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  • Boyd Ingram posted an update 2 weeks, 1 day ago

    Timing and extent of precipitation can differ even for identical samples investigated in the same study [31]. Several factors that are not easily controlled can influence the question of compatibility; e.g. the temperature, light conditions, different batches of tested products etc. Even though acceptance limits are difficult to define, some measure of what is a large or a small change compared to controls is important in order to interpret the results. Based on the current experiences we suggest some arbitrary limits for each method of the test program: 1) Visual examination: No clear signs of Ndicates that the observed precipitation must be from calcium phosphate. Ondansetron particles or increased Tyndall effect should be detected. 2) LO: It is difficult to set a fixed limit for what is an alarming increase in sub-visual particles. Particle counts above 0.5 m approaching 1000?000 particles/ml (provided that both drug and TPN are filtered 0.22 m before mixing) is approximately 10?0 times the background count of TPNaq, and should be a reason to react. It is also important to look for growth of larger particles (c.f. Ph. Eur. limits) and to see how the particle counts develops over time. If there jir.2013.0113 is no clear increase over time, either ajhp.120120-QUAN-57 in number or particle size, it might be a compatible blend. Noteworthy, in ampicillin: TPNaq (Table 5) samples, and TPNaq: NaOH, the Ph. Eur. limits were not exceeded, even though a large increase in smaller particles (e.g. from 485/ml immediately to 9550 particles/ ml 0.5 m after four hours for ampicillin: Olimel?N5E) indicated precipitation. These small particles might grow and aggregate with time and constitute a risk if infused. This suggests that using the Ph. Eur limits only, may not be sufficient when it comes to dynamic situations asprecipitation and compatibility studies. For the evaluation of “static” particles such as dust, fibers, glass etc. the Ph. Eur. limits are more applicable. 3) Turbidity: Attention should be payed to turbidity values > 0.20-0.30 FNU, although this has to be seen in comparison to the background turbidity of both TPNaq and drug. Based on experience with incompatible blends that did not exceed the currently applied limit of 0.5 FNU, a lower level might be suitable, and results from complementing methods will be required for reliable judgment of compatibility. However, we have occasionally measured Milli-Q-water as high as 0.18 FNU. Care should be taken to avoid disturbing factors like scratches on sample cells, bubbles etc. 4) pH: The pH values should be interpreted in relation to the pKa value of the drug and the pH of the TPN. If mixing moves the pH in direction of less ionized drug, the solubility decreases. It is also alarming if the pH approaches 7 with regard to calcium phosphate precipitation, and if it is below 5.5. The latter is due to phospholipids being ionized at pH values 5.5-9.0 [33]. At pH values below this, the charge might start to neutralize, increasing the risk of emulsion destabilization. However, some phospholipids are not completely neutralized before reaching pH 3.2 [8], therefore the emulsion might stand lower pH values than 5.5. 5) PFAT5: It is difficult to define an alarming increase based on the current data, and we therefore lean on the PFAT5 limit of < 0.40 .