Single-Use Systems (SUS) in Biopharmaceutical Manufacturing
As clinical and commercial biopharmaceutical manufacturing continues to increase, smaller batch sizes and ambient processing conditions have led to a rapid increase in single-use systems (SUS) and SUS components. These systems often improve cost effectiveness, operating efficiency, and the environmental sustainability of processes. Some examples of SUS components that come into contact with product or process fluids include:
- mixing bags
- tank liners
- elastomeric parts
- chromatography columns
Though a key advantage of a single-use component is that cross-contamination is reduced, there are simultaneously concerns that the component itself, especially when polymeric, may leach compounds into the drug product. While regulatory guidelines and regulations from organizations such as the US Food and Drug Administration (FDA) and International Council on Harmonization (ICH) have been established, it remains the responsibility of SUS manufacturers to demonstrate process performance as well as the safety, quality, and stability of the final drug product. SUS suppliers need the data from these studies in order to ensure the safety of their products. Biopharmaceutical end-users need SUS extractables testing data and leachable evaluations to assess the fitness of a given SUS component for their manufacturing processes and in preparing risk assessments for submission to regulatory agencies.
What are leachables?
Leachables are chemical substances that leach or “come out” under normal conditions of exposure over the natural use and lifespan of a product. Some examples of leachables include antioxidants, cross-linking agents, adhesives, colorants, and monomers. Leachables and extractables studies are commonly performed in tandem. Extractables are substances which can be “pulled out” using aggressive conditions such as strong solvents, elevated temperatures, and/or increased surface area. Extractables studies are often performed prior to a leachables study in order to identify and target potential leachables.
Where does BPOG fit in?
The BioPhorum Operations Group (BPOG) is a collection of companies encompassing approximately 80% of the global commercial biopharmaceutical capacity. Collectively they’ve published “Best Practices Guide for Evaluating Leachables Risk from Polymeric Single-Use Systems Used in Biopharmaceutical Manufacturing” and “Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing.” These documents are gaining traction across the biopharmaceutical and biopharmaceutical supply industries as a “one stop shop” for extractables and leachables testing principles.
Is BPOG a regulatory document?
The short answer: no. The FDA does not formally recognize either BPOG document as a standard for assessment. While BPOG claims the requirements of these documents have been adopted as policy for 20 of their member companies, best practice cannot be equated with regulation. BPOG does make acknowledgment of USP standards and chapters throughout both documents, establishing that their guides extrapolate particularly from interpretations of the regulatory requirements for existing container closure testing methods and from elemental impurities. The documents themselves make it very clear that the testing described within is NOT intended to be passed directly to a regulatory agency and is NOT intended for final container closure systems. However, BPOG also claims there is an “absence of specific regulatory requirements for extractables testing of Single-Use Systems (SUS) components” which is not necessarily true, as described below (Ding 1). The conclusion of the extractables protocol does state: “This standardized extractables testing protocol also will be made available to standard-setting organizations, such as ASTM and USP for consideration in developing a consensus standard” (Ding 7). Indeed, this influence is apparent in the drafted USP chapters <1665> and <665>, which will apply directly to SUS and SUS components.
What about USP?
USP chapters are recognized regulatory standards directly enforceable by the FDA. Between the extractable and leachable requirements in USP <661> (materials of packaging construction <661.1> and packaging <661.2>) and the elemental impurities testing outlined in USP <232>/<233>, the USP provides standards for plastic materials used in pharmaceutical and biopharmaceutical manufacturing and components for medical devices. The USP’s upcoming general chapter <665> (formerly drafted as <661.3>) Polymeric Components and Systems Used in the Manufacturing of Pharmaceutical and Biopharmaceutical Drug Products, with its focus on manufacturing components, will likely fill in many of the regulatory gaps, particularly in SUS testing where BPOG has been an unofficial gold standard. A common critique of the USP chapters, however, is that they thoroughly describe WHAT is required but not HOW to meet these requirements (and often the language used is difficult to decipher or interpret practically). For example, the USP chapters feature some introduction to risk assessment, along with risk level tables, but it can be very challenging it fit SUS components and a wide variety of unique products neatly into USP categories. BPOG provides a broader, more comprehensive, and more flexible risk assessment, written in a straightforward manner.
If BPOG isn’t regulatory, are these documents relevant to me?
In research and developmental phases and even while following USP, these BPOG documents provide well-sourced, thoroughly explained and justified, and comprehensive extractables and leachables testing guide. One of the greatest strengths of the BPOG documents over USP is their accessibility. They use simple yet precise language, present a logical information flow, provide clear definitions at relevant points in the text, and utilize flow diagrams and other graphics. They pay careful attention to detail and to unique circumstances (for example: including notes about the correction of analytical results for evaporation of test solvent).
These documents have been adapted, to some degree, by many major biopharmaceutical companies, making BPOG an industry end-user consensus document. BPOG asserts:
“Because it is in the interest of SUS suppliers, SUS end users, and patients in need of the biopharmaceutical products to accelerate the implementation of SUS components within the biopharmaceutical industry, a standardized extractables testing protocol with an agreed-upon set of testing methods to generate and analyze extracts is needed to establish common expectation among suppliers, end-users, and regulators on the type of extractables testing data to be generated” (Ding 2).
What information will I find in these documents?
Between these two documents, you will find a risk assessment guide and study design protocol to optimize the detection of potential leachables and extractables (as necessary), including:
- An extensive guide to risk assessment
- Distinct guidance for sample pre-treatment and preparation by type of SUS component
- Comprehensive overview of testing conditions (extraction solvent, exposure temp and time) by SUS component type
- Six carefully chosen extraction solvents to represent a variety of conditions (high pH, low pH, saline, water, organic, surfactant)
- Recommended surface area to volume ratios
- Component-dependent exposure times
- Considerations for the analysis of volatiles vs semi volatiles vs non volatiles vs elemental impurities
- Recommended analytical techniques based on risk assessment, sample type, extraction solvent, etc. (including columns, mobile phase, standard recommendations, specifications to be met)
- A section addressing common pitfalls in E&L testing
- Recommendations on reporting
- Example data collection tables
- Templated summary extractables statement
The BPOG Update
Since publishing the 2014 standardized extractables protocol, BPOG has been collecting the now directly comparable extractable data generated per the protocol from over 90 manufacturers and suppliers. After five years of data review, BPOG determined that they had both acquired enough BioPhorum partners and obtained enough data through these partners to determine what extractable testing was necessary and sufficient for the industry. In April 2020, BPOG released an update to their extractables protocol titled “BioPhorum Best Practices Guide for Extractables Testing of Polymeric Single-Use Components Used in Biopharmaceutical Manufacturing”. This document revises the initial protocol according to the data and feedback received since 2014.
What information will I find in the April 2020 revision?
- Four recommended extraction solvents to represent a variety of conditions: water for injection (WFI) or deionized (DI) water, low pH (0.1M phosphoric acid), high pH (0.5N NaOH), and 50% ethanol
- A recommended sample surface area to extraction solvent volume ratio of 6 cm2/mL or higher
- Consideration for extraction controls
- Specific guidance for handling solvent evaporation loss (which is sometimes unavoidable)
- A consistently proposed extraction temperature of 40°C
- Component-dependent exposure times (24 hours, 7 days, 21 days, and/or 70 days)
- A helpful table of specific considerations for extraction by potential sample type
- Recommended approaches for the four major established analytical techniques (including instrument parameters and specifications to be met)
- LCMS: high pressure/performance liquid chromatography coupled with mass spectrometry
- GCMS: gas chromatography with mass spectrometry, direct injection
- GCMS: gas chromatography with mass spectrometry, headspace
- ICP-MS: inductively-coupled plasma mass spectrometry
- Guidance for standard selection and quantitation methods
- Reporting recommendations
What major changes have been made since the first BPOG protocol?
- Clarifications about the purposes and application of the protocol
- A reduction in the number of recommended extraction solvents (5M sodium chloride and 1% polysorbate 80 solvents were shown to have low unique extraction capability)
- No elemental analysis of 50% ethanol extracts is recommended (again due to low unique extraction capability but also due to instrumental limitations)
- Removal of assessment of “time point zero” extracts
- Additional detail on standard preparation and instrumental qualification (including specifications)
Extractables and Leachables Studies at EKG Labs
Understanding the complex chemical interactions between pharmaceuticals and materials is critical to designing a proper extractables and leachables program. The head of our analytical team, Dr. Allen Kesselring, is known throughout the medical device development industry for designing and managing large E&L programs. We can perform E&L analytical studies with the ultimate goal of submitting data for FDA review and approval. EKG Labs is familiar with guidance from organizations such as ICH and USP. Our capabilities include:
- Full scale GMP analytical extractables and leachables programs
- Method Development
- Method Validation
- Chemical Characterization
- Impurity Identification
- Storage and Stability
<665> Polymeric Components and Systems Used In The Manufacturing Of Pharmaceutical And Biopharmaceutical Drug Products.” United States Pharmacopeia and Pharmacopeial Forum (USP-PF 43(3)). Rockville, MD: United States Pharmacopeial Convention; 2017.
Ding, W., Madsen, G., Mahajan, E., O’Connor, S., and Wong, K. “Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing.” Pharmaceutical Engineering, Vol. 34, No. 6, 2014, pp. 1-11. Available from biophorum.com here.
Sexton, A.W., et al. “Biophorum Operations Group (BPOG) Best Practices Guide for Evaluating Leachables Risk from Polymeric Single-Use Systems Used in Biopharmaceutical Manufacturing.” BioPhorum Operations Group, 2017, pp. 1-35. Available from biophorum.com here.