9 Common Tech Transfer Pitfalls To Avoid
By Jon Strauss, FASTFORWARDBIO
To develop a biologics-based drug, a biopharma company will likely need to outsource the drug’s manufacturing process and analytical testing to an external manufacturer one or more times during the product’s development cycle.
The process of moving procedures, knowledge, staff, and molecules from one place to another is called technology or tech transfer, and it’s riddled with pitfalls, which we will explore here.
Tech transfer varies through the phases, and it’s worth pausing for a moment to describe the differences.
Preclinical Phase: Around 60%-70% of manufacturing is outsourced during this phase. Biopharma companies may have their own internal R&D organization or rely on CROs to produce small-scale batches of the drug for testing in vitro and in animals to achieve necessary results to warrant proceeding to clinical trials. Often, however, the developed process is not operated at sufficient scale and efficiency or with sufficient control to proceed directly to manufacturing clinical trial material (CTM) under current cGMP. While larger biopharma companies may have internal capability for further development and scale-up of the process, and cGMP manufacturing, smaller companies typically need to outsource these activities to a CMO. The company may have to outsource formulation, filling, labeling, or packaging to a different CMO if the first CMO does not have that capability.
Clinical Phase: During clinical trials, the outsourcing rate is lower, approximately 50%-60%, but still common. The need for larger batch sizes and higher regulatory requirements for late-phase clinical trials and commercial supply may necessitate the biopharma company to transfer the existing manufacturing process and associated analytical methods to a different CMO. Since validation of both the process and the analytical methods is required for regulatory approval of the product, the new CMO is additionally tasked with these activities. This typically includes further process development prior to validation.
Post-licensure Phase: Post-licensure commercial manufacturing sees an even lower rate of outsourcing to CMOs, but still significant, approximately 30%-40%. Large biopharma companies may prefer to bring production in-house from a CMO to maintain control over the manufacturing process, ensure quality, and protect proprietary technologies. It should be noted that recently U.S. lawmakers have initiated legislation that could force a sponsor to move manufacturing out of a country considered to be at-risk for drug supply, i.e., China. If that happens, we could see a wave of tech transfers as sponsors reshore production or move to other countries deemed safe. Otherwise, a company may seek to change CMOs or add capacity if they’re facing increased demand or mitigating supply chain risk.
Tech transfer involves a series of important steps to ensure that the new manufacturer can produce the product consistently and according to regulatory standards. However, pitfalls are often encountered, which can delay tech transfer and result in delays to clinical trials, product approval, or product shortages.
Pitfall 1: Insufficient Process Understanding
Lack of deep knowledge about the manufacturing process or the product itself is a fatal pitfall to any tech transfer endeavor. Critical process parameters (CPPs) and quality attributes (CQAs) might not be well understood or documented, leading to delays in tech transfer, scale-up, or manufacturing. Companies that acquire the drug asset from another company, have a high rate of personnel turnover, or outsource their R&D are at higher risk of this pitfall.
Recommendations
Perform a detailed risk assessment (RA) of knowledge gaps at the outset of tech transfer. This should also be part of due diligence, prior to acquiring the asset. The RA should then be presented to the prospective CMO for consideration in establishing the contractual scope of work necessary to mitigate the risk.
Take the time to talk to the people who developed the existing process and analytical methods and get their thoughts regarding knowledge gaps and possible improvements. Since they are the process or method owners, it may be challenging to draw out honesty and transparency about possible inadequacies with the work. Good listening skills and acknowledgement of their challenges and efforts go a long way in establishing rapport.
Unexpected results that occurred during previous development and scale-up can offer valuable clues that certain parameters are more important, perhaps even critical. Review deviation logs, investigation reports, and trend data to see if corrective and preventive actions were effective.
Pitfall 2: Inadequate Documentation
Lack of detail, context, or clarity in development reports, SOPs, testing protocols, manufacturing batch records, or laboratory notebooks is more than a nuisance; these can trigger serious issues in production and product quality. Poor or incomplete documentation of the manufacturing process or analytical testing can result in errors and inconsistencies during tech transfer.
Recommendations
Create a centralized knowledge management system to store and share all relevant documentation and process information.
Perform a risk assessment of documentation gaps in the existing process and analytical methods.
Have translators with science backgrounds available if the documents need to be translated from another language.
If the tech transfer is from an existing CMO or CRO, formalize an agreement with them for risk mitigation regarding missing or unclear documentation, including rework if necessary.
Regularly update documentation to reflect any changes or improvements in the manufacturing process.
Pitfall 3: Differences In Equipment And Facilities
Variability in equipment types, capabilities, and scales between the original and new manufacturing sites can lead to delays during tech transfer. The incompatibility of the new site’s facilities with the specific requirements of the biologics process can also cause delays.
Recommendations
Conduct a thorough assessment of the new site’s facilities and equipment and compare them with those of the previous manufacturing site to ensure compatibility with the biological production requirements.
For the process to be scaled up, the existing technology at the previous manufacturer or used by R&D may not work or may be impractical, i.e., switching from batch to continuous centrifugation. Process adaptation may be required with confirmation testing of one or more batches produced with the different equipment.
For fixed equipment that services other clients, i.e., a bioreactor, it may not be possible or may be too costly for the new CMO to purchase new equipment or modify the equipment to fit the new process. Adapting the process to the existing equipment at the new CMO will be necessary and may require confirmation testing at scale.
Even slight differences in environmental conditions such as temperature and humidity between the existing and new manufacturer may impact yield or product quality. Careful review of facility controls and historical data from both facilities is needed.
Pitfall 4: Variability In Materials
Differences in material sources, specifications, and handling can affect the quality and consistency of the biologic product. Lack of standardized material specifications and quality control measures can also affect the consistency of the product.
Recommendations
Perform an RA of the criticality of each material previously used in terms of what it’s used for, where it’s used, its availability, specifications, and consistency in performance. For materials determined to be high-risk to yield or product quality, i.e., cell culture media, chromatography resins, filters, formulation excipients, vials, or syringes, any required changes of sourcing, specifications, or handling may require performing the process at an appropriate scale using the new material to assess impact.
Develop standardized material specifications and quality measures for multiple sources.
Pitfall 4: Regulatory Compliance Issues
Navigating different regulatory environments and ensuring compliance with all relevant guidelines and standards can be challenging. Delays in regulatory approvals may occur due to insufficient documentation or process changes.
Recommendations
Engage with regulatory authorities early on to ensure compliance and obtain necessary approvals. Prepare comprehensive documentation to support regulatory submissions and facilitate a smooth approval process.
Ensure the new manufacturer is aware of and has input on regulatory strategy. Determine what support you need from them and define timelines for expected completion. It is all too common for a client company to omit key regulatory strategy details in conversations with its CMO. Failure to do so will likely result in delays in successful tech transfer and make for bad feelings.
It is also common for a CMO to lack transparency with the client company about timing, results, and responses for regulatory inspections that occur for other clients, which can impact the client’s manufacturing schedule or its regulatory strategy. There should be a formalized agreement between both organizations on notifications of regulatory events and changes.
Pitfall 5: Lack Of Personnel Expertise And Training
Differences in personnel skill levels between sending and receiving sites are almost inevitable. Inadequate training programs for the receiving team can lead to operational inefficiencies and quality issues.
Recommendations
Implement comprehensive training programs for the new manufacturing team, focusing on process specifics and quality standards.
Facilitate hands-on training sessions and knowledge transfer activities between existing and new site personnel. It is recommended that the appropriate personnel from the new CMO observe a small-scale run performed by personnel from the original site. Then the new CMO should attempt to replicate the process on a similar scale, with the appropriate personnel from the client company and/or existing CMO on hand to supervise. Finally, the new CMO should perform the process again, this time on its own, with a review of results by all parties.
This is a proven training model, and it can be combined with site visits, team building, and other activities to build camaraderie and trust.
If the existing process is currently outsourced to a CMO, it is the client company’s responsibility to ensure that the existing CMO is engaged with the tech transfer, even if they will eventually be phased out from manufacturing the drug. This may require financial incentives and overcoming confidentiality and logistical challenges. Failure to do so, however, puts the tech transfer at risk, since they possess knowledge and experience that may be vital to successful tech transfer.
Pitfall 6: Process Scale-up Challenges
Difficulty in scaling up the production process from pilot to full commercial scale without affecting product quality is another potentially fatal pitfall. Inconsistencies during scale-up can lead to process deviations and product failures.
Recommendations
Failure of the process to result in comparable product quality when scaled up typically can be traced back to lack of understanding of the effect of changes to facility, equipment, materials, methods, or personnel on one or more product quality attributes. Effective risk management at the outset of tech transfer for each of these types of changes is key to preventing scale-up failures.
Pitfall 7: Communication Breakdowns
Good communication is not just a priority in kickoff meetings, it’s an ongoing exercise. Poor communication between the original and new manufacturing teams can lead to misunderstandings and errors.
Recommendations
Establish cross-functional teams involving R&D, manufacturing, quality, regulatory, and other relevant departments.
Create a robust, step-by-step transfer plan that outlines all necessary activities, identifies stakeholders, assigns responsibilities, and establishes communication channels and governance. Risk assessment is a critical tool in ensuring activities are prioritized and timelines are realistic.
Maintain open lines of communication with regular updates and meetings to ensure alignment and address issues promptly.
Pitfall 8: Analytical Method Transfer Difficulties
Transferring analytical methods can be complicated, with the potential for variability in test results between sites.
Recommendations
As with process transfer, conduct an RA of the existing analytical methods, including talking with personnel at the existing analytical site(s).
Develop detailed protocols for the transfer and validation of analytical methods to ensure consistency and accuracy.
Analytical methods deemed by the RA as high risk should be first performed by personnel from the sending site with supervision by analysts from the new site, then the exercise flipped. Lastly, the analysts perform the testing without supervision.
Conduct inter-laboratory comparisons to verify that analytical results are consistent between the original and new sites.
Pitfall 9: Quality Control And Assurance Gaps
Quality control and quality assurance practices ensure consistency and compliance. Gaps in those systems, not surprisingly, can lead to product quality and regulatory issues.
Recommendations
Align quality control and quality assurance systems between the original and new manufacturers.
Implement continuous monitoring and quality oversight mechanisms to ensure ongoing compliance and product consistency.
Conclusion
Avoiding these pitfalls requires a thorough and well-planned tech transfer process that includes detailed documentation, robust communication, comprehensive training, and careful alignment of processes and quality standards between the original and new manufacturing sites. By following the listed recommendations, manufacturers can significantly enhance the efficiency and success of tech transfer processes, ensuring seamless transition and maintaining product quality and compliance.
About The Author:
Jon Strauss is an industry consultant and founder of FASTFORWARDBIO LLC. Previously, he was the director of CMC operations at 89bio and before that the CMC director at Calibr-Skaggs Institute for Innovative Medicines, a division of Scripps Research. He’s held positions of increasing responsibility at Ambrx, Abzena, and Genentech. He’s also worked for CMC Biologics, now a division of AGC Biologics; Momenta Pharmaceuticals; and Bayer. He received his bachelor’s degree in chemistry from James Madison University and a master’s degree in biochemistry at Johns Hopkins University. Contact him at www.fastforwardbio.com or connect with him on LinkedIn.