All Eyes on E&Ls

What is your role at MilliporeSigma?

I moved to MilliporeSigma around four years ago from a contract research organization, where I was working as a project manager in the field of extractables and leachables (E&L) studies. Today, as Manager, E&L and Packaging Materials at Site Management Analytics, I run a laboratory where, unsurprisingly, the primary focus is on E&L, coupled with some other packaging analysis work. Our services are available to all of MilliporeSigma’s businesses, but much of our work is performing extractables studies for our life science business, which supplies single-use equipment and process materials. We also do quite a bit of work in the healthcare business.

Why is E&L so important for the industry and so fascinating for you?

E&L is a crucial topic for everyone in drug development because we all want to ensure that products and drugs are safe for patients. But from my perspective, it is also a very intellectually rewarding area to work in. Every material you examine is different, with different polymers, different uses, and the need for different extraction methods depending on the material. I am never bored! Once the first studies have been done and I’ve extracted the materials, the real puzzle begins. I rarely know what I am looking for, so I have to use a good number of orthogonal analytical techniques to cover everything that is in the extract.

Some confusion persists in the E&L space... Why?

Many people use the words “extractables” and “leachables” synonymously, but there’s a big difference between the two. An extractable is a chemical entity, both organic and inorganic, that will extract from components of the packaging or process system into a solvent under controlled conditions (we usually experiment with harsher conditions than normal use) – we’re talking about high temperatures, extended contact time, and the use of organic solvents or those with strong PH values. Extractables are important because they help us to identify the potential for leachables. Leachables are those chemical entities that migrate from components into the drug product over its lifetime, or during manufacturing.

E&Ls can theoretically come from any product contact material, such as primary packaging or process systems in contact with the drug product, but will vary depending on the activity of the material. A material like Teflon, for example, is very inert and we tend to only observe a few contaminant peaks (compounds) during our analytical tests. Natural rubber, on the other hand, can produce hundreds of peaks, all of which require thorough investigation.

Leachables can be a big risk to patient safety. In extreme cases, they can have a toxicological effect. They can also interact with the drug product, potentially reducing efficacy.

What do the regulators have to say about E&L?

E&Ls must be evaluated when determining the purity of the final product, but there are no clear regulatory guidelines on how to go about the analytical process. For primary packaging, there is USP <1663> and <1664>, but for process materials and single-use equipment, there is no real guidance – and that can be quite frustrating for the industry. Some industry working groups, such as the BioPhorum Operations Group have examined the issue and published a standardized protocol for performing E&L studies and defining thresholds for how deep your analysis has to go; however, not everybody uses this protocol, and so it can be difficult to compare results between two different vendors when trying to choose the right product.

What is MilliporeSigma’s approach to E&L studies?

Actually, there is no one-size-fits-all approach for us either, because we have three business groups within MilliporeSigma that all need to deal with this topic. In the healthcare group, we must guarantee the safety of drug products and the E&L risk during production and packaging. In the life sciences group, we need to provide pharmaceutical customers with E&L information about MilliporeSigma’s products, such as single-use systems. We conduct extractable studies according to standardized protocols, but if the information is insufficient then MilliporeSigma also offers BioReliance® Validation Services, which generate more E&L data in line with what the customer wants.

Generally, after performing our first extractables studies, we summarize the results, which includes the identification and quantification of extractables. Then we hand over the results to our tox department, which calculates a permitted daily exposure limit (PDE) and compares this with results from the extractable studies. If the amount of the extractables is below the PDE, then you’re safe. If it’s above, then you have to perform leachables studies and look directly into the product. Depending on the results of these studies, it may be necessary to change something in the packaging or the process.

For our performance materials group, where product performance is crucial and can be influenced by leachables, we need to be very specific in what we are looking for. Some leachables can have a negative effect on performance. And sometimes the limits for these substances are much lower than the toxicology limits for drug products.

What are the main techniques used in your lab?

We rely heavily on combinations of chromatography to separate substances and mass spectrometry MS to elucidate those substances. We use both normal and head space gas chromatography GC–MS, as well as liquid chromatography LC–MS, depending on the nature (molecular weight, for example) of the compounds, but we may also need to work with a number of other analytical techniques to cover all possible entities, such as inductively coupled plasma ICP-MS for elemental impurities or ion chromatography for ionic species.

We also perform some other a analytics, such as total organic carbon and non-volatile residues, to find the total amount of extractables present in the extract. In addition, there are some material specific analytical techniques, such as the determination of nitrosamines for rubber stoppers, for example. For nitrosamines, the limits are so low that conventional techniques don’t capture them, so we have to use specialist analytical techniques, such as GC-TEA for nitrosamines or LC-MS/MS for perfluorinated compounds.

What is the biggest challenge you face in your role?

The biggest challenge is handling all of the requests I receive! Our laboratory is so important for Merck’s businesses – and the topic of E&L is only becoming more crucial as time goes on. We started in 2014 with just two people in the lab. There are now eight of us and there are also more people in the specialized labs that perform more detailed structure elucidation. We have worked hard to recruit people with the right skills. A good analytical background is key, of course, as is knowledge about the product and the materials that come into contact with drug products, including pre-treatment steps such as sterilization. You need to understand how substances from the materials can be extracted and how they behave in the extract, and be able to set up a good study design. If the study set up is not adequate, then all the results you gain are useless. 

Can E&Ls ever be completed eliminated?

I don’t think so. I don’t see E&Ls ever going away, despite the huge progress that has been made with companies really understanding their products, and developing specialized materials or coatings. Single-use products are becoming more popular in the pharma industry, but they are still relatively new and I don’t think all suppliers out there at the moment can support their customers with good E&L data.

There will also always be changes in certain products. For example, if you look at resin manufacturers, they are often looking for new additives that can help them control costs. And when there is a change in the additives to the polymer, new compounds or substances will show up during extractables studies that we need to investigate.

However, I think the industry is constantly acquiring new knowledge around E&L, which can only be a good thing. In time, if we can move to more standardized approaches, then it will be a huge benefit to the industry, saving many companies a lot of time and money.

What is the biggest challenge you face in your role?

The biggest challenge is handling all of the requests I receive! Our laboratory is so important for MilliporeSigma’s businesses – and the topic of E&L is only becoming more crucial as time goes on. We started in 2014 with just two people in the lab. There are now eight of us and there are also more people in the specialized labs that perform more detailed structure elucidation. We have worked hard to recruit people with the right skills. A good analytical background is key, of course, as is knowledge about the product and the materials that come into contact with drug products, including pre-treatment steps such as sterilization. You need to understand how substances from the materials can be extracted and how they behave in the extract, and be able to set up a good study design. If the study set up is not adequate, then all the results you gain are useless. 

Can E&Ls ever be completed eliminated?

I don’t think so. I don’t see E&Ls ever going away, despite the huge progress that has been made with companies really understanding their products, and developing specialized materials or coatings. Single-use products are becoming more popular in the pharma industry, but they are still relatively new and I don’t think all suppliers out there at the moment can support their customers with good 
E&L data.

There will also always be changes in certain products. For example, if you look at resin manufacturers, they are often looking for new additives that can help them control costs. And when there is a change in the additives to the polymer, new compounds or substances will show up during extractables studies that we need to investigate.

However, I think the industry is constantly acquiring new knowledge around E&L, which can only be a good thing. In time, if we can move to more standardized approaches, then it will be a huge benefit to the industry, saving many companies a lot of time and money.