By Graeme Proctor, Product Manager (Single Use Technologies), Parker Hannifin Manufacturing Limited and Nick Morley, Principal Scientist, Hall Analytical
The increased focus by biomanufacturers on smaller patient populations is driving the adoption of technologies and solutions that can improve flexibility and process efficiency while also lowering overall costs. As a result, the application of single-use technology (SUT) is growing rapidly, this technology is being used for a range of applications in drug development. Its benefits include reduced cleaning requirements, decreased plant footprint and capital investment, improved batch turnaround times, increased process flexibility, and a significantly lower risk of product cross-contamination.1 Yet, while SUT offers a number of advantages, there are also factors that must be considered when adopting an SUT strategy, such as the presence of extractables and leachables (E&L).
Various interested parties have developed guidances that discuss extractable analysis of single-use components/systems, each with subtle differences. It is critical that anyone utilizing SUT understands these differences and which testing approaches are most suited to the study goals.
The Concern Of Extractables And Leachables
There are many reasons why E&L is important within the biopharm industry, especially with single-use equipment, which is made predominately from polymers (e.g. plastics or elastomers). This substance creates the potential for plasticisers, additives, and release agents etc to be released into a process stream, threatening patient safety and/or product quality. Single-use components, such as tubing, connectors, bags, biotainer bottles and filters, are not used in isolation but instead to create a larger assembly specific to a single purpose. They all contribute to the correct operation, yet each have the potential to produce E&L. The entire assembly needs to be assessed collectively with this in mind, taking into consideration factors such as surface area, contact solution, temperature, and contact time.
Every polymer will have some degree of compound leaching or release, but each compound may not have equal impact as far as patient safety or product quality. Therefore, as there is no one size fits all, the individual end users need to assess the risk based on many factors. Risks (all of which can have a large financial impact for the end user) can be categorized into three key areas:
These factors can create a somewhat complicated and confusing landscape when it comes to assessing any E&L requirements for both the end user and the supplier of the single-use consumables. The assemblies used to manufacture, store, and deliver a drug need to be collectively assessed for E&L. Every material will have some degree of leaching or release, but not every compound will have equal importance to patient safety and product quality.
The Responsibility And Importance Of E&L Testing
The traditional customer/supplier relationship when using stainless steel is a transactional one limited to the buying and selling of equipment (capital expenditure) and, possibly, future maintenance. In the move to SUT, though, the relationship between customer and supplier changes dramatically (to a consumable expenditure). In other words, the supplier must be able to ensure they can provide the necessary consumables consistently, so as not to interrupt the customer’s ability to manufacture its product.
In addition, it is also the responsibility of suppliers to scrutinize the selection of components and their materials of construction to ensure a high quality of industry standard materials are being used. It gives customers confidence in the parts they are buying. Suppliers will also assess stability to sterilization to ensure control of bioburden levels as well as stability to common biopharmaceutical process solutions and chemicals. Once the preliminary data from this testing is available, the supplier would then either perform their own extractables study or obtain an extractable data set from within their supply chain. Doing so allows them to identify “worst case” released compounds under extreme conditions, as component suppliers typically only supply extractable data in water and ethanol. The outcome of this data generation would be to ensure the products they supply always have patient safety at the forefront and that their manufacturing process and drug product are consistent and controlled, in order to receive regulatory approval.
However, extractables testing does not determine what happens once the equipment comes into contact with a product’s process stream, as this is not feasible for suppliers to perform prior to the consumables being used due to the wide range of process conditions used in biopharmaceutical production. That is why product specific extractable studies and/or leachable testing must be performed by the end user. Product-specific extractable studies may better determine the likely potential leachables, while leachable testing determines the actual compounds that migrate from the materials into the drug product and, therefore, what might be dosed to patients. Even though the focus is on the end user’s proprietary process, a competent supplier can offer expertise in testing and interpretation of results.
The type of solvents, duration of exposure of the component to the process stream, temperature of contact, and surface-to-volume ratio are all important. The latter stages of the purification process are often considered to be a more important area in terms of patient safety, since the drug is closer to its final composition and concentration and has fewer remaining purification steps. It is also important to understand the potential for impurities entering anywhere in the process as these can have a negative impact on product quality.
Current Industry Guidances On E&L Testing
With biopharmaceutical companies increasingly adopting single-use systems in drug manufacturing, there has been some debate as to how to compare data from the three main documents available that discuss extractable analysis of single-use components/systems. These include recommendations from Bio-Process Systems Analysis (BPSA), the Biophorum Operations Group (BPOG) extractables testing protocol, and the draft United States Pharmacopeia (USP) <665> chapter. Each document is aimed at slightly different audiences; therefore, it is important to understand which one is most suitable for the end requirements.
All three approaches discuss the need for multiple analytical techniques to characterize the organic and inorganic extractables. However, that is where the similarities end. Figure 1 below shows a comparison between the three documents.
Standardized Extraction Protocol
While both the BPOG and USP<665> detail a Standardized Extraction Protocol, the BPSA recommendation provides suggestions and thought processes for developing an appropriate approach, but not for a single standardized approach. The BPOG protocol also includes additional detail regarding the analysis of the extracts and reporting formats.
Looking at the number of extraction conditions discussed in the three documents, BPSA recommends at least two solvents at one temperature and timepoint.
The BPOG protocol uses six model solvents to represent a wide range of formulation solutions used in biopharmaceutical manufacture processes. It also uses various timepoints with two temperature conditions, the actual timepoints required are dependent on the component being tested. Due to the large amount of information generated from multiple solvents and components, you must not only be prepared to pay higher costs but also know how to properly evaluate all of the data. The BPOG protocol does not offer flexibility for alternate conditions.
The draft USP <665> chapter uses three model solvents described as being likely to generate extractable profiles that can be used to select components for most manufacturing processes. Its flexibility allows different extraction conditions when required and justified. This is subtly different to the rationale for the BPOG list of solvents. The USP also states that, where appropriate, additional solvents/conditions should be used, especially if the model solvents are unlikely to generate an extractable profile that mimics the in-use conditions, i.e., if the manufacturing process conditions are at higher temperatures or use more aggressive solvents.
BPSA does not provide a recommendation for a reporting threshold but discusses the requirement for an end user to perform a toxicity assessment.
The BPOG protocol uses a threshold of ≤ 0.1µg/mL, which is fairly low and not based on safety concern thresholds. This can create technical challenges, as it can be difficult to identify compounds at such low levels. On top of this, some of the solvents used are not well suited to some of the analytical techniques.
The reporting threshold for the USP chapter is based on a safety concern threshold, which can be determined only by the end user. This is project specific and requires in-depth knowledge of the manufacturing process. This makes it difficult for a supplier to generate data that meets all customer requirements.
BPSA discusses the use of risk evaluation by taking various factors into account, including but not limited to time, temperature, surface area, compatibility, and location in process. However, the BPSA protocol does not suggest a specific approach. The output of the risk evaluation means extraction studies may or may not be required.
BPOG does not discuss a risk-based approaches as part of its extraction protocol, but it is covered in a separate document for evaluating leachable risks, which is aimed at end users. The extraction protocol is designed for single-use suppliers to detail the type of data the end users may require for material selection.
While the USP chapter provides a risk matrix in the supporting guidance document <1665>, it is yet to be fully finalized. When applied, the output of the risk matrix defines the level of testing required. Currently, organic extractable characterization is required for only single use components used with moderate and high-risk manufacturing conditions. Again, this can only be determined by the end user.
The BPSA recommendation acknowledges the requirement in North America for biological reactivity tests to be performed (i.e., USP<87> or <88>).
Although the BPOG protocol does not discuss biological reactivity, it is designed to provide a standardized protocol for chemical characterisation.
Approaches to biological reactivity testing have already been provided by in USP <87> and <88>.5 Either of these guidances can be used to meet the baseline requirement for biological reactivity in the draft USP<665>.
Where Do You Go From Here?
With so many changes in the industry, it might seem confusing for a biopharmaceutical manufacturing company to understand what steps to take with E&L testing in order to successfully implement and manage single-use technology. And even though the end goal may be the same, a supplier and an end user may have different reasons for performing extractables testing. Regardless of which approach is taken, product-specific studies are likely to be required to satisfy the regulatory authorities. This means there may not be a one-size-fits-all approach when it comes to extractables testing.
Nevertheless, using one of these recognized approaches will go a long way to providing the confidence needed to determine your equipment and product compatibility. Overcoming the complexity of this task may require support from a supplier that has experience in the technology, understands the regulatory environment, and is committed to ensuring you can deliver a product that is safe and reliable for the patients you serve.
The Parker Advantage
Parker is committed to providing high-quality products, together with extractable testing data to pharmaceutical companies interested in employing single-use systems in their drug manufacturing, storage, and delivery processes. We strive to make high-quality, relevant data available on all of its products and prequalified assemblies. Our single-use systems are carefully designed to minimize the risk of leachables that could impact drug safety and efficacy.
Parker is in the process of aligning its extractables approach to the draft USP <665>. It has chosen draft USP <665> since FDA regulators together with industry experts have been involved in developing the document, and regulators throughout the world are expected to use it as a standard. We are currently in partnership with Hall Analytical, which is dedicated to standardizing E&L testing for single-use products and making extractable data easily accessible for end users.
The Parker-Hall Analytical Team can help its end users design and/or facilitate extractables studies for custom components, assemblies, or whole processes. We are positioned to support end-user leachable studies and risk assessments and can help an end user address issues related to extractable and leachable testing protocols, understand the changing industry guidance, and adapt single-use products to fulfill their intended roles.
Active discussions and advice can be found on Parker’s LinkedIn page and website. White papers and webinars keep end users current on topics relevant to their success in selecting and testing single-use products. Visit www.parker.com/bioscience and https://www.linkedin.com/company/bioprocessing-and-pharmaceuticals.