Although most companies refer to “technology transfer” as if it were a standard process, there are several forms of this transfer, each requiring different degrees of process development. For a large pharmaceutical company that already produces a particular drug on a commercial scale and wants to hand off the production to a contractor, the transfer process can be fairly straightforward. In this instance, detailed documentation and an analysis of equipment and process compatibility may ensure a smooth transition.
When large-scale production has not been achieved by the client on a consistent basis, however, the client and contractor must see to it that every step of the process in scale up will meet regulatory requirements as well as quality, cost and time targets. For a client that has lab-scale technology and wants large-scale production from the contractor, extensive process development may be required.
Having dealt with scale-up and regulatory issues for many clients, the major biopharmaceutical contractors are in a position to provide a global perspective on the entire process, often (1) saving their clients time in moving to scale up, (2) heading off regulatory problems, (3) increasing quality and yields and (4) providing the client with economical yet high-quality production.
Challenges
The 10 biopharmaceutical contract manufacturers interviewed for this article cite numerous challenges involved in transferring technologies from their clients’ sites, challenges they attempt to mitigate by establishing technology transfer teams, technology transfer plans and standard contracts.
Because of the time-to-market pressures in the pharmaceutical industry, clients often urge contractors to get a product into large-scale production quickly; speed is of the essence. This urgency, however, should not provoke the client or the contractor into moving too quickly without an understanding of the full project and operational logistics. A test of all processes at scale-up level—such as analytical methods, cell lines and recovery and purification—as well as a thorough review of regulatory compliance issues, should be completed first.The scale-up production phase will be reached more quickly if problem areas are identified and solved early on. Experienced contractors may be able to speed the technology transfer and process development phases of the project based on the exper-tise they have developed over time. In addition, contractors with a strong service orientation will be able to react quickly to any changes that may be required.
The move to large-scale production can be a challenge if the client has not consistently run the process at full scale already. In some cases, it is also a challenge for the contractor and client to agree on what is needed to proceed to commercial production.
Strong communication between client and contractor is essential, as is a process for developing agreements. Contractors say that communication skills are the keys to a successful outsourcing partnership and that flexibility is important on both sides when adjustments need to be made. Critical process information from the client site—such as hold times between steps, purification data, cell line stability and complete batch records—must be communicated. A complete process history should be transferred so the contractor knows as much as about the process as the client does, once the project begins.
Not all clients want to communicate in the same manner. Contractors must accommodate a broad spectrum of communication styles, from clients who only want to receive weekly updates on the progress of their process development and scale-up production to those who want to have a “man-in-the-plant” so that joint decisions can be made daily.
Key Elements
Contractors, from the full service providers to the smaller niche service and materials suppliers, must deal with the unique aspects of their clients’ cell lines and processes. A summary of the key elements of successful technology transfers and process development programs for scale-up manufacturing of biopharmaceuticals, as suggested by contract manufacturers, is listed in Table 1.
The following comments from 10 contract manufacturers can help sponsors understand how contractors address technology transfer and the accompanying process development and scale-up challenges.
The Technology Transfer Team
Bio Science Contract Production has a technology transfer plan that involves an integrated team of professionals from production and quality groups as well as a liaison for internal and external communication. Dr. Don Durham, vice president of technology management and process development, said, “Forming this team is the core step in securing the success of the project. The transfer team is involved throughout the entire start-up phase until the cGMP production is running smoothly and the production record is finalized.”
After the team has been formed, it is important to ensure that all of the required information has been transferred, including information on equipment, raw materials, processes, analytical and quality requirements and assay . Said Dr. Durham, “It is preferable that we go to the client facility and observe their process. Then we make detailed schematics and process flow diagrams for each unit of operation and include all aspects, such as equipment, supplies, part numbers, SOPs and in-process assays, among many others.” The diagrams are used to train staff and to write production records, which the client reviews as part of an ongoing line of communication.From this documentation a demonstration run is conducted to identify any possible problem areas. “In short,” Dr. Durham remarked, “the technology transfer team works out all of the engineering aspects, ensures all information is transferred, plans for scale up, makes the site visits, identifies the material, drafts the documentation, participates in the demonstration run, assists with finalizing the documentation and then participates in the production run.”
Louise Campbell-Blair, the company’s vice president of business development, added, “Many clients want to transfer their technology directly to us and have us start production immediately, but we find that we often need a process development step first. Clients might not think about how resins, column loading or membranes scale up, for example. It is essential that the time be spent upfront to ensure cGMP compliant production of an acceptable product and avoid costly delays that might occur later in the production run if these steps had not been taken. The advantage of our approach is that process development and technology transfer are in the same department.”
Face to Face and Team to Team
Exchanging personnel from team to team at the beginning of every project is a key for DSM Biologics North America. Dr. Peter Van Hoorn, the company’s marketing and sales director, remarked, “Learning about team chemistry is important to successful technology transfer. All members of the DSM project teams that are assembled on a contract-by-contract basis have to be aware of their roles and responsibilities: Who is our client and its representatives? Who is my individual counterpart? What are the client’s expectations? Who makes up the team from the client side? What is their mindset?”
It is important to lay the foundation for a successful project in the very early stages. Dr. Van Hoorn commented, “If you casually stroll into the process, both the client and the contractor can get hurt. Even before the contract is signed, the potential problems and pitfalls must be gauged and the deliverables from both contractor and client accurately assessed. For example, if a client tells us an assay is robust for Phase I, and we later find out that such a validated assay can be anything but robust, then we have a problem.”Timelines are often based on early assessments, so projects that have been started superficially or under extreme time pressure tend to have ever-changing schedules. Situations need to be turned around quickly. Clients want an aggressive timeline and this can only be facilitated by laying down a strong foundation in the beginning of the project.
For DSM, if an upstream process must be developed, the process personnel from the client side will come to the DSM site to re-run what has already been performed; the DSM team will build the process up from there. Client personnel is often on-site and DSM has taken precautions to ensure that confidentiality between different projects is maintained on those occasions. “Analytics and downstream purification steps tend to transfer and scale well if the equipment is similar, scaleablity has been addressed and deliverables from the client have been verified,” Dr. Van Hoorn commented. “But upstream processes, which entail highly critical customized components in cell culture and fermentation, can cause problems. Having a ‘man-in-the-plant’ is key, especially for the upstream processes. This is also true for recovery operations in E.Coli fermentation.”
Think Through the Process
For a pharmaceutical or biotechnology company developing a drug, the most important question is whether the molecule will work or not. The contractor is often responsible for ensuring that the expression system will work, is economical and will be approved by the FDA. Dr. Claire Thuning-Roberson, executive vice president of corporate development and chief scientific officer of Goodwin Biotechnology, said, “It is crucial that the process be thought through from start to finish. Each division needs to be aware of the entire process. The movement from research to development should not be a leap of faith.”
The contractor should be an extension of the client company’s capabilities and all critical information between partners should be communicated. Dr. Thuning-Roberson added, “We look at the process, the systems and what is expected. Is it scaleable, validatable, measurable, reproducible, controllable, compliant and humanly possible? Regarding the raw materials, one problematic area, are they traceable, measurable, acceptable or removable?”
The contract manufacturer must strive to understand not only the manufacturing technology required for each product, but also the client’s strategy for product development. “By understanding this,” Dr. Thuning-Roberson continued, “the vendor can work with the client to develop a manufacturing strategy that assures objectives are met with no surprises. For example, we are often asked for regulatory advice. Selecting a host cell line that will withstand FDA scrutiny is an important consideration at the research bench. Before entering into manufacturing contracts, the host cell line and manufacturing technology must be evaluated and its compatibility with FDA regulations determined.”
Purification processes developed at the research bench often require modifications in order to be scaleable and FDA compliant. Dr. Thuning-Roberson commented, “One project involved the transfer of a five-column process without stability data on bulk intermediates. Consequently, a 24-hour processing was required to minimize holding times. In another situation, reversing the order of columns in a transferred process resulted in reducing viral and endotoxin levels that were contaminating subsequent columns and equipment.” Forward thinking is vital as products are moved through process development and production toward FDA approval. She explained, “This translates into identifying potential problems and addressing them early on during technology transfer and in development.”The Technology Transfer Plan and Timeline
The client-contractor relationship is best established by a comprehensive technology transfer plan and a timeline showing all deliverables and expected lead times for both parties. This should be preceded by an exchange of complete and accurate documentation, a site visit and an analysis of the details that may affect the transfer such as product sensitivity to environmental conditions and toxicity. Julie Carrière, manager, PDS systems & technology transfer at Patheon, recommended that business contracts be developed and signed by both parties. “There should be one contract for the technology transfer and one for on-going commercial production at the contractor site,” she said. “Both parties can then enter the relationship with a clear understanding of expectations.”
The technology transfer plan she suggested details the steps of the transfer, including final equipment and batch sizes for commercial production. The topics cover a wide range of issues that impact the transfer strategy and timeline, including documentation of toxicity, production size requirements, processes and equipment, capital expenditures, drug substance availability, analytical methods, materials sourcing, transfer and strategy, regulatory filing requirements and approval dates, product launch and contacts at both client and contractor site needed for each step of the project. Ms. Carrière said, “We understand the importance of accurate plans that detail the responsibilities and expected turnaround for each deliverable. Each party agrees to this plan up-front and there are no surprises.”
A Complete Process History
Marathon Biopharmaceuticals provides process development, scale up and commercial manufacture of recombinant proteins at the 10- to 2500-L scale in its FDA-inspected cGMP facility. The company was purchased by CoPharma, Inc. in January 2000.
Dr. John T. O’Loughlin, vice president and chief technical officer at Marathon, commented that the need for a complete detailed process history during the technology transfer process cannot be overstated. “It should start with a process diagram containing stepwise recovery and mass balance calculations for the unit operations. We must know as much as we can about the host strain and any unique growth requirements,” he remarked.A thorough description of the primary recovery and downstream purification processes should be available, he contended. The documentation should include a sampling plan, potential hold points and a complete list of raw materials and their sources.
“At bench or early pilot scale, process hold points and the stability of process intermediates are generally not issues,” he assured. “However, implementation of the process at production scale in a cGMP environment imposes a different set of logistics. The stability of process intermediates must be known so we can define the unit operations. This knowledge allows us to forward schedule equipment and personnel.”
Dr. O’Loughlin added, “A clear development history will help to identify critical steps in the process and will become invaluable during process .” This process history becomes an essential component of final submissions to regulatory agencies. He said, “We are one of the few independent contract manufacturers that is producing a licensed biologic. To do so, our personnel performed all of the development and CMC work on that product.” Dr. O’Loughlin added that the FDA looked closely at the company’s experience in development and processing during both the pre-approval inspection at Marathon and during a series of CMC meetings at the Agency.”
Prepare for Regulatory Requirements
To ensure regulatory approval, it is critical that time be spent upfront to ensure the production process will be cGMP compliant. Ed Branson, vice president of manufacturing at Covance Biotechnology Services, commented, “We work with our clients to ensure all our ducks are lined up for cGMP operation and as we make clinical materials. For clinical materials, we validate equipment, systems and utilities; process comes at a later time. We use extensive analytical support from the QC department to maintain the quality of the process.”
Clients sometimes expect that production is standardized and that scale-up production will be similar to lab scale. But no two cell lines are the same; large scale is sometimes vastly different from lab scale. Mr. Branson explained, “We work with a dozen new cell lines a year and some never make it to production, often for productivity, stability or biological activity reasons. We tweak the media, purification scheme and other components to make the process work, which can involve some hard choices.”
Working together toward regulatory approval of a production process requires a solid understanding of expectations and trust between client and contractor. Mr. Branson remarked, “Our clients give us their baby to bring to adulthood. They have taken it as far as they can and they must trust that we have their best interest at heart. This requires that they tell us everything they have learned about the process so far.” Covance has a process development group that typically works on stability testing and scale-up issues. Afterward, a project is turned over to the technical services group, which specializes in transferring the process into large-scale manufacturing.
If the project requires a straight transfer of the technology from the client site, the company minimizes the regulatory impact by running the process as a mirror image of the client’s process. “We come as close as we can to the original process so the FDA can see that the material made at our facility is the same as the material made at the client site,” said Mr. Branson.
Communication is Key
The underpinnings of a good technology transfer program include a clear and effective mechanism for communication between the client and the contractor. Dr. Mark Carver, head of research and development at Avecia LifeScience Mol-ecules, explained, “The first thing is to ensure that what the client wants is actually what the client needs. For example, some of the analytical methods used by clients could be suitable for current requirements but unsuitable for and verification down the road. These things have to be determined upfront by establishing a good mechanism of communication and a clear understanding of where we are and where we are going.”
Dr. Carver stated that the client and the contractor should agree in advance to a clear, relevant structure for the technology transfer program, defining what information and processes are required. All of the issues in the technology transfer process should be reviewed and verified. He remarked, “Our client might have a recombinant microorganism, but in scale up the recombinant could be unstable, produce an aberrant form of the protein product or not produce a high enough yield. We have to verify with the client that what the client thinks has been transferred truly has been transferred, so we have a real starting point to the project.” Without a clear starting point, he added, the endpoint will be unclear.Dr. Carver commented, “Our philosophy is that the customer is an intrinsic and fundamental part of our team and we involve them throughout the project. For technology transfer, their involvement is essential if we are to deliver a good cost and a quality product quickly. We have experience in knowing what questions to ask and what is involved in the critical path. With good experience, discipline and communication, we can move quickly to the project’s endpoint and deliver the customers’ needs.”
Flexibility
Because customers’ projects and cell lines are so different, it is essential that a contractor design flexibility into the facilities, equipment and company mindset. Dr. Friedrich Nachtman, head of bioproducts at Biochemie, said, “It is not realistic to think that a cookbook solution will work for each of our clients. One of the benefits of our service is our flexibility in equipment and people to adapt to the needs of the client and still meet high quality standards.”
This flexibility extends to the way the company personally in-volves key people from the client company. Technical experts from Biochemie will visit customer sites to observe the process and work with the client. When the production is started at the Biochemie site, the client comes to give input and make joint decisions. Dr. Nachtman commented, “People are the important part of this process. With the right attitude on both sides, the whole project will work. In addition, it is important to set realistic expectations with the client, establish clear timelines and write up a precise agreement describing the deliverables of both parties.”
Biochemie produces recombinant products for its own use and for outside clients. Explained Dr. Nacht-man, “We treat our clients’ products as if they were our own. We treat all things in the same way to ensure the clients get what they want.”
Extensive Documentation
INTELLIgene Expressions devotes a separate ‘pilot’ facility for those technology transfer and process development needs that typically arise in advance of cGMP-level needs. For projects in the early stages of technology transfer, this work is instrumental in paving a smooth transition to cGMP-level production. Dr. Fahar Merchant, the company’s president and chief executive officer, explained, “We invite our clients’ technical scientists on site to work with us to develop their process. Through this collaboration we become familiar with their therapeutic in our process development facility before the full production run.” This tacit knowledge of the client is then made explicit through careful record-keeping. The level of documentation is extensive.
INTELLIgene’s technology transfer process begins with a 12-page questionnaire used to obtain all of the technical information about the client’s process. Next, clients are asked to provide internal SOPs and batch records so that they can be examined well in advance of beginning a run in the process development plant. This information, along with other supporting documentation, helps to identify potential problems before they happen and ensures a smooth transition, according to the company.
Clients are encouraged to take an active role in the process, but the level of involvement varies, according to Dr. Merchant. “Sometimes, client personnel will join us at all of the different stages: molecular biologists for development, process engineers for production, quality control staff for analysis and monitoring.” Once the process is successful, the company readies the developmental batch records for cGMP production, has its internal QA group review all documents and seeks client approval. This close association facilitates creative problem solving. Dr. Merchant noted, “For a recent customer, this work we performed upfront resulted in a successful tenfold scale up the first time we did the run in the cGMP production facility.”
Other clients, for geographical or other reasons, are more removed from the process. In these cases, INTELLIgene controls the trouble-shooting. One such customer requested that the company produce a clinical batch in a very short timeframe. Dr. Merchant recalled, “The project manager and process scientists could visit us only sparingly. They gave us home phone numbers so we could call them in the middle of the night if absolutely required.” To complicate matters, the client’s process was not economically viable. “They came in with a 12-step purification process: a nightmare,” he said. “We determined a way to decrease their purification process to two chromatography steps. As a side benefit, this also increased the yields.”
Maximum Productivity
At Lonza Biologics, clients do not typically transfer in technology. Instead, they request that Lonza develop the process technology for efficient scale-up production. The first step in the process at Lonza is an upfront, detailed discussion with clients to define the overall objectives and to understand how Lonza’s knowledge and experience will be used to fine-tune the process to meet time and price goals. Clients may choose to incorporate Lonza’s proprietary expression system into their production plan.
As Mike Chaffee, director of marketing, described it, “To produce robust, scaleable processes, we evaluate a number of critical parameters maximizing the expression levels from the cell line.” He added, “We also examine batch or fed batch production strategies utilizing airlift or stirred tank technologies. In addition, we typically examine media selection and look at the benefits of utilizing serum-free or protein-free conditions. It is amazing how minor changes in the process, such as changes in pH or media components, can have dramatic results in productivity. Downstream, for purification, we look at filters, centrifuges, chromatography and overall recovery to maximize the productivity of the process.” Each project is customized and the client has the option of transferring all or some of Lonza’s relevant intellectual property back in-house.
Ultimately, there is no single recipe for all projects. In more complex situations, working with cells can be more of an art than a science. The expertise or intellectual property that a contractor offers the client will often significantly help bring that product to the market. Mike Chaffee noted, “We have helped dozens of clients speed their product to market by utilizing our knowledge base in development, optimization and scale up of the production process.”
The 1998 PAI data shows facilities abroad outperforming U.S. plants. These favorable foreign PAI results parallel FDA’s enforcement data for fiscal year 1998, which shows a significant reduction in the number of warning letters issued to overseas plants. This improved compliance record reflects a concerted effort by the agency over the past few years to bring foreign Active Pharmaceutical Ingredient (API) manufacturers into compliance through increased enforcement oversight and better GMP guidance. During 1998, FDA’s field organization conducted 1,016 inspections. The types of plants covered included contract laboratories, packagers and manufacturers as well as bulk and finished dosage manufacturers.
Contract manufacturing organizations have the advantage of possessing the facility, systems, technology and personnel to offer to the prospective client. FDA requires the industry to provide evidence that the firm knows what it is making and knows how to make it. As has been seen time and again, the first objective of the PAI program is to assure that the facilities listed in the application have the capabilities to manufacture, process, package and provide adequate analytical controls according to the cGMPs.
Regulatory and legal issues are also involved when a drug company uses a CMO. The CMO must comply with cGMPs. Also, the drug company must consider the CMO as an integral part of the drug application and must include the same information for the contractor’s facilities that it does for its own. The CMO shares responsibility for following all the steps necessary for gaining approval for the application. 
in mind. As a result, common design criteria used for finished dosage form manufacture (such as flow of material from receipt through production, flow of personnel, pressurization of areas so that no cross-contamination can occur) are never considered. Other concerns during the PAI are the water system, poor documentation regarding the equipment qualifications, technology transfer, change control, SOPs and good laboratory practices. As FDA is gradually applying GMPs to the upstream processing of pharmaceuticals, API manufacturing facilities will be required to comply with the same guidelines that the dosage form manufacturers are judged by during the PAI. Therefore, the same consideration should be given in selecting a cGMP compliant contract API manufacturer as one would select the finished dosage form contract manufacturer.
compliance letters that FDA sent to foreign firms. Overall, finished product formulators fared better than API manufacturers during 1995 and 1996; 11% of inspections resulted in noncompliance letters compared with 17% of API inspections. Of all the foreign inspections conducted by FDA in 1996, approximately 90% (258) were PAI, compared to 429 domestic PAIs. Nearly one-half of the warning letters sent to foreign bulk chemical manufacturers during 1996 cited problems with the firm’s stability testing program, which included sample storage, evaluation procedures, number of batches tested, control of labeling and type, amount of supporting data, retesting and out of specification (OOS) results investigations.
