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.