A technology transfer (“tech transfer”) for cell therapy manufacturing is the transfer of knowledge, experience, specifications, procedures, and data for manufacture of a cell therapy product from a sending site, such as the cell therapy developer, to a receiving site, such as a contract development and manufacturing organization (CDMO), in order to establish qualified capability for GMP manufacture of the product. From that basic definition, it sounds like it should be an easy process.
However, completing a cell therapy technology transfer can be an incredibly difficult task—often because there are so many little details that can be overlooked or addressed incorrectly during the transfer and sometimes amplified because of the challenges in transitioning from an R&D mindset to a GMP mindset and if these problems are not properly addressed, they will directly impact the time and cost in getting to the starting line for the clinical manufacture of products. Of particular concern is the risk to the quality of the product that may be inadvertently introduced due to insufficient readiness for tech transfer or a deficient tech transfer process. So, before you start a technology transfer, it’s important to make sure you’re fully prepared.
Is your organization fully prepared to handle a technology transfer of a cell therapy product?
Here are a few warning signs that you might not be ready:
1. Insufficient Documentation of Procedures and Methods
Many new cell therapy developers can easily forget that the receiving site for the technology transfer won’t be as well-versed in the technical details of a cell therapy product as the team that developed it. Prior to the tech transfer, development of a cell therapy product is frequently in the hands of a small team of highly skilled staff — the Subject Matter Experts (SMEs) that have accumulated extensive and deep knowledge on the procedures and methods to make or test the product. A typical outcome is “tribal knowledge” — details important to the manufacture of the product, such as some quirk in the process that requires special attention or extra steps to manage, that are not written down anywhere in the documentation. In some cases, these details are not even obvious to the SMEs because they are so familiar with the steps needed and subtle nuances which developed gradually over time. One approach to help mitigate this issue is performing a methodical walk-through of the procedure or method, where an SME performs the procedure while a less-familiar observer follows along with the documentation. Additionally, observation of receiving site personnel by the sending site SME during training can facilitate detection of tribal knowledge.
2. The Product Isn’t Sufficiently Characterized to Verify Product Quality After Transfer
The bottom line for a successful tech transfer is demonstrating that comparable product quality is achieved after the transfer is complete. Certainly, a minimum goal is to meet product specifications, which are typically based on critical quality attributes (CQAs) identified for the product, such as identity, potency, purity, dosage, and safety attributes. However, the complexity of most cell therapy products as well the complexity of methods used to test them presents the real risk that products manufactured following the transfer pass specifications but are nevertheless significantly different. Further product characterization, such as additional identity and functional testing, is often critical to verify product quality. In fact, for early clinical stage programs, product specifications may be fairly limited and data from additional product characterization is critical. Also, while analytical methods may not be fully qualified before transfer, particularly for early clinical programs, there needs to be some confidence established in the methods to ensure test data generated at the receiving site is representative. One approach that can be taken is to have both the sending site as well as the receiving site test the same product lot, whether made at the sending site or receiving site, to verify comparable results are achieved.
3. You (Or the Receiving site) Don’t Have Sufficient Resources to Manage the Transfer
Many cell therapy developers and CDMOs have the expertise needed to manage the cell therapy technology transfer. However, what organizations often lack—or fail to allocate—is the time to properly handle the transfer. Instead, the responsibility for the transfer is placed onto someone who already has a substantial workload with the expectation to manage the technology transfer on top of everything else they already have to do. Because staff are pressed for time with other responsibilities, they may neglect to follow up with staff on the other team to make sure that all relevant documentation and resources were successfully transferred. Also, they may not be available for meetings to answer important questions that need to be addressed before the transfer can move on.
So, there needs to be someone on both ends of the technical transfer that can manage it — someone who is given both the time and resources to ensure that the transfer is successful.
4. Lack of Clarity Regarding Business Milestones/Objectives Surrounding the Transfer
While a tech transfer is inherently a technical undertaking that involves scientists and engineers, it must be planned and executed within a business context. A key planning element for tech transfers is setting the right high-level milestones and objectives for the transfer so a realistic timeline can be established and sufficient resources (people and facilities) can be allocated. While an experienced CDMO can help guide these considerations, sending sites — particularly early stage cell therapy developers that are handling a tech transfer for the first time — often have not fully thought through where they are strategically headed. The sending site should establish clarity around the mission-critical milestones and objectives for their business success. This can include regulatory considerations (e.g. timing and content of a CMC submission for an IND filing and when non-clinical manufacturing data is needed for the submission), clinical milestones (e.g trial start/end dates, patient accrual projections), and, where applicable, commercial milestones (e.g. market projections, cost of goods target).
5. Gaps in Readiness of the Process for GMP Implementation
The receiving site’s requirements for GMP-compliant production of a cell therapy product for human use are often substantially different than what may be sufficient for producing the product at the sending site, particularly if the tech transfer is from development laboratories where a highly robust process, strict control over raw material quality, and near-absolute mitigation of product safety risks (e.g. microbial contamination) are not a primary focus yet. A manufacturing process can be viewed as a series of unit operations in which a “5M” outline can be used to define the elements of each unit operation – Man (e.g. operators), Machine (e.g. equipment), Materials (e.g. reagents, disposables), Method (e.g. procedure, master batch record), Milieu (e.g. cleanroom). To ensure comprehensive readiness, a “5M” solution set must be identified for each unit operation that is sufficient for GMP implementation. As one example, the industry has recognized the need for closed, automated systems as a strategically important approach to address not only quality risks, but cost of goods and scalability challenges. However, there are a variety of technical approaches that can be taken to address gaps, including the appropriate implementation of open, manual unit operations.
HCATS has recognized the need to analyze these gaps in readiness and has established a Strategic Manufacturing Assessment (SMA) as a consultative service offering to methodically assess manufacture of a sending site’s cell therapy product. The SMA begins with defining a quality target product profile (QTPP), then defining critical quality attributes (CQAs), and then breaking down the process into unit operations and the 5Ms for each. Analysis is then performed to identify quality risks, GMP-implementation risks, opportunities for optimization including fit with the technology landscape. and a strategic roadmap that is looking into the future of the product including commercial manufacturing considerations where appropriate. A report is issued that summarizes the assessment along with recommendations for moving through the journey of clinical and commercial GMP manufacturing that is synchronized with the cell therapy developer’s general business plan for development of the cell therapy product.
Want to learn more about how you can successfully complete a technology transfer of your cell therapy manufacturing process? Contact the HCATS team today to learn from our almost two decades of experience.
