FDA's Draft Guidance for Process Validation: Can It Be Applied Universally? 3

Critical process utilities. These systems are largely mechanical and include multiple components assembled to deliver an essential process utility throughout the facility. The equipment components of these systems are easily addressed in a manner essentially identical to that defined for production equipment. The major difference is that the utility equipment requires substantially less development to place it into operational service. The processes to prepare the liquids or gases are largely unchanging, and thus the concepts such as design of experiments (DOE) and multivariate analysis are of limited value. The process utility is performance qualified using a sampling plan that may have statistical elements, though they are not necessary. These systems are customarily subjected to routine monitoring on a frequent basis; many water systems are monitored daily. These systems include stages of initial and ongoing performance qualification, but the attributes of greatest concern, microbial identity and population, are poor fits with most statistical tools. Thus the guidance is not readily applicable to these systems.
Classified and controlled environments. Similar in some ways to the utility systems described above, these systems provide a condition rather than a specific material at a well-defined state. The equipment-qualification side of these systems fits the guidance model reasonably well. Because the systems perform in essentially the same manner at all locations and for nearly all applications, development in the sense required in the guidance does not apply at all. A design phase certainly exists, but its elements are not at all like those related to formulation or synthesis processes.
The simplest of these systems (e.g., cold boxes, incubators, and similar items) require little performance qualification, and the use of statistics is hardly warranted. At the other extreme, aseptic processing areas, the evaluation of successful performance is subject to numerous external influences, so these systems can't be considered performance qualified at all, at least not in an independent manner. Acceptable results in an aseptic processing environment result more from diligence in manual routine decontamination, housekeeping practices, operator gowning, and the like. It would be inappropriate to suggest that once the environment is properly qualified, the activities performed inside it would always be successful. Success simply can't be guaranteed, at least not in any manned environment. The application of the guidance to classified environments without adjustment is not feasible.
Computerized systems. Computerized systems are well established in pharmaceutical manufacturing. The validation of these systems within the GMP environment was outlined by a Pharmaceutical Manufacturers Association committee many years ago (9). The original document described a life-cycle approach that was openly adapted from the software-development life cycle. The similarity between the computerized system and draft process validation guidance life cycles is primarily in their cradle-to-grave treatment of the system being validated. The similarity ends there. The methods for software and hardware development for computerized systems are substantially different from those recommended for process validation. The software and hardware elements of computerized systems roughly parallel process methods and process equipment in the production environment. The equipment components have some degree of similarity, but software development bears little resemblance to the development of a pharmaceutical process on a small scale. The performance qualification of computerized systems in the pharmaceutical industry should be considered a background activity and has neither a requirement for repetitive confirmation nor a statistical component. The real proof of a computerized system in the pharmaceutical industry is in the end-product, be it a completed product, test result, or data field that resulted from the operation of the system. The draft guidance is an extremely poor fit for computerized systems because the testing and documentation required is so different from that associated with process and product situations.
In-process inspection of product attributes. The inspection of pharmaceutical products is an important part of the overall process for their preparation. The purpose of the inspection is to identify and remove nonconforming units before further processing or final release. Inspection processes are quite varied. They include:

• Inspection of filled parenteral containers for visible particulates
• Inspection of uncoated and coated tablets
• Lot-number and expiry-date inspection for printed materials.

The design and development of inspectional systems can be a hybrid of process development and equipment design. The use of DOE practices can be effective in establishing the inspection parameters for automated systems. When the inspection is performed by qualified personnel, a certain amount of that evaluation is possible, but because the operator's inherent diligence and visual acuity are perhaps of greater importance than the controllable inspection parameters, statistical inferences are less useful. Initial and ongoing qualification of these systems is reconfirmation of the optimized inspection parameters in commercial settings with real-world defects. The life-cycle model for process validation appears to fit inspectional systems reasonably well.