There are two groups in biopharma today: those who “get” tech transfer and those who don’t. For those in the first group, technology transfer is a mature discipline that follows a structured approach, with predictable outcomes. For those in the other, tech transfer is a perennially new frontier with surprises at every turn. In the biopharmaceutical industry today, surprises cost projects months or even years on the timeline and can add an entire multiple to the project cost.
This article will examine the best practices for ensuring success with tech transfer, and present the most important elements of a universal approach. Although it will focus on biotechnology tech transfer to a 3rd-party contract manufacturing partner, the same basic principles appy to any type of tech transfer, whether site-to-site, process scale-up or process scale down.
Each type of tech transfer project presents its own set of unique risks: When transferring a new process from the lab to the plant, new unit operations, different raw materials and new assays may be required. New processes must be well developed and understood (i.e., characterized) before they are transferred to manufacturing. This will require extra time, and may delay the initial transfer to manufacturing, but will speed up the overall process and the time it takes to achieve the overall objective.
With initial scale-up at smaller or virtual companies, there is often limited process history and overall organizational experience doing the transfer, limited knowledge of scale-up principles or models and scaling factors larger than 10X.
With site-to-site transfers, issues focus on different personnel, departments and often companies. As global tech transfer increases, there are different cultures, languages and time zones to contend with, and different standards and utilities.
Any successful tech transfer boils down to the following principles:
1. Robust information exchange, providing the receiving party with all information that is relevant to the process and associated assays.
2. Careful front-end planning and project management, with the designation of point people for specific portions of the project.
3. Ensuring that analytical assays are transferred ahead of the process
4. Performing small-scale verification at the receiving site. This provides confirmation that the information exchange was successful and allows the receiving party to be more self-sufficient going forward.
5. Always perform pre-GMP engineering runs.
6. GMP runs are the end game. Put your tech transfer project in context by defining GMP success and failure and don’t dismantle your team until success here has been verified.
None of these steps can be omitted without serious consequences. In this article, I’ll offer a few examples of the consequences of some companies’ decision to bypass any one of these steps.
To avoid project creep, it is extremely important to establish boundaries between development and tech transfer at the outset of a project. Tech transfer does demand some process adjustment, but when things go beyond mere tweaking, the process needs to go back to development. An extreme example would be changing the cell line specified for an expression system as part of the technology transfer.
Let’s examine a case involving a manufacturer and a contract manufacturing company located halfway across the world from each other. Analytical assays were transferred to the CMO, but the sending party did not provide complete information and some of the information was out-of-date. In addition, there was no master document to track all the information and it was sent out piecemeal to different points of contact.
As a result, the CMO spent months trying to qualify assays based on the data sent by the manufacturer, but could not achieve reproducible results.
The partners decided to have an onsite visit, where the CMO learned that one assay required a very specific reagent made by only one manufacturer in the world (who had just stopped manufacturing the product). They also learned that the target pH of elution changed during one of the identity assays. No central point person had been assigned to stay on top of the data for this project; there was no information tracking or a way to validate information.
The on-site, face-to-face meeting was a great success, and the assay transfer problems were solved, but by that time, the company had lost six months of precious time.
The moral of the story? There is no such thing as “too much” or “too detailed” information. Such dedicated tools as assay summaries, detailed process descriptions, and bills of materials should be created and used . Other information from the sender, such as regulatory submissions, development reports, raw data, validation reports, etc., can be extremely useful. This work would have to be done anyway as part of the future process validation and to support regulatory submissions.
Remember that information must be packaged for the benefit of the receiver, including detailed and contingency information. It’s better to err on the side of too much than too little. Send over relevant raw data and let your CMO sort through it and decide.
Plan Your Project
Remember that tech transfer is a project and as such requires a plan. Ideally, there will be separate plans for the transfer of the assays and the the process as well as an overall project plan that ties everything together. Planning also should take risk management into account and ensure that tasks are prioritized and supported properly. By definition, these plans will be critical deliverables for your project.
Consider one CMO that transferred a process with a token plan. The company started tasks ahead of schedule and sent a “feel good” report to the management. Eventually, the sender insisted that a plan be put in place, but that plan didn’t reflect activities already performed and it wasn’t even followed. By that time, process performance was inconsistent with what had been previously achieved. The business relationship between the partners was severely damaged and the project ultimately failed.
Transfer Assays Before the Process
Many companies put the cart before the horse, by moving too quickly into process transfer. Instead, analytical assays should be transferred and qualified first.
Based on Kymanox’s experience, analytical assay transfer problems are the top reason for biotech tech transfer delays. They must be the first priority because it is impossible to know what you cannot reliably analyze. Assays should be treated like standalone tech transfers, after all, many assays are processes in themselves and all of them need to be qualified in the receiver’s hands.
Avoiding assay transfer won’t work, and, with assays that will be sent back to the client or a third party laboratory, supporting sample storage and stability data will also be needed. Transferring the assays first also adds time to allow success to be confirmed, or failure identified.
Consider what happened with one company, which was working to transfer a chromatography-based purification process to a CMO.
The CMO failed to analyze any of its in-process samples for cell-based impurities; instead, the CMO relied on the final sample only. Over time, the contract manufacturer developed what was thought to be a good process, but when the in-process samples were analyzed for the first time, it was found that cell-based impurities were out-of-specification for one of the three in-process control points.
The CMO introduced new operating ranges which were later determined to cause the material to miss its IPC specifications. Four months later, it was back to the drawing board.
Trust, but Verify: The Role of Bench-Scale Confirmation
Any process must be adequately confirmed by the receiver at the bench scale prior to scale-up and large scale production. Consider the case of a biopharma company that planned to automate the last three steps in its purification process which involved a buffer exchange, concentration and final filtration
A single lab experiment was done successfully at the 5 L scale to prove the concept. Scale-up design was finalized, based on the experiment, and the equipment was manufactured and all programming completed.
Unfortunately, the first 500-L large-scale engineering run failed and the equipment had to be re-designed. After the re-design, several other large-scale engineering runs were performed and the equipment and programming were further modified as the process was understood better. Finally, the lab-scale model was revisited to complete needed temperature and pH DOE studies. The equipment—and its automated processing steps—were eventually completed two years behind the original schedule
Remember that small scale verification is much less costly than experimentation at large scale. It is also a key indicator that overall transfer of information, materials and assays, is on track. This can be also used as a milestone progress update to the senior management.
In addition, bench scale models can be used to support the transferred process after the tech transfer is complete and long forgotten. Bench models are great for numerous process-related studies and can help in failure investigations or provide supporting data for process improvements.
Engineering Runs – The Dress Rehearsal for GMP
Engineering runs are important for tech transfer success. In fact, they are the dress rehearsal for GMP. They help ensure that batch records and SOPs are correct and offer the opportunity for operator training at scale, sometimes this is the only one they get.
They allow to shakedown equipment and check automation programming and provide the first real soils for cleaning validation studies. Engineering can often be a source of representative material for non-GMP use (i.e. reference standards, stability and other non-clinical studies). Water simulation runs are usually done in advance to augment the full engineering runs.
Depending on the risk involved in the process, the number of engineering can be as low as one and as many as half a dozen or more. However, since additional engineering runs mean additional costs, some companies are tempted to dispense with what they often see as an extra expense, or luxury. If they do, most learn to regret it.
Take, for instance, the biotech company transferring a Phase III cell culture-based therapeutic protein to a CMO. No scale up was performed. Instead, the process was transferred directly to a receiver site. It seemed straightforward and low risk at the time. Since the two facilities used very almost identical equipment and no process changes were needed. Both the client and CMO had sufficient resources dedicated to the project to ensure success, so a decision was made to skip engineering runs to save time and money.
The first GMP run was a technical success, and the CMO issued a certificate of cGMP compliance.
However, the client refused to accept the batch as a cGMP lot, due to excessive number of deviations. No single deviation justified the batch failure but, taken as a sum, they demonstrated that the CMO was not in control of compliance. Additionally, the numerous deviations created a burden for both companies, due to the effort required to address all deviations formally and complete CAPA’s as required.
Not surprisingly, the first lot to be released for GMP was significantly delayed, and so was the client’s clinical study.
GMP Success: Have you Defined It?
Finally, it is important to define what is meant by “successful” transfer. The ultimate success of a Technology Transfer should be a success of the first GMP manufacturing campaign.
Consider a “by the book” tech transfer that was done for a monoclonal antibody. The process was going to run in a brand new facility and everything was going according to plan. After a single successful engineering run, logo tote bags were issued to all team members as a way to recognize everyone’s contribution.
Then the team was disbanded and moved to other projects and organizations. The first GMP run was attempted a few months later, unsuccessfully. In fact, the success of the engineering run was never repeated, even after many attempts. The project was eventually terminated.
Points to ponder: Had the team defined the correct success criteria upfront? Would it be one GMP run, three GMP runs, or an entire GMP campaign? Would good lots be determined by initial testing only or fully released lots?
The team must be kept intact until the final GMP goal is achieved. Also, there must be a support system in place for manufacturing, including access to the entire tech transfer archive for the project, and access to key subject matter experts when issues arise.
Tech transfer is not a random process. Universal methodologies do exist and are followed by many companies transferring processes internally or to CMOs. Communication, planning, discipline and documentation are the keys to success.
The author would like to thank Vladimir Kostyukovsky, PhD, Senior Technical Manager at Kymanox for his considerable contributions to this article.
The Author - Stephen is the founder and president of Kymanox (www.kymanox.com), a company whose Process Operations group specializes in managing biopharma technology transfers and maintains the free search engine at CMOLocator.com. Stephen has over a decade of cGMP biopharma manufacturing experience as a process engineer and project manager. Before starting Kymanox in 2004, Stephen had various leadership roles supporting successful scale-up, start-up and commercialization initiatives at Abbott Laboratories, Covance Biotechnology Services, Diosynth Biotechnology, and Human Genome Sciences. Stephen received his BS degree in Chemical Engineering from the University of Notre Dame