Medical Packaging Validation: Complying with the Quality System Regulation and ISO 11607

By identifying the optimum time frame for each key process variable, validation achieves process control and ensures that package requirements are met.

Denis G. Dyke

Packaging validation is a total process involving the identification and control of materials and processing variables that affect the ability of a packaged device to meet its acceptance requirements. The results of validation produce several benefits. Through identifying the optimum windows for each key variable, process control is achieved, as well as the confidence in meeting the device package requirements. Equally important are the financial benefits that can be realized through reduced inspection, increased output, fewer complaints, and minimized scrap and rework. In May 1997, validation was raised as a GMP requirement with the issuance of Guidelines on General Principles of Process Validation. The new quality system regulation now specifically lists process validation requirements, and ISO 11607 provides key validation steps specific to sterile packaging. This article provides an integrated approach for complying with these standards.

Packaging validation must address three basic elements: requirements, assumptions, and capability assessments (of materials, equipment, and processes); it examines variations within a package, from package to package, and from lot to lot. Validation also examines the interactions within the handling and use system, which encompasses the manufacturing system (including sterilization), human interaction with the package, and the distribution and storage system and environment. To help ensure that the anticipated results are achieved, validation must be performed by someone with the necessary education, background, training, experience, and qualifications for each particular function. At both onset and completion, the validation program must be documented and approved.

In current terminology, there are three possible approaches to validation: prospective, concurrent, and retrospective. Prospective validation is performed before the packaged device is commercially distributed. Concurrent validation is also performed before the device is commercially distributed or packaged but assumes that the devices produced during validation will be distributed. Obviously, these two types of validation significantly overlap, because packaged devices produced during prospective validation are also typically sold at commercial release. Concurrent validation could better be defined as a validation process applied to products of limited commercial applicability, produced only once or a few times a year. The validation will continue with each production run until the requirements have been satisfied. Both prospective and concurrent validation are used for new products and existing products that undergo significant changes; these methods are also used when a manufacturing process or piece of equipment experiences a change that can affect product characteristics or quality.

Retrospective validation is performed after the packaged device has been commercially distributed; it is based on the review of data collected and maintained during production. Retrospective validation is difficult to justify because it typically requires appropriate and accurate product data, generated by qualified test methods, with the corresponding manufacturing records, procedures, and continuous monitoring of key parameters (controllable and uncontrollable). For these data to be valid, the process must be functional, as evidenced by few rejections and complaints. Retrospective validation is generally only useful for confirming continued validation of an already validated process.

Not all processes require validation. Verification can be used for processes that allow product requirements to be fully evaluated by inspection and testing. For example, 100% automated inspection of a packaging process would qualify for verification; however, if 100% inspection is not used and variation within the process prohibits full confirmation of requirements, then validation must be used.

There is much confusion over the terms verification, qualification, and validation. For the purposes of this article, we shall assume that the combined test results for a requirement provide a verification that the product or process meets those requirements within a snapshot in time. A capability assessment requires a broader analysis than a requirement. To determine the capability of a material, equipment, process, or final product to consistently meet the package requirements, a combination of verifications to the requirements over time is necessary. This combination of verifications provides a qualification. Specific examples of packaging qualifications are: materials, initial design, equipment, process (performance), and product (performance) or final design (all of these qualification processes will be discussed later). The combination of the appropriate qualifications results in validation.

THE VALIDATION PLAN

The validation process begins with a validation plan, consisting of individual plans for each qualification to be performed. To appropriately address the qualification requirements, the plan must be based on a thorough understanding of the package requirements as they relate to the material; the design, design output, and other functional requirements; and the manufacturing equipment and process. In general, the plan should identify all pertinent factors.

For example, the validation plan should delineate what is and is not covered by the study. This would include a list of products or product families. For a family of products, a worst-case product should be selected to be representative of the most difficult product to manufacture; a rationale for why that product was chosen should also be given.

The validation plan should also spell out clear and concise objectives with an understanding of what constitutes a successful validation. All assumptions should be identified. A key outcome should be process control; therefore, the process capability index (Cpk) should not fall below 1.33. Plan developers should specify the references to be used.

The validation plan should describe the package design configuration to be qualified. This description should include the final product information, such as mass and fragility levels, and the product unit of sale configurations to be evaluated. Process variables should also be addressed, such as the inherent variability of the primary package materials, additives, and manufacturing materials. The document should indicate the equipment and process parameters to be monitored and controlled--including the methods of monitoring--as well as the package requirements or characteristics to be monitored. Environmental conditions should also be defined, and rationales stating why certain conditions do not require control should be given.

The validation plan should address the validation process with its elements of qualifications and verifications. A determination of the test methods to be used should be supported by the rationale for each test along with the intended means for collecting accurate and complete data. Careful consideration should be given to the appropriateness, accuracy, reliability, precision, and bias of the test methods and procedures and to the ease with which the output can be measured. All preparations, samples, tests, and test sequences to be performed should be included, along with the acceptance criteria with measurable pass/fail end points for each evaluation. Determining an appropriate sample size is critical in achieving reliable data, and the evaluation must be based on sampling plans employing a sound statistical approach. Testing should be conducted under conditions that simulate actual product use. All tests should be analyzed both individually and within the context of the full process.

The plan should also cover manufacturing and distribution methods, systems, and environments, and storage environments. The document should define the full data analysis required for each phase of validation and its integration for the full validation assessment. Finally, the validation plan should define how results will be approved and documented. Before instituting this protocol, it should undergo a design review with the appropriate approvals.

MATERIALS AND INITIAL DESIGN QUALIFICATION

The next step in packaging validation entails the qualification of materials and the initial package design qualification. A materials qualification plan should be developed to analyze the material requirements with respect to safety, product performance, sterilization compatibility, shelf-life stability, and suitability for the intended manufacturing, handling, distribution, and storage methods. In forming material requirements, lot-to-lot variations must be considered in order to establish the minimum performance requirements. To ensure reproducibility, the variability range, sampling plans, and test methods must be established and agreed upon with the supplier. Limiting values are to be determined not only for adverse physical interactions but also chemical interactions, such as potential migration and transfer between the package and device. A fingerprint or other identification should be documented for each material. To ensure that properties are maintained, all materials should be kept under proven storage conditions or those specified by the supplier.

The product design should be qualified to the product requirements before proceeding with the development project. The design should be reviewed to input requirements, and initial testing should address end-use requirements and device protection as well as the manufacturing and distribution requirements. Design performance testing should be conducted under actual use or conditions that simulate actual use. (Applicable evaluations are described within the product qualification section.)

Initial evaluation of both the material and design prior to process qualification can save a tremendous amount of effort and time. If either the material or design does not meet the requirements, process qualification is useless.

EQUIPMENT QUALIFICATION

After process equipment is designed or selected, the installation must be qualified to establish confidence that the process equipment and ancillary systems meet the established requirements and that they can provide consistent operation within limits and tolerances. Software systems must also be validated.

A separate plan should be drawn up for installation qualification. The plan should include: a formal set of requirements for the equipment or process; documentation of equipment conformance to design, specifications, blueprints, and drawings; determination of the utilities required for proper operation; verification that the equipment has been installed to specification and codes; manufacturer's guidelines and other requirements that must be met to achieve specifications and other performance criteria; identification of critical equipment characteristics and systems; determination and verification of the required safety features; requirements for calibration, maintenance, spare parts inventory, and adjustments; a short-term reliability or capability study, typically performed at nominal or optimal settings; and an analysis of the contamination potential from wear debris, manufacturing materials, and external factors.

Upon completion of the installation qualification, the equipment can be released for operational qualification. Operational qualification is the dynamic test of a piece of equipment; it verifies that the equipment will operate as intended. Operational qualification normally includes a full functional test, verification of machine operating ranges, and experiments to begin to define process ranges. Operational qualification is the first step in developing standard operating procedures (SOPs) for monitoring and control; therefore, the equipment must be fully calibrated and able to monitor key parameters. Corresponding written procedures, specifications, and schedules should be in place along with certification of all relevant monitoring, sensing, and measuring equipment. Note that calibration and measurement requirements should be assessed during all phases of validation and should include a verification after validation.

A documented procedure should be established for the routine inspection of the forming, sealing, and other closure systems; tooling; and machine settings. Procedures and schedules for preventive maintenance, adjustment, and cleaning should be established. Documents should also define and describe initial setup, startup, and operating process procedures, and include documented operator training. Also, any inherent machine variability should be identified (e.g., the temperature along the sealing die, bar, or platen).

Operational qualification begins to identify the equipment elements that affect the package; the process also serves to establish environmental control and procedures and determine the range of operation.

PROCESS (PERFORMANCE) QUALIFICATION

Process qualification is a critical step toward achieving process control. Through an understanding of the key process parameters and their resultant monitoring and control, the product requirements can consistently and reliably be achieved. To begin, a qualification plan should be developed. Contained within this plan should be a description of the process along with a flowchart. This qualification plan should include an initial identification and assessment of key process parameters and their potential interaction for each step along the flowchart. Process qualification requires rigorous testing; thus, a quality assurance plan should be included along with the rationale for the methods, testing, and sampling. The qualification plan should identify the initial or draft setup, start-up, and operating procedures and specifications, with preliminary acceptance from operational qualification. This plan should also identify the requirements for operator training, defining and describing the process operating procedures and in-process and finished goods evaluations to be performed as well as actions to be taken. The language of these procedures and training must be specific and clear to ensure that the requirements are fully understood. Before starting process qualification, ergonomics and safety should be evaluated, because these issues can result in changes to the procedures.

All key process parameters should be monitored and documented, including settings and tolerances. Process parameters include those that are controlled during production as well as those that are not controlled through equipment or procedures (e.g., the environment). Important interactions should be identified to help center the process within the optimal processing window. To aid in the initial and subsequent identification of parameters that have the most effect on the process output and their potential interaction, the following tools are recommended: design of experiments, multivariate analysis, fault tree analysis, failure mode and effects analysis (FMEA), cause-and-effect diagrams, process capability studies, and (if available) historical information.

Process qualification challenges the process limits. Upper and lower control limits must be established for all key parameters, and worst-case or challenge conditions should be identified to establish process limits sufficiently removed from failure or marginal conditions. The qualification plan should include an explanation of how the worst case was determined and, if necessary, a rationale of why certain other items were deemed unimportant. Packaging processes typically involve more than one significant parameter for each step; therefore, there can be several combinations of extreme settings. For example, several combinations of temperature and dwell time provide a wide variety of extreme sealing conditions.

A minimum of three consecutive production runs, including setups, is recommended. Individual upper and lower control limits for each individual process parameter need not be run separately. A combination of the worst-case upper and lower control limits can be used to verify process reliability. The preferred operating conditions should also be included because the relationship between upper and lower control limits is not always linear. Each setup should be a distinct production or experimental run and not a continuation of previous setups. All acceptance criteria must be met during the test or challenge. The output must be in discrete terms--not a simple pass/fail rating--and a statistical comparison should be made between each trial. Variation due to all controllable factors should be identified and eliminated or reduced. The combined effect of the separate outputs on achieving the combined input requirements for the final product should be analyzed. In all cases, the output data must equal the input requirements.

Any failures or deviations from the acceptance criteria should be recorded in an issue log. An evaluation of each deviation should be conducted to determine the root cause of the failure and identify corrective or preventive actions. All information should be documented. Corrective or preventive actions should be verified with additional test runs and, in some cases, validated. Process qualification is a key transition into manufacturing. Consequently, it should be a test of the full manufacturing process, including operating procedures. This qualification should begin as a team effort and end with a full transition into manufacturing. The results of process qualification will be an established range of acceptable values for each key process parameter and the corresponding control procedures. With the goal of process control, key output from process qualification will be control charting of the significant process output values and measurement of Cpk. The result should be a minimum of 1.33 Cpk. To achieve this degree of process control for each specific attribute, process qualification typically is not a one-pass study. As information develops, further studies become increasingly focused on understanding and controlling key parameters.

PRODUCT QUALIFICATION

Product qualification establishes confidence through appropriate testing that the finished packaged product manufactured through a specified process meets all release requirements. A product performance evaluation and stability plan should be developed. The test packages should be produced on fully validated manufacturing lines; however, in situations in which this is not possible, they must be produced on equipment that is fully representative of the final process. If neither the prototype or 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 at the preferred setting. 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. For example, if resterilization is part of the requirements, the package must be evaluated under this double-exposure condition. Furthermore, all evaluations on irradiated products should be performed at the maximum tolerance level permitted by the process; cobalt 60 gamma radiation cycles, for example, can allow a 15-kGy variation. To achieve a minimum dose of 25 kGy, the exposure can be as high as 40 kGy. The package must permit attainment of sterilization, aeration, if applicable, and maintenance of sterility over the intended product shelf life.

Package integrity--a function of material properties, design, seals, and device mass and geometry--must be demonstrated under the full manufacturing, distribution, handling, and storage environment for the intended shelf life of the product. Limits for these conditions must be defined by the manufacturer.

In establishing storage conditions, temperature, pressure, humidity, and exposure to light (including UV), and their maximum rate of change, should be considered. Package stability should be demostrated by real-time aging to the worst-case storage conditions for a period of time equivalent to the intended shelf life. Accelerated aging can be used in parallel to real-time aging, but a rationale should be established for the accelerated-aging conditions selected. Product introduction can be based on accelerated aging studies as long as there is a correlation to real-time aging. In addition to the overall package, the package materials must also remain within the validated limits of the performance specification.

Test results should show that the process yields acceptable output in a consistent manner; documented evidence should be available demonstrating that the test results and conclusions are correct. Likewise, final product testing must show achievement of the product input requirements, durability in the manufacturing and distribution environments, and stability during storage. Handling and distribution testing is recommended at the end of stability testing. In addition to package integrity, verification of device retention and protection within the package must be demonstrated through appropriate testing. All of this information must be included in the final validation report.

CERTIFICATION AND REVALIDATION

A final step of the validation procedure is the certification of the equipment, process, and product through a documented review and approval process. All certification-supporting documentation must be included within the validation report.

The validation plan serves as the final documented review and approval of the validation process. Analysis of the data will establish the variability of the process and the adequacy of the equipment and process controls. The validation report should undergo a thorough final review before acceptance. Any process changes to equipment, product, components, materials, or process that can compromise the original validation and affect the package's ability to maintain sterility, safety, or efficacy should be revalidated. Additionally, there are a wide variety of other changes that may require revalidation. These include: process deviations; unexpected deviations (e.g., more rejects, stability failure); changes to specifications and those identified in process monitoring; complaints traceable to the process and an increase in returns, scrap, and rework; changes in supplier; equipment moves; and changes in equipment, environment, the order of operations, and process-control software. Note that if the root cause of problems can be isolated or if verification can show that there is no effect on the process, revalidation may not be required. In several cases, the entire process may not require revalidation for a specific change; however, in all cases the impact of the change should be assessed relative to the full process and the product. The need for revalidation should be considered on a periodic basis. This review can also be a part of the change-control procedure.

VALIDATION DOCUMENTATION

Documentation from validation activities should be maintained in the design history file. General validation protocols can be maintained in the quality system record. Validation documentation should include: the equipment and process validated, with dates; individuals performing the validation; the dated signatures of the individuals approving the validation; monitoring and control methods and data; and review and evaluation for possible revalidation. All process and product documents must be managed under a change-control procedure requiring analysis, verification or revalidation, and change approval.

VALIDATION OF PEOPLE-DEPENDENT PROCESSES

In the validation of people-dependent packaging processes, a key element is the elimination of controllable sources of variation. All equipment, materials, and components should be prequalified for the packaging operation. Where possible, the use of fixtures, holders, and special equipment should be implemented to reduce variation. Operating procedures should be developed, and the packaging operation should be outlined using written descriptions, illustrations, photographs, and samples. An important part of these procedures is operator training and qualification. Typically, training and qualification can be accomplished by a combination of observation of conformance to procedure, formal and informal testing, and inspection and testing of the packaged product. To evaluate the system, the manufacturing procedure should be challenged by having people unfamiliar with procedure perform it; if they have difficulty, the procedure should be refined and retested. Acceptance criteria (e.g., the maximum number of defects) must be identified.

Once satisfied that the packaging procedure is appropriate, a minimum of three consecutive lots, batches, or runs without direct observation is recommended to confirm that the process consistently produces a product that meets specifications. In general, people-dependent processes typically require more than three runs. The package should be thoroughly inspected or tested to determine conformance to specifications and the number of defects. The process performance must also be continuously monitored to detect drift. Operators will periodically require retraining and should definitely be retrained when drift is detected. Any process changes must be assessed as to the impact on the operator's ability to perform.

CONCLUSION

Package validation for validation's sake is worthless. The result of package validation should be full process control and the corresponding confidence in consistently achieving the package requirements. An additional benefit will be in the form of increased efficiency, cost reduction, and reduced risk. The validation plan should be reviewed both at the start and the end to determine the benefits derived, and the approach should be refined for future validations.

BIBLIOGRAPHY

Federal Register, 61 FR:52601­52662 (the quality system regulation).

"Guideline on General Principles of Process Validation," Rockville, MD, FDA, May 1987.

Packaging for Terminally Sterilized Medical Devices, ISO/DIS 11607, Geneva, International Organization for Standardization, 1995.

Denis G. Dyke is vice president, quality and regulatory affairs, Rexam Medical Packaging (Mundelein, IL).

Photo by Roni Ramos