ABSTRACT

It is essential to develop sufficient process history before transferring any process to a contract manufacturing organization. This article presents case studies illustrating two key components of technology transfer: demonstration and documentation of process reliability at two representative scales before technology transfer and the establishment of clear and rigorous process transfer criteria based on process history with which to gauge the efficacy of the transfer.

Millennium

Process history plays a critical role in the development and implementation of a manufacturing process at the CMO. If the client organization does not take the time and effort upfront to develop a robust manufacturing process, it is doubtful that a productive and robust process will evolve in the production suite of a CMO. If the client has insufficient process history at both bench- and pilot-scales, one cannot expect that process to operate in a sufficiently reliable manner at large scales.

Sufficient process history also is key to the rapid and efficient transfer of a client process to a CMO. Without a basis for comparison, the client and the CMO cannot determine if the process has been successfully transferred. For example, if the yield at the CMO is 25% lower than expected, are variant equipment design parameters or operational conditions in the CMO production suite at issue, or does the smaller yield simply reflect the normal variance of the process regardless of where it is manufactured? Without a sufficient process history, there is no way to know.

Finally, even after the process is operating in the production suite of the CMO, client process history can be invaluable if problems arise. Process history can provide impartial evidence when deviations occur or when the CMO suggests minor changes to the client process to achieve some benefit for itself (e.g., improved convenience, reduced labor, reduced paperwork, optimized suite scheduling).

DOCUMENTING PROCESS RELIABILITY

Developing a robust process and establishing clear and rigorous transfer criteria is highly beneficial for technology transfers. The first prerequisite for establishing transfer criteria is a documented process history.

A CMO will not agree to meet pre-set transfer criteria unless it has documented evidence that the client has met these criteria in the client's facility several times. Bench-scale demonstration of process reliability is necessary, but not sufficient. If process performance problems arise at the CMO and the only process history from the client was generated in the laboratory, one can be sure that the process variance will be attributed to an elusive "scale issue." Augmenting bench-scale data with pilot-scale data will demonstrate that the process can be scaled up and documents a rational basis for further scale-up.

Process history should be established using representative bench-scale and pilot-scale systems. As often as possible, these systems should be scaled-down versions of clinical and commercial scale processes. For example, equivalent cell ages (i.e., population doublings from thaw) should be used to inoculate both bench-top and pilot production-phase bioreactors and large-scale production-phase bioreactors. Additionally, the seed trains used to inoculate the production phase bioreactor should be equivalent to those used at clinical scale. Bench-top and pilot production-phase bioreactors should be inoculated from seed bioreactors rather than shake flasks. Clinical-grade raw materials, filters, and resins should be used whenever possible to maintain the same or equivalent materials during transfer to the CMO. Bench-scale and pilot-scale chromatography steps should be taken through entire cleaning, storage, and regeneration cycles, and evaluated with new and at least somewhat used (>10 cycles) resin.

Although the focus during process development often is centered on bioreactor titer and purification yield, it is vital that the process history also documents product quality characteristics.