Inadequate control and management of packaging materials is often cited. Most of the citations from these types of issues are focused on poor testing practices that don’t ensure the materials demonstrate they can adequately protect the product prior to its use.
Canyon Labs
Key Takeaways:
The warning letter, also known as a 483, identifies the concern(s), such as poor manufacturing practices, problems with claims for what a product can do, or incorrect directions for use.
While ISO 11607 is a voluntary standard, it is FDA recognized, making it the easiest and clearest route to follow to get clearance.
One mistake is over-reliance on the pre-qualification of the packaging. The FDA expects you to do your own qualification work on that package as well.
Each year, the FDA sends out hundreds of warning letters, which is really just the FDA’s way of notifying a company when it is in violation to federal requirements. Some letters address honest mistakes or oversights, while others address bigger issues like false label claims, selling an unapproved drug, and even refusing an inspection.
The warning letter, also known as a 483, identifies the concern(s), such as poor manufacturing practices, problems with claims for what a product can do, or incorrect directions for use. The letter provides an opportunity for the company or individual to address the FDA's concerns and request a response with a certain timeframe. According to the FDA, this response could consist of plans for correction and the FDA would then check to ensure that the corrections are adequate. To the extent the company or individual disagrees with the FDA's concerns, the company or individual has the opportunity to supply the agency with its reasoning and supporting information. These communications and other actions by FDA and/or the recipient of the letter may change the regulatory status of the issues discussed in the letter.
While companies may not directly think about how to avoid an FDA warning letter, and there are some key steps to take to do just that. One is keeping your facility clean, the next is never refusing an inspection. Also on the list is being sure to follow all cGMP (current good manufacturing practices), don’t advertise unapproved products, and lastly be sure your product has passed compliance testing.
Wendy Mach, Sr. Director, Technical Services, and Sarah (Rosenblum) Ptach, President, Canyon Labs, offer insights into how proper testing can ensure a letter doesn’t come your way. Canyon Labs offers consulting services and medical device and pharmaceutical compliance testing. Packaging testing methods have been developed by industry experts and regulatory agencies with the purpose to ensure safety and integrity up to the point of use.
“An FDA warning letter is usually the result of a condition that violates a regulation. Some of the most common I have seen are failure to follow procedures, inadequate training, and then not understanding the requirements of published standards (e.g. incomplete validations),” says Mach.
These test methods demonstrate how a package will perform after being exposed to different conditions experienced throughout the product lifecycle such as storage, handling, and transit conditions. Ensuring the device is safe and effective for market use is the goal. “If any aspect of this is deemed as insufficient, the result is an FDA warning letter,” says Mach.
Common mistakes
Mach and Ptach both agree that one common FDA strike that med device/ pharma companies encounter as it relates to the packaging is misbranding or incorrect labeling.
“According to the 2023 FDA Inspection Observations Database, multiple 483s were issued for not having a Unique Identifier (UDI) or incorrect accuracy of the UDI,” says Mach.
“Labeling is often glossed over, and key compliance items are missed. It contributes to the situation that labeling guidance has changed quite a bit over the last 10 years and there are more and more specific compliance requirements depending on where you are selling your product (the EU, USA, etc.),” says Ptach.
Another one? Inadequate control and management of packaging materials, or poor testing practices.
“Additionally, inadequate control and management of packaging materials is cited. Most of the citations from these types of issues are focused on poor testing practices that don’t ensure the materials demonstrate they can adequately protect the product prior to its use,” says Mach.
Both subject matter experts I spoke with agreed that some packaging fails or problems are only found through rigorously testing of the product.
“I’ve always heard the stat that over 30% of packages fail the first time they undergo distribution simulation,” says Ptach. “Typically speaking these failures are pin holes or cracks in trays or pouches. We see a lot of trays that have seal flange failures caused by drops. This means that when the package with the tray inside is dropped, the lid on the trays are popping upon impact due to poor distribution of the dynamic forces caused from the drop. Often, this can be solved by inserts that help make that impact not so pin-pointed on the tray. For orthopedics, people will often overlook how a device can be abrasive against a package during vibrations. I’ve seen knee implants rub like sandpaper against their PETG trays. The result is plastic flakes everywhere and a device that is contaminated and package that is broken. For pouches, people often fold these to get them to fit into cartons. These folds create an opportunity for cracks and voids as the fold compromises and stresses the structural integrity of the film of the pouch. All of these failure modes are typically caused by vibration and drop testing, but they are discovered once you conduct integrity testing such as visual (ASTM F1886) and bubble leak (ASTM F2096) testing.”
Gary Hutchinson,EVP, Managing Principal, Modality Solutions, a contract transport simulation lab, shares his insights into FDA warning letters that pertain to thermal shipping, and a common mistake he sees.
“One mistake is over-reliance on what we call, pre-qualification of the packaging,” says Hutchinson.
As he explained, a thermal packaging supplier can only test to one use case, and the company will then come up with one that it thinks is most appropriate. It then publishes data that says the packaging will meet a certain standard: duration/ temp range, etc. But that isn’t where testing should end.
“The FDA expects you to do your own qualification work on that package as well,” says Hutchinson. “We use the vendor (supplier) data as a baseline to get started. But you have to look at it yourself and confirm the packaging is adequate for your drug product in your shipping lanes. If the client accepts that data package and doesn’t do the appropriate technical review or follow up testing with their product, their lanes, they run into challenges.”
To avoid an FDA warning letter, keep your facility clean, never refuse an inspection, follow all cGMP, and be sure your product has passed compliance testing.Canyon LabsAdvice
So then how do you incorporate testing as a best practice to prevent a warning letter? Part of it may be changing how you think of packaging.
“While ISO 11607 is a voluntary standard, it is FDA recognized making it the easiest and clearest route to follow to get clearance,” says Sarah Rosenblum Ptach. “The standard provides a road map to ensure you are thinking and testing for all the variables that your packaging will experience in the real world. These stressors include the rigors of shipping your products to hospitals and the aging process of sitting on the shelf of a hospital while it waits to be used. It is vital that packages are strained to a worst-case level before they go experience the real world so that there are no surprises once the device is used. It’s not always evident that packages are damaged or no longer maintaining their sterile barrier, so a device could be used and cause a hospital acquired infection if the sterility is compromised. This can lead to terrible infections and even deaths of patients. This stresses the importance of understanding these pouches and trays are not ‘just packages’ and should really be viewed as the shining armor of devices getting to patients safely.”
Another aspect is prevention, like the adage says, “an ounce of prevention is worth a pound of cure.” To prevent a 483, it’s imperative to take the right steps well before a 483 is issued.
“If you have a new product, and you’re opening up a new lane, the first thing we recommend is that you validate the original risk assessment in that lane to confirm that nothing has changed; none of the risk profiles have changed,” says Hutchinson. Conduct a risk assess to understand the challenges that are going to be both in shipping lane itself and potentially the packaging.”
After the risk assessment, Hutchinson says then you can determine the packaging.
“How do you confirm you have adequate packaging? First is to do some sort of in-chamber testing. Sometimes the testing done by the thermal packaging supplier may be adequate. But there needs to be some technical assessment to confirm what they did meets your own internal requirements when it comes to validation.”
The second thing is confirming that the thermal mass testing is relevant to your product and that the thermal mass directly correlates to what you’re shipping. It is up to the pharmaceutical manufacturer to then re-test it with a more suitable mass. Hutchinson says these companies may not necessarily have to re-test, but they must use thermal mass/ heat transfer calculations to see how that impacts the performance of the shipper.
Confirming the data yourself gives you the knowledge and assurance that the testing is relevant to your product and your shipping lane. Don’t give the FDA an excuse to send you a 483.
“If a drug product manufacturing company takes a data package provided by the thermal packaging supplier but doesn’t do their due diligence to confirm in some meaningful way that the tests that were done matches what they‘re doing, the agency can come back to you and say, ‘You can’t just accept this on face value, you have to do something to confirm that it works in your specific use case for the drug we’re approving and in the lanes you’re going to ship it,'" said Hutchinson.
Luckily, he also shares that companies can do this most of the time with the data provided by the thermal packaging supplier, as long as the data is reviewed internally and the quality team signs off on the review.
Through the proper testing, companies get the assurance that their product and packaging will perform in the intended way to safely move through the supply chain and safeguard public health. And 483s? Forget about ‘em.
Discover the latest breakthrough packaging technologies shaping the pharmaceutical sector. This report dives into cutting-edge innovations, from smart containers that enhance patient safety to eco-friendly materials poised to transform the industry’s sustainability practices. All from PACK EXPO. Learn how forward-thinking strategies are driving efficiency and redefining what’s possible in pharma packaging.
Researched List: Blister Machines for Life Sciences
Need a blister machine for life sciences packaging? Our curated list features companies serving pharmaceutical, medical device, nutraceutical, and cosmetic industries. Download to access company names, locations, machine specifications, descriptions, and more.
