Originally Published IVD Technology January/February 2006
DIAGNOSTIC OUTSOURCING
A systematic approach to successful transfer of IVD manufacturing technology
Thomas Dzierozynski and John P. Karels
Early preparation and an adherence to sound organizational principles are essential components of a smooth transfer process.
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| The journey from test tube to marketplace has always been a challenge. A carefully devised technology transfer plan can help ease this transition. |
In the past, the transfer of IVD manufacturing processes from research and development (R&D) to engineering and production was more art than science. The technology transfer process was, in effect, a passing of the baton, with little or no planning or structure, and few requirements.
The actual transfer may have been based solely on the IVD product itself, with scant regard for the readiness of supporting aspects (e.g., analytical methods, stability, stability-indicating method, cleaning method, scalability, process parameters, etc.) or lessons learned in development. Neither did the transfer consider process or product characteristics, risk (safety, functionality, and reliability), receiving party capabilities, or the need for process changes or improvements. For the receiver of the technology, the art of the transfer lay in figuring out how to make the product with little or no data, expedited time schedules, and minimal guidance, while still meeting all regulatory expectations and requirements.
Today, for technology transfer to be successful, it must focus on business metrics in addition to quality and compliance. For example, paying too much attention to short-term business gains may result in long-term production and quality problems, and potential regulatory action. For IVD manufacturers to produce safe and effective products, the technology transfer process needs to be a forethought, not an afterthought, and must be integral to the life cycle of the IVD product. While the technical characteristics of the product and process should also be considered, their integration into the quality system and its components, and the management of risk, must not be overlooked.
This article examines how IVD manufacturers can ensure that the technology transfer process is performed both expeditiously and in compliance with FDA regulations. It describes a risk-based approach for determining the steps critical for product manufacturing and the actions necessary for ensuring that the processes are controlled. This approach applies to new design and development projects, as well as to products established before the design control provision of the quality system regulation.
Defining a Successful Technology Transfer
Every company strives to be successful. However, the way in which a company defines its success often depends on whose perspective is being considered. An R&D segment strives for functional and effective design, while an operations division typically demands low cost and high efficiency. Marketing looks for speed to market and market share, while a quality and regulatory group requires compliance.
The expectations of each group differ depending on a division’s needs and the product’s position in its life cycle. Ultimately, a successful technology transfer is based on the balance of each of these desires: cost, manufacturing capacity, equipment and facility capabilities, time frames, and regulatory requirements. Although simple in concept, this balance, as well as the fundamentals of defining requirements, managing risk, documenting results, and assuring communication among the groups, is often overlooked.
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| (Click on the image for a larger version) Figure 1. A model illustrating the relationship of individual tasks throughout the technology transfer. The actual process transfer takes up only a small part of the total project.1 |
Figure 1 depicts the relationship between the different technology transfer tasks. Each technology transfer is unique and should be viewed as such. Even so, there are a number of steps that manufacturers can take to validate or verify the journey of their particular products, thus ensuring consistent performance throughout the transfer process.
Planning for Technology Transfer
Careful planning is key to a successful transfer. Applying analytical design methodologies and design for six sigma, as well as meeting the regulatory requirements of design control, companies must anticipate design and development outcomes at the beginning of a project. Criteria determined during the planning process, and a thoughtful and consistent approach developed during the R&D phase, form a strong foundation for the transfer steps that follow.
As part of its planning, a company should include robust design-for-manufacturing steps, which look downstream at the required project scale and establish facilities, materials, and methods to fit this need. It is also important to apply lessons learned from other parallel scale-ups and to understand the issues involved with all restricted source materials.
During the early stages of IVD product development, specifications are often loosely defined and change as the design process evolves. To compensate, companies need to establish and maintain effective plans that describe or reference the design and development activities, assign outputs with measurable attributes, and define responsibilities, while meeting the design-control requirements.
In particular, it is important to assemble a cross-functional team that can knowledgeably represent the stakeholders. When each person’s accountability can be measured against a process, efficiency and compliance are enhanced. A company’s quality system provides management responsibility and the infrastructure for ensuring that everybody on the team is aware of the expectations and understands the consequences of their actions.
The Technology Transfer Plan
Once a manufacturer has defined and received funding for a development project, it should prepare a technology transfer strategy document. This document lists the high-level requirements for the transfer, as well as key assumptions and potential regulatory and business risks. Not all factors may be known at this early phase; even so, the strategy document provides the necessary framework for developing the technology transfer plan.
The document also provides background on the overall strategic approach to the transfer and obtains high-level management approval and commitment. The plan should include the following elements:
• A description of key design and functional aspects of the product.
• A description of the manufacturing process (with process-flow diagrams indicating verification and testing steps, and supporting risk management records).
• The roles and responsibilities of the sending party (in this case, R&D) and the receiving party (the manufacturing site or sites).
• A description of the manufacturing site or sites.
• An outline of the technology transfer strategy.
• Regulatory submission requirements.
• Documentation requirements.
• The technology transfer acceptance criteria, identifying the specific requirements necessary for a successful transfer.
• A technology transfer requirements checklist.
• A transfer schedule, broken down into detailed tasks with assigned resources (e.g., a Gantt chart).
Written approval of the plan should be obtained from the appropriate managers of both the sending and receiving entities. This will help ensure that the resources, budgets, and personnel needed to stay on schedule are provided.
For IVD products, the development of instruments, software, and reagents often takes place at different physical locations (sending sites) and may be transferred to more than one manufacturing plant (receiving site). This creates logistical challenges that must be addressed in the technology transfer plan. To provide adequate oversight and management, one person should be responsible for the overall transfer project. This person needs to have the authority to acquire necessary resources and to hold individuals accountable for meeting assigned objectives.
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(Click on the image for a full version of the table) |
Assembling a technology transfer requirements checklist before the start of commercial production is one way to keep pace with the transfer schedule and reduce the possibility of delay (see Table I). A comprehensive list of documentation should reflect the product design, risk management, and manufacturing processes. By assigning specific responsibilities and due dates for completing each line item in the list, companies can get a sense of the resources and time needed during the transfer phase.
Managing Manufacturing Process Risk
Product risk is identified and controlled at multiple points during the design and development process. Although determining manufacturing process risk may not be feasible until later in the development phase, managing potential problems as early as possible is crucial to a successful technology transfer.
A systematic risk assessment can identify verification, qualification, and validation requirements. In addition, it can help manufacturers determine the critical control points in an IVD manufacturing process and provide the foundation for evaluating and carrying out the transfer.
In assessing risk, companies should consider the following actions:
• Recruit a cross-functional team of experts. A broad team will apply the necessary experience, perspective, and rigor to the process. Typically, team expertise should include, but not be limited to, R&D, engineering, manufacturing, quality assurance, regulatory affairs, and customer service or field service.
• Obtain or create detailed process-flow diagrams. These flow diagrams help identify both process steps and existing controls, and should be maintained as controlled documents. The cross-functional team must verify the diagrams for accuracy and completeness.
• Apply comprehensive analysis. For complex IVD products, a fault tree analysis (top-down) approach should be used to identify the critical subprocesses. A failure modes and effects analysis (bottom-up) should then be used to further identify root causes and critical manufacturing steps.
• Use all available data. Sources of internal data include product development reports, product label claims, process or product failures during development, and stability data. Sources of external data include competitor products, field actions and medical device reports, and industry literature.
• Prepare a product data file. Building a permanent record of data to be reviewed can serve as a basis for evaluating both the effectiveness of the risk management as well as the impact of future process changes.
Freezing the Design
The design and development process is dynamic. Many times, new information uncovered during this phase leads to an important product enhancement or an improvement in the manufacturing process. The ability to make rapid changes is essential for producing a first-to-market advantage. To carry out a successful transfer, however, there must be a point at which the specifications are “frozen.”
This may prove especially challenging when using a phased-transfer approach, when certain aspects of the ongoing design and development process could affect those that have already been transferred. For example, if the process validation for reagent manufacturing has been completed at the receiving site but R&D wants to change the reagent formulation to increase test accuracy, this could drastically affect the transfer schedule if the reagent validation has to be repeated. Although this type of change could be characterized as a business decision, if all parties understand the point at which product design is frozen, then the transfer process will be more predictable.
DMR versus Approved Design Outputs
One of the last activities before releasing the process for commercial manufacturing should be a detailed verification that the finalized device master record (DMR) meets all approved design outputs. While the design controls that are exercised during the transfer process should be robust enough to assure that this is the case, a final verification can prevent a costly production or regulatory mistake after product launch.
A Successful Technology Transfer
A transfer can be deemed a success when the receiving site is able to routinely manufacture the product and meet all predetermined specifications. However, there are other indicators of a successful transfer, as well. One key is the toll the process has taken on the people involved. Every transfer project produces certain stresses, but a manufacturer must determine whether these were managed well. Did the transfer project burn people out to the degree that they will never participate in another technology transfer or will even leave the company? Or did it build a cohesive team and empower employees to take on new responsibilities? These questions have important implications for a company and its ability to learn and improve.
Post–Technology Transfer Review
A post–technology transfer review is useful for assessing the outcome of a transfer. The review should be conducted after the transfer process is complete and full commercial production has begun. The technology transfer plan should be reviewed to assess how closely the actual transfer met planned objectives, deliverables, schedule, and budget. Managers should solicit feedback from the transfer team members, stakeholders, and sponsors on the successes, unintended outcomes, and recommendations for improvement of the project. Personnel from both the sending and receiving parties should participate in this exercise.
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| Thomas Dzierozynski (left) is vice president and John P. Karels is senior consultant at Quintiles Consulting (Rockville, MD). The authors can be reached at thomas.dzierozynski@quintiles.com and john.karels@quintiles. com, respectively. | |
The outcome of the review should be documented in a technology transfer close-out report and made available to staff who will be involved in future transfer projects. Postproduction information should also be analyzed to determine any new risks and to see whether the initial risk-management plan is still valid.
Conclusion
The foundation for technology transfer should be laid early in the product development stage. Although defining transfer requirements at this time may be difficult, the fundamental benefit to the product development and transfer process is great. If, at the end of a technology transfer process, the receiving party and the sending party can demonstrate through clear documentation that requisite business needs and regulatory requirements have been satisfied, the technology transfer can be considered a success.
The benefits achieved through systemic technology transfer and industry-recognized risk-management tools are real, but a manufacturer must commit itself to realizing such success. The final goal of technology transfer should not be strict regulatory compliance but, rather, identified business benefits reducing development schedules, improving product quality, and, ultimately, delivering a technology to the market to advance public health.
Reference
1. ISPE Good Practice Guide: Technology Transfer (Tampa, FL: International Society for Pharmaceutical Engineering, 2003).
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