The recent revisions of the GFSI (Global Food Safety Initiative) standards and the FDA rulings to implement the Food Safety Modernization Act have increased the requirements for controlled environments to prevent contamination of high risk foods and high care areas. An aseptic cleanroom is a very controlled environment and is sometimes used in the food industry especially in aseptic filling of liquids. You will want to consult with several cleanroom design/build construction companies to get their proposals for building an aseptic cleanroom to your specifications as well as the ISO 14644 and IEST industry standards. The recent revisions to the standards also require validation and verification of the manufacturing processes for high risk foods in high risk areas.
What is validation?
Validation in the manufacturing world is the establishment of documented evidence. The data derived from rigorous testing, which results in a high degree of assurance that a specific process or system will consistently meet a predetermined specification or set of quality attributes, is the documented evidence required for validation. The validated process creates a validated product.
Why validate?
Similar to what the FDA has mandated in the pharmaceutical, bio-pharmaceutical, and medical device industries, the food manufacturing industries are being required to validate the manufacturing processes of high risk foods to ensure that all of the systems have a consistent high level of assurance to produce a product that consistently meets its pre-designed specifications. This gives a company a control system that is consistent and reproducible. Further, a validated process is credible and stable, because the acceptance criteria have already been specified in the qualification stages of validation.
If the specifications of the system, how it is designed, and how it is to operate are known, then it becomes possible to maximize the performance of that system. If validation is performed properly and with the right objectives, it can be a value-added process for the company.
Who is responsible for validation?
The FDA has stated that the facility using the system is totally responsible for validating the system. The site management team may either write their own protocols and perform their own testing, or they may contract with qualified outside validation firms to perform these services for them. If an outside firm is contracted to perform these services, the facility using that system is still responsible for assigning personnel to review and approve the protocols. Further, the facility is still responsible for executing the test procedures and the validation processes while assuring the protocols were designed to validate what is actually performed at their facility, under their control. Employees who perform the validation have ownership of the equipment and the process.
What does validation involve?
Validation is a multi-disciplined process consisting of the installation qualification, operation qualification, performance qualification, and change control. The entire process is mapped in the Master Plan.
The Master Plan
The project, or the overview of the validation process, is the Master Plan for the validation process.
Once there is an overview, then the validation protocol is written. The validation protocol consists of the design validation, a specific set of test procedures and their acceptance criteria for each of the systems being validated, and for the specifications that are required over the whole project. Once the validation Master Plan has been prepared, and during the preparation of the validation protocol, an assignment of responsible parties is determined.
• The installation qualification is defined. These are specifications that must be achieved during the installation phase of the project.
• The operation qualification is defined. These are all the operation specifications that must be met in order to assure that everything is going to operate as planned.
• The performance qualification specifications are prepared. This is taking all the information derived from the installation qualification and operation qualification and assuring that all the systems consistently perform as specified.
• Change control is defined. These are the steps to be taken if any changes are required during the validation process.
In all of these phases, SOPs are prepared and serve as the blueprint to perform each of the qualifications. These SOPs are contained in each of the phase method sections. A change control process is used, if any part of these results fail to meet the required specifications, to make a change to either the specification or the system. The change control is also outlined in the SOP in the corrective action section.
Work the validation Master Plan!
There are several components of the validation Master Plan, and it is imperative that the Master Plan be written before executing the validation process. Otherwise, the validation can be partially completed, and bits of information that are important can be lost. A validation Master Plan consists of all the steps involved in the entire life cycle of the validation. It will also designate responsibility and authority and who is authorized to approve changes in the process of validating the cleanroom. It will define the project purpose, scope, and definitions so that all the individuals working on the validation team are proceeding with the same directions, talking about the same pieces of equipment, and working on the same process.
Also defined in the Master Plan are specifications that are to be distributed to vendors and the documentation required to prove the systems and equipment meet the end-use specified requirements. The SOPs, in their entirety, become part of the Master Plan. These SOPs may become a separate volume that will be used on a continuing basis after the validation has been completed to prevent deviations from the validated program.
Within the Master Plan protocol is the full life cycle including schedules, deliverables, due dates, and responsibility and authority designations. A vendor audit protocol should be part of the validation process in the design specification portion of the Master Plan. The SOPs should be very specific to the system and equipment being used because they will become the method of determining how the system should be monitored once it is in place. The SOPs should be written clearly and concisely so they can be understood by everyone involved in validating the system.
Vendors are required to provide a complete documentation package including certificates of conformance on any of the specifications that are required. Prior to the start of specific validation testing, the necessary calibrations should be performed to NIST traceable standards. The purpose, scope, and function of the systems or equipment should be written so that all those individuals executing the validation project can understand the whole process flow, a detailed description of the system and how it functions, and where they fit into the scheme of the process. Flow diagrams and specifications, when documented, are very good ways of looking at the entire process and product flow. The validation protocol should outline each of the different steps used in the validation process. This will clarify that as one part of the process is completed and the next is begun, a different benchmark becomes the target.
Developing a validation protocol
There are different types of validation. The most frequently used is called a prospective validation. It is a validation that is planned and initiated at the very beginning of the implementation of any new instrumentation, equipment, process, or system. It is the easiest type of validation to perform because there is total control of the validation process from the beginning. It is started well before the system being installed is ordered.
The first step is to determine the scope of the validation, i.e. machinery versus systems. This includes evaluating the vendors and their capabilities to meet all the requirements within the scope of the validation, including supporting systems such as HVAC systems, electrical systems, purified water systems, etc. The manufacturer of each of these components is responsible for providing documentation regarding a particular system and its compatibility and its suitability for its intended use. The manufacturer is also responsible for any quality testing and should provide installation instructions, operating parameters, and technical support. This should be specified as part of the parameters in the purchase agreement with the manufacturer. The documentation package is the verification of conformance that is requested from the manufacturer.
After documentation is received from vendors of equipment and for systems installed by contractors, a facility develops specific SOPs for the operation of those systems. The manufacturer should provide adequate training for personnel to operate the system, including preventive and corrective maintenance. The facility is responsible for selecting the appropriate personnel and assigning specific responsibilities to each member of the validation team. These members probably have been designated in the writing of the validation protocol and are given necessary and appropriate responsibilities and authority. When the written validation protocol and test procedures are developed and approved, then the actual testing is performed as outlined in the protocol. It is performed as stipulated in the protocols, with each step being fully documented. All results are verified by a second-party to assure that (a) the test results are correct and within the specifications, and (b) that the test results are what was expected during this validation process.
Test procedures
These tests must show not only the responses under ideal conditions, but simulated worst case scenarios. Ideal operating conditions should be defined and then adverse conditions addressed in a disaster prevention/response/recovery plan in case of a partial or total failure of the process or system. Should there be a process or system failure, this plan defines the procedures to bring the process or system back in line and to assure it operates within the previously required specifications.
Once these test procedures are written and the specifications defined, alert and action parameters are established to set the limits of the system’s capabilities. This will assure that when the process deviates from normal operating ranges and trends towards upper or lower limits, the operator can take corrective action.
Training responsibility and authority
Prior to the execution of the validation protocol, all operators should be trained in procedures for operating the system, including specific goals and objectives. The parties responsible for validation are identified and recorded in the validation Master Plan. The qualifications of the personnel that are to perform the validation process are defined. Documentation that the selected personnel meet these qualifications, completed appropriate training, duration of training, and that the training was effective are retained in training files.
The core of the validation Master Plan is the execution of the installation, operation, and performance qualification.
Installation qualification (IQ)
The installation qualification (IQ) documents that all equipment, control loops, and devices are installed and functioning as specified. This includes any computerized hardware and software that control the installed equipment. The steps of IQ include ensuring that the equipment complies with the design specifications and a certificate of conformance accompanies the equipment or components of the systems.
The IQ documentation consists of a series of verification checklists and forms, P & ID drawings, electrical schematics, and equipment manuals.
An audit of the installed system is performed to confirm that the system installed meets the intended specifications.
Operation qualification (OQ)
The operation qualification (OQ) documents that each piece of equipment and its control system used in the process is performing within specified parameters. The OQ starts after the installed system has been thoroughly audited and deemed operational. Completion of the OQ ensures that all the installed equipment and processes operate as designed. It proves that all the alert and action limits and system tracking mechanisms that have been designed into the system by the manufacturer are in place and functioning as specified.
Performance qualification (PQ)
The performance qualification (PQ) starts as the system begins commercial operation. The PQ documents that the entire system can operate consistently and will produce a product meeting the predetermined specifications of the facility. Even though it has been established that all components of the system have been installed according to the installation specifications, and that they operate according to the specifications of the manufacturers, it is still uncertain that the system is robust and will function consistently over time.
Performance qualification puts the entire cycle of the process together to validate that it produces consistently according to specifications. The PQ also ensures that the equipment and personnel are adequately monitoring, sampling, and testing the product and process.
Additionally, performance qualification contains the disaster prevention/response/recovery plan. It ensures that mechanisms are established to trigger an action when an alert limit has been reached. Also, PQ documents action steps taken in the case of a facility failure or shutdown due to mechanisms beyond the control of the system, such as a tornado, hurricane, or earthquake.
Change control
During the validation process, changes may be required. Change control is the procedure to provide documented evidence of any change that has been performed. Once it is determined that a change is required, the change is documented and implemented. After implementation of the change, the changed process must be revalidated. Revalidation starts at the beginning and continues through the entire validation life cycle of the process, reviewing the effects of the change on the previously documented IQ, OQ, and PQ results.
The summary report
Once all the documentation is accumulated from the installation qualification, operation qualification, and performance qualification, a summary report is prepared. This completes the validation Master Plan. It consists of a summation of the life cycle that has been outlined in the validation protocol, documentation of the testing, and verification of the test data. Once data is compiled and verified, statistical analysis is performed on the data and included in the summary report.
Conclusion
The concluded validation process is a documented and verified record of the installation, operation, and performance of a manufacturing system, which was defined in the validation Master Plan. The execution of the validation process defines the normal operating functions, provides documented procedures to evaluate the system, and allows preventive and corrective actions to be executed in worst case scenarios. The facility staff is able to operate, monitor, and evaluate the validated system. The summary report becomes the reference that defines the operational and performance characteristics of the system that can be referred to when questions arise or changes to the system are proposed.
Jan Eudy is a technical resource for ESD, cleanroom, food, and healthcare garments and products. At Cintas, she directs the quality system and ISO registration for cleanrooms and supports validation and sterile services. She is President Emeritus and Fellow, Institute of Environmental Sciences and Technology.
This article appeared in the May 2013 issue of Controlled Environments.
