What are Extractables & Leachables?
The goal of extractables & leachables (E&L) studies is to determine if a drug product has interactions with contacting materials that will alter its’ safety or efficacy. The highest risk drug product contacting material is the final container/closure but upstream processing materials such as the final sterile filtration filter, tubing sets and purifying processes such as tangential flow filtration can also impart leachables into the drug.
E&L studies typically begin with an overall risk assessment of the manufacturing process and the final container closure system. Upon completion of a risk assessment, testing may be needed to qualify a material. E&L testing can be single or multi-staged involving extractables testing, simulation testing or leachables testing.
Extractables testing is performed in order to identify all of the compounds that have the potential to migrate into the drug product. We extract with multiple solvents representing a range of polarities and pH levels at elevated temperatures in order to create a long list potential leachables. We analyze the extracts using orthogonal methods so that we do not overlook any extractables (learn more).
Evaluation using a simulation solution (simulation test) is a recent addition to the E/L testing scheme because it adapts the laboratory extraction conditions to mimic actual product contact conditions with regard to time, temperature and the organic nature of the drug product or drug substance. We may replace the API with a mimic compound to reduce analytical interference and ensure that extractables are not missed. Extractables that we detect in a simulation study are considered to be probable leachables and will often require a toxicology assessment. This can be a stopping point for process contact materials upstream of the final container/closure.
Finally, in a leachable test, we use the actual drug product. We screen for leachables and test for target analytes based on compounds detected in the extractables or simulation tests. Since we are working with the actual drug product, we validate the appropriate sample preparation techniques that are necessary to remove the analytical interference. We utilize USP <1664> and ICH Q2(R1) guidelines to conduct these studies.
At all steps of the E&L process, we use toxicology to guide us. Initially we determine a Safety Concern Threshold (SCT) which can range from 0.15 mg/day to 120 mg/day. We then determine an Analytical Evaluation Threshold (AET). E&L detected at a concentration below the AET may not require additional risk assessment which can save you resources and speed up your approval process. (learn more)
Why perform an E&L study?
The short answer is because you must. The FDA, EMA, MHRA and Health Canada and other pharmaceutical regulatory authorities require that all NDA and BLA submissions include E&L data. While general guidance on the standards and approaches for E&L testing have been provided by the FDA, EMEA and the USP, these guidance do not provide prescriptive procedures. Therefore an understanding of acceptable protocols and reports is essential to avoid regulatory delays (learn more).
When to perform an E&L study?
While many drug developers have historically pursued their E&L qualification relatively late in development, often during Phase III clinical trials, the increased use of single-use systems in manufacturing can now cause significant delays if testing is put off until the last minute. A proactive approach is generally more efficient, and involves at least planning for E&L while still in clinical development. This is particularly true for developers of cell and gene therapies (learn more).
If you are a supplier of materials used to make or store drugs you are probably already receiving pressure from your customers to provide extractable data. Notably, certain biopharmaceutical manufacturers, represented by the BioPhorum Operating Group (BPOG), are requiring extractable data in order to be considered an “preferred supplier”. The BPOG protocol is extensive and requires extractable tests with six solvents at up to four time points (learn more).
Why use VR?
We are exclusively focused on E&L testing, and have performed over 1,500 E&L studies during our 17+ years in business. We have worked with large and small drug manufactures, for both patented and generic drug products, both large and small molecules, and have supported hundreds of successful regulatory submissions.
Our team has authored numerous publications and presentations describing advancements and best practices in E&L, including being the primary author for the first two white papers to describe recommendations for qualifying single use systems (SUS) for E&L testing.
We attend E&L conferences worldwide every year, and regularly present novel research conducted in our labs that answer important questions posed by the industry and lead to advancement of the field.
Our cGMP labs include analytical methodologies necessary for comprehensive E&L testing, and we place a very high priority on quality systems and scientific integrity.
Contact us today for an educational web-presentation of the key considerations in qualifying biopharma manufacturing and packaging materials for commercialization.