Every pharmaceutical process experiences one or more technology transfers during its lifetime. Each time, critical process knowledge moves from one group or organization to another.
Whether a transfer occurs according to the most exquisitely planned protocols or through the sledgehammer approach, it will, in the end, get done. Technology transfer is more of an indicator of overall manufacturing excellence than it is a predictor of anything larger.
But today, technology transfers significance is magnified as more products, particularly biologics, are outsourced through alliances and manufacturing-only relationships. Increasingly, tech transfer is becoming a core competency for companies developing novel therapeutics, says Matthew Hudes, a managing principal with Deloitte (San Francisco, Calif.). In the past, not that many companies recognized that.
Even the most successful companies wrestle with these problems. Genentech is one firm that Hudes believes has mastered scaleup and tech transfer, both internally and with its partners and contractors.
Although the functional aspects of tech transfer may be similar in customer-vendor arrangements, between partners, and within an organization, the incentives are aligned differently. Processes are likely developed by innovators and handed off to CMOs who are tending to other business. With more skin in the game, partners tend to become more involved in process development.
An incomplete or incoherent commercialization path, and lack of predefined success criteria can strain relationships between tech transfer partners. For example, a great chemical process can be a non-starter when ramped up to a larger scale. Something as simple as an excipients not being commercially available can ruin the transfer. More likely, performance metrics, particularly in-process analytical tools, lack the appropriate resolution and discrimination at larger scale. Poor manufacturability has sent more than one CMC filing back to the drawing board.
When it comes to transferring a product or process, the originating group or company must consider every material and activity. Even such basic components as the material used to manufacture a delivery device can throw roadblocks into the scaleup and tech transfer pathway. According to Bikash Chatterjee, president of PharmaTech Associates (Foster City, Calif.), a consultancy for regulated life sciences, drug delivery systems are a common source of trouble. Increasingly, sterile injectible drugs use novel delivery systems whose materials of manufacture lack adequate regulatory documentation as to compatibility and chemical stability. If the manufacturer of the polymer used to make the container wont divulge how the material was manufactured, you cant file the product. An even worse scenario occurs when an entire development program is based on that particular delivery vehicle.
Companies successful at tech transfer practice extensive upstream characterization of their molecules. In biotech, this means heavy reliance on design of experiment exercises to model large fermentations. The industry has invested in technology for producing robust, qualified, validated models at the 10-100 L scale that precisely mimic much costlier 10,000 L cell cultures to convince the FDA. Without data, says Chatterjee, its very difficult to tell your story.
Developing such models requires top-level science and documentation, which, not coincidentally, supports biopharms growing reliance on tech transfer to contract manufacturers. According to Chatterjee, that is a good practice. However, as CMOs get busier, relying on them to do development work will become a less attractive proposition.
Platform approaches smooth the transition
Pharmaceutical and biotech manufacturers have long appreciated the value of adopting platform technologies whenever feasible. Advantages include greater familiarity with unit operations, heightened confidence in the ability to deliver quality product and better deals from vendors for equipment and disposables.
Platform technologies and processes also facilitate technology transfer. The biopharm CMO Avid Bioservices (Tustin, Calif.), a subsidiary of Peregrine Pharmaceuticals, specializes in stirred tank cell culture for monoclonal antibodies. Avid uses CHO cell fermentation, Lonzas Glutamine Synthetase expression system, CD-CHO cell culture media from Gibco, disposable harvest systems from Millipore and, whenever possible, the same harvest, capture and purification steps for most of its approximately ten ongoing projects. The company uses batch fermentations, but is investigating perfusion reactors to improve volumetric throughput. Provided they do not insist on a home-brewed process, customers know what they are getting every time. The units operations are plug-and-play, so even when customers insist on bringing in home-brewed technology for some steps, platform operations can be woven in.
The platform approach works with scaleup and transfer of process analytical technologies (PAT) as well. Earlier this year, John Grosso, Ph.D., an executive director for Bristol-Myers Squibbs (BMS) analytical R&D department (New Brunswick, N.J.), presented a talk at the IQPC Forum on technology transfer and PAT. BMS considers PAT not only an agent for tech transfer Grosso placed it at the interface of this process but tech-transferable in its own right. Migrating PAT is the focus, he says.
The scalability of PAT becomes an issue during tech transfer. While offline or at-line analytics such as liquid chromatography are usually scalable (for example, it makes no difference to the chromatograph whether one is sampling a 5 mL round bottom flask or a 1000-L reactor), the same is not true for embedded analytical probes. Batch homogeneity, sensor placement and off-target variables like temperature and pressure can affect measurements.