Top 10 Common Mistakes Made In Package Validation
By Patrick J. Nolan
COO, DDL Inc.

The package for a medical device plays a key role in safely delivering specialized treatment to the patient.  The package must ensure the efficacy of the device from the point of manufacture to the point of final use.  Most single-use terminally sterilized medical devices must be delivered with a very high confidence that the device has remained in a sterile condition throughout its storage, handling and transportation environment.  The device components and the packaging system must combine to create a product that performs efficiently, safely and effectively in the hand of the user.

What makes this process so important is that the regulatory authorities recognize the critical nature of the sterile barrier system or primary package; by considering it as an accessory or a component to the medical device.  This implies that the package system is almost as important as the device itself.  And it is.  If product sterility is not maintained and it’s a class 3 device such as an active implantable, like a pacemaker for example, patient safety could be critically compromised. 

The design and development of the packaging system has come under closer scrutiny by both the international and domestic regulatory agencies.  This scrutiny has placed a great deal of emphasis on standardizing the package development process.  Some standardization of the packaging process has come in the form of the international standard entitled ISO 11607: Packaging for terminally sterilized medical devices. 

This article discusses some of the common mistakes made when developing and validating a package system for a terminally sterilized medical device.

Mistake #1 - Sterility Is Compromised

The most common defect in a medical device package system is the loss of sterile integrity due to pinholes, slits, cuts and tears of pouch packages and fractured thermoforms.  These defects occur from the impacts caused by dropping packages and general handling or mishandling, as well as from the vibration forces inherent in the distribution environment.   

Some defects like tears are caused from the manufacturing/assembly process; for example during insertion of pouches in cartons, or insertion of ‘Information for Use’ booklets (IFU’s) with sharp edges (staples) that ‘snag’ the plastic materials.

Companies can reduce and avoid defects in packages due to handling and shipping by designing sterile barrier systems (primary packages) and package systems (final packages) that reduce the possibility of creating pinholes, tears and fracturing. 

Mistake #2 - Too Many Corners Are Cut

There is a general lack of awareness in the manufacturing industry of the need to perform testing on package systems.  Many companies are not even aware that the ISO 11607 standard exists and is used by the FDA and the European Community within their regulations. In addition, many companies cut corners and try to complete package validations ‘on the cheap’ without using good, sound scientific practices.  In their haste to ‘get the product to market first’, companies cut corners in the process and risk violations in regulations or worse; allow suspect devices to reach the patient.  

The time to complete a full package system validation is dependent upon the expected shelf life of the product and the desired expiration dates.  The typical time frame from package concept to final qualification for a one year shelf life could be from 3-6 months.  There should be time allowed for any unexpected events in the validation. The process should be on a parallel path to the product development itself.  This can be accomplished by using prototype products for both design elements and package compatibility and testing requirements.  If a longer shelf life is desired, the process time line must be extended by about 45 days for each year of shelf life. 

Mistake #3 - The Package & Product Are Not Pre-Qualified for Compatibility

A common mistake in developing a package for a device is not doing the preliminary design evaluation work before diving into the whole package system validation.  This short sighted, ‘cutting corners to save time and money tactic’ usually results in extended development times and higher over-all validation costs because some attribute of the package system fails during validation and results in retests. 

Some of the common pre-qualification tests that should be used to detect potential design or manufacturing problems include seal strength and integrity tests on manufactured packages.  These tests will indicate any deficiencies in the manufacturing process and raise a red flag that corrective action was necessary on the production line.  This should be done far in advance of any package performance tests (e.g. transportation, sterilization, handling, etc.)  These tests should also be used as a basis for establishing target values for process quality control. 

Another test used in pre-qualification of package-product compatibility is the dynamic testing associated with transportation and handling.  Most sterile medical device packages do not typically lose their sterility simply by being stored on a shelf.  Package failures are usually a result of a dynamic event which may have occurred during the manufacturing process, during shipping and handling to the sterilization facility, or during distribution to the point of end use.  Therefore, the proposed package design should always be subjected to a pre-qualification process that isolates each potential hazard and determines the package-product response and compatibility.

Mistake #4 – No Allowance for Worst Case Scenario

One difficult issue, and sometimes a mistake in the package validation process, is determining which shipping unit to actually test.  It is important to determine the most common configuration for shipping the product prior to package validation to ensure that the ‘worst case’ scenario is determined.  In this way, any other package configurations of the same or similar product can be covered by the validation.  Forethought on this aspect of the package development may allow for the provision in the ISO 11607 standard that allows for families of packaged products to be validated, rather than each individual package configuration.

Mistake #5 – No Time for Protocol Development

Prior to beginning any work on a validation, it is essential to write a protocol.  The protocol provides a blueprint stating how testing is to be conducted, including the purpose, scope, responsibilities, test parameters, production equipment and settings, and the acceptance criteria for the test. 

The validation process consists of a series of qualifications of unique processes that make-up the complete package process system.  If one of these processes is not right, the entire system breaks down and the manufacturer is at risk of causing grave harm to patients.

Mistake #6 – Wrong Sample Size
The question of the ‘right’ sample size to use for testing is one of the most daunting to answer.  There are many factors that weigh into the determination of sample size.  The factors include; what type of test is it? (e.g. quantitative/variables or qualitative/attributes); what is the sample population? How many samples are available for testing? What are the economics? What are the risk factors?  (e.g. confidence intervals) .  Most often the sample size is too small and renders results that have no statistical significance. 

The table shows the upper boundary of the expected failure rate when zero or one failure is observed at various sample sizes.

Mistake #7 –Wrong Package Type/Material

Using the wrong package type or material for the product is a package-product compatibility issue, which could have been avoided if pre-qualification of the packaging had occurred at an early stage.  Some of the typical observations that are prevalent include fracturing of thermoform trays as a result of using the wrong plastic material for the intended product (e.g.  Product mass is too great for the impact resistance of plastic). 

This can be avoided for large, massive products, by using a high impact resistant plastic such as polycarbonate to reduce the possibility of fracturing during normal distribution and handling. The thermoform design is also critical to ensure that the product is held in place firmly so that a loose product is not jettisoned through the tray lid and fracturing of the plastic doesn’t occur from the inside-out.

Mistake #8 – Oversized Pouches Are Squeezed Into Cartons

Pinhole defects in pouches can be reduced by inserting the pouch into a carton without folding, wrinkling or creasing the ends.  Pinholes occur at the junctures of the creases and folds when they are vibrated causing the intersection to be ‘worked’ or fatigued at the juncture.   This effect is exacerbated by making complex folds of the pouch causing a very concentrated point of stress at the juncture of the materials.  This can be circumvented by using secondary packages (cartons/shelf boxes) that are large enough to allow for insertion of the pouch without folding.

Mistake #9 – Tyvek Separation Is Not Recognized As a False-Positive

One phenomenon that was discovered some years ago but only really came to light when medical device packages began to be integrity tested routinely using bubble and dye leak methods was ‘sheet separation of the porous web’ of Tyvek.  See photo below.

This ‘sheet separation’ can lead to a false-positive in the integrity test.  The false-positive occurs when the material is bent, folded, or 'wrinkled'. Dupont has proven that this phenomenon does not change the sterile barrier performance of the material and that any leakage of air or dye solution is only along the transverse direction of the material and not between the Tyvek and poly material, as would be the case in an adhesive (seal) failure.  There is no loss of filtration capability when this occurs.  However, when performing these tests it is incumbent upon the tester to analyze the failure carefully.  In some cases, when there is a suspect 'false-positive', it may be necessary to look at it under high magnification to determine the cause of the leakage.

Mistake #10 – Accelerated Aging Is Performed At High Test Temperature
In ill conceived attempts to reduce costs and time, some manufacturers decide to accelerate the shelf life or expiration date studies to unrealistic and indefensible limits.  This is done by raising the test temperature to a level that causes packages to melt-down, warp, or change in other uncharacteristic behaviors.  In addition, temperatures over 65OC are indefensible based on the rationale which is typically used to justify accelerated aging protocols.

Accelerated aging is performed on packaged medical devices to document expiration dates for products.  Real time aging can be performed; however, products are often obsolete by the time a three year expiration date is validated.  FDA does not require expiration dating for products without components with a defined effective life such as batteries.  The European Directives imply that all sterile medical devices must have an expiration date.  Therefore documented evidence must exist to substantiate those claims.

Temperature selection for the accelerated aging study should avoid unrealistic failure conditions such as deformation due to melting.  This advice is sometimes ignored in the haste to bring products to market faster. 

About the Author
Patrick Nolan, COO of DDL Inc (www.testedandproven.com), a package, product and material testing laboratory, has over twenty years of experience in the testing of packaging and products for shock and vibration hazards inherent in the distribution system.  Mr. Nolan serves the package testing industry as Chairman for the ASTM committee D-10 on Packaging and is also a member of the AAMI committee to draft a Technical Information Report (TIR), which identifies 11607 compliance regulation guidelines.

You can contact Mr. Nolan at Pat.Nolan@testedandproven.com or at 952 941 9226 ext 112