Two growing trends in pharmaceuticals prompted the development of a new high-performance pouch that addresses the mechanical and purity challenges of packaging a liquid biologic or vaccine that requires low temperatures. The Gore Sta-Pure Flexible Freeze Container maintains package integrity after freezing at ‑86 deg C. (‑123 deg F) and minimizes product loss due to package failure due to its durable design.
The company promotes the sterile pouch as able to withstand temperatures like those found “at the equator of Mars,” “at the South Pole” or “at the top of Mt. Everest.” That got my attention.
How is this possible? Five years in development, the Gore Sta-Pure Flexible Freeze Container is made of a proprietary biocompatible fluoropolymer composite film with an extremely low extractables profile. Additionally, the pouch itself is specially designed for extra strength.
Why is there a need for this when biopharmaceuticals are not currently shipped to Mars, the South Pole or Mt. Everest? Two reasons:
The first is the growing trend of biologic drugs, which by nature require cold-chain handling to maintain stability and efficacy. According to the 2018 Frost & Sullivan report Market Insight on Cold Chain Handling of Biologic Drug Substances, 49% of all the new drug and vaccine approvals issued by the Food and Drug Administration (FDA) in 2017 were temperature-sensitive products. And total global revenues of cold-chain pharma products in 2017 was greater than $280 billion (with a “b”)—and has grown at twice the rate of the total pharma market. Frost & Sullivan predicts there will be more than 400 new drugs and vaccines that will require cold-storage handling by 2024.
The second reason is the market trend to centralized production of active ingredients, which often means shipping them in bulk to a separate location for manufacturing the final drug. On the legislative agenda for many countries, making drugs locally offers several benefits beyond safety. It can often speed up distribution for critical meds (like vaccines), allow for the smaller batch sizes indicative of final drug production versus bulk active ingredients and improve a product’s economics. It might also give pharmaceutical companies the option of working with local contract manufacturers/packagers.
These two trends mean there is a strong demand for packaging that can store and securely transport frozen biopharmaceuticals and vaccines.
But polymer-based packaging faces challenges in low-temperature environments, such as becoming brittle and breaking—creating costly damage and product losses. But trying to solve that by adding layer after layer of packaging is costly and inefficient.
Also, typical additives used during plastic packaging manufacturing could affect material purity and leach into the product.
Joe Cintavey, product manager and specialist for the flexible freeze containers, explains more about how the Gore Sta-Pure Flexible Freeze Container addresses these challenges.
Is this Gore’s first product for frozen bulk drugs?
Cintavey: Yes, this is Gore’s first product for frozen bulk drug substance, although the company has a portfolio of products in the biopharmaceutical space, including high resilience tubing, lyophilization trays, and chromatography columns and syringe plungers that eliminate the need for silicone as a lubricant.
Do you have any numbers on the typical amount of frozen bulk product loss annually due to packaging damage or lack of integrity?
Cintavey: When we developed this product, we worked closely with biopharmaceutical manufacturers to understand the challenges they had with bag breakage during cold chain handling. Based on what they tell us, we estimate that the loss due to packaging damage or integrity issues is between 3% and 5% of containers, across the typical size bags (from 1 to 20 liters).
How much product damage do you anticipate Gore Sta-Pure Flexible Freeze Containers can prevent? Can you put a dollar value or percentage savings on that?
Cintavey: It is difficult to estimate a dollar value because the value of drug products varies so widely by customer, and each customer measures it differently. For instance, a single container of frozen bulk drug substance could range in value from $10,000 to $500,000. The value of using the Gore Container is in reducing the risk of losing product during handling or transport. Each customer does their own in-depth cost/risk analysis, but according to their information, it’s estimated that between 3% and 5% of packages are lost or damaged.
Do you have any patents pending or issued on the material, the package or the manufacturing process?
Cintavey: Gore’s expertise is in our ability to manipulate fluoropolymers like polytetrafluoroethylene (PTFE), the base material of the container, and engineer it to have particular qualities, depending on what’s required for the application.
In this case, we’ve developed a proprietary, high-strength, high-purity composite fluoropolymer material and engineered it into a patented container design to make a package that remains strong and durable at cold temperatures.
For more general information on PTFE, see www.gore.com/about/technologies#a-closer-look-at-eptfe.
What, if anything, is different or unique about how this bulk container is manufactured?
Cintavey: Traditional polymer-based materials used for bulk drug storage are proven to have problems with breakage at cold temperatures. We’ve heard this over and over from our customers. The Gore Container is unique because it combines a durable fluoropolymer composite and an innovative, patented container design to protect bulk drug product.
How does the bag design increase package robustness?
Cintavey: The issue with polymer-based packaging at frozen temperatures is a loss of mechanical integrity, whereby materials can become brittle at frozen temperatures, and it results in container breakage and leakage. This PTFE composite material is very durable at cold temperatures, and in combination with the patented container design, we’ve developed a more robust package.
How much does this container cost? How does that compare to alternatives?
Cintavey: Gore designs products that do what we say they will do, every time. That’s the promise we make to our customers. We know that Gore is not the lowest-cost alternative in this space, but we consider the Gore Sta-Pure Flexible Freeze Container a high-value, high-performing product, and we have been told by our customers that they consider the end-to-end value of the investment they are making in risk reduction worthwhile.
Why is it necessary to do 100% integrity testing and visual inspection of the containers during/after manufacturing instead of sampling for quality assurance?
Cintavey: Gore’s mindset around “Fitness-for-Use” provides excellent perspective on this question. Fitness-for-Use means that Gore’s products will do what we say they will do, every time. Thus, the company often develops tests that go beyond industry standards, because its own internal promise is so stringent. So in-depth application testing during development and 100% integrity testing and visual inspection is a strategy that Gore has chosen to ensure the very best product for our customers.
What existing testing protocols did you use?
Cintavey: If an external test existed and was aligned to how the product might be used in cold chain handling, we tried to use it. For example, we performed ISTA 3E distribution testing to simulate frozen container shipping. That was an exception though—we had to develop a lot of our own internal protocols because existing test protocols did not simulate the actual handling of a filled, frozen bag product.
For instance, test standards exist for frozen material strength alone but for a frozen, filled container as it would be handled, or likely mishandled, in use. This goes back to our Fitness-for-Use principle and ensuring that the product will do what we say it will do, every time.
A filled pouch enters the freezer. The robust container design was tested to withstand up to five freeze/thaw cycles.
How many freeze/thaw cycles can the package withstand and why is that important? Your website says it was tested up to five cycles. Is that typical for these drugs?
Cintavey: Every end-user has their own test protocols. In working with manufacturers, we found that these bags were typically used once or twice at most. To ensure durability, we added a safety factor and tested out to five cycles.
Do you have any customers yet?
Cintavey: We think it is progressing well, as several top biopharmaceutical manufacturers are testing this product. The time it takes for each company to evaluate the bag with their drug varies and the Gore Container was only introduced in late 2018.
What existing testing protocols will customers use?
Cintavey: Each end-user has their own evaluation protocols. We’ve tried to align our product testing with handling protocols common in the industry, where they existed. We have an extensive validation guide that also includes many of our internal protocols, including drop and impact testing, freeze/thaw profiles, and integrity and distribution testing, that we think customers will find useful during their evaluations.
What are the challenges of testing and how are these overcome?
Cintavey: For this product, the challenge for end-users is that there are no standard tests to evaluate how filled, frozen containers will perform during cold chain handling. This makes it difficult to compare products like the Gore Container against other products, other than by actually dropping bags and seeing if they break.
The packages are supplied as Freeze Container Assemblies inside two Tyvek pouches, and are ethylene oxide (EO) sterilized. How does this presentation change the typical handling and filling process for pharmaceutical companies packaging active ingredients?
Cintavey: Our Container Assemblies are pre-sterilized and packaged according to industry standards for similar products. The packaging system was evaluated per ISO 11607 Part 1 and is described in detail in the product validation guide.
Is there anything different, unusual or unique about the package design that improves product dispensing/handling during manufacture of the final drug?
Cintavey: No. The Gore Sta-Pure Flexible Freeze Container Assembly has standard-size tubing and fittings for easy integration into end-user filling, freezing and handling processes. Optional hard-shell carriers are available for easier handling and are designed to maximize space in both blast and plate freezers. The container comes in three standard sizes, with additional sizes and tubing and connector configurations being developed.
Do you have results on your extractables study yet? If so, what are they? If not, when will this data be available?
Cintavey: We conducted an internal evaluation and found that the Gore Container has an extremely low extractables profile, as expected. We’ve also completed a BPOG analysis and have the summary report available for end users upon request.
[Note: The BioPhorum Operations Group (BPOG) is a collection of approximately 50 companies encompassing 80% of the global commercial biopharmaceutical capacity. Collectively they’ve published “Best Practices Guide for Evaluating Leachables Risk from Polymeric Single-Use Systems Used in Biopharmaceutical Manufacturing” and “Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing.” These documents are gaining traction across the pharmaceutical and medical device industries as a “one stop shop” for extractables and leachables testing principles but are not yet fully accepted by FDA].
What are the numbers for leachables?
Cintavey: Leachables data can only be collected on the actual drug product so leachables testing is something our customers do themselves. Gore does not typically use actual drug product for testing. Instead, to provide benchmark information, Gore performs extractables testing with fluid solutions commonly accepted by the pharmaceutical industry.
Where are Gore Sta-Pure Flexible Freeze Containers made?
Cintavey: They are manufactured in the U.S. in Elkton, MD, at our dedicated manufacturing facility that is certified to ISO 13485 and ISO 15378. All manufacturing, assembly, inspection and packaging of the assemblies is conducted in a controlled environment, which is maintained to ISO Class 7 requirements.
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