The effectiveness of technology transfer is one of the key determinants in the success of a contract-manufacturing project. In most cases, it is the biggest unknown with respect to timelines, cost and expertise from both the client's and the contractor's viewpoints. In spite of the fact that it requires expertise and involvement of both parties, the burden is invariably on the Contractor to demonstrate to the client that it can successfully perform technology transfer. The proficiency of a CMO (Contract Manufacturing Organization) in performing Technology transfer is determined by its experience in dealing with several types of projects, coupled with the strategies and tools that it employs. The advances in software technology have provided the opportunity to develop customized tools to address specific needs of technology transfer in bio/pharmaceutical manufacturing. We shall examine some tools and strategies that can be used in representing, communicating and exchanging project and process information throughout the different phases of technology transfer.
Information Exchange in Tech Transfer:
Where It All Begins
Technology transfer begins with the first contact between the client and the CMO and ends with the timely execution of the production campaign. The first exchange of information occurs through an RFP/RFQ provided by the client or through the information provided in response to a CMO's questionnaire. In preparing these documents, every effort should be made to provide as much detail as possible about the project scope, the project deliverables and the extent of prior experience with the product and process. In addition, discussing the client's prior experience with contract manufacturing can provide very valuable information for the CMOs. However, some of these documents do not offer all the information to determine project fit. In order to obtain all the relevant information, we are developing a user-friendly electronic questionnaire with a click-choose-check interface, enabling clients to submit the information electronically in a secure fashion. The information provided in the questionnaire is useful as an initial screening tool, since it is impractical to respond with complete detail to every request. Detailed information, if available, will result in quality responses from the CMOs.
Project initiation typically follows the agreement between the client and the contractor. Project teams are assembled at this point with the respective project managers providing the interface between the teams for communication. An effective tool in guiding the project through its phases is a project plan, represented as a detailed Gantt chart. Several project definition activities occur during the project initiation phase (the details of which are beyond the scope of this article).
Process and project information transfer from the client to the contractor occurs typically by transfer of all the relevant documents. Information not received and distributed in a structured manner is of little value. Project managers play an important role in organizing the information available and presenting it to the entire team, as needed. Transferring the documents to departmental or functional managers may not be very effective, since everyone in the project team should know what information is available and be able to access the information when necessary. One effective strategy is to place any available document in a central document server. The meta-data of the information available could be summarized by the Project Manager to enable easy access to the appropriate files.
When detailed documentation of the process is not available, process templates can be provided to the client. The process template is a form interface containing placeholders for all the process and equipment parameters for each unit operation. These templates are useful in collecting information from all the relevant people.
Although vital, verbal communication between the client and the contractor team members, if undocumented, can result in significant miscommunication if the information is not conveyed to the entire team. A mechanism to record and distribute any information received verbally needs to be in place. An E-mail distribution list, coupled with a client E-mail folder on an E-mail server ensures that the team has access to all relevant information exchanged between both parties.
Information transfer and exchange have become even more challenging as companies are utilizing different CMOs during different phases of product development. Due to issues of confidentiality, open sharing of information is not possible between CMOs, requiring "indirect information transfer." In addition, product development involving multiple companies is becoming common in the biotech industry. Information transfer in such situations can be challenging. The Dynamic Process Flow Diagram (DPFD) tool, which will be described later in the article, serves as a valuable information transfer template in such situations.
Development &Review of
Process Design and Process Logistics
Transferred processes are often implemented at different scales or with modifications compared to the original process. The challenge of technology transfer stems from determining how the process can be implemented with the equipment, systems and space available to the contractor, while maintaining the quality requirements of the process/product. The process design should also take into account the expertise and extent of other support services (QC, raw materials testing, utilities, equipment wash, autoclaving, buffer prep, etc.) available to the project. The other dimension to this challenge is to achieve the throughput requirements dictated by economic reasons, especially in transferring in-house projects/ processes that may not have been constrained previously by time, resource and/or space availability. The only working strategy in overcoming these challenges is for the client and contractor teams to work very closely together to develop practical solutions. Early team building becomes valuable in these situations.
Scale-up/Engineering design calculations should be made to determine the size and scale of equipment needed, especially for long lead-time items. Quantity estimates of long lead time/large volume/quantity raw material should be made to ensure timely procurement. Developing and maintaining an updated equipment and materials database comprising selected high-quality vendors, lead times, scale, size, storage, quotations, package sizes, sampling and testing arrangements, can be very valuable in readily evaluating options.
Creating Detailed Process Description
Detailed process description is essential for generating the production requirement plan. Process details can be clearly represented and communicated with visual diagrams. A new tool for visual representation of the process, while preserving all the underlying information, has been developed. The following section provides the technical description of the tool with emphasis on how a detailed process description can be represented using the tool.
Icons for use in drawing DPFDs. Each Icon represents a component with associated custom properties, and can be dragged-and-dropped into the DPFD.
Dynamic Process Flow Diagram (DPFD)
Conventional Process Flow Diagrams have been used for visual depiction of the process. They illustrate the major steps and the key parameters of the process. Through customization and programming, the Processlow Diagram concept has been enhanced to provide the necessary communication interface for several technology transfer activities. A new Process Flow Diagram tool—Dynamic Process Flow Diagram (DPFD)—has been designed with the objective of generating dynamic information from the drawing, in addition to visual process representation.
The Dynamic Process Flow Diagram tool provides a simple, user-friendly interface for creating a detailed process description. Any process consists of a set of tasks and associated components required to perform the tasks. Most of the bio/pharmaceutical manufacturing processes involve the use of common components described below. For example, every process utilizes chemical or biologic raw materials, equipment and supplies, in generating in-process solutions (buffer, media, etc.), and in-process product (Chromatography pool, Filtered API). Samples are generated throughout the process for either in-process tests or QC tests. In using the equipment or performing tasks, cGMP processing requires the use of documents (SOP, batch records, etc.). Complete representation of a process will require representation of all these aspects.
Custom Properties associated with components. Each icon has its properties embedded in it and can be viewed by displaying the custom properties window.
In the DPFD, an internal computer object for each of the components has been created and is represented by the icons shown in Figure 1. These icons have been created in Microsoft Visio® 2002. The icons are part of a "Stencil" in Visio. For each of the components, a set of properties have been created. For example a "Supply" icon has such properties as Name, Part Number, Amount used, Process step used in, Status, etc. The properties for the icons in the Stencil can be customized to suit the needs of each company's systems and procedures.
A DPFD is created by dragging-and-dropping the icons from the stencil. When the icon is dropped onto the drawing, a copy of the icon representing the component appears on the drawing sheet. A pop-up window prompts the user to enter data for all the properties. Once the data have been entered, it remains with the icon on the drawing. For example, when a "Supply" icon is dropped, the icon shown in Figure 2 is created in the drawing page. The icon can now be made to represent a 200L Media Bag used in the process, by entering appropriate data for the properties. The properties stored inside the icon can be viewed at any time by choosing the custom properties menu for the icon in the drawing.
The entire process is depicted by dropping appropriate icons to represent task and other components. The process flow is indicated by using arrows and connectors as necessary.
Another pop-up dialog interface has been created to facilitate creation of the DPFD and to minimize data entry. For example, if a process utilizes the same Media bag (a "Supply" component) in two different steps, the second media bag icon's properties can be filled using the properties of the first Media bag icon. The pop up dialog (similar to that shown in Figure 2) provides a list of all the supply icons on the drawing, from which the first Media bag can be chosen. The properties can be inserted into the current icon by clicking "Insert in shape" button.
Alternately a "template drawing" consisting of all the chemicals, documents, etc. that are available in the manufacturing system can be created and appended to the new drawing. In creating a new DPFD, all the icons' properties in the template drawing can be utilized without the need to re-enter data.
A completed DPFD for the manufacture of a buffer is shown in Figure 5 . The diagram provides a clear, visual representation of the process that is easy to understand and follow. This document can be reviewed electronically by the client and the contractor team members and modified as needed. The user interface is extremely intuitive and simple allowing one to create the drawing and/or make modifications, with little training. The Microsoft Visio® application offers the ability to create multiple pages of drawing allowing the entire process to be contained in one document. For example, each step of the process can be depicted in one page and each buffer/solution preparation procedure can be in its own page. The first (index) page will consist of the page listing with links, allowing the user to jump to the page of interest.
At this phase of tech transfer, modifications to the detailed description range from minor to major and these changes should be readily known to the team, so that they can realize the impact of the changes and react to the changes. If the entire production process description is in a single (DPFD) document that is updateable, communication of the changes is simplified. The impact of the changes with respect to production requirements can be readily discerned using the reporting tool, which will be explained in the next section.
Summary report interface in DPFD. Allows user to choose the type, the category and the properties to report.
Develop a Production Requirements Plan
And a Project Plan
Once the process is defined, the requirements for the production campaign have to be determined. This includes the generation of a list of equipment, supplies, chemicals, assays, samples and documents. In addition, for procurement purposes, it is essential to determine the amount of chemicals and supplies. Generating these lists manually can be very time-consuming. A reporting tool in DPFD has been developed that can summarize the necessary lists. The reporting interface (written using Visual Basic®) provides the option to choose the category of summary report that is needed. Alternatively, a custom report can be generated for any component (or icon in the DPFD stencil). Within a category, specific component (icon in stencil) properties that are of interest can be chosen by clicking the check box in front of the property (see Figure 4). After the properties are chosen, clicking the "Generate Summary" button builds the reports in Microsoft Excel® Workbook format (Figure 5, bottom). A dialog box interface is provided to allow the user to choose a filename and folder location for the report. These reports could result in tremendous time savings for several groups involved in planning and executing the project. Convention-ally these lists are generated only after detailed Batch records are written.
While batch records provide detailed process information, quantities of supplies, chemicals, etc. are difficult to extract from them. In addition, Batch records are administered and monitored by the document control function of a QA unit and hence are not readily available to all the team members. Using these tools, complete lists of equipment, documents, assays, samples, chemicals and supplies (including quantities) can be generated. From these lists, a comprehensive production requirements plan can be generated.
At this point, along with the production requirements plan, a detailed, resource-loaded Gantt chart for the entire project is developed. This enables establishment of realistic timelines and allows the project to be tracked. Through the combined use of a Gantt chart as the "timeline" tool and the DPFD as the quantitative tool, a comprehensive process description and project plan can be developed and made available to the team.
Review and Finalize
Production Details and Plans
As the plan is being developed, process details may be refined and slightly modified. In addition to incorporating these modifications to the process, the impacts of such a change on production requirements need to be determined. This requires re-analysis of process and re-listing of the production requirements, which can be difficult to do manually. One of the distinct advantages of a DPFD is in its reporting feature. It provides an instant summary of the production requirements that can be used to generate and modify plans. The impact of any modifications to the process can be readily seen with respect to how it affects various aspects of the project plan.
Perform Transfer Runs
Performing transfer/scale-down runs are an excellent tool for information exchange during the technology transfer process in contract manufacturing. It enables the client and the contractor teams (process and production personnel) to exchange hands-on process knowledge and information. There is significant value to performing these runs, as they minimally impact timelines and cost. Experienced contract manufacturers and clients often insist on these runs since they establish the baseline/best-case performance yardstick for the process. These runs are typically performed by the technology/process and production groups working together. They provide hands-on familiarity with the technology behind the process.
During the execution of the process at production scale, equipment and scale logistics often overshadow the process understanding. In contrast, the overall process technology is readily discernible during the transfer/scale down runs, due to the simplicity of the process implementation. In addition, scale-down runs generate in-process assay samples for the quality control analysts to test and practice with the transferred assay. These runs also enable the production personnel to anticipate potential scale issues and provide insight into the relative importance of the process parameters and controls. In implementing this strategy in technology transfer, the process should be implemented with conditions that reflect large-scale limitations. If properly designed, they provide valuable training relevant and applicable during large-scale production. These runs are also useful in comparing an existing process to a modified process with respect to controls, assays, etc. They also serve to generate material to perform preliminary product comparability studies.
Implement the Production Requirements Plan
Document preparation, raw material procurement, and assay transfer are the main categories of activities in preparing for a production campaign. Batch production records, which comprise the most critical piece of the "product," are written by production personnel primarily using documents provided by the client and through constant communication with other team members. Precious time is lost in collecting and compiling information. DPFD can be an invaluable tool for writing the document as it clearly describes the process in significant detail. For example, if the equipment identification number is needed, it can be readily accessed by viewing the custom properties of the icon, rather than searching through databases and multiple documents. The DPFD can also be an easier template to discuss process details with client and team members due to its visual interface.
This phase also constitutes the core of the tech transfer process, and effective communication is of utmost importance. The client, the team members and the support staff need to know what is to be done when, and where each activity fits in the overall scheme of the project. Communication skills of the team and that of the project manager become extremely crucial at this stage. Project Central® (the Microsoft Project server) is a new and effective tool for enhancing communication between the team members. It provides an interface for task assignment and tracking. Team members can view the tasks assigned to them and enter the time they spent on each task on a daily basis. The project status can thus be updated instantly and is available for all the team members to view. This provides valuable feedback to the entire team.
In parallel, as documents are created, materials are purchased and assays are qualified, the DPFD can be updated to reflect the status of each of these, which can be summarized instantly to provide a status report the entire team.
Dynamic Process Flow Diagram for buffer manufacture
Training for Project Staff
Successful execution of the production requirements plan only sets the stage for the production to begin. Actual production operations cannot be initiated until the personnel involved in the project are well versed with the process/project and are completely trained in their specific area. Contractors and clients realize that training is an essential and integral part of any quality operation. While the ultimate goal of training is to enable production personnel to follow and execute the documents, additional tools are needed to facilitate training. DPFD serves as an excellent training tool, as it captures the details of the entire process and is available very early for staff training. DPFDs are relevant to the entire project staff, as they see how each of the activities is occurring and why and where these activities interface with others'.
|An instant report of Supplies generated through reporting tool.|
It is also essential to train individuals on process and equipment logistics. Floor plans with equipment configurations for each of the unit operations can be created in Visio and presented to the production personnel.
As mentioned earlier, process transfer runs provide hands-on training for the production and QC personnel. As these runs are jointly performed by the process development/tech transfer personnel, they are able to provide troubleshooting assistance during production runs, if necessary.
Engineering runs are performed at scale to identify and resolve process/equipment issues. It has become an accepted practice to include engineering runs as part of contract manufacturing projects, in spite of the Resources they consume. It has become clear to the clients and the CMOs that a successful engineering run guarantees quality for the subsequent cGMP runs. During engineering runs, reviewed draft cGMP documentation is used. Modifications are made as necessary, with the goal of making them permanent in the Master Production Record. Engineering runs should also serve as invaluablse tools for hands-on training. Adequate time should be allowed between the engineering runs and cGMP Production Runs for modification of the Master Production Record and for re-training as necessary. If the DPFD is updated with the information learned from these runs, raw material needs can be readily re-assessed and procurement plan can be modified, assuring adequate supply for the production campaign.
Troubleshooting of process should be done during engineering runs, and a minimum of one problem-free engineering run should have been done before initiating the cGMP production campaign.
Does Tech Transfer Ever End?
Completion of a few consistent cGMP production runs is the only indicator of the success of a tech transfer exercise and hence only then can tech transfer be considered complete. One cannot overemphasize the fact that a successful campaign requires concerted effort from all team members.
Ideally, a product will be produced by the same CMO from Phase I through to Phase III and commercial supply, taking advantage of the knowledge base and expertise gained by the CMO. However, it is not uncommon for clients to decide to manufacture in-house for later phase/commercial supply. In such cases, CMOs will have to perform tech transfer back to the client, following the same strategies outlined above. Updated DPFDs can be used to transfer the process information to the client team, including their production personnel. Therefore, a project may begin and end with Technology Transfer, requiring the team to be constantly aware of the progress of the project all the way through.
Contract manufacturing of bio/pharmaceuticals has be-come accepted as one of the primary routes of product development as companies are focusing more on discovering products. Technology transfer therefore will be one of the deciding factors in determining the fit between the client and the CMO, requiring both parties to learn to do it better. While we have introduced some of the tools that could be used to enhance the efficiency and overcome the challenges, there is clearly a need for "a better mousetrap." Software-based tools will constitute one of the major areas for such improvement, as the biotech industry has tremendous opportunities to utilize new software technologies. The most important requirement, however, is a partnership between the client and the CMO that is built on trust.