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.

Acknowledgement

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