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Volume 24, Issue 6
Clear documentation and open communication are essential for effective technology transfer.
During the production life cycle of biopharmaceuticals, the manufacturing processes always undergo technology transfer. In large biopharmaceutical companies, technology transfer usually takes place internally from the process development teams to the manufacturing teams. Technology transfers can also take place from one company to another when outsourcing manufacturing activities. There are several motives for outsourcing biopharmaceuticals production to a contract manufacturing organization (CMO). Numerous companies start up with product and process development, but lack a GMP infrastructure to produce their drug products for clinical studies. Technology transfer also takes place from one CMO to another, for example, when the infrastructure of the initial CMO does not support further scale-up of the process required for the next phase of clinical study or commercial production. Finally, some large biopharmaceutical companies with in-house GMP manufacturing capabilities sometimes outsource their production for clinical studies or even for commercial supply due to their own limitation in manufacturing capacity. In many cases, a CMO can supply the product cheaper and faster than in-house production (1, 2).
To maximize the success of technology transfer, each company uses its own technology transfer methodology, comprised of internal expertise and proven rules-of-thumb (3). The scope of this article is to demonstrate an effective technology transfer practice.
Regardless of the motive for technology transfer, the key objective of the transfer is to run the manufacturing process at the receiving site with no or minimal changes from the original process developed at the sending site. Therefore, most of the responsibilities lie with the technology receiving site, which is often a CMO. This makes the technology transfer of a biopharmaceutical manufacturing process challenging, particularly due to the following well known phenomena:
From a management perspective, the overall technology transfer program should offer a balance between budget, time, and risk management. Any inefficiency in technology transfer results in production delay, increased cost, and sometimes redevelopment of a part of the production process. From a technical perspective, the success of technology transfer mostly depends on the quality of the process itself, as well as on communication between both parties. The developed process must be feasible to scale-up at the desired level, and adaptable to equipment available at the receiving site. Otherwise, significant redevelopment would be unavoidable during the technology transfer. Therefore, it is wise to select the potential technology receiving site (e.g., the production site or the CMO) during the process-development stage, and consult the experts from the receiving site regarding transferability of the process being developed. The communication between both parties must be clear and open, which can be challenging when technology transfer takes place between one company and another. Any lack of clarity or secrecy of technical information is hazardous to the success and timeline of the technology transfer.
Figure 1 demonstrates an example of effective technology transfer practice used when a fully developed production process is transferred from a sending company to a receiving company for GMP manufacturing of a biopharmaceutical product. The technology transfer activities often start with the transfer of documents from the technology sending site to the receiving site. The technology transfer document package and technical communications between both sites should provide sufficient process understanding at the receiving site. With understanding of the process and the product requirement, the GMP manufacturing process can be designed on paper.
If GMP manufacturing is attempted at this stage based on the design on paper, the chance of success would be slim. Confirming technical feasibility and performance of the designed GMP-scale process by a small-scale prototype process would minimize the risk at lower cost. Therefore, a small-scale prototype process is designed and executed by directly scaling-down the designed GMP process. The designed GMP process may undergo redesign or changes based on any technical unsuitability experienced during the execution of small-scale runs and after evaluating the performance of small-scale prototype process runs.
Not all parameters and conditions applicable in a large-scale process can be mimicked exactly in a small-scale prototype run. Therefore, a full GMP scale process run, often called an engineering or technical run, using the GMP batch production protocols and equipment prior to the actual GMP runs, justifies the success of the GMP batch at first attempt. The product produced from such a successful engineering run can also be used for preclinical studies, a stability study, or assay qualification or validation. The design of the GMP process may again undergo redesign or changes based on the technical feasibility and performance of the engineering run.
Transferring documents containing the process description is usually the first activity to take place during a technology transfer program after the business agreement is signed. A typical technology transfer package includes the following documents:
Although a transferred process should ideally remain the same as the original, in practice, the process always undergoes adaptation at the receiving site, mostly due to the difference in equipment between the sending and receiving sites, as well as the need for scale-up of the entire process. The adaptation approach is different for different process steps. With an understanding of the process through the technology transfer document package and direct communication between sending and receiving sites, the anticipated GMP manufacturing process can be designed in detail.
Prior to the manufacturing process design, the desired scale of the overall process is often decided based on the amount of bulk drug substance required. The scale of each unit operation at the receiving site is then selected based on the scale-up factor and expected product recovery in each process step. The anticipated approach of operation and consequently the technical feasibility of each unit operation can be visualized at this stage. The decision to modify any process step or to split a part of the process into several runs in parallel or series can also be made. Eventually, a detailed process flow diagram containing in-depth activities in each unit operation can be generated (see Figure 2).
The operation of an overall biopharmaceutical manufacturing process is always executed in batch mode. The intermediate process bulks are stored at certain conditions before using in the next process steps. The required duration of each process step at the technology receiving site may vary from the sending site, particularly due to the difference in equipment and scale. This affects the storage duration of the intermediate process bulks. In addition, due to the larger volumes, the actual cooling and warming rates of intermediate process bulks may not be equal to the original small-scale process when both are stored at the same temperature. Scheduling of each process step in a biopharmaceutical manufacturing process, therefore, is a significant part of overall process design.
The selection and design of process conditions and process equipment are interrelated. The process conditions should be kept the same as the original process at the sending site or should be changed according to the scale-up factor. How to change different process parameters upon scale-up is not within the scope of this article and can be found in the literature (4). Critical raw materials, that define the performance of the process, should not be changed at the receiving site. The equipment selected or designed for executing the process must be compatible with the desired raw materials and must ensure the performance at the desired process conditions and parameters. In reality, however, the existing equipment often necessitates changes in process conditions and parameters due to the significant investment required for setting up new equipment for GMP production.
The design of a GMP manufacturing process can be considered complete with the selection of raw materials, scheduling of process steps, and design of process conditions, parameters, and equipment. Generation of GMP batch production protocols and records can be started at this stage.
Technology transfer starts with the transfer of the document package and ends with the successful engineering run. Technology transfer ensures the success of GMP production, although the GMP manufacturing operation itself is not a part of technology transfer. The success of GMP production can only be ensured upfront when the small-scale prototype runs and full-scale engineering run consistently meet the expected product yield and quality (e.g., purity, efficacy and safety). In fact, the product yield and quality after each process step should be comparable between sending and receiving sites. To evaluate the comparability, an expected or acceptable result range for each relevant parameter should ideally be set upfront. The acceptable range can be assigned based on the available data at the sending site on several runs of the process at the finalized conditions. Any significant discrepancy in yield or quality must still fall within the limit for desired application of the drug substance, whereas the technical reason behind the discrepancy must be well understood and under control.
Technology transfer of a biopharmaceutical manufacturing process can be very challenging, and any inefficiency in technology transfer results in serious loss of time and resources. Although a transferred process should ideally remain the same as the original, in practice the process always undergoes some adaptation at the receiving site, mostly due to the difference in equipment between the sending and receiving sites as well as the need for scale-up of the entire process. The success of technology transfer relies primarily on the adaptability of the production process itself as well as communication between sending and receiving sites. A systematic transfer methodology provides the best chance of a successful technology transfer.
Tangir Ahamed, PhD*, is a scientist, Michel Brik Ternbach, PhD, is a scientist, and Paul Ives, PhD, is director of manufacturing, all at SynCo Bio Partners B.V., Amsterdam, The Netherlands, email@example.com.
1. J. Lakshmikanthan, BioPharm Int, 20(2), 16–24 (2007).
2. A. Reinink, Entrepreneur, April 20, 2010.
3. D.C. Smith, BioPharm Int. 22 (4), 10s–17s (2009).
4. J.M. Liddell, BIOprocessing 1, 2–4, (2009).