Sterilization processes. All parenteral products include several sterilization processes for the formulation, equipment, and supportive elements. Depending upon the particular sterilization process, the number of parameters to be evaluated can be substantial, and the DOE or multivariate experimental designs mentioned in the design stage of the guidance may be appropriate. Included in most sterilization-cycle development efforts are activities such as component or container mapping, load mapping, and confirmation of material quality and stability postexposure. These activities are well established at many firms in a formal manner, and the application of more scientific approaches would be beneficial where such knowledge is not well structured. The draft guidance can be applied to the initial and ongoing qualification phases, because it would largely align with the statistical approaches for evaluating products exposed to the sterilization process.
The difficulty in applying the guidance to sterilization stems from the biological destruction aspects of these processes. Although statistics are commonly used to calculate sterility assurance levels and the probability of a nonsterile unit, these values are focused on biological-indicator results and usually do not consider the bioburden to a significant extent. The bioburden resistance and population in the commercial-scale process are of critical importance, but development knowledge cannot be translated to a larger scale easily. Sterilizing filtration, which is widely used, represents an even greater challenge because information about the bioburden is essential, and little can be done from a design or development perspective to support it more fully in a commercial setting.
On a basic level, there are simply too many independent—and interrelated—variables in aseptic processing, and the most meaningful one of all lacks metrics of any type. Personnel are an integral part of virtually all current aseptic processing systems. Their effect on the most important aspect of all, sterility, is also the greatest, and creates the greatest opportunity for failure. Aseptic processing performed by human operators is devoid of any measurable variable that could be used to predict the outcome.
Another concern regarding the adaptation of the draft guidance to aseptic processing is perhaps even greater. In 2008, FDA proposed a change to the CGMP regulations that required aseptic processing to be validated. To many in industry, this expectation could not reasonably be fulfilled with the available tools. The author provided the following comment to FDA:
Aseptic-processing simulations cannot validate an aseptic process. The results obtained demonstrate the capability of the facility, equipment and operational controls to provide a minimal microbial contamination rate in a single event. They cannot be utilized to predict the outcome of a similar process performed at a different time, and thus cannot 'validate' the aseptic process. Successful aseptic processing incorporates a myriad of necessary controls; however these controls, alone or in concert, cannot be relied upon to support the absence of microbial contamination as is routinely accomplished in sterilization validation.
There is sufficient support within the CGMP regulations [implied in 211.113(b)] and guidance documents for aseptic processing (explicit in the 1994 submission guide and 1986–2004 aseptic processing guidance) to support the periodic execution of process simulations. Considering these as validation overstates their utility, and implying that firms having successfully passed a process simulation have attained a 'validated' condition is inappropriate. Sterilization and depyrogenation processes are validated such that the routine controls utilized with them are adequate to support the efficacy of the process. Aseptic processing, because it relies on controls of limited sensitivity, poor robustness, and a substantially greater involvement of personnel with their attendant variability, is inadequately supported by the currently available in-process controls. To consider it 'validated' overstates our imperfect ability to measure and control it. In addition, it could be interpreted as license to relax the controls that are necessary for its success. Aseptic processing is perhaps the most difficult of all processes to control in this industry; suggestions that it can be 'validated' imply a level of control not yet attainable. (11)