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.
Current guidelines, including ICH M71, provide an overview of assessing and evaluating limits of pharmaceutical impurities suspected or classified as mutagenic impurities. These impurities may be associated with known added agents, environmental factors or degradation products from pharmaceutical compositions. Proposed limits for genotoxic impurities reside well below common impurities discussed in ICH Q3A2 guidance and require analytical techniques capable of detecting and measuring ppm to ppb levels. This presentation provides an overview of analytical technologies for detecting mutagenic impurities.
Investigational new drug development requires a demonstration of safety and efficacy. Over the last two decades the safety requirements for CMC have become more clearly defined. Specifically, evaluation of impurities of actives and drug products in relation to container closures, as well as manufacturing, are covered in the guidelines including ICH, regulatory agencies, and USP. The introduction of guidelines for trace metals and mutagenic impurities suggest rigorous control of impurities. The ICH M7 guidance outlines limiting carcinogenic risk by assessing possible mutagenic impurities in new drug substance and products. The primary challenge associated in measuring mutagenic impurities (MI) is often the need for low to very low-level detection limits.
Early industry articles and draft guidance often used terminology such a “genotoxic” and “carcinogenic” impurities, however the 2015 issued M7 guidance refers to mutagenicity. The significant difference is that a genotoxin may not be a mutagen and a mutagen is defined as follows:
Anything that causes a mutation (a change in the DNA of a cell). DNA changes caused by mutagens may harm cells and cause certain diseases, such as cancer. Examples of mutagens include radioactive substances, x-rays, ultraviolet radiation, and certain chemical3.
Assessing Levels of MIs
Non-mutagenic impurities are typically evaluated in drug substances at levels above 0.05% weight/weight or relative peak area using standard detection techniques (ICH Q3A). Suggested threshold levels of MIs are determined by daily intake and dose duration. These limit MIs to less than 1.5 µg per day for a concentration of less than 10 ppm. Therefore, a detection technique of 70-fold lower may be needed, as profiled in Table 1. One way to view the introduction of MIs is to categorize from three primary sources with the detection complexities differing based on the source of the MI.
Thus, it is clear from Table 1 and a little math, the MIs to be quantitated may require much higher sensitivity than for standard Q3A impurities at the 0.05% level and at 30% TTC (Threshold of Toxicological Concern.
This paper discusses two of the three sources of mutagenic impurities: things that are added and things that may form in the matrix. Environmental MIs, also known as leachables, are not covered here, as these are typically analyzed in independently defined programs.
MIs That Are Added
Finding “things that are added” is less complicated than “things that may form.” Both require an initial assessment. For example, knowing that an acid chloride was added at step 3 of a 5-step synthesis, a sample is available, and detection characteristics can be extrapolated, suggests a straightforward process of detecting the MI. In addition, available toxicological data simplifies the assessment.
When the assessment requires evaluating the final drug substance or intermediate for the presence of the added MI, a separation technique and detection technique is evaluated. This raises some questions to consider:
Does my current analytical methodology detect the MI, and if yes, what is the detection limit?
What is the desired detection or quantification limit based on TTC?
Is the compound volatile?
What is the expected ionization characteristic of the MI and its applicability to MS?
How reactive is the MI and should derivatization be considered?
In general, added MIs typically are of higher chemical reactivity and this should be considered during method development to assess stability of these reactive species when API is spiked into samples as part of accuracy. For example, alkyl halide MIs are known to react with amines and have been observed in GC headspace analysis to affect accuracy in recovery studies.
MIs as Degradation Products or Formed from Matrix or Process
More complex than “MIs That are Added” is the discovery of degradation products that alert for mutagenicity. If the Q3A(R2) process for impurity qualification or other information finds a degradation product with toxicological concerns, such as defined in Figure 1, additional efforts may be required. We find a subtle gap in both the Q3A(R2) decision tree and the note in the decision tree diagram stating, “Lower thresholds can be appropriate if the degradation product is unusually toxic.” This addresses toxic degradation products but at the same time does not suggest the need for identification. The decision tree suggests an option to reduce the degradation product to less than the identification threshold, thus no further action is needed. However, the note’s mention of the unusual toxicity of the degradation product implies prior identification. That is, how does one assess toxicity of an unidentified degradation product? M7 is a better source for assessing mutagenic impurities than Q3A R2.
Figure 1: A Q3B(R2) decision tree for the identification and qualification of a degradation product
Consider an example of a worst-case scenario:
The M7-like assessment identifies a possible degradation product of concern in API or the corresponding drug product contains two actives and many excipients.
Further studies may be considered such as purposeful stressing of drug substance to identify the presence of the alerting structure followed by insilico analysis, and a bacterial assay. Additional questions to ask in addition to the above in “MIs that are added”,
Is isolation and/or synthesis of the degradation product required to confirm absolute structure, provide analytical reference material, and provide material for in vivo studies?
Should this degradation product be monitored or evaluated in one’s complex drug product such as part of long term stability studies?
One situation that may arise is the presence of an in silico MI alerting functional group that is contained in the primary structure such as a substituted aniline. Clearly any proposed or known degradation product containing the aniline substructure would give an in silico alert. It is generally accepted if the parent molecule is shown not be mutagenic, then similar degradation products would follow this pattern. However, at least a risk assessment would be recommended. ICH suggests M7 is not applicable for advanced cancer drugs.
When we encounter the need to quantitate low level impurities, some options for detection prove more suitable than others. Table 2 profiles the general sensitivity of listed detectors where UV is arbitrarily assigned a value of 1 and the scale represents the relationship to other detectors. Thus, an electrochemical detector has a value of 0.1 or in general 10X more sensitive than UV. Note that these general sensitivities are very compound dependent.
Clearly mass spectrometry detection, as shown in Table 3, has superior sensitivity and the added advantage of identification potential. For example, a trap MS with single ion monitoring capability with instruments such as a Q Executive® Orbitrap allows for low level quantitation in a complex matrix and is very useful in both screening and/or monitoring MIs.
When assessing and possibly quantitating MIs, it is important to have input from synthesis, toxicology, analytical, and manufacturing experts to apply a compound specific strategy with continual evaluation through drug development.
Three sources of MIs may arise from
Things that are added (included in-process impurities)
Low level detection capabilities are often required for mutagenic impurity profiling
Many techniques and detector options are available
Newer MS technology is a useful tool for ID and quantitation
The complexity of identifying and quantitating MIs is related to whether the MI is a known or an unknown entity, its compound properties, and the required level of detection.
Harley Everett Wilcox brings 25 years of experience in drug research and development to EAG Laboratories. Prior to joining our team, he served in various technical and management positions with both large and startup pharmaceutical companies, including working as director of manufacturing responsible for CMC regulatory support and CRO/CMO outsourcing. He served as a CMC project leader for Anzemet® NDA, and has supported numerous IND’s, CTA’s, and CTX’s as well as an ANDA. Having begun his career as an organic chemist, Wilcox’s expertise includes analytical methods development and validation, isolation and identification of impurities in drug products, and in-vitro metabolic characterization supporting pre-clinical research; he also has assisted many small and virtual pharmaceutical companies with regulatory aspects of early CMC development programs, and has participated in collaborations, contracts, and intellectual property management in support of business development objectives. Wilcox is recipient of the Marion Laboratories presidential award for developing a high yield reclamation process for the active ingredient of a commercial formulation.