Dr. D hopes that each of you living in the States had an enjoyable President’s Day weekend. For those readers living in the Northeast, please stay warm. That is why Dr. D lives on the left coast.

Each year the doctor is sentenced to one week of zoo duty as my wife and her friends take off for their annual vacation. Dr. D gets stuck feeding her zoo, which is an arduous task at best. This is especially true when the doctor has been slowed by a series of injuries (leg, hip, and back). Regardless, the week allows for Dr. D to catch up on my much needed drink’n and think’n sessions.

For this week’s guidance, my dear friend and evil twin (Jim Twitchell) recommended a review of another prized warning letter that contains ten Form 483 observations and numerous subparts. That being said, the FDA investigator targeted product packaging, which is an observation Dr. D does not see written-up on too many occasions during agency inspections. However, if the FDA investigator, during one of his or her friendly visits for a cup of coffee and inspection, ascertained that a terminally sterilized medical device was not properly validated in its packaging, then a Form 483 Observation denoting the issue is well-deserved. In the eyes of FDA, any response trying to rationalize why a packaging validation has not been properly executed is considered “folderol” (look-it-up). Enjoy!

Warning Letter – 09 December 2014

The doctor has mentioned on multiple occasions that establishments receiving double-digit Form 483 observations, during an inspection, should always be the not-so-proud recipients of a prized agency warning letter. The establishment being scrutinized in this week’s guidance also received several of the infamous “your firm’s response is not adequate” comments in their warning letter. To error is human and to error again by providing the FDA a response that is not adequate, well that is just folderol. Regardless, one of the observations made during the inspection, which pertained to product packaging and associated validation issues, will be the focus for this week’s guidance.

Warning letter excerpt

Observation Five: “Failure to ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution, as required by 21 CFR 820.130. For example, your firm has not adequately demonstrated that the terminally sterile medical packaging and product can withstand the rigors of transit, handling and storage environments without compromising the sterility of the pack, product features and performance. Your firm provided shipping validation documents conducted June 2006 that included products packaged in trays or breather bags including convenience packs intended for cardiovascular and ophthalmic surgeries. Review of the shipping validation protocol demonstrated that your firm performed EtO validation using the outside cardboard shipping containers in June 2006, but did not perform validation of the inside convenience packages after the EtO Sterilization process in order to verify the integrity of the packages.”

“Your firm’s response dated August 21, 2014, is not adequate. Your firm committed to (b)(4) products; however, it was found deficient because you did not consider the stability or shelf life of the sterile barrier that the devices and kits are packaged in. Additionally, packaging and shipping validation protocols, describing the testing to be performed to demonstrate the sterility and stability of the packaged device was not compromised after manufacturing and distribution, were not submitted including a timeline for implementation of corrective and preventive measures.”

Subpart K – Packaging and labeling control

Section 820.130 Device Packaging

“Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution.”

Compliance for Dummies

Obviously, many of you may already be wondering how failure to comply with a one-sentence requirement resulted in a Form 483 observation. Let Dr. D begin by restating a basic medical device industry tenant; “Finished medical devices that are designed, developed, manufactured, and introduced into commerce are expected to be safe and effective in their intended use.” It makes no difference if the targeted market is the United States or outside of the United States. Guess what people, packaging is part of the manufacturing equation required to introduce a medical device that is safe and effective into commerce, including terminally sterilized devices.

Guess how a device establishment determines if their packaging is appropriate and capable of protecting their finished medical devices? If you answered packaging validation, you would be correct. In fact, FDA recognizes, as consensus standards, two ISO standards that pragmatic medical device establishments can employ in support of developing packaging validation modalities: (a) FDA Recognition Number 14-454 – ISO 11607-1:2006; and (b) FDA Recognition Number 14-455 – ISO 11607-2:2006. Remember, FDA expects medical device packaging to adequately protect finished medical devices from “alteration or damage during the customary conditions of processing, storage, handling, and distribution.”

For those of you that are not involved in your establishment’s packaging validation process; the process is actually pretty simple.

• Step one – write the validation protocol.
• Step two – execute the validation protocol.
• Step three – review the data collected, while employing appropriate statistical rationale.
• Step four – write the validation report (hopefully it passes).
• Step five – clearly define what constitutes the need for revalidation.

Now granted this is a tremendous over-simplification on the part of Dr. D; however, there are organizations that can help with the packaging validation, including the scripting of the protocol. Dr. D has worked with DDL (Eden Prairie, MN); WestPak (San Jose, CA); and UL (multiple locations in the United States). Each of these organizations can provide significant value and support for a device establishment’s packaging validation efforts. They can:

1. Support scripting the protocol;
2. Perform the actual validation testing; and
3. Script the validation report.

However, if a device establishment wants to go out and procure all of the shake, rattle, and roll equipment needed to perform packaging validation, please feel free to do so, but Dr. D’s question would be why?

Additionally, the sterilization methodology is to some extent going to drive the packaging modality selected, i.e.: (a) Tyvek/poly pouch configurations for Ethylene Oxide; and (b) foil pouches for achieving a terminally sterilized device through irradiation. However, make no mistake, regardless of the sterilization method employed; the packaging modality selected must be appropriately validated.

Furthermore, if an establishment’s supplier of packaging materials introduces changes to the packaging materials, such changes need to be appropriately evaluated. This includes Tyvek^® for those of you familiar with the current DuPont™ Tyvek^® Medical Packaging Transition Project (MPTP). Dr. D recommends that you visit the DuPont Website (see references).

Now Dr. D is not stating mandatory revalidation is mandatory when a material change occurs; however, such changes need to be appropriately evaluated. When in doubt, repeat packaging validation. If you believe the scientific evidence/rationale is adequate, then write a robust rationale as to why repeating packaging validation is not required. Either way, the ball has been squarely placed into the courts of the device establishments, so please take the appropriate steps for your organizations.

Takeaways

For this week’s guidance Dr. D will leave the readers with two takeaways. One – the packaging modalities employed for finished medical devices, regardless of sterilization method, shall be appropriately validated to protect finished medical devices from “alteration or damage during the customary conditions of processing, storage, handling, and distribution.” Two – if packaging materials change, such changes in packaging material may warrant the repeating of a packaging validation. As a minimum, written rationale, premised on robust scientific evidence, must be provided, if a decision is made not to repeat packaging validation.

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success.

References:

1. Code of Federal Regulation. (2014, April) Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon. Devine, C. (2013).
3. Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
4. DuPont™ Tyvek® Medical Packaging Transition Project (MPTP). (2015, February). http://www.dupont.com/products-and-services/packaging-materials-solutions/pharmaceutical-packaging/brands/tyvek-sterile-packaging/uses-and-applications/tyvek-medical-packaging-transition.html
5. FDA’s enforcement page. (2014, December). FDA.gov Website. Retrieved February 16, 2015, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm433090.htm
6. ISO 11607-1 (2009) – Packaging for terminally sterilized medical devices – Part 1: Requirements for materials, sterile barrier systems and packaging systems.
7. ISO 11607-2 (2006) – Packaging for terminally sterilized medical devices – Part 2: Validation requirements for forming, sealing and assembly processes.