The Role of Process History in Establishing Clear Technology Transfer Criteria

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: The Takeda Oncology Company has outsourced the manufacturing of several biopharmaceuticals at every stage of product development. A critical element of the success of those projects was developing sufficient process history before transferring the process to the contract manufacturing organization (CMO). This article presents actual case studies illustrating the following key components of technology transfer:

• demonstrating and documenting process reliability at two representative scales before transfer to the CMO

• establishing clear and rigorous process transfer criteria based on process history with which to gauge the efficacy of the transfer.

Millennium

THE IMPORTANCE OF SUFFICIENT PROCESS HISTORY BEFORE TRANSFER

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.

ESTABLISHING PROCESS TRANSFER CRITERIA

After sharing client process history with the CMO, discussions to establish mutually agreeable transfer criteria can begin. Examples of cell culture process transfer criteria jointly agreed to by Millennium and a CMO are shown in Tables 1 and 2.

Table 1. Process transfer criteria for transferring Millennium (MPI) bench-top cell culture bioreactor process to a CMO

These tables demonstrate a few key features. First, the transfer criteria should be a direct comparison: compare bench-top data with bench-top data and pilot-scale data with pilot-scale data. If undesirable results are attained, a comparison of CMO pilot data to client bench-top data alone or to client pilot data alone cannot distinguish between generic transfer issues (e.g., a misunderstanding of the process by the CMO) or a scale-up issue. Thus, it is prudent to first evaluate the efficacy of the transfer with a laboratory-scale to laboratory-scale comparison as illustrated in Table 1. There typically is much more client laboratory-scale data than pilot-scale data available to enable statistically valid comparisons. Only when the efficacy of this laboratory-scale transfer is confirmed should a pilot-scale to pilot-scale comparison be completed (Table 2), although these activities can overlap to save time.

Table 2. Process transfer criteria for transfer of pilot-scale cell culture bioreactor process to CMO

Figures 1 and 2 present actual data generated by the transfer activities represented in Tables 1 and 2, and illustrate the wisdom of this approach. Figure 1 demonstrates similar titer performance between the CMO's 2-L bench-scale production-phase bioreactors and Millennium 5-L bench-scale production-phase bioreactors. However, Figure 2 shows that the CMO's 300-L pilot-scale bioreactor generated approximately 20% lower titers than the Millennium 100-L pilot-scale bioreactor. In light of the close agreement between bench-scale systems in Figure 1, the CMO quickly agreed that there was an implementation problem with the 300-L process that required investigation.

Figure 1

This evaluation procedure quickly identified a serious issue well before current good manufacturing practices (cGMP) manufacturing was scheduled to begin. Moreover, this procedure pointed to the most fruitful area for investigation. A careful comparison between the operation of the CMO's 300-L bioreactor and the Millennium 100-L bioreactor and both sites' bench-scale bioreactors identified three operating variables that were unique to the 300-L bioreactor: the age of the bioreactor feed; the percentage carryover of medium from the inoculum bioreactor; and bioreactor pH. Regarding the pH, the set points were identical for all systems. Unfortunately, the actual pH of the 300-L bioreactor was approximately 0.1 pH units lower than all the other systems, because of differences in control algorithms and the reduced frequency of re-calibration of the pH probe in the 300-L suite.

Figure 2

Based on this investigation, a factorial-designed experiment with three variables as inputs was executed in the Millennium 5-L bioreactors (Table 3). The data clearly demonstrated that only the pH had a significant impact on the titer. Consequently, the CMO changed its bioreactor pH control and recalibration procedures for the large-scale GMP runs, which were successfully implemented without an engineering run.

Table 3. Bench-scale bioreactor experiment to troubleshoot a lower- than-expected titer from a CMO pilot-scale bioreactor

This example highlights another benefit of establishing a process history and transfer criteria before transferring a process to a CMO. Most CMOs have established their own tightly controlled procedures over many years. These procedures have been proven to meet practical, regulatory, and business needs, making CMOs reluctant to change standard practices. However, when scientifically sound data suggest that deviation from standard practices is warranted, most CMOs will be quite willing to cooperate.

Another essential feature of process transfer criteria illustrated in Tables 1 and 2 is the comparison of key product quality attributes. The acceptance criteria for product quality presented in this example were intentionally vague. Unless there is significant process history approaching the level attained nearing a formal process validation or a biologics license application filing, there is usually insufficient process knowledge either to establish definitive product quality acceptance criteria or to guide process troubleshooting efforts.

Therefore, it is best if the CMO and client assess the quality of material produced at the CMO in a collegial and collaborative manner. If there is a significant variance from expectations, there are several possible responses: 1) delayed progression into GMP production while troubleshooting efforts are undertaken to determine the cause of the variance; 2) delayed progression into GMP production to generate more pilot runs or engineering runs at scale that can define the variance, so that new specifications can be established to release CMO-produced lots; or 3) live with the variance and proceed as planned, which is probably acceptable only for early-stage projects.

Figure 3 presents one such example evaluation, where Millennium and a CMO statistically compared the peaks from an oligosaccharide analysis of product from the pilot plants at both organizations. The analysis of both samples should be analyzed by the same assay from the same laboratory, especially if the assays have not yet been qualified or validated, as is often the case during process transfer.

Figure 3

Process transfer criteria also should be established for all downstream purification steps. Table 4 presents an example illustrating the benefits. This table represents the process transfer of a polishing chromatography step to a CMO (a different CMO from the one used in all the previous examples).

Table 4. Transfer of early-development process to a CMO. Data represents the purification yield and percentage of high molecular weight (HMW) species in the load and eluate of a polishing chromatography step for lots from the Millennium (MPI) pilot facility, the CMO pilot, and the full-scale manufacturing suite at the CMO.

In this case, because of time constraints and the early nature of the project, a full-scale engineering run was deemed prudent because of the limited process history generated at that point. Millennium and the CMO decided to generate more process history as part of the transfer by executing pilot lots in parallel at both sites. Data from these seven pilot lots are presented in the first seven columns of Table 4. The percentage of high molecular weight species (% HMW) in both the load to and eluate from this step was similar at both sites and the two organizations agreed that this step was transferred successfully.

However, after executing the first cycle of the full-scale engineering run, it was clear that the HMW percentage in both the load and eluate were significantly higher than in the transferred process. Because the process was transferred successfully, it was neither a process issue nor a transfer issue. Instead, focus was trained on the scale-up parameters and the full-scale equipment. It was quickly determined to be an equipment issue with the full-scale chromatography skid (imprecise valve timing resulted in brief product contact with sanitizing solution). After correction, the second cycle of the engineering run and the next two GMP runs achieved a HMW percentages of 0.6%, 0.3%, and 0.3%.

CONCLUSION

Good transfer criteria based on solid process history can foster and enable effective client–CMO interactions. It is vital to clearly demonstrate process reliability before a transfer and to set guidelines for evaluating a transfer based on client process history. If these guidelines are followed, standards will be met and client–CMO interactions will be smooth.

Michael Glacken is the director of biologics process development at Millennium: The Takeda Oncology Company, Cambridge, MA, 617.679.7000, michael.glacken@mpi.com