Single-Use Systems (SUS) in Biopharmaceutical Manufacturing
Smaller batch sizes and ambient processing conditions have led to a rapid increase in single-use systems (SUS) and SUS components in biopharmaceutical manufacturing. These systems often improve cost effectiveness, operating efficiency, and the environmental sustainability of processes. However, as many of these components are polymeric (plastic), there is growing concern about leachables in the manufacturing process. Examples of SUS components that come into contact with product or process fluids include:
- Tubing and connectors
- Tank liners and mixing bags
- Elastomeric parts
- Filters and chromatography columns
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. In order to identify and target potential leachables, extractables and leachables (E&L) studies are commonly performed in tandem. Extractables are substances which can be “pulled out” using aggressive conditions, representing a worst-case scenario.
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 pharmaceutical and medical device industries as a “one stop shop” for extractables and leachables testing principles.
Is BPOG a regulatory document?
No, the FDA does not formally recognize either BPOG document as a standard for assessment.
How do USP standards relate to BPOG?
Unlike BPOG, 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>), 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.
If BPOG isn’t regulatory, are these documents relevant to me?
These documents have been adapted, to some degree, by many major biopharmaceutical companies, making BPOG an industry end-user consensus “best practices” document. In research and developmental phases, these BPOG documents provide a well-sourced, thoroughly explained, 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, 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).
What information will I find in these documents?
- An extensive guide to risk assessment
- Distinct guidance for sample preparation by type of SUS component
- 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 temperatures and times
- 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
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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
To find out more about BPOG and E&L programs, contact EKG Labs at 810-354-5229.
About EKG Labs
EKG Labs is an analytical service provider for the pharmaceutical and medical device industries. Our analytical services support product development, regulatory filings, and analytical chemistry investigations.