The Importance of Extractables and Leachables Analysis of Pharmaceutical Products

Extractables and leachables are an important consideration during the development of pharmaceutical products. Pharmaceutical container closure systems, process equipment, and medical device packaging must be tested to determine the quantity of leachable impurities and assess any associated risks. Lauren Everett, managing editor of Lab Manager, speaks with Katie Grayson, general manager of Infinity Laboratories, about extractables and leachables studies.

Q: Why are extractable and leachable studies important?
A: Extractables and leachables (E&L) studies are in-depth analytical investigations of the chemical interactions between:

• A container closure and a drug product or pharmaceutical formulation
• A drug delivery system and a drug product or pharmaceutical formulation
• An implantable medical device and the human body
• Between different materials comprising a medical device
• Manufacturing components and finished products
• Other component interactions relevant in the pharmaceutical or medical device industries

The primary purpose of an E&L investigation is to identify any potential chemicals derived from the interaction of constituent parts and then to determine the impact to human health and/or drug efficacy that those chemicals pose. 

Q: Can you explain the differences between extractables and leachables and some examples of each.
A: Extractables are substances in a device, manufacturing component, or container closure system that can be “pulled out” using stressing conditions such as strong solvents, elevated temperatures, and/or increased surface area. Substances observed in this stage are characterized and identified per FDA guidelines and further evaluated by a toxicologist to determine if the substance is a potential hazard. Common extractables include plasticizers, surfactants, processing aids, degradants, and other materials.

Leachables are substances that leach or “come out” under normal conditions of exposure over the natural lifespan of a product. Sources of leachables are potentially numerous and can include anything from residual manufacturing solvents to ink and adhesives from labels of secondary packaging material. FDA guidelines monitor known extractables and leachables to ensure human exposure levels do not exceed appropriate safety limits.

Q: What types of analytical methods are used to detect extractables and leachables?
A: Potential chromatographic techniques to detect extractable and leachable components include HPLC, LC/MS (Q-Tof), GC/MS (Triple Quad), GC/FID,  GPC/SEC, and ion chromatography.

Potential spectroscopy techniques to detect extractable and leachable components include ICP-MS, NMR, MS, UV-Vis, FTIR, and Raman. 

Lastly, potential extraction techniques include soxhlet, reflux, immersion, and agitation

Q: What are the potential issues or hazards of undetected extractables or leachables?
A: The potential issues of undetected extractable components is that you may discover it during a leachable study.  In cases where this happens, you then need to revert to identifying what it may be and assessing the potential health risk to the patient.

The potential hazards of undetected leachable components are having a compound that has toxicological risk to the patient and not being able to mitigate it from the product to reduce or eliminate the risk.  

Q: What steps can analytical teams take to ensure they are designing a proper extractable and leachable study?
A: Understanding complex chemical interactions is critical to designing a proper extractables and leachables program. We routinely perform E&L analytical studies with the ultimate goal of submitting data for FDA review and approval. Guidance is provided from organizations such as the FDA, ISO, ICH, BPOG, and USP. 

Q: What level of sensitivity, accuracy, and precision is required for a successful extractable and leachable study?
A: The goal is always to have the highest sensitivity (lowest detection limits), accuracy, and precision. With that said, the level required is dependent on the type of material/product in question and the potential interaction that material/product may have with a patient. A container holding oral solid dose forms, such as tablets, does not require the sensitivity, accuracy, and precision as the container holding a high-risk dose form, such as a pulmonary inhalation device, might.  Similarly, a device that is permanently implanted in a patient requires significantly lower detection limits than a device that only has short term contact with a patient.  

Q: What are the most challenging parts of doing extractable and leachable studies?
A: The most challenging parts of doing extractable and leachable studies are:

1. During the design phase, ensuring the correct guidance is utilized (especially in a combination type product) and that the analytical thresholds are accurately determined based on the material/product risk.
2. During the execution phase, identifying all the peaks that are detected in the study. While the regulatory bodies (and toxicologists) would like everything that comes out in the study to be identified with chemical structure and CAS number, this is normally not possible. While the analytical tools utilized are amazing, chemical entities vary greatly and not all respond well on the instruments, making identification challenging if not impossible.  
3. During the reporting phase, helping the client who may not interact frequently with these types of studies, understand the data and how it impacts their product.

Q: What other guidance or comments do you think are important to mention?
A: These studies take time and investment to complete.  Due to this, they need to be adequately built into the development plan.  A lot of times this is considered late in development and the timeline causes delayed submissions or the study shows a potential problem with material, which in turn may require a material change.  

Also make sure you work with a team that understands the type of extractable and leachable study you need. There are significant differences in how you need to approach pharmaceutical packaging/product and an implantable medical device. If the lab you work with does not have the proper experience, you may be wasting a lot of time and money.

Katie Grayson is the general manager of Infinity Laboratories. Grayson began her career at Ethyl Petroleum where she supported quality control and analytical services. In 1996, she joined Chemir Analytical Services where she filled several positions and then established the company’s first quality assurance unit. Grayson played a key role in developing the organization’s expertise in testing pharmaceutical and medical device products including extractable and leachable testing, impurity analysis, and method validation. 

Grayson spent time with both UPM Pharmaceuticals and Chemic Laboratories before transitioning to Evans Analytical Group, Life Science Division (Cyanta) in 2010, where she managed the business development and technical affairs groups. In 2013, Grayson, along with business partners Jennifer Eagan and Dr. Allen Kesselring, started EKG Labs, a testing laboratory specializing in extractable and leachable studies. In 2022, EKG Labs was acquired by Infinity Laboratories where Grayson now serves as the site’s general manager.