Process Development: Maximizing Process Data from Development to Manufacturing - - BioPharm International


Process Development: Maximizing Process Data from Development to Manufacturing

BioPharm International
Volume 20, Issue 7


Figure 1
It was apparent early in the project that consistent, standard terminology for representing bioprocesses is essential in order to create a data model with broad application. The general model for batch manufacturing defined by the Instrumentation, Systems, and Automation Society—the ISA-88 Standard for Batch Control—seemed a good starting point, given its widespread use for control systems and automation.4,5 Two aspects of ISA-88 are especially useful for defining a bioprocess model: a separation of process requirements from equipment capability, and a modular design approach. The concept of defining a process in dimensionless terms is inherent to scale up and facility fit assessments, and the practice of defining bioprocesses as a sequence of unit operations is essentially a modular design. Because ISA-88 is a standard for batch control, some simplifications were made to apply the standard to a knowledge-management model.

Figure 2
The focus of the knowledge-management model is the general recipe—the processing sequence required to produce a given product defined in dimensionless terms. There is one general recipe per product, regardless of scale. When the general recipe is carried out for a specific batch size, the resulting process sequence is the master recipe, and the equipment required to produce the product is defined in the physical model. The process of mapping a general recipe to a particular set of equipment to create a master recipe takes place through the use of transform components—a combination of equipment-sizing calculations and descriptions of process requirements and constraints. From the perspective of a biopharmaceutical company, the key activities are the creation of a general recipe during process development, and the transformation of a general recipe to a master recipe during technology transfer. This is summarized in Figure 1; Figure 2 illustrates how the ISA-88 model maps to the typical biopharmaceutical product development cycle.


A general recipe can be seen as the final result of a series of development studies: a checklist for ensuring that sufficient information has been specified to enable an independent organization to manufacture the product; or a process model to evaluate the manufacturing requirements for a proposed new product; or any combination of these. Ideally, the information contained within the general recipe provides sufficient guidance for the operations staff to generate manufacturing procedures and operate the process at any scale. In reality, process scheduling and performance is constrained by facility, resource, and equipment availability. Furthermore, the difference in requirements for non-GMP (good manufacturing practices) and cGMP (current good manufacturing practices) manufacture can have a significant impact on timing and resource usage. For this reason, supporting information about the criticality of parameter ranges, particularly hold time and temperature for process intermediates, is vitally important for troubleshooting during the technology transfer phase and must be incorporated into the data model. One challenge of defining bioprocesses in dimensionless terms is the wide range of unit operations and the requirements for in-process monitoring and control. The approach taken for the knowledge-management model is to define a library of standard process actions to represent basic processing steps, such as "heat," "agitate," "pressurize," etc. and the associated parameters. These defined process actions can then serve as building blocks to be assembled in different sequences to generate a general recipe, with control points clearly identified.

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