Extractables and Leachables Testing - Confidence®
Ensuring Safe Adoption of Single-Use Systems in Biopharmaceuticals
The importance of extractables and leachables (E&L) testing has grown with increased utilization of single-use systems. Biopharmaceutical manufacturers must demonstrate that the concentration of contaminants from plastics entering production and ultimately medical products do not exceed regulatory thresholds.
Validation is critical to ensure product quality and patient safety. For decades, Sartorius, through its Confidence® services, has been a trusted partner for extractables and leachables validation, including customer-specific solutions. Our risk-based approach helps manufacturers of medical products determine optimal processes as they scale up from lab to commercial production.
Sartorius has been a leader in the field of extractables and leachables since 1996, which means we bring deep understanding of the science of extractables to every customer project.
The Extractables Simulator from Sartorius is unique in the industry. It provides scientifically accurate scaling data for Sartorius products and assemblies, making it possible to provide quantitative data for all product sizes, from development to large process scale.
Sartorius provides reliable extractables profiles, identifying all relevant chemical entities. We have identified more than 95% of all compounds across the Sartorius consumables portfolio.
Thanks to our Extractables Simulator, we can offer rapid provisioning and rapid turnaround of extractables validation. Even with calculations made on complex assemblies, data can be available in less than 1 week. 10 weeks for extractables or leachables testing.
Cost reduction of 40% in the assessment creation. More savings in comparison to analytical testing.
Extractables Simulator: Replace Physical Testing With Predicted Results
The Extractables Simulator (ExSim) is an important internal tool that supports our Confidence® Extractables and Leachables services and paves the way for the future of validation. It is a qualified software platform that scales extractables data for Sartorius products and assemblies and predicts the total amount of extractables based on your process:
- Scaling algorithms for short and long contact times
- Thousands of combinations and assemblies possible (including CTOs and ETOs)
- Fast retrieval of legacy and calculation data
- A reliable source for up-to-date extractables data, substance data and toxicological data
How We Help You to Succeed
Confidence® Extractables and Leachables Services address all of your validation needs. The strategic approach for each customer can be customized for specific processes and needs. During an initial assessment, the Confidence® team considers your drug development phase, route and frequency of administration, product quality parameters and step in the manufacturing process. We provide the right validation for all products in the process chain, including container closure systems, filters, and disposable systems.
Confidence® E&L Portfolio
In addition to consumables, Sartorius provides extractables guides, which present the methodologies and results of in-house extractables and leachables studies for all of our products and identify virtually all extracted compounds (more than 95% for the whole Sartorius consumables portfolio). Each is a quality-controlled and approved document that can be used to qualify design and installation qualification and to determine the need for leachables testing.
The guides provide:
- Identification of all relevant extractables
- Extractables quantification
- Extractables toxicological information
With an Extractables Assessment, substances found in the standard extractables analyses under reasonable worst-case conditions can be evaluated for individual customer processes. This provides you a comprehensive understanding of, and confidence in, the Sartorius components used in your processes. This risk assessment — informed by our proprietary Extractables Simulator (ExSim) platform, which predicts the concentration of extractables for single-use systems and assemblies and scales data appropriately based on process needs — is the comprehensive first step of your validation
Extractables Assessment, basic
Extractables Assessment, complex
Number of devices
Number of solvents
Number of formulations
Rationale for chosen comparison solvent
Scaling of extractables results according
Conclusion on further validation steps (if any)
Risk classification of process step (USP <1665>)
*If available for selected device/assembly
Note: Any third-party product evaluation (not standardly used by Sartorius) is automatically categorized as complex.
Besides our Extractables Assessment, we also offer Extractables Studies to identify and avoid potential leachables to your final drug product. Extractables Studies are just what you need during the selection of appropriate packaging materials or processing equipment, e.g. during drug product development. It is the perfect fit for you if the temperature, timepoints, or solvents recommended by the Sartorius approach do not suit your purpose. We create extractables data according to your individual requirements.
As part of Confidence® Extractables and Leachables Services, our team provides complete leachable analyses — including leachables screening analyses or special leachables target analyses — if more detailed investigations are required. In these analyses, we test for compounds present in the actual medical product. Using our specifically evaluated and qualified methods, we can detect leachables known to be found in consumables in nearly all complex pharmaceutical solutions.
Our Safety Evaluation takes assessed extractables or leachables results coming from an Extractables Assessment or study or a leachables testing and correlates the data to the patient situation. Knowing a patient’s medicament application, we can calculate the possible daily intake of potential leachables against dedicated exposure limits, such as the permitted daily exposure (PDE) rate or the threshold of toxicological concern (TTC).
When pharmaceutical drug products contact single-use components, leachables can accumulate in the drug product and potentially compromise patient safety, either directly or by interfering with the active pharmaceutical ingredient. Extractables and leachables testing is a regulatory requirement to demonstrate that degradants from plastic materials used in the processing of a medical product won’t cause harm to patients.
Determine Impact of Potential Leachables on Drug Efficacy and Activity
Most of the leachables from plastic products are harmless to the human body. Nevertheless, some leachables, such as bDtBPP (bis(2,4-di-tert-butylphenyl)phosphate), may interfere with the active pharmaceutical ingredient (API). This interference could result in inactivation of the API and endanger patient safety. With the support of detailed investigation in the form of extractables and leachables testing and toxicological evaluation, any risk coming from leachables can be excluded.
Regulatory Authorities Require E&L Validation for Single-Use Systems
Before manufacturers incorporate plastic-based container closure systems (CCS) or single-use systems (SUS) into their processes, they must demonstrate the safety of these components before regulatory bodies. The scope of validation for CCS is very simple in the form of a leachables study. However, the extent of E&L validation for a single-use system depends on the assessed risk.
"Equipment shall be constructed so that surfaces that contact components, in process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirement."
Source: Code of Federal Regulations (CFR) Title 21 Part 211.65, CFR
"Components shall be characterized to the extent that is consistent with the risk that the component could add PERLs into a process stream that could persist through the manufacturing process and adversely affect the suitability for use of the process output. Matching the risk with the required level of characterization is achieved by a two-stage component assessment approach consisting of an initial assessment followed by a risk assessment."
Source: 〈1665〉 Characterization of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products, USP
"The presence of leachables during any stage of the production process or storage may pose a safety risk due to their potential to cause toxicity, carcinogenicity, immunogenicity and/or endocrine dysregulation … Therefore, well-designed extractables studies are important to provide an analytical road map to identify early warning signs regarding leachables released during upstream or downstream operations or in storage."
Source: Application of Single-Use Systems in Pharmaceutical Manufacturing, PDA Technical Report No. 66
Beyond Patient Safety, Ensuring Product and Process Quality Is a Priority
Another important role of extractables and leachables testing is to ensure high levels of process performance and product quality. Although rare, it’s possible for leachables to interfere with the active pharmaceutical ingredient (API) or, in the case of biologics, inhibit cell growth.
The scope/effort for testing for extractables and leachables correlates with the assessed risk based on the customer’s unique development scenario. In particular, the following factors must be taken into account:
- The proximity of a process step to the patient
- The consumables used
- The product and the process parameters
- The drug development phase
The starting point is the evaluation of existing extractables data for the specified consumables and a risk assessment based on it. This approach is strongly recommended by regulatory authorities, including USP, PDA, and EMA, which is why Sartorius offers it as part of our Extractables Assessments, providing you with a cost- and time-efficient first validation step. Based on the assessment, further validation in the form of leachables testing can be performed, if needed.
If you need assistance in identifying the validation-critical steps in your process, we are here to help. Our Confidence® experts will perform an initial assessment and guide you through the entire validation process.
Sartorius has developed its own approach to extractables characterization — the Sartorius Extractables Approach, which builds on USP guidelines to define our process for extractables profile creation. Determining extractables profiles using combined methodologies allows optimal material characterization and validation, leading to a more robust, more detailed assessment of potential leachables in all Sartorius consumables. The component-based approach reveals the comprehensive identity and quantity of single-use consumable’s extractables, allowing a straightforward validation of single-use equipment that considers both material safety and process performance.
Our customers benefit from:
- High-quality data derived from state-of-the-art analytical methodologies
- Proven data scalability
- Comprehensive extractables profiles
Sartorius has been a leader in extractables and leachables testing for decades. Our experts participate in regulatory working groups, such as USP, the BioPhorum Operations Group (BPOG) and FDA, to shape the future of leachables validation.
Consult Our Experts
Comparison of Extractables Protocols
USP <665> (draft)
Described in USP <1663>
Broader scope in method selection
+ (TOC, pH, NVR)
All approaches consider pre-treatments, are component-based, and focus on fluid contact
*Solvents vary for products. WFI and pure ethanol always included.
**Depending on the component