Fluorescence Spec Mass Spec

Fluorescence Spec Mass Spec conformed to the known reference standard and the expected specifications. Despite a change in cell line and media, no significant change was measured, including the oligosaccharide structure. In 1995 changes were made in order to meet Phase-3 clinical needs and to continue to improve the productivity, quality and control of the commercial process. Several changes were made for the Phase-3 process, as follows:

• Improved media composition

• Increased bioreactor run time

• Fourfold scale up of the purification process including high performance resins

• Formulation change from liquid to lyophilized

In 1996 and 1997, additional changes were made after Phase-3 and consistency lots. A relatively minor change was made to the infliximab formulation post-Phase-3, decreasing the container size from 250 to 100 mg. Comparability was demonstrated by testing the clinical lots side-by-side using WEHI bioassay, pharmacokinetics AUC, and assays which probe the mechanism of action (such as inhibition of TNF-a receptors p55 and 75-sf2, neutralization of TNF-a, and complement-mediated lysis of a transgenic cell expressing membrane-bound TNF-a).

As the market projections were being estimated for REMICADE, it became apparent that the Phase-3 process would not supply the commercial needs. The initial process validation included both a 1 x and 4 x purification process (Stages 4 to 9 in Figure 18.2). To expand the scale of the purification process further to 8 x, the regulatory agencies required Centocor to verify comparability for additional consistency lots.

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