ABC Webinar Archive: "The Critical Role of CMC in Your IND Submission"

Early stage drug developers generally have their sights firmly set on the initiation of clinical trials, focusing on toxicological and pharmacological studies. Often, the importance of Chemistry, Manufacturing and Control (CMC) data is underestimated. But the CMC package is critical to IND approval, and meeting all FDA requirements demands careful planning and sound execution.

This discussion will focus on the primary CMC requirements for a biopharmaceutical IND submission. It will cover the risk/reward criteria for determining the level and degree of method validation, reference standard characterization and formulation; as well as potential pitfalls and ways to streamline the entire development process.

"The Critical Role of CMC in Your IND Submission"

Featured Presenter:
Glenn E. Petrie, Ph.D., Senior Scientific Advisor, ABC Laboratories

Metabolite Profiling and Identification - (More Than) 150 Years of Good Advice

 

Over the past few months I have been writing a chapter on "Metabolite Profiling" for the forthcoming book, New Horizons in Predictive Drug Metabolism and Pharmacokinetics (Royal Society of Chemistry, 2015).

I began the chapter with one of my favorite quotes related to drug metabolism:

“In order to understand the actions of drugs it is an absolute necessity to have knowledge of the transformations they undergo in the body…we must not judge drugs according to the form and amount administered, but rather according to the form and amount which actually is eliciting the action.”

From where did this sage advice arise? Another recent book on metabolite profiling? No. A regulatory guidance document? No.

In fact, this statement was written more than 150 years ago, in 1859, by Rudolph Buchheim (1820-79), a pioneer in experimntal pharmacology.

The quote appeals to me for several reasons; first, as someone interested in the history of chemistry and science; second - and more important - because it lays out as elegantly as any modern statement the very mission and importance of drug metabolism ("form") and pharmacokinetics ("amount") and pharmacology ("action"), especially the role of metabolite profiling and identification.

Though the basic mission has not changed over the past 150 years, what has evolved is the tools at our disposal to execute that mission.  I've witnessed some of that evolution in my nearly 30-year career in xenobiotic metabolite profiling, isolation, characterization, and identification, especially the shrinking footprint (and cost) of high resolution mass spectrometry and improved in silico tools for data mining and prediction.

What do you see as potential advances (or unmet needs) in metabolite profiling and identification technologies in the coming years?

ABC Webinar Archive: "Are Extractables and Leachables Going Phase Appropriate?"

Not long ago, it was more or less conventional wisdom that E&L studies should be performed late in the development cycle—even after the final container/closure system is known. But current regulatory trends suggest that, like many things GxP, expectations for early E&L data are on the rise. 

In recent years, multiple drug sponsors have been required by authorities to provide detailed E&L packages or address specific questions during phase I/II. It’s not only clinical trial material containers causing concern, but also the equipment used in manufacturing and dosing devices. As a result of these new expectations, several programs have been put on a clinical hold pending E&L data, causing significant delays and unplanned expense.

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CGMP Radiosynthesis - Will Your CRO Be There When It Counts?

Expert ¹⁴C radiolabeling for human clinical programs requires extensive training and experience. Having supported radiolabeled studies for more than 30 years, ABC Laboratories was one of the first to produce ¹⁴C-labeled API and formulate CTMs under CGMP requirements. Our experienced radiosynthethic chemists have worked with many drug candidates so we can help guide you through the detailed CGMP process. We work in tandem with your chemistry, regulatory, and QA personnel to ensure that a high-quality API or drug product CTM, that meets your specifications, is delivered to the clinic on time.

We know you're counting on us

ABC's experienced scientists have worked on both sides of the outsourcing relationship, so we understand the criticality of meeting timelines while supplying high quality products and data. ABC maintains a dedicated Quality Control and Quality Assurance staff with extensive experience specifically supporting isotopically labeled compounds. Nowhere will you find a team with more skill in developing efficient synthetic routes, commitment to delivering your labeled drug candidate, batch records and Certificates of Analysis in the agreed-upon time at the level of quality needed to meet today's high standards.

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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.

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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.