Excipient exchange in the comparison of preparations of the same biologic made by different manufacturing processes: An exploratory study with recombinant human growth hormone (rhGH)

Demonstrations of bio-similarity between subsequent entry (follow-on) biologics and innovator’s formulated drug products may depend upon methods that either remove excipients completely or allow the exchange of excipients to give equivalent formulations. Excipient exchange through dialysis is perhaps the simplest of such methods but its use has been hotly debated. This debate, in the absence of published data, has relied largely on theoretical considerations. This study presents data that indicate that excipient exchange can allow comparisons of different formulations of the same therapeutic protein. The use of excipient exchange to and from one concentration of mannitol to another or to a mixture of glycine and mannitol was reproducibly demonstrated for recombinant human growth hormone (rhGH). We show that marketed rhGH products from several different manufacturers exhibit differences in conformational stability when compared directly. These differences, however, are shown to be the result of differences in formulation rather than in the drug substance itself and were removed through excipient exchange. The data presented, therefore, also indicate that failure to assure a common excipient background can lead to erroneous conclusions about the similarities and differences in the physico-chemical properties of two preparations of the same therapeutic protein made by different manufacturing processes.