Prevalidation Study of a Form-Fill-Seal Packaging Machine
A case study illustrates what kind of tests to perform in a prevalidation study and how it contributes to the entire validation process.
by David R. Dills, corporate manager of quality engineering, Medtronic Xomed (Jacksonville, FL)
Medical device packagers need to qualify and validate the packaging sealing process because it's a good business practice and it makes logical sense. Furthermore, it is the only way to ensure that the machine will consistently produce packaging with an acceptable sterile barrier. A prevalidation study (PVS), which is used to finalize parameter settings and process documentation as well as to qualify packages, can provide valuable information. This article will attempt to demonstrate its value through studying the case of a form-fill-seal packaging machine.
The PVS is part of a six-step validation process, which includes the following steps: supplier qualification, factory acceptance tests, installation qualification (IQ), operational qualification (OQ), PVS, and performance qualification (PQ). The article is intended to emphasize the PVS as it relates to the equipment qualification and sealing process validation. Thus, the details of IQ, OQ, and PQ, such as protocol development and testing methodologies, will not be discussed.
FDA requires that the packaging process be validated. Remember FDA's doctrine in section 820.75 of 21 CFR Part 820 on process validation: "Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures."
Moreover, ISO 11067, "Packaging for Terminally Sterilized Medical Devices," covers the development and production of the package, laying out the fundamental requirements for selecting materials as well as developing and validating the processes that go into producing the final package. EN 868-1, "Packaging Materials and Systems for Medical Devices Which Are to Be Sterilized, Part 1: General Requirements and Test Methods," deals only with the selection and testing of materials that make up the package. It does not address process development or validation. However, there is some overlap between the two standards. For example, both require that manufacturers demonstrate and document the suitability of their packaging materials for the chosen sterilization process.
A packaging machine must be qualified and the sealing process validated before releasing product. What tests need to be performed? How should they be performed? How many tests are required? The following case study will attempt to answer these questions.
The qualification and validation of such a complex piece of equipment needs to start during the design phase, especially for the software aspect of the machine. That is easy to say, but it is difficult to validate a machine that you did not design yourself. To ensure that the machine software has been designed and tested in accordance with prescribed quality, validation, and regulatory requirements, the best approach is to purchase the machine from a company that has a software quality assurance system in place.
To be successful, a validation project needs to be correctly and strategically planned. Formulating and using a validation master plan should be one of the first tasks. A project team involving the various functional groups, including manufacturing engineering, quality engineering, and packaging engineering, is also essential to guarantee a successful outcome. As with any project, the use of a Gantt chart or other project-tracking tools for effective and efficient project management, scheduling tasks, and resources is highly recommended. Such tools help identify critical path items and tasks in order to ensure timely completion.
In order to select a machine supplier, it is helpful to evaluate more than just cost, conformance of the machine to specifications, and the technology used. An equipment supplier evaluation questionnaire provides an adequate assessment of the supplier's quality assurance program, and the supplier's answers or responses form the cornerstone for future on-site audits. They can also be used to evaluate the supplier's validation efforts and resources that are required to bring the equipment into a qualified and validated state. The questionnaire can address items such as security, company background and organization, functional description documents, software development procedures, change control, and disaster recovery/contingency planning.
THE PVS: A CASE STUDY
The basic principles for initiating and executing a PVS are:
- Establish that the process equipment has the capability of operating within required parameters.
- Demonstrate that controlling, monitoring, and measuring equipment and instrumentation are capable of operating within the specified parameters prescribed for the process equipment.
- Perform replicate cycles (runs) representing the required operational range of the equipment to demonstrate that the process has been operated within the prescribed parameters for the process and that the output or product consistently meets predetermined specifications for quality and function.
- Monitor the validated process during routine operation. As needed, requalify and recertify the equipment.
The form-fill-seal machine discussed in this study is capable of producing seven types of packages by index. In order to decrease testing and to reduce the cost of validation, a study should be performed to determine whether the seven cavities of one index were significantly different.
During the OQ phase, the process parameters were challenged to ensure that they would result in a product that met all defined requirements under all anticipated (i.e., worst-case) manufacturing conditions. A manufacturer can use statistically valid techniques such as screening or design of experiments to establish key process parameters, such as dwell, pressure, and temperature to optimize the sealing process.
Thirty indexes (210 packages) were produced, and all packages were tested using an ARO restrained burst test. The test should be done in accordance with a firm's corporate standard operating procedures (SOPs) and the package testing equipment manufacturer's recommendations. Then, an analysis of variance (ANOVA) was performed on the results of the ARO tests. If this study's results show no significant differences at a confidence level of 95%, then only cavities one, four, and seven need to be tested. This will reduce the testing costs by more than 50%.
As the materials and the techniques used to generate the packages were not different from the ones already used on similar packaging machines that the case study firm is currently using, the package tests did not include aging. The low setting (all process parameters set at their minimum acceptable operating values) and high setting (all process parameters set at their maximum acceptable operating values) used during these tests were determined during the OQ. Some manufacturers may prefer to set parameters during the PVS. The PVS is often approached and executed differently from company to company, so the one described here represents just one approach.
First, 480 package samples were produced at the low setting and 480 package samples at the high setting. Second, 120 package samples formed at each setting were sent for 2 x EtO sterilization, a hot/cold cycle, and International Safe Transit Association (ISTA) 2A testing. ISTA 2A testing simulates package shipping and transportation and consists of the following tests: vibration test, drop test, and static compression test. Third, 120 package samples formed at each setting were sent to 2 x gamma sterilization, a hot/cold cycle, and ISTA testing. Fourth, 120 package samples formed at each setting were sent to 1 x EtO sterilization, a hot/cold cycle, and ISTA testing.
Then the tests shown in Figure 1 were performed. All were done in accordance with corporate SOPs, using methods based on historical data and validated in-house. Remember, all test methods must be validated by the user as required, unless the firm is referencing a recognizable standard like an ASTM standard.
|Parameter Settings||Sterilzation Methods||Number of Tests per Cavity|
|Leak Test||Peel Test||Restrained Burst Test||Visual test|
|Post 2x EtO||30||30||30||90|
|Post 2x gamma||30||30||30||90|
|Post 1x gamma and 1x EtO||30||30||30||90|
|Post 2x EtO||30||30||30||90|
|Post 2x gamma||30||30||30||90|
|Post 1x gamma and 1x EtO||30||30||30||90|
Figure 1. Package testing performed during a prevalidation study of a form-fill-seal machine. Peel tests were performed on the four sides of the package (top, bottom, left, and right). Visual tests were performed on each of the test samples before destructive testing.
A statistical analysis was run on the test results, which involved normal distribution testing to determine average and standard deviations (±3 standard deviations).
If the distribution is normal, the following studies can be performed. If the average plus three standard deviations value is equal to the maximum acceptable value and if the average minus three standard deviations value is equal to the minimum acceptable value, this means that 99.7% of the packages produced will be acceptable. If the acceptance criterion is only a minimum (or maximum) value and if the average minus (or plus) three standard deviations value is equal to this minimum (or maximum) value, this means that 99.85% of the packages produced will be acceptable.
Therefore, setup, inspection, and process documentation, which were generated and developed during the OQ phase, could be finalized during the PVS before starting the PQ phase.
The test packages should be produced on fully validated manufacturing lines; however, in situations for which this is not possible, the packages must be produced on equipment that is fully representative of the final process. If neither the prototype nor the final process is used, the manufacturer assumes the burden of proof of equivalence. Package performance testing should be conducted under actual use or conditions that simulate actual use. Both shock and vibration testing of the final packaged product should be considered.
Package seals must demonstrate continuity and impermeability. Seal strength must be determined at the upper and lower control limits of the process as well as the preferred settings. All seals must demonstrate their suitability to the package materials, intended package requirements, and means of access. Physical test methods can be employed. Peelable seals must meet criteria concerning particulate generation, splitting, or tearing for aseptic presentation. Final package testing must be performed using the maximum sterilization exposure and tolerance level identified for the product.
In summary, the qualification of a form-fill-seal machine and validation of the sealing process requires careful planning, time, and effort on behalf of several parties close to the process. The six-step validation approach is a basic concept that indicates that you should qualify the supplier's software QA system before issuing the purchase order, especially if the packaging machine is controlled by software.
The PVS in this case study determined that operating parameters for the form-fill-seal process were established by objective evidence. The test objectives were satisfied, and the process performed subsequent to the tests was consistent and repeatable.
Package validation and equipment qualification should achieve complete process control and the corresponding confidence in consistently achieving the packaging requirements.