Reducing the risk of non-sterility of aseptic handling in hospital pharmacies, part C: applying risk assessment and risk control in practice

Participating hospital pharmacies

There is no correlation between the results (cumulative RPNs as well as microbiological controls) and the kind of hospital, nor between the results and the age of the cleanrooms. Hospital pharmacies 1 and 9 had the overall best results at the end of the study (see tables 2 and 5).

Comments on the risk reduction of the different sources of risk

In this section comments and additional information about risk reduction of the different sources of risk are given.

Air

Most hospital pharmacies own a particle counter, but only one did quarterly non-viable particle counting at rest around the work zone (‘at rest’ and ‘work zone’: definitions are given in online supplemental file 1); this lack of counting is a shame because non-viable particle counting is a simple experiment, while the results will give valuable information about complying with the at rest criteria for airborne particles.5

In hospital pharmacies 1, 8 and 9, videos about the risk of blocking first air by materials were used to find the correct position of materials inside LAF/SC.11

The results of viable air sampling are already far below the MM limits of up to 10% at the start of the study and did not really change during the study period (see table 4). This is not surprising because there are no distinct sources to contaminate the air inside LAF/SC.5

Worktop, walls and ceiling of LAF/SC

In all hospital pharmacies, except numbers 2, 3 and 7, the frequency of worktop disinfection increased (see table 2). However, the expected decrease of the CRRs of the worktop prints could not be assessed because the number of samples was often too low to get reliable CRR values (marked as ‘x’ in table 4).8 But a positive outcome was the number of pharmacies where daily monitoring of the worktop was being implemented at the end of the study (increased from four to seven hospitals; see table 4).

Materials with a sterile surface (sterile medical devices)

Even after thorough disinfection, the worktop has to be considered as a non-sterile surface. Therefore, a sterile pad is advised to prevent contact between critical spots (syringe tips, needles, openings of tubes) and the surface of the worktop.12 By the end of the study this pad was being used in four hospital pharmacies (see table 2). An alternative is to put syringes and needles on a sterile holder. Online supplemental file 5 gives an example.

Materials with a non-sterile surface (ampoules and vials)

Hospital pharmacies 5, 6 and 9 implemented the validated two-towel disinfection technique by using commercially available impregnated sterile polypropylene wipes.13 The two-towel technique was also introduced in hospital pharmacies 1 and 8, but these hospital pharmacies used cotton gauzes or medical non-woven wipes, submerged in alcohol 70%. Compared with the commercially available polypropylene wipes, these gauzes and wipes are less expensive. However, a disadvantage of cotton or medical non-woven is the higher emission of particles and fibers. Hospital pharmacies 3 and 4 also improved the disinfection technique (see online supplemental file 4).

Dragging microorganisms across materials with a non-sterile surface is a serious risk.4 Therefore, regular surface monitoring after disinfection is strongly advised.13–15 This has been implemented in hospital pharmacies 8 and 9 (see table 2). A procedure for routine monitoring of materials with a non-sterile surface is described by Boom and colleagues.16

Operator’s hands

This section refers to the hands of the primary operator (a definition of which is given in online supplemental file 1). The MM results of glove prints improved during the study period (see table 4). In addition, the frequent glove disinfection which started at the end of 2019 in hospital pharmacy 4 also led to results below the limit of 10% in the next year. Better results for glove prints are not only the result of more frequent glove disinfection, but also the result of more frequent worktop disinfection and better disinfection of materials with a non-sterile surface.5 However, if all these improvements are not implemented, a result below the MM limit of up to 10% is also possible (see figure 2, hospital pharmacy 7). Possible explanations for this finding are a low surface bioburden of materials and/or concurrent disinfection of the gloves by the impregnated wipes used during the disinfection of materials and/or frequent glove changes. Besides, the technique of performing glove prints itself can have a great influence on the results.8 17 Contact time that is too short, for instance, as well as a too small printed surface of the distal phalanx of the fingers, will have a negative influence on the recovery and therefore on the results.

Operator’s forearm

This section refers to the forearm of the primary operator. At the end of the study sterile sleeves were used in five hospital pharmacies. As mentioned in part B, sterile long-sleeved gloves will give the same protection as separate sterile gloves and sleeves.5

Working procedure

During the whole study period all contamination rates after APS are very low (see table 3). These results show, despite possibilities for risk reduction, that the operators were capable of producing products with a low chance of microbial contamination. However, a few remarks about these results can be made. First, during aseptic handling sometimes the preparation time is longer, and the number of preparation steps is larger compared with the usual applied broth simulation. Therefore, APS is not always a worst case simulation. Second, a more precise way of working during APS, compared with ‘normal’ aseptic handling, is not inconceivable. Third, not all aspects of the way of working can be measured by APS.18

In this connection, we emphasise the importance of a yearly audit of all operators as well as stimulating a policy of correcting each other. This not only has a great influence on risk reduction of working procedures, but also on many other sources of risk (see checklist in online supplemental file 2). At the end of the study auditing has been implemented in six hospital pharmacies (see table 2). More information about auditing can be found in part B.5

As mentioned in part A, two operators working together during processing is strongly recommended4; it makes a policy of correcting each other more workable as well as dividing activities that occur outside and inside LAF/SC and transferring materials into LAF/SC. All hospital pharmacies, except numbers 6, 8 and 9, were already working with two operators during processing at the start of the study. This did not change during the study.

Reducing the risk of non-sterility in nine hospital pharmacies

The cumulative RPN values at the start of the study varied from 630 to 825 (table 2). At the end of the study the differences were much greater, which leads to a cumulative RPN variation of 230 to 725 (see table 2). The improvement ratios also show great differences (see table 2). A sense of urgency and the time available for the implementation of the additional risk reducing measures are the main reasons for these differences. To enforce process changes, involvement of the responsible staff and the operators is an essential precondition. To enhance this, some hospital pharmacies work with a lean board and stand-up sessions and/or stimulate a policy to correct each other during operation. Additionally, for observing follow-up activities, it is important to use a system for corrective and preventive actions.19

Microbiological controls are an important part of the overall assurance of product quality.20 Unfortunately, except for glove prints, we did not find a correlation between process improvement (lower cumulative RPN) and the results of microbiological controls. Explanations are given in the subsections above.

It is well known that microbiological controls alone will not cover all sources of risk of non-sterility.18 Therefore, according to the principles of a pharmaceutical quality system, it is necessary to evaluate all these sources.21 The relevance of each, in combination with the effort to reduce them, can be made clear by the RA and RC model, described in parts A and B.4 5

Obviously, the implementation of the risk reducing measures will take time and/or will involve expense. For example, having an audit of two operators requires about 4 hours' work by the auditor.5 However, various measures can be implemented by only changing the way of working, without loss of productivity (for example, working without blocking first air on critical spots). Of course, a change itself will take time and energy, but a more robust process is a valuable result. Some measures will even save time, like transfer of ampoules and injection vials in their original white cardboard boxes into the background area (a definition of which is given in online supplemental file 1). This way of working keeps the surface bioburden of ampoules and vials low and shows no measurable influence on the particle burden in the background area.12

Application of risk assessment can also cast doubt on habits that have become general practice after years and years. For example, in previous articles we made clear that viable air sampling inside LAF/SC is not sensitive enough for controlling the environment inside LAF/SC or for detecting a filter failure.5 8 Therefore, based on the principles of risk assessment, discontinuation of this MM method is a serious option.

Assessing aseptic handling in other hospital pharmacies

Assessing aseptic handling in other hospital pharmacies can also be done with the checklist available in online supplemental file 2. As mentioned above, an instruction for the assessment is given in the checklist. For determining the RPN values and the remaining risk, a ‘blank’ RA and RC template is available in online supplemental file 6.

The determined RPN values can be used for prioritising additional measures for risk reduction. RPN values over 30 are called ‘not safe’ (red) and must be reduced first.4

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