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.
Challenges and Solutions
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:
- Does the process fit in the receiving facility and its established platform?
- Are the requirements for the material and timelines realistic?
- Are any long lead times required to run the process? (Raw materials, equipment, and consumables can play a major factor in
causing long lead times. For example, differences in raw materials can produce product characteristics that do not fit the
specification of the sending unit. New suppliers may cause delays and add costs.)
- Is the process scaleable and robust? Has it been shown to perform acceptably over tested ranges during development?
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.
Figure 1. Technology transfer approach
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's Good to Talk
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
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:
Relationship building: multiple contacts from both parties working together as a team ensure that strong relationships are built across multiple
departments in the companies involved.
Information sharing: by working with multiple contacts rather than single points of contact in each company, there is less chance that important
information will be overlooked, and there will be more direct contact between the people asking the questions and the people
who know the answers.
Equal responsibility: working together makes the project a team effort with the sending unit often working side by side with the receiving unit
to resolve issues and tackle challenges. This helps to avoid the adoption of a blame culture—something that would always be
detrimental to team morale and the process as a whole.
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.
Lessons to be Learned
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, firstname.lastname@example.org