Lack of Content Uniformity in MMR Vaccine

Abstract

The measles, mumps, and rubella (MMR) vaccine is a vaccine used to prevent measles, mumps, and rubella (German measles). The vaccine is mandated for children to attend public school in nearly all US states. However, measles cases have been increasing in the past decade, and quality problems have recently been noted by the US Food and Drug Administration (FDA) with the vaccine manufacturer. Intra-lot and inter-lot variability in the spectra of MMR (measles, mumps, and rubella) vaccine was detected in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). Six vials of 12 (50%) sampled from Merck lot U006488 appeared 14.5 SDs from the other vials on a subcluster detection test, suggesting that they represent different material. Spectra of 198 vials from 12 lots in the spectral library contained 140 vials in one tight ellipsoidal group, and 58 vials (30%) were outside that group (39.7 SDs using a subcluster detection test), suggesting that the library vials also contain differing materials.

Figure 1.

Measles cases have been increasing in the US for the past decade. The blue line depicts actual annual case numbers, while the red line is the moving average.

Figure 2.

Spectra of 12 vaccine doses from the same lot, U006488, vary. In general, drugs in the same lot have similar spectra. However, in this figure two distinct groups of spectra are found, with 6 in each group. One group of spectra has peaks at 4490, 4580, 4832, and 4687 cm⁻¹ that the other group does not have. In the other group, the location of the major peak varies, appearing sometimes at 4592 cm⁻¹ and other times at 4604 cm⁻¹.

Figure 3.

Spectra of 12 vaccine doses from the same lot, U006488, in a different spectral region from Figure 2. Again, 2 distinct groups of spectra are found, with 6 spectra in each group. Peaks at 5863, 5973, and 6020 cm⁻¹ are present in one group of spectra, but absent in the other.

Figure 4.

Principal component (PC) plot of the spectra of the 12 vials sampled from lot U006488. Group membership is indicated by the superimposed ellipses. The group of spectra with the extra peaks in Figures 2 and 3 is the group on the right.

Figure 5.

PC plot of the spectra of the 12 vials sampled from lot U006488. These are the same groups as Figure 4 but the ellipses are not shown, and the plot shows PC 1 and 3 instead of 1 and 2.

Figure 6.

3-D PC plot of components of lot U006488 lower than Figures 4 and 5. In these PCs only vial 1 seems an outlier.

Figure 7.

PC plot of components of lot U006488 on PCs 4 and 5. Only vial 1 seems an outlier.

Figure 8.

PC plot of components of lot U006488 on PCs 4 and 6. Only vial 1 seems an outlier.

Figure 9.

Plot of the loadings spectrum for PC 1 of lot U006488. In NIR spectra PC1 usually reflects some kind of baseline variation, even in scatter-corrected spectra.

Figure 10.

Plot of the loadings spectrum for PC 2 of lot U006488.

Figure 11.

Plot of the loadings spectrum for PC 3 of lot U006488.

Figure 12.

Plot of the loadings spectrum for PC 4 of lot U006488.

Figure 13.

QQ plot from the subcluster detection test on PCs 1 and 2 of the spectra of lot U006488. (r_lim=0.95, r_tst=0.88, p=0.02) The clusters are 14.5 SDs apart by the subcluster detection metric.

Figure 14.

Photograph of MMR vials. Spectra were collected using diffuse reflectance from the lyophilized cake through the bottom of the vials.

Figure 15.

3-D PC plot of the spectral library of MMR vaccine. A total of 198 vials were scanned from 12 different lots.The tight ellipsoidal group on the right contains 140 of the 198 vials.

Figure 16.

A 2-D PC plot of the spectral library without the blue line connecting the vials in the order in which they were scanned.

Figure 17.

PC plot of PCs 1 and 3 of the spectral library. Some of the outliers are different in this view.

Figure 18.

PC plot of PCs 2 and 3 of the spectral library. Some of the outliers are different in this view.

Figure 19.

3-D PC plot of PCs 4, 5, and 6 of the spectral library. Some of the outliers are different in this view, with vial 135 being farthest from the cluster (7.2 SDs).

Figure 20.

3-D PC plot of PCs 7, 8, and 9 of the spectral library. Some of the outliers are different in this view, with vials 144 (6.1 SDs) and 145 (4.9 SDs) being farthest from the cluster. Vial 134 is 3.7 SDs away, vial 13 is 4.0 SDs away, and vial 154 is 3.4 SDs away from the center of the cluster.

Figure 21.

3-D PC plot of PCs 10, 11, and 12 of the spectral library. Some of the outliers are different in this view, with vials 154 (5.9 SDs) and 76 (6.0 SDs) being farthest from the cluster. Vial 33 is 3.5 SDs away, vial 135 is 5.3 SDs away, vial 147 is 4.0 SDs away, and vial 151 is 3.0 SDs away.

Figure 22.

3-D PC plot of PCs 13, 14, and 15 of the spectral library. Vials 15 (7.0 SDs) and 154 (5.5 SDs) are farthest from the cluster center. Vial 145 is 4.3 SDs, vial 147 is 3.7 SDs, vial 144 is 3.4 SDs, and vial 62 is 3.6 SDs away from the center of the cluster.

Figure 23.

3-D PC plot of PCs 16, 17, and 18 of the spectral library. Vials 134 (6.3 SDs) and 171 (6.3 SDs) are the farthest away from the center of the cluster. Other outlier vials include vial 102 at 3.4 SDs, vial 133 at 4.0 SDs, vial 135 at 4.4 SDs, vial 147 at 5.1 SDs, vial 151 at 3.8 SDs, and vial 174 at 4.4 SDs.

Figure 24.

3-D PC plot with no outliers. Drugs normally project into hyperspace with shapes like this.

Figure 25.

QQ plot from the subcluster detection test on PCs 1 and 2 of the spectra of the library of 198 vials. (r_lim=0.98, r_tst=0.86, p=0.02) The clusters are 39.7 SDs apart by the subcluster detection metric.