October 5, 2023
by Jesse Harris, Digital Marketing Coordinator, ACD/Labs
Getting Control of Extractables and Leachables Data
Many medicines come in a container, whether a bottle, blister pack, syringe, or inhaler. We rarely think about these container-closure systems, but what if they adversely interacted with our medicines or slowly released a toxic contaminant?
Extractables and leachables (E&L) is a specialization within pharmaceutical development that studies these questions. These researchers must bring together physical, chemical, and safety data related to the materials used to manufacture, package and deliver medicines to ensure drugs are safe and effective. Unfortunately, this is a major challenge due to the variety of file formats and data sources scientists must handle.
The Extractables and Leachables Safety Information Exchange (ELSIE) is a consortium formed to support E&L research. AstraZeneca was a founding member of ELSIE. One of their initiatives has been to enable member organizations to share knowledge. In March 2023, ELSIE and ACD/Labs announced they had partnered to create a searchable knowledge repository of pre‑competitive E&L data called the ELSIE Knowledge Base.
Stephen Warren is an Associate Director in Inhalation Product Development at AstraZeneca and has two decades of pharmaceutical experience with much of it spent in the field of E&L. Stephen is a member of the ELSIE Board of Directors and active in the ELSIE Materials Information Working Group. We talked to him about the ELSIE Knowledge Base to understand how it meets the needs of E&L researchers.
How did you get into extractables and leachables research?
I fell in love with chemistry in school. I’m from North Carolina, which is a rich area for pharmaceutical development. After graduating, I found a job in the area and got the opportunity to go into inhalation chemistry, which I’d never done before. It was around 2005 when I first got into E&L work. Around that same time, E&L was becoming a hot topic area. Back in 1999, the FDA issued its draft guidance for container-closure systems that stressed the need to consider extractables and leachables but with no specific guidance on what that entailed.
Eventually, I was hired by a small start-up because of my inhalation expertise. I came in to support inhalation testing, but they were also beginning their E&L program to address the leachable risk associated with inhalation drug products which are one of the highest risk dosage forms according to the FDA draft guidance. It was a very small company, and they said, “Based on your resume, we know you’ve got some experience in this area. Can you look at some of the data we’re generating at the CRO?”
From there, I transitioned out of the lab to focus on E&L, and it took off. AstraZeneca later acquired the start-up, which is how I joined.
Why are extractables and leachables particularly important for inhalation-based medicines?
With inhalation medicines, you’re targeting the lungs. You’re dosing a diseased organ as well as providing an avenue for the drug to get directly into the bloodstream for systemic distribution throughout the body, which poses risks.
With a metered dose inhaler your formulation is contained within the inhaler, which has plastic and elastomeric components in direct contact with an organic propellant system. These organic propellants are safe for use, but they have the propensity to pull substances out of the materials when they interact with the plastic components that make up the inhaler. Chemicals can leach out over time that can potentially be dosed to the patient.
For solid oral dosage forms the risk of leaching is lower since it is a solid-solid interaction between, for instance, tablets and a plastic bottle.
E&L is a specialized field with unique data needs. What kinds of data are most important to specialists who work in this area?
Oftentimes we’re dealing with the final components. We work closely with engineers, who are looking at it from a functionality perspective: they need something that’s not going to degrade, that’s going to give them the flexibility or rigidity and the stability needed.
This is when E&L should first be considered – during material selection. What is the material made of? What could potentially come out of it? Could leachables interact with the drug product leading to an adverse quality impact? An interaction that could change the properties of the active ingredient itself and reduce efficacy or the ability to deliver the API to the patient as intended.
Couple that with the safety element. You want these plastic components to serve their purpose, to protect and deliver the drug product. You don’t want them to release chemicals that could potentially be dosed to patients leading to a safety risk.
We care about all this information, but it can be tough to access. We work closely with our suppliers, but these materials are, more often than not, proprietary blends. Suppliers are often reticent to share the material formulation details. They are also part of a complex supply chain, which may include other suppliers further up the chain who aren’t familiar with the standards of the pharmaceutical industry.
Having good relationships with your supplier to get material information is critical to ensure that you have the appropriate procedures in place to assess and control risk. We need to know whether we must develop test methods to obtain or confirm the information ourselves.
Once you have that chemical knowledge of what is being extracted or leaching, then you work with the toxicologists to perform an appropriate assessment. That’s why this database is fantastic. It brings the two together for assessing the potential risks. Are there concerns around toxicity? Carcinogenicity? Sensitization concerns? We want to know the toxicological endpoints that could be problematic for a particular chemical entity. The database seeks to provide both the chemical and safety information associated with materials and extractable compounds in one place.
We certainly don’t want to be surprised by what could leach out of the container closure system and into the drug product. You don’t want to get your product on the market and give it to a patient to then find out that chemicals are leaching in a way you did not expect.
Before ELSIE, how would you manage this information?
It can be tough in a large organization. There are so many different functions and areas all contributing. Trying to get our data catalogued and harmonized has been a challenge. How can we best manage data from our suppliers or data that we generate? Right now, we are working on making this information more easily accessible via the appropriate database.
For instance, one area of the organization might be using a SharePoint application. Another department could be using a simple Excel spreadsheet or even a JMP file. How do you communicate this? How do you connect it? You might have knowledge of existing data through your interactions with others, but there is often more information available that you’re just not aware of.
There’s that underlying concern that you know information exists, but who do you need to connect with to find it? That’s the worst, because it can lead to wasted resources if you end up generating duplicate data.
How do we bring all this knowledge together in one place? That’s why AstraZeneca was interested in what ELSIE was doing with the Knowledge Base. Not only can we bring our relevant information together in one place, but we can also work with others to expand the knowledge pool. We are invested in ELSIE, and we are doing everything we can to support this effort and contribute, but there is also interest in leveraging this work for our internal use and database development.
How does the ELSIE Knowledge Base address the challenges and needs of E&L researchers?
Prior to this effort, ELSIE had a repository for a fair amount of safety information, which was extremely helpful, but there has been a gap when it comes to material information.
Now, the Knowledge Base is being expanded to include materials information. This will allow us the means to better access information currently scattered across our organization as well as the member companies and potentially suppliers.
We work with a mix of analytical data, materials information, and safety information to assess the risk of E&L. The ELSIE Knowledge Base aims to put this in one place, and that’s fantastic!
Member companies contribute the data to the ELSIE Knowledge Base. Why is AstraZeneca contributing data to the consortium?
The database only works if we contribute. There’s a wealth of knowledge in AstraZeneca. I see it; I have access to it. But there’s more out there that can be and should be shared for the betterment of everyone. That’s what I want to bring to the surface within AstraZeneca and encourage others to do the same.
The intent of the Knowledge Base initiative is to serve as an educational tool. It can be a first step in gathering information for risk management or to develop the appropriate methods to ensure that your product is safe and doesn’t present a risk to product quality or patient safety.
The key to success will be based on company contributions. If you build this and nobody contributes, we will have to rely on what is already in the public domain. The more information companies can feed into the Knowledge Base, the better it is for everybody. It will only be as good as we make it. Every company has sensitive information that needs to remain internal, but we should strive to share the generic high-level “extractables” information that is deemed appropriate.
Do you also see this as an opportunity to produce safer medication in the long run?
Absolutely! More information and greater understanding are what drives improvements to your processes and practices. It can aid us with material selection and risk assessments, and provide more info around chemical safety, which is the center of much debate – establishing appropriate, data driven safety thresholds.
There’s a bit of uncertainty around what needs to be done and what requirements to measure against. If we can build out this Knowledge Base, it can hopefully address some of these issues. Improving upon current recommendations and requirements, supporting E&L activities across industry, ultimately benefiting patients in the end.