ABC Company News: Downloads from 2014 AAPS Annual Meeting

CGMP Radiosynthesis for Early Phase Clinical Trials

Radiolabeled drugs are used in Human ADME and bio-availability studies. While the regulatory requirements for traditional “cold” clinical trial materials are well understood, the regulatory requirements for radiolabeled are much less understood by industry. The synthesis of radiolabeled compounds sometimes requires development of new synthetic pathways which can be significantly different from the traditional synthetic pathway. The radiolabeled drug can have significantly different stability and impurity profiles from the non-labeled drug and thus require special considerations. These special considerations may pose challenges in terms of ensuring CGMP compliance and safety for the patient during the clinical trial.

To download the whitepaper, click here.

How to Evaluate Manufacturer-Provided Extractable Information

Most pharmaceutical container/closure systems in use today are purchased from component manufacturers, who often provide material characterization information on their products. A common and often expensive misstep is to assume manufacturer-provided information will suffice as Extractables and Leachables (E&L) data. This paper will help you understand what information regulators require in your filing, provide questions to ask suppliers, and explain how to evaluate manufacturer-provided information relative to your unique product.

To download the whitepaper, click here.

ABC Company News: ABC Adds iCAP Q ICP-MS to Mass Spec Capabilities

To better meet new regulatory requirements for elemental impurities and other trace analysis, ABC Laboratories has added Thermo’s high performance iCAP Qc Quadrupole ICP-MS Spectrometer to its fleet of mass spectrometers. ABC’s newest ICP instrument enables single mode analysis that covers the mass range of 4-290 amu, while delivering low abundance sensitivity and ultra-fast scanning. This is the same instrument that USP used to help develop new chapters <232> and <233>.

“ABC continually evaluates its technology to ensure we are meeting our clients’ needs and enhancing operational efficiency,” said Joe Troxell, ABC Vice President of Product Development Services. “While this purchase is part of our ongoing capital program, it’s made particularly important by new regulatory requirements for metals analysis in pharmaceuticals.”

To learn more about implementation of new elemental impurities UPS Chapters <232> and <233>, download this working paper.

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.

Click here to watch now.

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.

click here for more.

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.

New, earlier E/L requirements for infusion sets?

by Dr Wayland Rushing, Ph.D.

Over the last several months we have had multiple clients come to us after being put on clinical hold for their clinical trials. The formulations are all parenterals, which utilize some kind of infusion set-up (IV bags, infusion pumps, etc). The FDA has requested determination of the extractables and leachables of the contact materials of the infusion sets.

In the past, minimal work was done on these sets and the main issue was compatibility between the drug and the materials (i.e. does the drug adhere/absorb onto the materials). Now the FDA is specifically asking for E&L evaluations of the materials, this includes going beyond the standard USP polymer characterization tests.

I have chatted with a couple of consultants on this and it is new to them as well. This seems to be something rather recent wherein the FDA is actually placing them on clinical hold until the information can be provided. As expected, this is a major concern for the companies being placed on hold, as it can be expensive and puts their development plans into a tailspin until they are able to generate the data.

Unfortunately, generating the data is not a quick and easy fix, but we have a process which seems to be appropriate. We design a study that generates the extractables data and the leachables data on the material in a side-by-side fashion. Allowing for at least a rapid generation of data to correlate to determine if any additional studies are going to be required.

PTM by MRM: Introducing New Methods to Solve Old Problems

PTM by MRM: A More Efficient Way to Find What You're Looking For

In biotherapeutic development, post-translational modifications (PTMs) can be as elusive as the proverbial needle in a haystack. Traditional methods for identifying and quantifying PTMs involve a painstaking, linear process of individual assays performed one after the other. They require multiple sample preparations and precious time, and findings are often found insufficient by regulators. ABC Laboratories is pleased to introduce a better way.

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Biosimilars: They Look the Same... But One is a Real Stinker.

Biosimilars Sometimes Behave Differently. The Key is Knowing When it Matters.

Biosimilars by nature look much like their comparator products, but they sometimes behave quite differently. That's because the two products often originate from different cell lines or expression systems. And no matter how hard you strive for parity in the way they're cultured, minor differences in manufacturing can lead to sticky variations in primary amino acid sequence, glycosylation chemical modifications and protein folding issues. The FDA understands biosimilar products sometimes behave differently than their name-brand counterparts. But, they do expect you to understand why those differences occur, and to demonstrate that they have no clinical significance. That's where ABC Laboratories comes in.

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Agrochemical Product Development: Taking Your Product to New Markets?

Get Post-Registration Support from the Product Development Experts at ABC

These days, it takes roughly 10 years and a development budget with eight zeros to successfully register a new crop protection products. But being first to market is just the beginning. Whether you expand into new territories, seek label expansions or require ongoing environmental monitoring, a trusted development partner is just as important post-registration as it is prior to initial regulatory approval.

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Environmental Assessments: Don't Let Your Environmental Package Be a Regulatory Sticking Point

Seamless E/A Solutions from the Drug Development Experts at ABC

A quality Environmental Assessment (EA) package is a critical component of many new drug product submissions. Not having the right data—or not starting EA investigations soon enough—is an often-underestimated development risk. In fact, these common missteps can lead to lengthy environmental fate or ecotoxicity studies that will delay a drug's approval by up to two years. ABC helps develop drugs and evaluates their environmental impacts. Click here for more.

Cytotoxic Drug Development: Choose Your Partner Well

Choose Your Partner Well - Ask ABC

Although regulatory requirements are fundamentally the same for all investigational drugs, working with cytotoxic materials presents unique challenges. Heightened safety procedures and encumbering personal protective equipment can be a drag on timelines—or worse, lead to procedural or analytical errors that compromise data integrity. It's critical to choose a CRO with cytotoxic expertise, yet the field of competent outsourcing partners is small.

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

Better Insight, Better Outcomes

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. Click here for more.

Extractables & Leachables: Feeling Spooked by E/L Risk?

Let ABC Help Reduce the Risk of E/L Surprises.

When late in development, few unknowns are as worrisome as potential impurities from your packaging or delivery device. That said, it is well understood that container-closure systems can interact with even the most stable formulation. By applying Quality by Design (QbD) principles to your extractables and leachables program, the experts at ABC Laboratories will help reduce the risk of surprises and keep your NDA filing on track. Our approach combines a solid understanding of compound chemistry, careful analysis of potential E/L risks and well-thought-out study design to address regulatory data requirements in an efficient and cost-effective manner. Click here for more.

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

We Know You're Counting on Us.

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. Click here for more.