Overview: Process Validation

According to the definition published in the FDA Guideline on General Principles of Process Validation, 1987, validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes (FDA, 1987). 

Process validation is also defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process validation involves a series of activities taking place over the lifecycle of the product and process.

Simply stated, process validation is a method of proving that a process is right and discovering if it is wrong. Process validation is lifecycle concept rather than a single event. Validation of the process begins during process design and development and extends to process testing intended to provide confidence of process effectiveness to allow commercial product distribution. Once confidence for commercial distribution is achieved, the monitoring of the process should be continued to confirm a state of process control.

Validation of the Aseptic Process

Aseptic processing is designed to protect sterile product from microbiological contamination by eliminating or mitigating the risk of contamination. This is in contrast to terminal sterilization processes, which are designed to eliminate the contamination, which, may be present in the product.

Validation and the Assurance of Product Quality

“Manufacturers should be able to detect the presence of process variation, determine the degree of variation, understand the impact of variation on process and product, and control variation in a manner commensurate with the risk it represents to the process and product.” (CDER, 2008) A validation program succeeds depending on the information and data from thea process to product development. This knowledge and understanding is the basis for establishing an approach to control the entire manufacturing process.

Risk Management

Processes and process steps which present a risk to product quality and patient safety are of concern. Risk is the anticipation of harm. It is the combination of a hazard present and the likelihood that the hazard will occur to an extent that it will result in the harm. Process failure is a hazard that can result in harm to product quality or patient safety. Detection of the failure may prevent the harm from occurring. It is the harm that must be avoided. The harm may be an adverse effect on the patient, as would be the case with infection or it could be an unwanted effect on the process as would be the case with a process failure. Avoiding harm is the objective of risk management. Risk management is a process by which one recognizes sources of risk and take steps to mitigate, reduce, or eliminate the chance of harm. In the context of aseptic process validation it is important to recognize the riskier process steps and put the correct level of effort into assuring that failures do not occur.

The first step is to determine the potential harm to product quality and to patients by an unwanted event or hazard resulting from the failure of the aseptic manufacturing process.  The next step is to determine which process activities, events, and conditions affect product quality and patient safety. If possible, the risk of failure or contamination should be mitigated by process change. Process change is not always possible and to a practical level, all risk cannot be eliminated, therefore these steps and conditions should be addressed in the validation approach.

Risk assessments can be used to design effective process control test and validation studies including determining the most challenging study conditions and line/component configurations, set reasonable study durations and sample levels, and provide information needed to determine when and to what extent additional runs are necessary.

The Validation Program

The validation program is designed to provide assurance that the variation in the process is controlled to provide assurance that the variation in the process is controlled to the point where product quality is not adversely effected.


Validation efforts may be time-consuming and resource-laden and therefore need careful planning and forethought. The validation master plan (VMP) is a high level, living document which describes the approach to the validation of a site, product, or operation. The objective of VMP is to provide a basis of understanding for approach to personnel responsible for planning, execution, documentation, operation, management, quality, and reporting of validation effort and the process being validated. It should provide information on scope, objective, resources, responsibilities, materials needed, schedule, approach, methodology, documentation format, acceptance criteria rationale, and risk assessment of process. The VMP provides an opportunity to think through the program. It is an opportunity to assess relative risk of process, to determine and prioritize those elements which will be qualified and validated, to design experiments or tests with acceptance criteria to achieve qualification and validation objective, and to understand relationship of process step to critical product attribute to determine impact and resolution of deviations. The validation project plan (VPP) is similar to the VMP, but more focused on a single project. Validation protocols provide instruction on the execution of the study, including test function and acceptance criteria. Validation reports present and summarize the results of the studies.

Design Control

A good design is essential for effective product manufacture. The design phase of any project is the time when the requirements of the user are translated into a workable process and operation. Information developed and articulated during this phase is important to the validation effort. This information will form the basis of determining the approach, tests, and acceptance criteria required to qualify the facility and validate the process.


The process, equipment, facility, utilities, and instrumentation must be compliant with applicable regulatory requirements and standards, and should, wherever possible, be aligned with current regulatory guidance and expectations. These aspects often include materials and elements of construction which may result in adulteration or contamination of the product; such as cleanability, reaction to contacting materials, shedding, critical utilities, environment and personnel flow.


Good engineering practices should be employed in the design of the facility, equipment and process. Special attention should be paid to design-related documentation, especially documentation which will be helpful or needed to support later qualification and validation efforts.

Expected results

The design should result in a properly installed and operated process which will work. Each user requirement should be reflected in a specification and the specifications should be included in the design.


The design should be adequate to maintain process performance given a normal level of maintenance and repair. Variability of performance results should be understood, minimized and controlled. Where applicable, redundancy may be placed into the design to overcome unanticipated design flaws, defects, or consequences.  Designs should not be on the edge of capability of capacity. Normal system wear and tear may result in performance falling out of acceptable ranges.


The ability to validate or qualify the system. This is a way to confirm or test the system performance. There should be sampling ports, valves, instrumentation, and access points to facilitate testing and sampling.

Equipment Qualification

Product quality is a matter of process control. Consider process control as the theory and validation as the test or proof of the theory, Validation of the process begins with process understanding. Specifically, understanding the process steps and variables which, if they fail, can adversely affect the quality of the product. It is important to understand the data which can support the critical manufacturing steps, and the process, and their effect on product, the relationship between equipment, systems, instrumentation, and facility aspects which have an impact on product quality and performance.

The qualification of equipment, systems, and facility involves confirmation that the items have been installed and maintained to specification, operate in a manner meeting process needs, and that their design and proper utilization will result in consistent outcome. Items should be designed and installed using good engineering practices, with results and changes notes and well documented. Qualified items should be maintained in a state similar to that observed or documented during qualification.