OR WAIT 15 SECS
Volume 2009 Supplement, Issue 3
Effective tech transfer can save time and effort in later manufacturing processes.
Technology transfer is a complex technical process that does not often receive the resources or considerations that it needs to ensure success of complex manufacturing processes. Ideally, technology transfer should be managed by a dedicated division or specialist group, which is one of the benefits gained by outsourcing manufacturing projects to an established contract manufacturing organization (CMO). A dedicated team knows that technology transfer programs are not always straightforward, quick, or easy to perform and that there will always be challenges to overcome and problems to resolve to achieve success. Their experience will also have taught them that clients often have very little idea as to what the transfer process involves, which means that the development of a trusting relationship between the client and the CMO is essential.
At many stages during biopharmaceutical product development, it will be necessary to transfer processes from one place to another. Whether this is internally between teams within a company (for example, from the process development team to the scale-up or manufacturing team) or externally, from one company to another, the key objective is to execute the transfer with minimal disruption or unnecessary cost. This can be an overwhelming proposition for small- to medium-sized start up companies (usually with an academic or research background). These companies will prefer to transfer early-stage processes to a CMO for the first time-for scale-up and manufacture of Phase ½ clinical trial materials-and have limited experience of scale-up or the regulations and expectations surrounding a current good manufacturing practices (cGMP) process. Poor planning, unclear documentation, and bad communication all can lead to an inefficient transfer program, and more often than not will lead to the receiving team having to develop parts of the process that have already been established. Any inefficiency in the technology transfer program will inevitably result in delays in production, with the related theoretical loss in revenue and additional increases in the cost of the transfer. It is therefore essential to put serious time and resources into the planning stage of a technology transfer program.
There are no fool-proof strategies that can guarantee a smooth technology transfer, but certain factors have a large influence on success: meticulous planning, technical understanding of the manufacturing processes, and good communication. A strong emphasis need be placed on a risk-based approach. This involves the identification of risks, both technical and scientific, and logistical, at an early stage, to develop avoidance or mitigation strategies far enough in advance to help keep the transfer program on course. This kind of strategy relies on a highly knowledgeable team of people who have the necessary experience to be able to anticipate the issues that may arise, and excellent communication between the sending and receiving units.
For a CMO, one of the biggest challenges in technology transfer can be dealing with client expectations. For first-timers, the idea of technology transfer can seem quite simple and straightforward: "We've developed this process at our facility-how hard can it be to do the same thing in a new place?" The truth is that even transferring the simplest process will be a complex progression of planning, testing, and optimizing, especially considering that most biotech products being transferred to a CMO will be moving into clinical trials with the intention to eventually manufacture commercially. This should mean that processes are, at this stage, being looked at critically to assess suitability for scale-up and regulatory compliance. Clear communication and the development of a good relationship between both parties is clearly of benefit to all from the very start of the project.
A risk-based approach not only maps out potential issues and allows contingency plans to be put in place, but it also facilitates communication between the sending and receiving parties. The approach allows a sturdy but flexible framework, which provides structure to the technology transfer program. Having such a systematic and forward-looking procedure can help during the initial stages of the program when readjustments of expectations (with regard to time and cost) are taking place, and also establishes a climate that is pragmatic and professional, leading to an increased level of success.
A risk-based approach involves asking a lot of questions before the event, rather than after it. Before a technology transfer program even gets off the ground, the following questions must be addressed:
The answers to these questions help to ascertain the suitability of the CMO as a good partner for the manufacture of that particular product, and also highlight the need for process development to prepare the product for scale-up.
Common technical issues that arise during a transfer program involve the technical understanding of the process: are all the parameters used in the process fully understood, and what happens if the exact parameters cannot be duplicated? Challenges also arise involving the understanding of which parameters are critical and which are not. All of the necessary information to address these challenges can come directly from previous data recorded by the sending unit-but only if documentation is clear, and a culture of open communication has been developed. It is very important to see all of the data, especially the data from development runs when the process may not have worked optimally, so a full picture of the range of parameters can be developed and better understood. Other issues involve understanding the operational windows for the process, in other words, understanding how the product behaves during the process so that operations can be run on successive days. Therefore, it is very useful to have in-process stability data transferred before the technology transfer begins.
Understanding equipment differences between the CMO's equipment and that used at the sending unit's site is also very important. No two sets of equipment operate and perform in exactly the same way, or to the same level of tolerance. Just because a piece of equipment can report a certain value to a number of decimal places, it does not follow that the value shown is accurate to those decimal places. Therefore, if critical parameters are set around a specific piece of equipment, it is very important to understand the tolerance and accuracy that the equipment has been calibrated to report to.
Logistical issues to consider can be as obvious as the time it takes to order and receive consumable supplies and ingredients, but if these factors are overlooked, it could result in an unscheduled halt in production for days, or even weeks, which would play havoc with timelines and budgets.
The approach taken at Cobra Biomanufacturing is outlined in Figure 1 and consists of an initial evaluation of the program against the business model and scientific expertise and technical fit. At this stage, the strategy and approach to the program would be developed and defined. Information regarding the process would be transferred and communicated by technical visits to the client's facility to observe the process in operation and through documented information transfer. The outcome of this stage is an assessment of the process for transfer and whether or not additional development activities, equipment, or approaches are required to transfer the process. If additional work is required, it is done before any transfer run is performed. Historical data generated from early development and defined process runs performed at the client site is then used to set the acceptance criteria for the transfer runs. Agreement for the criteria is achieved through communication and meetings with both parties. Transfer runs are then performed (which can include technical staff from the client's site) at the receiving site, to the defined scope. The success of the transfer run is assessed through measurement against the predefined criteria. The final stage of the initial technology transfer is a report and review process where all operational, technical, and scientific information is assessed for the program's progression. It is necessary and essential that all stages of this process require communication, collaboration, and team work between the sending and receiving parties.
A lot of clients expect that their process is ready to transfer directly into a CMO and can be run straight away. This always leads to issues if the middle steps are ignored, or performed inefficiently. Transfer into a CMO should not be looked on as a quick and cheap option-the cost for additional development works to ensure the process is in compliance and technical equipment fits in the CMO facility should be discussed at an early stage.
It may appear that the need for good communication has been over emphasized in this article, but the truth is that it can't be emphasized enough. And it's not just clear communication that is essential-it is just as important that an atmosphere of open, two-way sharing is fostered between the sending and receiving unit. It is not unusual for sending parties to be nervous about sharing all the data related to their product, especially if there is negative data, but once confidentiality agreements are in place, there should be no need for hesitation. Holding back information can invite unforeseen challenges further down the line.
As with any outsourced contract project, success is always more easily achieved when both client and contractor pull together to achieve a common goal. This is never truer than with technology transfer. A collaborative team approach accomplishes a number of key objectives that help to drive the success of a project. These include:
It is important to understand that the technology transfer process will involve almost every function in a CMO, not just the dedicated technology transfer team. It is, therefore, important that the culture of open, transparent communication is not limited to the technology transfer function, but is indicative of the overall corporate culture in that organization.
As with everything, the devil is in the details-transferring the exact procedure for an operational step is extremely important. If critical information is not included in the documentation or the transferred information (verbal or other), then the receiving unit (CMO) does not know that it is important or needs to be done.
For example, it might be that the CMO usually autoclaves media for fermentation processes to sterilize it for use. This can be fine in the majority of cases. However, if the client has only used filtered media, or knows that autoclaving may be detrimental to the media, then this is important information to pass on. Time, cost, and resources can and have been wasted performing large-scale fermentations that resulted in poor cell growth because the media was prepared in a manner detrimental for the growth of a specific cell type. Clients must not assume that just because they perform a relatively straightforward and basic operation a certain way, the CMO will perform that operation in the same way. This is not carelessness or incompetence on the part of the CMO, it is just that not all basic operations are performed the same way everywhere. This example may seem obvious but it is fair to say that in 90% of technology transfer cases, it is the small, seemly insignificant details that are overlooked, which in turn results in delays or failures of the transfer.
No CMO will run 100% perfect technology transfer programs 100% of the time. There will always be challenges to learn from, and so it is essential that the CMO has some kind of feedback and review process in place. For example, at Cobra Biomanufacturing, the technology transfer team has full visibility of all programs in development and cGMP manufacture, as well as those in technology transfer and scale-up. The team develops and refines its approach through contract-specific review meetings at key stages of the program. All areas involved in the overall program are represented, irrespective of the stage at which the contract is. For example, a development stage is reviewed by the manufacturing, testing, and quality staff-so that there is continuity for the program and feedback and learning from all functions. Operating an integrated approach with teams consisting of cross-functional staff for each stage also maintains and fosters a climate for continual improvement, both in a specific program and also across programs.
Technology transfer is unavoidable if you intend to develop a biopharmaceutical from initial identification through to clinical trial and on to market. A successful technology transfer program must have a strong basis in clear and open communication with all parties, and the development of a relationship built on trust. A strategic and scientific risk-based approach facilitates clear communication between both parties involved in the technology transfer, and ultimately raises concerns and questions at an early stage, enabling avoidance or mitigation strategies to be developed far enough in advance to promote the smooth running of the transfer program. This kind of approach helps to foster and develop a climate that is pragmatic and professional and will help match the expectations of both parties and lead to an increased level of success.
Daniel C. Smith, PhD, is the head of technology transfer at Cobra Biomanufacturing Plc., Keele, UK, +44 (0) 1782 714181, email@example.com