connor et al. 2005 ; Delporte JP, et al.,1999 ; Favier B, et al. 2003 ; Mason HJ, et al. 2003)and is still an issue in 2012 according to recent papers published (Touzin et al,2008, Schierl et al., 2010, Hama et al., 2011). Vials contamination contributes to widespread contamination inside working areas within the collective protection (isolator or BSC) but also in their immediate environment. Despite implementation of corrective measures by manufacturers i.e. cleaning procedure of vials and protective overwrapping (i.e shrink wrap and plastic containers) there is still a residual risk of contamination. Cleaning procedure with washing machine is routinely used by pharmaceutical companies during manufacturing process (pharmaceutical companies’ debate, GERPAC, 2009). But it has been specified that this process is unable to remove potential contamination between flip off cap and rubber stopper. This contamination risk was previously highlighted by V’Ian Fenton-May during GERPAC, 2004. All manufacturers confirmed during the GERPAC debate in 2009, the inability of the washing process to remove the rubber stopper contamination. Moreover, it has been shown that outer packaging of vials may be contaminated as well (Hedmer et al., 2005) and when manufacturer used the same production plant, cross contamination with other cytotoxic drugs was possible as shown by Schierl et al., Hedmer et al., 2005 ; Mason et al, 2003) for cyclophosphamide & ifosfamide. The level of contamination found on vials over the different studies was unpredictable, from no contamination (under the detection limit of analytical method) and detectable contamination with large amounts up to µg scale.
Considering the protective systems, shrink wrap was shown to considerably reduce the vial contamination (Schierl et al, 2010), but it must be taken into mind that contamination under flip off cap is still an issue. The problem is then to be able to implement procedures to limit exposure of operators. Main issue for operators’ exposure risk is the handling procedures of vials outside equipments. A study presented in 2009 by Podilsky (Mosset et al., GERPAC 2009) simulating the procedure for introducing vials into BSC pointed out the risk of using spraying method with disinfectants and suggested the substitution of spraying by wiping method to limit the spread of contamination. In a similar way, Mason et al., 2005 pointed out the risk of dermal exposure outside isolators when spraying vials outside isolators. To limit exposure of operators with contaminated vials, simple protective measures can be implemented and will be discussed.
When considering the residual contamination of vials in combination with the process of preparation, contamination can be transferred to the final products as previously shown by Gilles et al, 2004. In similar way as the manufactured vials, the final product is also chemically contaminated and probably cross contaminated by more than one cytotoxic inside the collective equipment. Proper gloving, with high frequency of changes is able to limit this contamination. Kamguia et al., GERPAC 2005, reduced the contamination of final product by implementing additional cleaning method using anionic surfactant agent. More recently, Queruau Lamerie et al, GERPAC 2011, highlighted the interest of surfactant agents for removing cytotoxic contamination on surfaces. So, more than an universal method for degradation of cytotoxic which is not available, it is worth to use a cleaning method able to remove the contaminants from surfaces (i.e. surfactant) in combination with proper methods for containment and destruction of waste.
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