BFS PROCESS CHARACTERIZATION AND VALIDATION
A biological manufacturing validation program encompasses equipment qualification, cleaning validation, and process validation.
The BFS equipment suppliers and manufacturers usually have well-established practices for performing equipment qualification
and cleaning validation. Process validation, however, could be a challenge for biological manufacturing using BFS technology.
The goal of process validation is to provide a high degree of assurance that the specific manufacturing process will consistently
produce product meeting predetermined acceptance criteria. Modern-day process validation programs consist of process characterization
studies and full-scale qualification lots produced under GMP conditions. Process characterization can be performed on each
unit operation to evaluate and characterize an acceptable range of operating conditions that yields acceptable product quality
and process performance. A quality-by-design (QbD) approach, which systematically uses risk assessments and multivariate characterization
studies, is the current state of the art. Process characterization may be carried out at different scales, and it may also
include engineering runs to mimic the overall process flow. Based on the outcome of process characterization, full scale GMP
batches are manufactured under normal settings. Both physical attributes (such as ampul appearance, integrity, fill volume,
and wall thickness) and chemical attributes of the product are checked to ensure that the process performs as expected.
It is important to recognize the uniqueness of the BFS process when applying the above process characterization and process-validation
approach. The BFS machine is a custom-built machine. The equipment setup and operation often involves both automation control
and manual adjustments. The operator experience or "know how" generally is very important to the proper operation of the BFS
equipment. Such operator-dependent performance, to a certain extent, is in contrast to the QbD paradigm of pharmaceutical
manufacturing, where critical process parameters (CPPs) are identified, understood, controlled, and monitored to achieve a
robust manufacturing process. The large number of controllable and uncontrollable parameters in the BFS process makes process
characterization and process validation much more challenging than conventional biological filling processes. For instance,
the filling speed for a peristaltic or rotary piston pump is the typical process parameter that can be evaluated during stand-alone
process-characterization studies. The filling speed, however, for a BFS process is mostly fixed, due to constraints from synchronized
movement of the extruder, mold, filling, and seal operations. Only minor adjustments can be made to the duration of each of
the BFS steps (extruding, molding, and filling), and such adjustment may be necessary to achieve optimum product appearance.
Another example of manually adjusted parameters is the plastic-resin weight. The resin weight determines how much plastic
is extruded to form the container and directly correlates with the container wall thickness. Too much resin may result in
containers with "bulky" appearance or problems with deflash while too little resin may cause issues for container integrity
or ampoule leakage. The appropriate amount (or range) of resin is typically determined from equipment qualification. It can
only be manually adjusted through a few mechanical parts at the beginning of each product run. Therefore, the process and
product development for BFS process needs to balance an empirical approach and a systematic approach. The biological manufacturer
needs to collaborate closely with the BFS equipment supplier or contract manufacturer to design a robust program for process
characterization and validation.
Figure 4 provides an example of the potential roadmap for process characterization and process validation. Risk assessments
are highly recommended for each unit operation as well as for each of the steps from the BFS operation in order to identify
potential failure modes from equipment and mechanics, as well as product-impact aspects. The output from the risk assessments
would be a list of process parameters that could affect the overall process or product quality. Further development and characterization
studies should be designed for these parameters either as stand-alone studies or overall engineering runs. CPPs are selected
based on the outcome of process characterization. Finally, full-scale qualification lots should be produced (typically at
target settings of the process parameters) to demonstrate the validated state of the end-to-end process.
Figure 4: Process flow for blow–fill–seal (BFS) process characterization and validation (CPP is critical process parameter;
PC is process characterization).