Design Verification: The Testing Phase

By Roberta Goode
January 4, 2016


• Categories: 04-Product Design & Development, 05-Quality/Regulatory

The following article is the third in a series on design verification. Read Part II, “Design Verification: Process Considerations before Testing”.

Build and Package the Product

After considering the design and process parameters noted in the previous article, manufacture and package the product. The units should then undergo the maximum number of sterilization cycles or the maximum dose of sterilization, which represents worst-case conditions. Following sterilization, it is advisable to perform a visual inspection of the shipping cartons, unit cartons and inner packaging to ensure they have withstood the sterilization process and transport. After the sterilization is complete, a visual inspection is recommended, as follows:

1. Ensure no major damage to the outer shipping carton by visual inspection.
2. Ensure the inner unit cartons are intact and capable of being stored on a shelf.
3. Ensure product labeling has remained adhered to the carton and that the information printed on all labeling is legible.
4. If you have printed directions for use (DFU), ensure they are not torn or severely wrinkled, and that any staples they may contain are not rusted.
5. Inspect the inner product’s packaging to ensure no channels, pinholes or other breaches to the sterile barrier are evident with visual inspection.
6. Ensure the inner product labeling has remained adhered to its intended surface and that the printed information is legible.

If your supply chain calls for re-packing the product into distribution shippers following sterilization, then that should be done next. Remember to include an array of re-packing configurations to simulate the actual conditions of the distribution center (full and partially full shippers, etc.).

Climatic Conditioning
The next step is to expose the packaged product to climatic conditioning. This can take many forms, but standard practice would include the following climatic conditioning cycle, per ASTM F2825 – 10 (2015) (see Table 1).

Step	Temperature	RH	Time (hour)
1	Ambient	Ambient	6
2	-29°C ±2	Uncontrolled	24
3	Ambient	Ambient	12
4	38°C ±2		24
5	60°C ±2		6
6	Ambient	Ambient	6
Table 1

Conduct another visual inspection at this point, if desired, in order to ensure traceability of any defects to the climatic conditioning and to avoid confounding with further testing.

Distribution Simulation

In order to simulate the distribution of product from the distribution center to its intended use point, the packaged and sterilized product will be subject to an appropriate distribution test standard, such as ASTM D4169 or ISTA 2A Series or ISTA 3 Series, which are the primary test standards used for distribution simulation.1 After the simulated distribution is complete, another visual inspection is recommended, as defined following product sterilization above.

Read Part I of this series, “Design Verification: Ensure Product Protection throughout the Supply Chain”Stability Testing (Accelerated Aging and Real Time Aging)

Divide the packaged product among the aging groups as dictated in the test protocol. For example, if we desire a two-year shelf life, then depending on the risk tolerance of the company, best practice would be to have product in the following categories  (We suggest the additional month in each group to satisfy Japanese test requirements):

• 25 month accelerated aging
• 25 month real time aging
• 13 month accelerated aging
• 13 month real time aging
• Un-aged product

Each group must contain a statistically significant sample size, as previously discussed.

The un-aged product can proceed to seal strength, seal integrity and product functional testing without further delay.

Place the 13- and 25-month accelerated aging units into oven(s) according to Table 2. This table defines the accelerated aging time (in days) for specific shelf life periods based on the Arrhenius equation (Q10 theory), the assumption of ambient storage condition at 25°C (77°F), and the shelf life requirements of Japan to add one month of additional aging.

Accelerated Aging Temperature		Desired Shelf Life and Accelerated Aging Duration (months)
°C	°F	7	13	19	25	37	49	61
40°	104°	75	140	204	269	398	527	656
50°	122°	38	70	102	135	199	264	328
60°	140°	19	35	51	67	100	132	164
Table 2. Desired shelf life in days computed as (365/12)* X months; final result rounded up to the nearest whole day.

When the accelerated aging time is up, test the aged product for seal strength, seal integrity and product function. This testing should include the visual inspections described previously, as well as the following tests:

• Package Integrity Tests
  • Ensure the sterile package is free of channels, pinholes and all other sterile barrier breaches under 10X magnification, following dye penetration testing.
  • Seals must be continuous and uninterrupted.
• Peel Testing
  • Pouch seals tensile strength must meet minimum acceptance criteria as established in the product specification. (If the data are variable in nature (i.e., numeric rather than pass/fail), then a normality test is required prior to calculating process capability.)
• Simulated Pouch Opening
  • Open the pouch approximately half-way down. Visually inspect the opened seal area to ensure there is no delamination of the two pouch layers or fiber tears.
  • The pouch should open steadily and easily.
• Product Inspection
  • The product must not be broken or damaged under visual inspection.
  • The product should be easy to remove from its packaging and must remain secured in its packaging during the DV testing.
• Product Functional
  • The product must meet all acceptance criteria as noted in the product specification.

Global regulatory bodies allow the commercial release of product following all appropriate testing and clearances, with accelerated aging data. This compromise allows manufacturers to bring life-saving devices to market quickly based on the proven Arrhenius model. However, the model cannot be certain to capture all material interactions and combinations of stacked challenges. Therefore, most regulatory bodies require that real-time aging accompany accelerated aging testing to ensure alignment and agreement of the two groups and the veracity of the Arrhenius method for each unique product.

At the same time as the accelerated aging units are placed into ovens, place the 13- and 25-month real-time aging product in a temperature- and humidity-controlled and tracked area under ambient conditions until the required time(s) have elapsed. Upon the conclusion of the elapsed time, remove the product and test the seal strength, seal integrity and product function. Compare these results to the results obtained for un-aged product, in order to identify any existing trends in stability or degradation of the product or packaging. Further, compare the test results of the real-time aged units to the test results of the accelerated aged units in order to ensure the real time aged units will perform acceptably in the field.

This test progression can be more simply visualized with a map as seen in Figure 1.

Once all the testing is completed and the data are analyzed, you are ready to write the DV test report. Remember to include all raw data sheets, training records, and data analysis, including normality testing, in the report. It is generally advisable to release multiple DV reports, one for each period of accelerated and real-time aged product. You may report product functional testing separately as well. There are no specific requirements for the contents of the DV reports in terms of aging periods or packaging versus product results—this is a function of convenience and practicality for the manufacturer to determine. You may encounter a critical reporting circumstance if non-conformity is discovered during testing. Unless the data can be definitively shown to be the result of an assignable cause (e.g., transcription error, improper loading of the package into the sealer, etc.), then the company must be ready to determine the impact and potential necessity for a field action or other remedial action. For this reason, it is recommended that a notebook study be performed prior to the DV testing in order to characterize any potential shortcomings of the design of the package, the product, or the interaction of the two. By the time you get to DV testing, there should not be any surprises.

There are myriad regulations and standards that require and prescribe design verification testing of packaged product. Some of them are included in Table 3.¹

Packages must be able to withstand the typical events associated with distribution of the product without defect or loss of sterility. Manufacturers are responsible for evaluating and documenting the package’s ability to protect the product throughout handling, distribution as well as within the storage environment.²

However, perhaps the most compelling reason to perform DV testing, especially with the stacked challenges recommended herein, is the potential for discovering untoward post-market outcomes before they cause harm to the patients whose health is our responsibility. Clearly, anything less is not only unethical, but invites unwanted product liability actions, potential damage to a manufacturer’s good name, and in the event of a field action, erosion of market share.

References

1. Goode, R. D., (February 2003). “Planes, Trains and Automobiles: Simulated Distribution of FDA-Regulated Products for Packaging Validation,” Journal of Validation Technology, Vol. 9, No. 2, pp. 181.
2. Distribution Dynamics Certified Testing Laboratory. “Package Testing, Product Testing and Materials Testing for the Medical Device Industry”. Retrieved from: http://www.testedandproven.com/