A Risk-Based Approach to Transferring a Mature Biopharmaceutical Process - The authors present risk-evaluation and mitigation strategies for transfer of the manufacturing process of a recombinant gly

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A Risk-Based Approach to Transferring a Mature Biopharmaceutical Process
The authors present risk-evaluation and mitigation strategies for transfer of the manufacturing process of a recombinant glycoprotein.


BioPharm International
Volume 25, Issue 2, pp. 41-49

Since 1986, Genentech has achieved 25 successful transfers of commercial drug substance (DS) processes to both internal manufacturing sites and external manufacturing facilities such as Genentech's partners and contract manufacturing facilities. These 25 transfers include both recombinant protein and monoclonal antibody products from E. coli and Chinese Hamster ovary (CHO) host cells. More than 80% of these transfers have occurred since 2000 (1). This 26th article in the Elements of Biopharmaceutical Production series presents an overview of the various challenges that are encountered during technology transfer of biotech processes along with potential solutions that can address theses challenges. The artlcle describes the process-transfer strategy, which includes three key steps: facility fit analysis, risk-mitigation plan preparation, and risk-mitigation plan execution.

The first step, facility fit analysis, or gap analysis, is a thorough process walk-through at the receiving site based on process-requirements documents. This exercise involves a detailed step-by-step analysis of how the entire manufacturing process would be performed at the receiving site and its goal is to identify any potential process, facility, or procedure changes that may be necessary to fit the process into the receiving site facility. The output of this exercise guides the scope of the process-transfer project. Therefore, the exercise must be detailed and cover the entire manufacturing process as well as required ancillary equipment, analytical instruments, small-scale laboratory capabilities, and all relevant operational practices at the receiving site. The output of the facility fit analysis should be a comprehensive list of possible gaps and should be jointly developed by both the sending and receiving sites.


Table I: Risk category.
The second step is to analyze each gap, assess its potential risk to the process and product, and formulate a risk mitigation plan using the quality risk management concept. Each gap presents a potential risk to the process, product, or both. The risk is classified based on its potential effect (2). The risk classification criteria are shown in Table I. Risk assessment relies on process and product knowledge obtained throughout the lifecycle of the product. The rationale for the risk classification of each gap must be scientifically sound.

For risks that are considered medium or high, a risk-mitigation strategy is assembled. In this case study, four risk examples and their risk-mitigation strategies are discussed in detail. In general, the risk-mitigation effort is proportional to the risk classification (i.e. high risks require a larger effort to mitigate and control than do low risks). Ideally, the risk-mitigation effort results in the reduction of a risk. In cases where the risk effect can not be reduced, additional risk-control strategies should be put in place. The risk-assessment, risk-mitigation, and risk-control strategies are documented in the risk-mitigation plan. This document is revised as additional information becomes available.

The third step is to execute the risk-mitigation plan, which includes four sets of activities: transfer and verification of a scale-down model (SDM), evaluation of potential process changes using the SDM, execution of full-scale engineering runs, and evaluation of results from engineering runs. Establishing a SDM at the receiving site enables the receiving site to prospectively evaluate potential process changes that may be necessary for facility fit reasons, and to troubleshoot performance issues during and after the completion of a transfer. Process changes that are evaluated using the SDM should be independent of scale and of the equipment involved. Two examples of this type of change are given (see examples 2 and 4). For changes that are scale- or equipment-dependent, it is typically necessary to conduct full-scale evaluations (i.e., engineering runs) before the initiation of the qualification campaign. Examples 1 and 3 describe this type of situation. The execution of the engineering runs serves two purposes. First, it provides an opportunity to evaluate the full-scale process performance at the receiving site and to verify the findings of the small-scale studies for potential process changes. Second, it is used to assess the readiness of the receiving site for the qualification campaign to ensure a high degree of confidence that the qualification campaign will be successfully executed.

The predefined evaluation criteria for the engineering runs are developed jointly by the sending and receiving sites. Genentech uses two-tiered success criteria for this evaluation. The primary success criteria are the same as the acceptance criteria for process and product comparability. The secondary success criteria include criteria for secondary process-performance indicators (e.g., cell culture metabolic profiles), equipment-performance criteria (e.g., bioreactor temperature, agitation, pressure, dissolved oxygen, and pH control performances), and performance criteria for full-scale media and buffer solutions preparation. These secondary success criteria serve to identify any subtle performance differences between the sending and receiving sites. If the engineering runs fail any of the primary success criteria, a root-cause analysis must be performed and a path forward must be identified before the initiation of the qualification campaign.


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