In the biopharmaceutical industry, extractables and leachables have come under the spotlight as stainless steel manufacturing systems have given way to single-use assemblies in manufacturing operations.
Yet, there is some confusion as to what the terms 'extractables' and 'leachables' actually mean. They are often talked about interchangeably, but there are actually distinct differences between the two.
Extractables studies are an assessment performed on a material. They are performed to identify substances that a patient may be exposed to and are typically conducted using 'worst-case' conditions.
Leachables studies are an assessment performed on the drug product to identify substances that patients are potentially exposed to and are typically conducted using 'true process' conditions.
Learn about different approaches to extractables and leachables testing in our white paper: Demystifying Extractables Testing
So why are extractables and leachables so important?
Due to the nature of plastics and the potential release agents and plasticizers used in their manufacturing processes, there is potential for some of these to be released into the biopharmaceutical process stream.
In a single-use assembly, numerous components have the potential to contribute to extractables and leachables. These include tubing, connectors, bags, bottles and filters. Therefore, the whole assembly should be assessed collectively.
Every plastic will have some degree of compound leaching or release, but each compound may not be given equal importance with regard to what is allowed or is applicable to the process stream.
As there is no 'one size fits all' with regard to what is and isn't allowed for many compounds, end-users need to assess the risk based on a number of factors.
Risks and assessment can be categorised into:
- Those which impact on patient safety, for example toxicological effects
- Those which relate to technical factors, such as process control and regulatory approval
- Those which relate to social factors and perceived negativities, such as social media trending of compound 'buzz words'.
Areas of responsibility
Vendors usually take on the responsibility of performing extractables studies, while end-users taken the leachables part - as these studies should be conducted using 'true process' conditions. However, there remains some confusion over what a vendor should provide.
In our Demystifying Extractables Testing webinar, we asked participants what their expectation was of a single-use vendor's role in extractables and leachables studies.
While more than 70 percent of respondents believed that the vendor could only offer extractables data, more than 20 percent responded that both extractables and leachables data should be supplied by the vendor. However, leachables data needs to come from a true process stream that only the end-user would have access to.
The extractables process - the vendor's point of view
The vendor would take the following steps:
- Selection of component parts - selection and materials of construction would be scrutinized, ensuring that as much as possible, industry-standard components or materials are used
- The material of construction - product contact materials and additives would be considered
- Assessment of stability to irradiation
- Assessment of stability to common biopharmaceutical process solutions and chemicals
- Assessment of further manufacturing process steps which would have the ability to change or add compounds which could be released
The vendor would then either perform their own extractables study, or obtain the extractable data set from their supply chain in order to identify 'worst-case' released compounds under extreme conditions.
The outcome from the vendor's point of view would be to:
- Ensure that products have patient safety at the forefront
- Instill confidence with their customers that they are supplying good quality characterized consumables
- Ensure that, throughout the supply chain, there is control over the individual component parts
- Understand any interactions which may occur that could have the ability to negatively affect customer processes
The extractables process - the customer's point of view
The customer would take the following steps:
Selection of component parts - customers may have experienced negative effects on their own processes with specific components used within singe-use assemblies. This may inform their choices
- The material of construction - product contact areas and any additional additives would be key considerations
- Stability to irradiation, process streams, solvents and chemicals would be assessed
The process would then be mapped out to ensure that all components are compatible for their intended use. The next step would be to take the 'worst-case' extractables data from the vendor and risk assess this based upon knowledge of their process.
This helps the customer understand how componentry will behave, but to satisfy regulatory bodies, further 'leachable' studies may need to be performed using the actual process stream intended for use with the assembly. There is generally more process risk from extractables and leachables as the process progresses. Released compounds early in the process may be removed through processing steps, but as the process reaches its final formulation, the risk attached to any released compounds present exponentially increases.
The outcome of this data generation from the customer's point of view would again be to:
- Ensure that the products they supply always have patient safety at the forefront
- Ensure that their manufacturing process and drug product is consistent and 'in-control', in order to receive regulatory approval
- Ensure that there is control over the individual component parts throughout the supply chain, and to understand any interactions which may occur and could negatively affect processes
It is vital that there is clarity across the biopharmaceutical manufacturing industry on the importance of extractables and leachables studies and who should carry out the studies. And, while both vendors and customers may have different reasons for carrying out testing, the end goal for both parties is the same.
Learn more about extractables and leachables testing in our white paper: Demystifying Extractables Testing
What approach does your company take to extractables and leachables testing? Let us know in the comments below.
This post was contributed by Graeme Proctor, product manager (single-use technologies), Parker Bioscience Filtration, United Kingdom.
Parker Bioscience Filtration specializes in automating and controlling single-use bioprocesses. By integrating sensory and automation technology into a process, a manufacturer can control the fluid more effectively, ensuring the quality of the final product. Visit www.parker.com/bioscience to find out more.