O

Laboratory

Substance (98.7%) (100.2%) Pouch (97.2%) Cell (93.9%)

B. Metronidazole Photolysis Cool White Radiation

Laboratory

Figure 4 Summary of Metronidazole drug substance and formulated product photolysis with UV-A (a) and Cool White (b) radiation. The entries in parentheses are the intralaboratory average.

the quinine actinometer system for UV-A photolysis. The efficacy of this system for both UV-A and Cool White photolysis is demonstrated by comparing the interlaboratory standard deviation for samples that undergo photolysis with the variation in lamp intensities as reflected in the photolysis apparatus system linearity studies (Tables 1 and 2). The variation in Cool White and UV-A source intensities, as indicated by the photolysis slope (AU/hr, Tables 1 and 2), differs by a factor of about two with a percent relative standard deviation of 27.4% and 33.2% for the UV-A and Cool White photolysis sources, respectively.

The function of the quinine actinometer system is to monitor photolytic exposure and thereby normalizing the inherent intensity variations due to lamps, applied power, sample positioning, etc. To demonstrate the efficacy of the quinine actinometer system, the photolysis results for the Furosemide and Metronidazole Injection formulations with UV-A radiation are tabulated in Table 3.

The Furosemide Injection results indicate that the brown wrapper provides excellent protection from UV-A radiation. The inter- and intralaboratory standard deviation from the wrapped results for the Furosemide Injection reflects the standard deviation of the assay procedure. The Furosemide Injection results with the wrapping removed clearly indicate substantial photodecomposition. Although each laboratory confirms that the Furosemide Injection solution is susceptible to UV-A photolysis, the results show considerable variation between laboratories.

In the Metronidazole studies, sample presentation was controlled for the samples photolysed in the quartz cell. Note that the inter- and intra-laboratory standard deviation for the Metronidazole photolysis in the quartz cell (2.8) is comparable to the standard deviation due to the assay method alone (2.2). Thus, when the sample presentation is properly controlled, it appears that the quinine actinometer system provides reproducible monitoring of UV-A radiation.

Reproducible sample presentation will significantly affect the reproducibility of photolysis studies. In testing formulations in their primary or secondary packaging, adequate control of the sample presentation may not be possible. Such is the case with the pre-loaded Furosemide syringe formulation. Replicate photolysis with the same photolysis apparatus offers only a modest improvement in reproducibility as compared to the precision observed between laboratories in the collaborative study. Unfortunately, drug formulations are not ideal optical devices.

The ICH protocol recommends photolysis studies of the formulation directly and, if necessary, further studies in the primary and secondary marketing pack. Direct photolysis of formulated solutions in a quartz spectrophotometer cell, as with the Metronidazole solution in the FDA/PhRMA collaborative study, provides a well controlled sample presentation to the photolytic radiation.

4.2 Sample Photolysis Procedures

In general, the sample photolysis procedures for the drug substances and dosage forms in this study appear adequate. In photolysis studies, solid samples, drug substances, and solid oral dosage formulations are not expected to undergo extensive photolysis, given that the

Table 3 Inter- and intralaboratory variation in UV-A photolysis of injection formulations.

Percent Drug Substance Remaining Furosemide Injection Metronidazole Injection

Lab UV-A Lamp3 _ Intensity (AU/hr)

Wrapper No Wrapper Pouch Quartz Cell

0 0

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