Spectrometric Analysis of Process Variations in Remifentanil

Abstract

ULTIVA® (remifentanil hydrochloride) is a sterile, nonpyrogenic, preservative-free, white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution. Each vial contains 1, 2, or 5 mg of remifentanil base; 15 mg glycine; and hydrochloric acid to buffer the solutions to a nominal pH of 3 after reconstitution. ULTIVA® is a μ-opioid agonist with rapid onset and peak effect, and short duration of action. Intra-lot and inter-lot variability in the spectra of ULTIVA® was measured in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). In 6 vials sampled, 1 came from lot 220453F while 5 came from lot 30020BF. The 1 vial sampled from lot 220453F appeared 122 multidimensional SDs from the other vials from lot 30020BF, suggesting that it represents a different formulation or material. Consequently, additional spectra from other lots were analyzed. Spectra of 90 vials from 9 lots in the spectral library contained vials that were outside the main group (50.3 SDs using a subcluster detection test), suggesting that the 35 library vials (39% of the total) contain different materials from the other 55 vials.

Figure 1.

Vials of ULTIVA®(remifentanil) for injection. The drug appears as an off- white freeze-dried powder in the vial on the right. The vials were scanned nondestructively in the near-infrared spectral region through the bottom of the vials.

Figure 2.

FTNIR spectra of vials of Lots 220453F (Vial 1) and 30020BF (Vials 2–6) from 4000–4800 cm⁻¹. In the PC plot (Figure 4), both vial 1 (dark blue line) and vial 4 (violet line) appear to be outliers from the main group. However, only vial 1 is displaced orthogonally (122 SDs) from the maximum variation (major axis) of the group of spectra.

Figure 3.

FTNIR spectra of vials of Lots 220453F and 30020BF from 5600–6300 cm⁻¹.These are the same vials depicted in the spectra in Figure 2.

Figure 4.

PC score plot of the spectra of the vials in Lots 220453F and 30020BF. VIal 1 is displaced 122 SDs from the other vials.

Figure 5.

PC 1 loadings spectrum for Lot 220453F and Lot 30020BF. Baseline variations are weighted most heavily in forming this principal component.

Figure 6.

PC 2 loadings spectrum for Lot 220453F and Lot 30020BF

Figure 7.

PC 3 loadings spectrum for Lot 220453F and Lot 30020BF

Figure 8.

PC score plot of the spectra of the 90 vials in the remifentanil library. The group on the right with more spread contains 35 vials, while the tighter group on the left contains 55 vials. The 2 groups of spectra are 50.3 SDs apart using the subcluster detection test (r_tn=0.99, r_tst= 0.86).

Figure 9.

The extreme spectra from the larger group on the right of Figure 8 look similar, but there is a baseline difference as well as a small difference in peak heights near 4100, 4160, 4220, 4530, and 4720 cm⁻¹.

Figure 10.

The lower extreme spectrum from the larger group on the right of Figure 8 (vial 82) looks very different from a central spectrum of the group on the left (vial 11). Most of the vials in the spectral library (55) look like vial 11, with only 35 looking like vial 82.

Figure 11.

The extreme spectrum from the larger group on the right (vial 82) of Figure 8 looks very different from a central spectrum of the group on the left (vial 11).

Figure 12.

PC score plot of the spectra of the 90 vials in the remifentanil library. The two groups seen in PCs 1–3 are gone, but in these smaller PCs some apparent outliers still appear (vials 75, 88, 89, 90).

Figure 13.

PC loadings spectrum for PC 1 of the remifentanil library. Like Figure 5, baseline variations are weighted most heavily in forming this principal component.

Figure 14.

PC loadings spectrum for PC 2 of the remifentanil library. PC 2 is a major descriptor in Figure 8.

Figure 15.

PC loadings spectrum for PC 3 of the remifentanil library. PC 3 is a major descriptor in Figure 8.

Figure 16.

PC loadings spectrum for PC 4 of the remifentanil library. PC 4 is a major descriptor in Figure 12.

Figure 17.

PC loadings spectrum for PC 5 of the remifentanil library. PC 5 is a major descriptor in Figure 12.

Figure 18.

PC loadings spectrum for PC 6 of the remifentanil library. PC 6 is a major descriptor in Figure 12.

Figure 19.

QQ plot of the spectra of the remifentanil library. The 2 groups of spectra are 50.3 SDs apart using the subcluster detection test (r_tn=0.99, r_tst= 0.86), suggesting that the two groups represent a different formulation or material.