The Future of E&L – A world without extractable studies?

The field of E&L has undergone a number of significant changes over the years and is likely to continue to evolve in the future. It is a field that has grown throughout its short history. The potential impact to human health and product quality (from materials used to manufacture, store and deliver products) is increasingly a concern to regulatory bodies.

In order to understand what the future direction of extractables and leachables might look like, it is important to understand how the field has developed over the last 30 years. What the regulatory trends have been and what scientific advances have been made, that have led the field to where it is today.

The Evolution of E&L

The field of E&L developed in the early 90’s from the discovery of contaminants in drug products which were attributed to the packaging material. Specifically, elastomers used in metered dose inhalers leaching polycyclic aromatic hydrocarbons into products. This led to the release of the US FDA’s “Guidance for Industry: Container Closure Systems for Packaging Human Drugs, Biologics, Chemistry, Manufacturing and Controls Documentation”, May 1999. This document stated that “Packaging components should be constructed of materials that will not leach harmful or undesirable amounts of substances to which a patient will be exposed when being treated with the drug product.” However, this guideline provided little specific guidance on how this should be achieved. This was followed by the EMA’s “Guideline on plastic immediate packaging materials”, May 2005. Like the FDA document this guideline provides little specific guidance on what is required. The field of E&L has rapidly grown and evolved with the release these guidelines.

The main focus for labs performing extractable and leachable studies in the early days was on the development analytical methods, building analyte libraries, understanding the impact of different extraction methods and conditions on the extractable profile, validation of targeted methods and understanding the correlation of extractables and leachables.

In September 2006, the Product Quality Research Institute (PQRI) released the following document “Safety thresholds and best practices for extractables and leachables in orally inhaled and nasal drug products”, which provided more detailed guidance on the analysis and assessment of extractables and leachables (E&L). The main focus of this document was orally inhaled and nasal drug products, such as metered dose Inhalers, dry powder inhalers, inhalation solutions and nasal sprays.

This document set the foundation from which modern extractable and leachable studies are based. It introduced key concepts from the design of extractable and leachable studies to the reporting and evaluation of the data.

The majority of guidance documents that followed this document, built upon these principles and/or expanded them into different therapeutic areas or industries. Some of these documents have also had a large impact on the field of E&L.

Documents such as:

The BioPhorum extractables protocol - with the increase in biopharmaceutical products entering the R&D pipelines organisations started to focus on understanding of extraction conditions which more matched the process fluids and manufacturing processes. Due to the large number of different components used in biopharmaceutical manufacturing processes and the large number of potential options for each component many biopharmaceutical companies using single use manufacturing systems wanted to be able to compare the extractable profiles between different vendors or set ups. This could be costly for individual organisations to perform given the number of single use components that might be used in a given manufacturing process. Biopharmaceutical companies were requesting more information from suppliers, but in order to make comparisons as part of material selection, it was important for studies to be designed in a similar manner.

In November 2014 the BioPhorum (formally BPOG Extractables Work Group) published the “Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing” this was updated in April 2020 based on learnings from a large number of studies historic studies performed using the original protocol.

The risk-based approaches to defining testing strategies for single use manufacturing components presented in the BPSA’s “Recommendations for Extractables and Leachables Testing” published in 2008, BioPhorums “Best practices guide for evaluating leachables risk from polymeric single-use systems used in biopharmaceutical manufacturing” published in March 2017, and the USP monographs <665> and <1665> “Plastic components and systems used to manufacture pharmaceutical drug products and biopharmaceutical drug substances and products” released in May 2022.

The International Organization for Standardisations “Chemical characterization of medical device materials within a risk management process” ISO 10993-18 published in January 2020. Which lead to a greater focus on the qualification of the non-targeted analytical methods used in extractable and leachables studies.

So, what might be next? Where might the previous developments lead the field of E&L?

The near-term Future

Over the years the number of E&L studies performed has increased dramatically. In the near future we are likely to continue to see the number of E&L studies performed increase. The increase may result from new requirements to specific product types or as new regulations come into force.

The release of ICH Q3E is likely to have an impact on the industry and will hopefully bring further clarity to the field of extractables and leachables.

There will be a continued focus on improving the analytical methods and the accuracy in identification and quantitation. Collaborations between instrument vendors and analytical labs are particularly important to help drive these improvementsforward, for example instrument vendors such as Waters are helping analytical labs build analyte databases which help improve the accuracy of identifications. Additionally, as improvements in the hardware and software of analytical equipment are made this will continue to drive improvements in the analytical methods.

Automation of sample work up is becoming more popular and as vendor software improves automation of data processing and analyte identification will drive efficiencies in E&L studies. However, the true benefits of automation are still a number of years away from being fully realised. It is still very important that identifications, and to a smaller extent integrations, are cross checked by an expert to ensure the automated process have made the correct assignments.

Knowledge management is an integral part of extractable and leachable analysis and evaluation. Whether it is an analytical lab utilising analyte libraries or knowledge databases to help with identification of analytes in a sample. Project teams gathering data from suppliers or other projects to define their E&L testing strategy. Or toxicologists building databases of safety information to improve the evaluation of analytical data. Knowledge management will become increasingly important.

The longer-term future

Where might all this lead us in the longer-term future?

Through more sophisticated knowledge databases and mathematical modelling, the number of extractable and leachable studies being performed could well reduce. We are already seeing this to a small extent in the biopharmaceutical field with the reduction in testing performed on single use components used in manufacturing processes. Suppliers of these components are testing the components in a standardised format which is then provided to many different end-users. The data can be used by the end-user to evaluate the potential risk from using the component. As data is shared between a number of organisations, testing isn’t repeated multiple times.

Industry is still a long way from reducing the number of extractable and leachables performed, for many good reasons, not least because our knowledge of the materials used and the process which cause chemical species to migrate is still not mature enough for regulatory agencies to not require testing. Overtime it is likely that our understanding in the following areas will increase through continued testing and better knowledge management:

• How changes to the manufacture of polymers impact the chemical species which migrate from a material. The differences between polymer suppliers, grades and batches are well understood and all unknowns are identified
• The effect different extraction or in-use conditions have on the chemical species which migrate.
• Which extractables will become leachables
• How to make analytical methods more accurate and precise
• What reaction products are generated depending on the product
• The effect leachables have on patient safety or product quality and efficacy

A lot of work has already begun in many of these areas and our understanding will improve over time. As our knowledge base increases, artificial intelligence could be used to create models which could be used instead of analytical testing.

What are the challenges

We are a long way from eliminating the need for extractable and leachable studies. A lot of evidence will be required to convince regulatory authorities that E&L testing isn’t required. Especially when it comes to patient safety.

Building enough knowledge so that one day E&L studies would no longer be required is very challenging. Even though some materials may have been tested hundreds of times by a number of different companies, industry has found it difficult to share this data more freely between each other in a collaborative manner. There are a number of reasons for this including, intellectual property relating to the data and test articles, and the perceived commercial advantage across industry of not sharing data more freely. It can be costly to generate extractable and leachable data, so testing is often performed on a small number of samples.

Understanding which chemical species which actually migrate into pharmaceutical products or end up in humans (leachables) is more challenging than understanding which chemical species migrate from a material under controlled laboratory conditions (extractables). There are a number of reasons why performing leachable studies on certain product types is challenging. This includes for example: products that have formulations make it challenging to detect leachabes; products which are only available in small quantities, such as Cell and Gene therapies which are specifically made for each patient; products which directly contact humans, such as implants, which makes performing a leachable very difficult as this would involve sampling from humans.

Additionally, there will always be innovations in the materials and formulations of products which will likely require some kind of testing.

Conclusion

Could the future of E&L be a day where very few if any extractable and leachable studies are required?

In reality probably not, but the knowledge generated in the field of E&L is continually growing and we have many of the tools needed to make this a reality. The future of E&L is more likely to be a world with fewer extractable studies. Currently a larger number of extractable studies are performed compared to leachable studies. Thus, the extractable knowledge base is growing more quickly.

Generating leachable data is more challenging from an analytical point of view. The variety of matrices and potential matrix interferences mean more sophisticated analytical methods are required. For some products generating leachable data is nearly impossible because of the nature of those products e.g., medical implants. It is also difficult to build a leachable knowledge base because of the variety of ways materials are used and the variety of products they are used with. The migration of species into drug products during typical use and the potential interactions with pharmaceutical products will be much more challenging to model.

The knowledge gained from testing materials over the years may eventually lead us to a world where the number of extractable is reduced, so that testing is focused on innovations in material science, periodically verifying well characterised materials and performing leachable studies.

Databases which contain good quality data sets, will become increasingly important. Generation of such databases is most effective through collaboration. Groups such as ELSIE have seen this benefit and have built databases based on E&L safety information. There are many other well-established collaborations within the field of E&L. Healthcare companies are collaborating with each other to define what they need as an industry from material suppliers and analytical labs, toxicologists are working together to better understand the toxicity of specific chemical species and triggers for toxicological end points. Analytical labs are working in a collaborative manor with customers to deliver better designed studies and industry is working with software developers to develop better software for processing data and developing databases.

COVID have certainly highlighted the importance of being able to accelerate the development of drug products. Accelerated development of a drug can add increased pressures on project teams to deliver data, which would normally take a number of years to generate, in a shorter time frame. Using well characterised materials which have extractable data can help speed up the development process.

Safety or quality concerns related to specific chemical species or group of species will continue to evolve as our understanding of the impact of chemicals improves. This will inevitably lead to focused testing, such as the current case with nitrosamines.