BioProduction by SEKISUI’s Kirsty Bellchambers and Aurore Laborie-Thompson share insights into what drug developers need to know about transferring their biologics processes to a CDMO partner.
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Biopharma developers may choose to partner with a contract development and manufacturing organisation (CDMO) at various points as they progress their program, to develop, transfer, and/or scale-up manufacturing of their proteins. Depending on the relative maturity of the program, there can be any number of internal processes developed that must be replicated with a partner. Therefore, technology transfer may look different from one program to the next, depending on both unique aspects of the process and the stage at which it will transition.
The most seamless tech transfers happen when developers take future scale-up into consideration early, particularly during research and development. Here, we will outline some areas worth consideration as early as possible for developers requiring microbial-based protein manufacturing, which can set a program up for success – whether long-term plans involve internal or external manufacturing. However, since this kind of planning is not always possible, we will also highlight how experienced contract manufacturers can be partners in planning, and are often well-positioned to help get a listing program back on track.
Setting expectations
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In our experience, developers can sometimes be faced with the challenge that not all processing steps that worked well at a smaller scale can be transferred to an analogous large-scale process. Common examples include the transfer of high-oxygen demand fermentation, and the use of certain types of centrifugation, dialysis, affinity chromatography or size exclusion methods. Worse still, some of these processing steps cannot be recapitulated at all, and must therefore be replaced.
Beyond identifying these problematic processes, a successful technical and process knowledge transfer from a developer to the CDMO partners also requires devoting the appropriate amount of time to identifying the key process parameters (KPPs), to ensure optimal process control is maintained during manufacture.
Some of the partners that are most impacted by the challenges of tech transfer – or the time it can take – are those that have already attempted to scale-up internally. There can be different motivators in a developer’s decision to work with a CDMO; in some instances, demand has pushed them to seek help from a contract manufacturer, while others may wish to avoid significant investment in internal manufacturing capabilities given the long-term challenge of successfully getting a drug approved. These developers recognise that the transition to contract manufacturing can bring benefits to both quality and the ability to scale out, but they are also facing economic pressures that may compromise the ability to produce their protein efficiently.
Especially in these instances, requested timescales therefore can become unrealistic. The most useful contract partners will be well-positioned with strong relationships with suppliers of qualified raw materials, as well as service providers for specialist analytical testing requirements, helping streamline project progression. Still, none are entirely immune to the kinds of externally driven difficulties in scaling up that in-house manufacturers would also experience.
CDMOs: helping to course correct
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Depending on where they are in their life cycle, developers can have various degrees of preparation for the tech transfer. What a CDMO looks for first are the key starting elements: the cell banks, fermentation and purification processes, and a robust way of assaying the protein. Depending on the stage of development and level of preparation, we have found that customers may have none, some, or all of these elements defined with consideration for scale-up and commercial production when they first engage with a CDMO. As a result, our first steps together can be shoring these up or filling in any blanks.
From there, it may be necessary to set and agree on clear expectations for scaling up. Transfer of unnecessarily long processes built without scaling consideration will have a cost implication, as they would likely require more plant occupancy time, as well as increased material and energy usage. Conversely, the timing of certain processing steps at scale are commonly underestimated, and may lead to protein degradation and impact overall step yields. In cases where this is anticipated or evidenced, it may be preferable to shift the focus of a customer’s fermentation from high volumetric titre to achieving maximum cellular productivity, easing the relative burden of increased contaminating proteins on subsequent downstream processing steps.
Balancing perfection with practicality
Release specifications are crucial to ensuring the quality of drug products produced by CDMOs. These specifications are informed by the developers’ experience, regulatory guidance, and interactions with other partners. Sometimes, specifications can be designed based on insufficient data and there are instances when a developer might be reliant on an assay that isn’t fully characterised or qualified. It is important to understand the CDMO’s analytical capabilities before and during the tech transfer process, to best support their analytical development. When working with a truly collaborative and knowledgeable partner, part of the tech transfer of their process might mean getting feedback that adjustments are necessary to an assay and/or the product specification, or that the CDMO would propose further development of the manufacturing process to ensure that the product will consistently meet specification.
Developers can make decisions intended to simplify processes before transfer that ultimately could create more problems than they solve. For example, some developers seek to manufacture at ambient temperatures, thinking it will offer greater flexibility. However, this may drive problems with product instability that may not readily be overcome. Another example is reducing or amalgamating column chromatography steps in an attempt to save processing time or costs at scale. This is likely to compromise purity, introducing contaminants that may place a greater burden on subsequent processing steps. Additionally, if column cycling is necessary, it may actually add to processing time, driving up costs and potentially introducing stability challenges.
It is not possible to eliminate the unforeseen variables that sometimes arise during tech transfer in therapeutic protein manufacturing. However, with careful preparation and an experienced contract manufacturing partner, it is possible to reduce complications and make the path to scaling up a smoother one.