Ins & Outs of Tech Transfer

Pharmaceutical outsourcing is a mature industry but remains huge. A study by Cepton Strategies (Münich, Germany) estimates the value of outsourced R&D in 2008 at $18 billion, and of contract manufacturing at $39 billion. Technology transfer — the handover of knowledge between organizations — is the seminal event in all outsourcing arrangements, particularly for manufacturing. 
 

Tech transfers may occur internally, within a company, or involve two or more corporate entities. Lateral transfers involve the same development or manufacturing stage; more commonly transfers involve successive lifecycle stages, such as development and scaleup. 

Tech transfer issues arise from inconsistencies and miscommunication between donor and receiving organization, says Wei Chen, Ph.D., chief scientist at Phage Pharmaceuticals (San Diego). “These encompass the entire development environment comprising materials, equipment, disciplines, people and culture — all the physical, biological and interpersonal factors, both macro and micro.”

External tech transfers are the most prominent and prompt the most discussion. Contractors and sponsors have developed their own unique tech transfer subcultures. The key to success is not allowing those cultures to clash.

AMRI (Albany), a CMO that also offers scale-up development services, takes a two-pronged approach to external technology transfer that includes accompanying strategies for internal transfers. The first component, explains Christian W. Phillips, senior director, operations, involves the transfer of drug product knowledge from the innovator company to the CMO. “At this stage, a process engineer assimilates that knowledge and designs a development transfer plan, and ultimately a GMP process.” 

This is the step where the CMO comes to understand the product’s critical quality attributes and known process control parameters within the scope of the customer’s business objectives. Once this occurs, a CMO should have a good idea of process design options.  

What follows is a second, internal, technology transfer process whereby the CMO’s process engineer(s) transfer product/process knowledge to the manufacturing group. “These two successive tiers of technology transfer ensure that product knowledge is not only captured, but maintained within all organizational levels and throughout the project’s lifecycle,” Phillips says. After selecting engineering and quality controls, engineering presents QA a development plan to ensure consensus. 

Because CMOs often work with many different products and platform technologies, manufacturing teams must possess deep understanding of GMP, and recognize potentially adverse process issues early enough to implement preventive actions proactively, rather than reactively. “It’s this depth of floor-level, product-specific manufacturing knowledge that provides the best chances of overall success,” Phillips adds.

A common misalignment involves deliverables. Sponsors unfamiliar with formal requests for proposal fail to communicate their needs; contractors misinterpret poorly conceived RFPs. A sponsor reading three widely varying quotes will face an “apples-to-oranges” comparison. CMOs tend to respond to RFPs according to their skill sets: When your only tool is a hammer, every problem looks like a nail. Sponsors must detail everything they need in an RFP, and set clear expectations on deliverables and milestones, Soltero advises.

PharmaDirections, which serves as an intermediary between CMOs and sponsors, recommends including a demo or engineering batch into CMO contracts. “Hardly anything works right the first time,” Soltero says, “but it takes a lot of persuading for sponsors to understand that.” He views demo batches as insurance: It adds about one month to the project, but can help avoid much longer delays associated with a failed clinical batch. 

According to Alex Kanarek, Ph.D., senior consultant at Bioprocess Technology Consultants (Woburn, Mass.), hurdles when moving a process to a CMO typically involve inadequate specification of the transferred processes, and failure to create a satisfactory quality agreement. “The agreement must be sufficiently detailed so there are no equivocal requirements in the process or product specifications that CMOs may misinterpret. There is a slight tendency for CMOs to assume that they ‘know it all’ and apply some familiar technology that is unsuitable for the product, or make incorrect assumptions.” 

Patheon (Monza, Italy) initiates tech transfer with a tightly structured and documented kickoff meeting with the customer. Andrea Como, site technical business senior manager, calls this step “information transfer.” During this consultation, the business partners assemble a detailed technology transfer list that includes everything required to initiate and understand the project. After the CMO has reviewed the sponsor’s documentation package comes a “technical kickoff” meeting where the parties cover specific, anticipated chemical/engineering issues.

Bottlenecks arise when the sponsor does not or cannot provide a robust data package. Reports of sponsors holding back for reasons related to intellectual property emerge occasionally, but most are probably apocryphal. More often, sponsors may not fully understand tech transfer and the CMO’s expectations. Many small sponsors lack GMP, regulatory or analytical experience, and may underestimate their significance. As long as both parties appreciate the potential for adverse issues, appropriate precautions can be built into the project. 

This assumes that the CMO is both prepared and willing to undertake what Como refers to as “gap analysis,” and to explain to the sponsor-specific activities that it may not have anticipated before the tech transfer. “The two sides must agree on how gaps should be filled before the project begins.” Only then, Como says, will the CMO be capable of satisfying their customers’ demand for “better, faster.”

A less common disconnect occurs when a process transfers from one CMO to another. The switch could be based on production scale, capacity, scheduling, or dissatisfaction with the first contractor. Transferring such processes through the sponsor — think of the childhood game of telephone — practically guarantees a disjoined information exchange. 
 

Transfer between CMOs is often more complex than other external transfers. Pilot-scale CMOs gain valuable process experience, and therefore possess “the book” on both product and process. One would expect this experience to flow freely and comprehensively to the second contractor, but that is rarely the case, says Jordi Haro, project manager for tech transfer at Recipharm (Barcelona, Spain) as both parties may be unaware of the other’s existence relative to the specific project. 

Even when everyone cooperates and is well-informed, involving three parties rather than two is inherently confounding. In some instances, the innovator and the first contractor have intellectual property to protect surrounding the product, proprietary know-how, or patented technology that they prefer not to share.

Tech transfer for biologics is significantly more complex than for small molecules: As they say in biotech, “the process is the product.” Since biomanufacturing platforms are living organisms rather than chemicals, documentation-based tech transfers have a low success rate. “Biologics rely much more on interpersonal contact, training and cross-technical discussions,” says Tony Hitchcock, head of manufacturing technologies at Cobra Biologics (Keele, UK). Paper-based transfers sometimes work, but when they fail, the ensuing problems are difficult to resolve. 

Cobra, which manufactures biologics to support clinical trials, prefers a transfer process involving the exchange of its manufacturing experts to the sponsor, and the sponsor’s experts at Cobra. This engenders what Hitchcock calls “the degree of ownership” for both parties. 

Often the sponsor itself lacks full understanding, not just of concrete unit operations, but of process excursions, tweaks and judgment calls. Such deviations from the straightforward development create knowledge gaps that are difficult to communicate. Knowing and documenting them — even while lacking full understanding — at least alerts the contractor that potential failure points exist, and should be transferred, even if the sponsor believes the CMO doesn’t require it, says Susan Dexter, principal consultant at Latham Biopharm Group (Maynard, Mass.). 
 

Given differences in corporate cultures, external tech transfers present the sponsor and CMO with the most challenges. In the competitive, time-constrained business of pharmaceutical manufacturing, it is easy to ignore the value of direct human interaction for smoothing out rough spots. “Teleconferences are over-used and abused,” admits Haro. “One face-to-face meeting can often solve more problems than 10 teleconferences. Interpersonal dealings also positively affect the parties’ sense of ownership of the process.”

Organizations often treat internal and external collaborations differently — the “us vs. them” syndrome. In reality, both share more characteristics than differences. 
 

Tech transfer within organizations, say from development to scaleup, should proceed more smoothly than between sponsors and CMOs, says Como. “When the initial transfer stages proceed according to our established procedures, and if the customer provides all necessary information, no significant difference should exist between internal and external transfers.” 

Yet familiarity does not always facilitate internal transfers. “Internal transfers are more relaxed,” says Haro, “and internal customers may not be viewed as real customers.” Scheduling, milestones and resource allocation items on an external transfer checklist might be taken for granted during an internal project. Development groups may assume that manufacturing will take care of a product’s industrialization, rather than considering it from product initiation, and cautions normally taken with scaleup might be ignored. 

Tech transfer snags should not occur between development and pilot plant, says Kanarek, “provided development and pilot plant jointly participate in product development discussions from an early stage, and use common or well-known platform technologies.”

Difficulty arises when the pilot group is unfamiliar with technology used during development. As with external transfers, this triggers a new learning curve. Unfortunately, development staff is not always perfectly suited to transferring technology to the next stage, and timing pressures may lead to inappropriate shortcuts. 

A related issue occurs when development employs operations that do not scale: Larger equipment may be unavailable, mixing or mass transfer problems might arise, or a resin may be too expensive. “If the process is only suitable for bench scale, development should never have used it. This situation is avoidable through appropriate communication at appropriate development stages.”
 

To Kanarek, the key to avoiding internal (and external) transfer hurdles is having the process under the control of an experienced manager who understands the science and each group’s capabilities. “Someone who recognizes where problems may arise and can update the next-stage group or bring in someone who can, while ensuring that sufficient time is allotted in the project plan for learning.”
 

Internal tech transfer is about assuring that internal teams overlap at critical junctures, to assure that what occurs during development is feasible during manufacturing. “The transfer goes more smoothly when manufacturing does not make many changes,” says Dexter. 
 

Most companies have developed good scaledown models that predict scaleup, and have become more adept at transferring technology suitable for and compatible with both development and manufacturing. “It’s like building a car,” Dexter says. “You have to understand how an automobile performs before you can specify the parts.”
 

The main difference between external and internal transfer, says Como, is the level of flexibility required by transferring and receiving teams, particularly the latter. “With internal transfer, the two groups already have set protocols in place. Being in the same organization, they should have similar ways of thinking about these projects, managing tasks and troubleshooting.” Consequently, when corporate cultures clash, it is up to the CMO to exercise tractability, particularly with regard to project management.

As the principal means of assuring chemical identity and purity, instrumental analysis is the lifeblood of pharmaceutical development and manufacturing. In addition to standard instrumental methods, molecules may undergo enzymatic or cell-based assays to demonstrate some critical quality. Products often become “married” to analytical methods, and transferring this panel of tests requires care.

Analytics tend to transfer more smoothly through internal projects because companies are more likely to standardize instrument platforms, instrument configurations and method transfer protocols across their laboratories. 
 

Analytical method transfers can stall when instrumentation or skills at the two organizations differ, or if the contractor simply lacks certain expertise. CMOs try to duplicate the sponsor’s analytical capabilities as much as possible, but with the sponsor’s approval they may outsource esoteric assays to third parties. 

Contractors need time to work out the kinks in an analytical method, “to put the tests into their own vernacular,” according to Soltero, while simultaneously maintaining fidelity to the originator’s methods and goals. He advises parties in a method transfer to conduct parallel assays on the same test items at their individual sites, and to compare results. This adds time, but Soltero compares this exercise to engineering batches — insurance that methods are consistent and robust. Equipment should be as well-matched as possible, as factors as seemingly trivial as the age of an HPLC column can produce different impurity profiles. Similarly, Soltero urges harmonization on more complex assays. “Not everyone conducts dissolution tests identically. There’s some art in addition to the science.”
 

Problems are common in analytical method transfer because many methods are specific to the product or to the development group. Qualifying analytical methods depends heavily on the analyst’s skills, and sometimes on the source of a critical analytical reagent, especially antibodies. The solution, says Kanarek, is to employ a formal qualification/validation protocol. “This will help identify potential variability and communicate it to the receiving laboratory. An exchange of reagents and cross-training of analysts, if possible, is a great help. Certainly parallel testing of standards is essential.”
 

Analytical methods transfer more easily “on paper” than process methods, but problems still arise. Hitchcock suggests that both parties institute “cross-checks and balances, making sure they go through methods qualification.”
 

Many methods for quantifying impurity levels have become standardized in biotech, particularly within drug classes or expression systems. By contrast, product-related assays are unique. Cell-based and enzymatic tests for potency or activity are highly user-dependent, and require more cross-checks than HPLC assays. For transferring these, Hitchcock urges communication and “investment of time and effort to take the black art out of the assays and make them GMP-compliant.”
 

Transfer of analytical methods is time consuming for CMOs and costly for sponsors, who frequently complain about time and expenses. Most CMOs possess extraordinary competence at standard assays. Still, even off-the-shelf methods require validation to assure that the product does not enhance or inhibit results. “CMOs must qualify methods for GMP runs,” Dexter says, “and this needs to be a high priority for all parties. At the end of the day, your analytical data is all you have. If you don’t trust it you have nothing, you’re in no-man’s land.” 
 

Successful technology transfer involves process understanding, a willingness to admit and document knowledge gaps, communication and trust. When executed intelligently, tech transfer adds value through the synergy of complimentary needs and competencies, and reinforces efforts at continuous improvement.

Recipharm’s Haro says that a post-project, lessons-learned exercise strengthens the business relationship between sponsor and CMO and leads them individually to best practices for future projects — whether conducted together or separately. Haro compares this tech-transfer endgame to soaking by a fine mist. “Learning from many tech transfers is a slow process leading to operational excellence for both CMO and sponsor.”