Genotoxic Impurities - A Mathematical Approach?

As part of the ongoing effort to define impurities in drug substance and drug products, CDER’s has issued the Genotoxic and carcinogenic (GTI) Impurity draft Guidelines for evaluation of mutagenic impurities for clinical drugs from IND to registration. One of the first steps in addressing such impurities is determining potential GTI’s. The next step is to determine the therapeutic toxicological concern TTC. Finally, are the impurities present and at what level in the drug product or active ingredient?

One reasonable approach for determining impurity levels would be a paper analysis of the known GTI to show it is well below the threshold limits. For example, a dilution scheme followed through the synthesis shows a GTI impurity exists, if at all, well below the relevant threshold.  Recent trends suggest this approach will not be accepted as it lacks definitive data. This outcome is expected as the paper approach is similar to determining an API-related substance is below the monitoring threshold based on mathematics alone.  GTI impurities levels will likely need assessment with analytical methodologies and monitored. In addition, these methodologies often require validated methods at the ppm/ppb level.

Let me know if your thoughts on the discussion

Novel MS Techniques Speed Detection of Biopharmaceutical Product and Process Impurities (an ABC Webinar)

Product and process impurities in biopharmaceuticals are often present in very low abundance and are often “lost in the noise,” making their analyses quite challenging and time-consuming.

In this webinar, learn about a novel mass spectrometer-based approach that can speed detection and quantitation while achieving the required specificity and sensitivity—and how multiple reaction monitoring (MRM) techniques can be effectively applied to CMC-related development activities.

Case studies will be cited to demonstrate how internally standardized LC-ESI-MS/MS methods can be designed and validated to meet regulatory requirements.

Click here to watch now.

Extractables and Leachables in Early Phase Development

 

 

By Wayland Rushing, Ph.D.

 

Over the last couple of decades we have observed ever increasing expectations for extractables and leachables.  Initially this was focused on the final container/closure systems of inhalation products, which quickly expanded to parenterals and ophthalmics.   Over the last few years the expectations have continued to expanding including additional expectations for dermal products, veterinary products and manufacturing equipment.  The media coverage surrounding Bisphenol A and recalls involving popular medications due to leachables has helped to drive extractables and leachables into regulatory and public crosshairs.

 

Recently a new trend has been encountered during early phase development.  Drug sponsors have been required by regulatory authorities to provide detailed E&L packages and address specific questions during phase I/II.  Several of these sponsors have reported being placed on a clinical hold until the information is provided.  This can be of concern for many companies as the typical E&L program can be a time-consuming and expensive endeavor and most have not planned on this requirement in their development plans. 

 

Coming in September, I will be presenting a webinar which will discuss the overall regulatory trends being observed and how to establish an appropriate early phase E&L program for to avoid delays in early phase development. 

Please let me know your thoughts on the continued increasing expectations or if you would like more information on the upcoming webinar.

ABC Laboratories Role in a New Century of Environmental Chemistry

By Jim Schmidt

An article in a recent (23 June 2014) issue of Chemical & Engineering News which commemorated the centennial of the Environmental Chemistry (ENVR) Division of the American Chemical Society (ACS) really captured my interest.

Originally chartered as the “Division of Water, Sewage, & Sanitation Chemistry,” the original focus of the division was stewardship of the nation’s water resources.  The mission and names of the division then evolved with increasing interest in wastewater; air, soil, and groundwater quality; hazardous waste; and other areas of concern and interest.  Today, the division “reflects the ever-expanding complexity of the environmental field, as well as the need to integrate problem-solving across various disciplines,” across the globe.

Exactly! It’s that interdisciplinary approach that initially attracted me to – and continues to inspire me – in the study of environmental fate and metabolism of chemicals in the environment, animals, and humans. It would be interesting enough just for the intersection of experimental and analytical science, but it’s all the more interesting and dynamic when one includes regulatory, intellectual property, commercial product development, public education, and other aspects as well.  No wonder I love what I do!

I’m very excited to help open a new century for ENVR: I am co-organizing a symposium on “Enantioselective Biotransformation of Chiral Pollutants in Soils and Water,” for the ACS national meeting in Denver, Colorado, 22-26 March, 2015.  I’m so pleased that Izabela  Kania-Korwel, PhD, a scientist with the Environmental Health Sciences Research Center at the University of Iowa will be joining me as co-organizer.  Stay tuned to this blog for the Call for Papers and more information!

What interesting opportunities do you see for environmental chemistry in the 21st century?

ABC's Connection to the Apollo 11 Mission (Launched 45 Years Ago Today for the Moon)

Forty-five years ago today, the Apollo 11 astronauts launched toward the moon.

Lunar samples returned by Apollo Flight 11 (as well as 12-17) provided scientists with an opportunity to examine extraterrestrial material for clues to the chemical origin of life. NASA, the National Academy of Science, and the scientists from the University of Missouri and the University of Maryland, studied samples returned from the moon. They were looking for the presence of amino acids and previous life forms. The scientists showed that chemical evolution of "life molecules" had not occurred on the surface of the moon.

Among the few chosen to analyze the moon rocks was a scientist named Charles Gehrke, who would go on to become the founder of ABC Laboratories.


Click here to see more photos of Dr. Charles W. Gehrke and his colleagues analyzing the moon rocks in 1969.

Glycan Analysis for Monoclonal Antibody (mAbs): What Makes Them Beautiful Also Complicates Their Analysis

Glycoproteins are enormously diverse and mutable macromolecules. In monoclonal antibody development, manipulation of the glycosylation process has critical impacts to stability, activity, antigenicity and pharmacodynamics. Accurately correlating functional features with glycoform structures is essential, and early insight can lead to downstream efficiencies with better decision-making related to the manufacturing process. Yet the inherent heterogeneity and mutability of glycans pose technical challenges in the laboratory.

ABC offers you a team of biopharmaceutical veterans with decades of experience fully characterizing monoclonal antibodies (mAbs) and other recombinant protein biopharmaceuticals. We have the instrumentation necessary to...

Click here for more.

OTC Process: Future Changes for Non Prescription Drugs?

By Harley Everett Wilcox, MBA

Recent FDA public hearings in 2012 and 2014 regarding non-prescription drugs suggest the agency is interested in modernizing the over-the-counter drug process. The 2012 docket discusses topics on providing citizens with more options for obtaining prescription drugs including relying on self-diagnosis, new technology, and pharmacies vs. standard physician visits.

The 2014 docket outlines current issues with the OTC monograph system and requests public comments for improvements. There is yet an outcome of these meetings and suggested changes to the OTC process and regulations.  A more in-depth examination of the current processes, weaknesses, and possible changes will be addressed in a future presentation. The discussion will cover the monograph system, types of submissions, and possible OTC changes that may include  new guidelines or updates to current procedures such as the NDA Deviation.

Let me know what you think about the dockets and possible outcomes in the comment section below.