Pharmaceutical & Biopharmaceutical Development Services
EAG brings unparalleled expertise to the development and commercialization of small molecule drugs, biopharmaceuticals, antibody-drug conjugates (ADCs), drug-device combination…
EAG brings unparalleled expertise to the development and commercialization of small molecule drugs, biopharmaceuticals, antibody-drug conjugates (ADCs), drug-device combination products and other therapies. From designing IND-enabling studies to delivering full CMC analytical and QC support, we join your R&D team as a true partner. EAG scientists take time to understand both your commercial goals and the unique characteristics of your compound. We provide expert guidance to balance regulatory expectations with expediency and cost, and approach technical challenges with flexibility and resolve.
When it comes to understanding the physical structure, chemical properties and composition of materials, no scientific services company offers the breadth of experience, diversity…
When it comes to understanding the physical structure, chemical properties and composition of materials, no scientific services company offers the breadth of experience, diversity of analytical techniques of technical ingenuity of EAG. From polymers to composites, thin films to superalloys—we know how to leverage materials sciences to gain a competitive edge. At EAG, we don’t just perform testing, we drive commercial success—through thoughtfully designed investigations, technically superior analyses and expert interpretation of data.
Having helped develop the test methods that shape current regulatory guidelines, EAG chemists, biologists and toxicologists have evaluated the environmental impact of thousands of…
Having helped develop the test methods that shape current regulatory guidelines, EAG chemists, biologists and toxicologists have evaluated the environmental impact of thousands of active ingredients and formulations—from pesticides and pharmaceuticals to industrial chemicals and consumer products. Whether you are exploring “what if” scenarios, registering a new active ingredient or formulation, responding to a data call-in or seeking to understand the latest guidance, turn to EAG for technical excellence, sound advice, GLP-compliant study execution and expert interpretation.
Whether connecting the internet of things, guiding surgical lasers or powering the latest smart phone, integrated circuits and microelectronics touch nearly every aspect of human…
Whether connecting the internet of things, guiding surgical lasers or powering the latest smart phone, integrated circuits and microelectronics touch nearly every aspect of human life. In the world of technology, innovation and continuous improvement are imperatives—and being able to quickly and reliably test, debug, diagnose failures and take corrective action can make the difference between a doomed product launch and building a successful global brand. EAG offers you the world’s largest and most diverse collection of specialized analytical instrumentation, capacity to perform a variety of microelectronic tests in parallel, and the multi-disciplinary expertise required to draw true insight from data.
No contract service provider has more experience performing custom synthesis and producing isotopically labeled compounds to support product development in life science, chemical…
No contract service provider has more experience performing custom synthesis and producing isotopically labeled compounds to support product development in life science, chemical and related industries than we do. From 14C and 3H radiolabeled clinical trial materials synthesized under cGMP, to stable-labeled active ingredients for metabolism and environmental fate/effects testing, turn to EAG. We have extensive experience with multi-step and other complex synthesis projects, and our comprehensive, in-house analytical services ensure quick turnaround of purity and structural confirmation.
EAG combines biotechnology and protein characterization expertise with more than 50 years' experience analyzing chemical compounds in plant and environmental matrices to address…
EAG combines biotechnology and protein characterization expertise with more than 50 years’ experience analyzing chemical compounds in plant and environmental matrices to address the growing needs of the biotechnology crop industry. We offer a wide range of techniques required to fully characterize the event insertion and expressed proteins, as well as the various studies required to confirm the food, feed and environmental safety of products that represent the trait. From early-stage protein confirmation to GLP-compliant EDSP and allergenicity testing, we help you make faster, more informed development decisions and comply with evolving global regulations of genetically engineered crops.
When you need solid science and investigative engineering to address product failures, inform legal strategy, protect intellectual property or address product liability disputes,…
When you need solid science and investigative engineering to address product failures, inform legal strategy, protect intellectual property or address product liability disputes, turn to EAG. We’ve provided technical consulting, analysis and expert testimony for hundreds of cases involving the aerospace, transportation, medical device, electronics, industrial and consumer product industries. Our team of experts understands the legal process and your need for responsiveness, effective communication, scientifically defensible opinion and confidentiality. From professional consulting to data review to trial preparation and expert witness testimony, ask EAG.
Using an array of advanced separation techniques and innovative technology, we conduct highly precise analytical chromatography for various industries. Whether you want a closer…
Using an array of advanced separation techniques and innovative technology, we conduct highly precise analytical chromatography for various industries. Whether you want a closer look at the purity of your pharmaceutical or need to better understand an agrochemical’s components, EAG has the expertise to separate and evaluate any compound.
Need to evaluate the molecular structure of a compound or identify its origins? EAG knows how. With state-of-the-art tools, we can separate, vaporize and ionize the atoms and…
Need to evaluate the molecular structure of a compound or identify its origins? EAG knows how. With state-of-the-art tools, we can separate, vaporize and ionize the atoms and molecules in almost any pure or complex material to detect and obtain mass spectra of the components. We rely on decades of experience in mass spectrometry to provide our clients with precise analyses and the best detection limits.
EAG is a world leader in high-resolution imaging down to the atomic level. We offer unmatched analytical know-how, generating extremely detailed surface and near surface images…
EAG is a world leader in high-resolution imaging down to the atomic level. We offer unmatched analytical know-how, generating extremely detailed surface and near surface images for various industries, from consumer electronics to nanotechnology. Using state-of-the-art equipment and innovative techniques, we conduct expert imaging to aid in failure analysis, dimensional analysis, process characterization, particle identification and more. If you want to investigate a material with angstrom scale resolution, you can count on EAG to get the job done quickly and precisely.
EAG offers a vast array of spectroscopic techniques to clients in various industries, from defense contractors to technology pioneers. We combine unparalleled expertise and…
EAG offers a vast array of spectroscopic techniques to clients in various industries, from defense contractors to technology pioneers. We combine unparalleled expertise and methodology with cutting-edge technology to analyze your organic, inorganic, metallic and composite materials for identification, compositional, structural and contaminant information. Whether you need expert spectroscopic analysis to improve your production process or to surmount a technical challenge, EAG is up to the task.
Need to identify your unique material? Want to analyze the thermal properties of a sample, or measure the success of a process step? If it has to be done quickly and it has to be…
Need to identify your unique material? Want to analyze the thermal properties of a sample, or measure the success of a process step? If it has to be done quickly and it has to be done right, you can count on EAG. We offer a range of adaptable techniques and innovative methods to evaluate the physical and chemical characteristics of any compound. Our highly precise testing and analytical services will improve your production process, expedite R&D and help you conquer any technical challenge.
One of the most respected names in contract research and testing, EAG Laboratories is a global scientific services company operating at the intersection of science, technology and…
One of the most respected names in contract research and testing, EAG Laboratories is a global scientific services company operating at the intersection of science, technology and business. The scientists and engineers of EAG apply multi-disciplinary expertise, advanced analytical techniques and “we know how” resolve to answer complex questions that drive commerce around the world.
Science and technology transcend industry boundaries, and so does demand for EAG’s expertise. We partner with companies across a broad spectrum of high-tech, high-impact and…
Science and technology transcend industry boundaries, and so does demand for EAG’s expertise. We partner with companies across a broad spectrum of high-tech, high-impact and highly regulated industries. We help our customers innovate new and improved products, investigate manufacturing problems, perform advanced analyses to determine safety, efficacy and regulatory compliance, and protect their brands.
EAG’s corporate culture is firmly rooted in four guiding principles: “foster a growth mindset,” “find a better way,” “earn more loyal customers,” and “win…
EAG’s corporate culture is firmly rooted in four guiding principles: “foster a growth mindset,” “find a better way,” “earn more loyal customers,” and “win together.” Across all of our 20+ locations, you will find a true passion for science and the power of science to improve the world we live in. Hear what some of our ~1200 scientists, engineers and support personnel say about what it means to be part of EAG Laboratories.
EAG is growing, and we are always looking for talented, problem-solving oriented individuals to join our company. If you have a “we know how” spirit, we want to hear from you.…
EAG is growing, and we are always looking for talented, problem-solving oriented individuals to join our company. If you have a “we know how” spirit, we want to hear from you. Browse current openings now, and re-visit our careers page often.
Implementing Extractables and Leachables into Quality Control Testing Programs
By Wayland Rushing, Ph.D., EAG Laboratories
One of the many challenges of E&L programs is encountered when the testing transitions from the E&L lab to a routine QC environment. Initial E&L work is typically performed by specialized labs with specialized equipment/personnel which may not be conducive to routine QC testing. Understanding the limitations and challenges of the routine QC environment is key to avoid issues down the road. This presentation will cover the following areas, along with representative case studies are:
QC method development: How to design the development with the QC lab in mind to ensure success
Method Validation: How to perform validations for E&L methods and common challenges
Stability Programs: How to implement stability testing and what does the data mean
Release Testing: Testing the final product vs. testing incoming components
The initial steps of an E&L study are often performed using generic scanning methods utilizing specialized equipment in an R&D lab environment. These methods are typically not fully validated and are used primarily for the determination and identification of extractables and leachables observed. The E&L program continues beyond the initial steps and in many cases programs are required to move the E&L program from the R&D lab and into the QC lab. Figure 1 represents a typical E&L program. The sections in green highlight the QC steps which move into the QC testing arena. The two areas in which you may be required to institute QC testing are:
When required to set up incoming release testing of components
When required to set up release and/or stability testing on your final product or API
Figure 1: Typical E&L study design
INCOMING COMPONENT RELEASE TESTING
You may be required to set up incoming testing on the container/ closure components depending on the results of the controlled extraction studies and depending on the testing performed by the manufacturer. These methods should be validated generally in accordance with ICH guidelines:
Accuracy, Precision, Linearity, Specificity, Sensitivity, Limit of Quantitation
LIMITS TEST METHOD
LEACHABLE TEST METHODS
Establishing QC leachable method may not always be required, there are multiple cases where it may be possible to justify not establishing leachable QC testing.
No extractable peaks detected. If no peaks are observed under the worst case scenarios it is possible to justify not pursuing any additional testing.
All extractable peaks are below reporting analytical evaluation threshold.
The threshold is established based on the safety concern threshold and any peaks observed below the threshold are considered to have minimal risk of having a toxilogical aect.
No leachables above reporting threshold
Extractable/Leachable found has no toxic concerns
Identified extractables/leachables found above the safety concern threshold should be evaluated for potential toxic affects by performing a QSAR analysis or performing a paper tox assessment if tox information is already available on the compound
If required to establish QC leachable methods, the methods should be validated in accordance with ICH guidelines. Leachables are considered as impurities in the final Drug Product and as such the method should be validated identically as one would validate a DP impurities method:
There are two typical types of methods which may be employed: Quantitative and a limits test. The specific validate parameters are listed below:
Accuracy, Precision, Intermediate Precision, Linearity, Specificity, Sensitivity, Limit of Quantitation, Limit of Detection, Robustness, Solution Stability
CHALLENGES OF E&L METHODS
Due to the unique nature of the extractables/leachables and the methods typically employed there are many challenges associated with establishing QC testing methods for extractables and leachables testing
Don’t expect extractables and Leachables to behave as API/DP related impurities. API and DP related impurities are typically related species which behave similary. Leachables can be a wide variety of compounds ranging from small polar solvents to large macromolecules. As a result their behaviors can be substantially dierent than the “normal” impurities.
Don’t blindly set “typical” acceptance criterion for the method validations based on similar criteria that might be used for DP related impurities. Critieria need to be set on the required performance of the method and the limitations associated with it.
Method development may be extensive and complex.
May not be able to identify all leachables. They may not mass spec well or have diculty in isolating.
Analytical levels can be significantly lower than ICH impurity levels. In typical cases it is not uncommon for leachables to be 10-100X lower than impurity reporting levels.
API and Formulation impurity interferences. Due to the low levels which leachables are needed to be monitored to, API impurities and formulations impurities which typically may not be observable may cause interference with the leachable peaks.
To reach to the low analytical levels it is not uncommon to have to perform sample concentration steps in order to obtain the needed AET. The concertation can range from 2X to 100X in some cases. This can lead to challenges with some formulations as they may gel/solidify or precipitate out.
Many of the identified leachables may not have any commercially available standards available, making validating methods dicult.
METHOD VALIDATION CHALLENGES
API/DP degradants can cause significant issues. Not only the impurities that are known, but due to the significantly lower levels which leachables are required to go down to, it is not uncommon to observe significantly more API/DP related impurities than what the normal impurity methods monitor for. As a result it is highly recommended that aged API/DP is used to track these impurities. If aged material is not available, stressing the API/DP to artificially generate impurities should be performed.
Formulation/placebo impurities need to be accounted for as well. As with the API/DP impurities, it is not atypical to observe significantly more excipient related peaks that expected.
Co-elution of extractables/leachables can be a challenge. In some cases the leachables being monitored for may have extremely similar chemical structures making their chromatographic separation challenging if even possible. In some cases it may not be possible to completely separat e the leachable.
Non-Homogeneous samples are a challenge. Whether testing DP or extracts the variance in the samples can be significantly greater than one might expect for API/ DP related impurities. This can make performing sample precision testing more challenging as it can result in testing the variance of the samples rather than the method.
Traditional precision testing is typically performed by preparing multiple replicated from lots of material. However, leachable may not be present in the lot until it has aged long enough for them to be present.
Using spiked samples (homogenized) can be a preferred way to perform both accuracy and precision testing of the method. This would involve preparing three levels across the range of the method prepared in triplicate. The precision is determined by calculated the %RSD of the recoveries.
Use internal standards/surrogate standards as needed and especially when actual standards of the leachables are not available.
There are some challenges/cautions to be considered when using surrogate/internal standards.
They should be carefully chosen based on what is known of the target compounds.
If a range of leachable is being monitored for it may be appropriate to use multiple standards rather than a single standard in order to cover the potential range of the various leachable compounds.
Surrogate/internal standards may not mimic behavior of actual extractables/leachables and as a result the method may have issues later down the road during routine testing.
Wider acceptance ranges than would be applied to API/DP related impurities may be justifiable based on the performance of the method and the intent of the testing.
Use standards of the known leachable (if available) and surrogates and/or internal standards if no other standards are available.
Some of the analytical techniques are inherently non-linear and will require special treatment. This can be accomplished either by transforming the responses to generate a linear curve or fitting the curve with a non-linear regression analysis. These techniques may be able to be fit with a linear regression under smaller ranges of use and approximate a linear response. Some of the common techniques which can generate nonlinear curves are:
Corona Aerosol Detector (CAD)
Evaporative light scattering detector (ELSD)
Some extractables/leachables inherently unstable or reactive making monitoring and setting solution stability ranges a challenge. For example the anti-oxidant Irgafos 168 readily oxidizes to form “oxidized irgafos 168”. It is difficult to control or prevent the oxidation from occurring and is commonly accepted that if you observe one you will have the other as well.
Stability programs for leachables (if needed) should be established per ICH Q1 guidelines. Testing under both nominal storage conditions and accelerated conditions. However, the data interpretation can be more complex and needs to be evaluated separately from normal API/DP related impurities.
Arrhenius equation doesn’t apply.
There are two main forces which determine if a compound will leach into a drug product.
Migration kinetics – the rate at which the will migrate through the material. This rate is temperature dependent.
Solubility/Partitioning – this is the ratio of how soluble the compound is in the DP formulation and how soluble the compound is in the component material. While the solubilities due vary with temperature, they won’t vary proportionally and it is possible that the material solubility increases greater than DP formulation solubility resulting in the potential that a leachable will be observed at higher levels under lower temperatures.
Regression analysis can be used to model the rate at which leachable appear but the resulting kinetic curves can be significantly different than typical reaction kinetics.
EXTRACTABLE – LEACHABLE CORRELATION
If possible one of the main goals of an E&L program should be to establish the extractable to leachable correlation. What this means is that enough data is generated and the leaching is understood to the point that you can directly relate the observed leachable level to the known extractable level of the component.
For example based on the data sets, it may be possible to correlate that if a component have a compound that extracts 30 μg this will equate to a total of 2 μg of the component leaching into the product.
If it is possible to establish an extractable to leachable correlation it may be possible to either reduce or eliminate the leachable testing and establish control of the leachable by controlling the extractable in the incoming material.
E&L methods can pose a series of challenges when they transition from the R&D environment an into the realm of routine QC testing. It is important to understand these challenges and limitation prior to implementing avoid costly delays as a result of validation failures or QC investigations as a result of poorly developed/validated methods or poorly established routine testing protocols.