March 20th, 2019 by Aryo A. Nikopour
By Aryo A. Nikopour, Nitto Avecia Pharma Services
Extractable and leachable safety assessments can be some of the most challenging review issues in an FDA application, according to an agency official.1 That is because they require a coordinated effort between review staff from Chemistry, Manufacturing, and Controls and Toxicology.
FDA’s Dan Mellon, a toxicology supervisor with the Center for Drug Evaluation and Research, addressed these issues during an interview with the Parenteral Drug Association.
On the industry side, a coordinated effort is also necessary to conduct successful extractables and leachables studies, according to Nitto Avecia Pharma Services.
The contract development and manufacturing organization addressed this need for coordination in a 2018 webinar hosted by Xtalks.2
Answers to audience inquiries were provided by Aryo A. Nikopour, Nitto Aveci Pharma Services’ Senior Vice President of Scientific and Technical Services. For more information, please click here for the webinar recording: A Systematic Approach to Extractables and Leachables.
Below is the Q&A from the webinar:
QUESTION: At what point in clinical development should extractables/leachables testing be completed according to the FDA? And does EMA consider it differently?
ANSWER: Very good question. Generally, people postpone the E&L studies until Phase 3 for a variety of reasons (e.g., changes in the final formulation or container/closure). My recommendation is to at least commit to controlled extraction and model extraction studies to reduce the risk. It is established in literature that certain potential leachables from PFS may directly impact product quality when used for a mAb drug product (e.g., causing aggregation of the protein). Waiting until late in the process before determining extractables and leachables is a risk. If you’re using single-use systems, my advice is you need to look at your Phase I study supplies. You need to get there early in development and see your potential issues.
As far as the FDA versus EMA, I have nearly 30 years of experience supporting companies in the EU and U.S., and I haven’t seen any differences in how the two health authorities approach extractables and leachables.
QUESTION: During the identification of leachables, what percent confidence is deemed acceptable?
ANSWER: When working with a GC-MS library — even if the match factor is 100 percent — you need to confirm it by finding an authentic standard. But there are times in the early part of the extractables studies when you may rely on a match factor and surrogate standards to move forward.
QUESTION: Do I have to worry about extractables and leachables testing when it comes to medical device packaging?
ANSWER: With medical devices, it depends. We have completed E&L testing for some devices. For instance, a marketed surgical device used a laser and FDA asked the manufacturer to do some leachables testing. So, we had to come up with a very special design to collect the leachables because they were all volatiles. After a series of studies, we identified some serious leachables caused by heat generated by the laser. And so, it’s required for certain devices. We have also done studies for multilayer disposable bags sold to hospitals. For these medical devices, we determined material was leaching into the products, causing potential safety issues.
QUESTION: If I’ve previously conducted an extractables and leachables study on some form of packaging, do I need to test it again when I plan on using the same packaging for another drug product?
ANSWER: Good question. I showed you during the webinar a prefilled syringe model extraction study. That was an extensive study with four different types of prefilled syringes from different manufacturers and using different buffers. The goal was to do the model extraction studies and then identify if it’s suitable for various products. And then the only thing that needs to be repeated in my opinion would be the leachables study. Because every drug is different you need to also look at the impact of the drug interaction with the material. So yes, you can rely on the past controlled extraction studies and model extraction studies. But you have to do the leachables part.
QUESTION: Is a glass delamination study part of a leachable study?
ANSWER: Yes, it is. Glass delamination is a serious issue in pharmaceuticals and biopharmaceuticals. Each component of glass containers is potentially the source for an extractable and/or leachable. Further guidance is available from U.S. Pharmacopeia (USP) chapter 1660 Evaluation of the Inner Surface Durability of Glass Containers.
Aryo A. Nikopour is Senior Vice President of Scientific and Technical Services at Nitto Avecia Pharma Services.
- Stauffer R. Strategies to Address E/L Container Closure Challenges. PDA Letter, August 23, 2018.
- Xtalks Webinar: A Systematic Approach to Extractables and Leachables: A Review of Guidance from the Industry, April 3, 2018.
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