The Most Important Symbol in Science (it may not be what you think!)

By Jim Schmidt
Sr. Scientific Advisor
ABC Laboratories
www.abclabs.com

Symbols.  We use a LOT of them in doing scientific work.  Every letter in the alphabet from a to z (acceleration to complex variable), and from A to Z (ampere to altitude); for good measure, every letter in the Greek alphabet as well, from alpha to omega (angular acceleration to frequency).


Some perform multiple duties: the Greek letter mu, µ, can represent absorption coefficient, chemical potential, magnetic dipole moment, mean, micro–, muon, permeability, and reduced mass.


And then there are the unique ones such as Å (Angstrom).


As it happens, I actually think the most important symbol used in science is the question mark: ?


It's the launch point from the simplest science fair experiment to the most advanced research:


"I wonder if...?"
"What happens when....?"
"Why does the....?"
"How can we...."?


Indeed, about a decade ago, Science published a special issue devoted to "125 Questions: What Don't We Know?" and it included everything from "What is the Universe Made of?" to "Why do Humans have so few genes?" to "Are We Alone in the Universe?"


Questions are also the foundation of the important and interesting regulatory-driven research we perform on behalf of our customers here at ABC Labs:


"What happens when this product is....?"
"How quickly does this chemical degrade when exposed to...?"
"What is the identity of the unknown component in...?"

In looking ahead to 2016, here are two more:


What product development challenges do you face in the new year? 
What can we do to help?

I-SPY and now AGILE Cancer Programs

By Harley Everett Wilcox, MBA

Senior Scientific Advisor

ABC Laboratories
www.abclabs.com

Historical clinical cancer studies lack efficiency and require significant time for often an overall survival improvement of only 60 days versus standard treatment. The inefficiencies may be related to the need for adequate safety evaluation, single agent studies, and limited tumor biological information for individual patients.  Approval of a new oncological agents require 10-15 years of clinical drug development and in rarer cancers, patient populations available for study are lacking .New investigation drugs require evaluation in diseased patients prior to approval and often before combination with other attractive agents. With the advancements in biological test procedures, and better understanding of cancer biology, an individual tumor may be profiled to determine the theoretical optimum drugs, combination of drugs and dosing schedule.

The I-SPY program is a novel personalized cancer treatment study supported by the FDA, NIH and a consortium of pharmaceutical companies via the Foundation for the National Institutes of Health (FNIH). The design allows for investigating new drug therapies with standard treatment and flexibility to modify treatment protocols on the fly, saving time, money, and optimal treatment regimens for breast cancer patients.  Multiple company intellectual property have been combined in a single phase II like program to access the best therapy based on tumor biology and proof concept of activity prior to surgery in resistant tumor types. The goal will be to bring effective treatments to market with fewer patients and in less time.  

Targeting another type of cancer in an adaptive trial approach is MD Anderson and the recently announced AGILE study.  Glioblastoma multiform has yet to see a new chemical treatment option in ~10 years with the standard chemotherapy Tremodar and radiation providing an overall survival improvement of just 2 months.  MD Andersons’ Mitchel Burger, MD states the uniqueness of the study, like the I-SPY uses biological tumor profiling and Bayesian statistics to limit the number of clinical patients.  The statistical method allow for a probability approach to advance drug winners more quickly. As stated earlier, one issue with rare cancers is adequate patient populations for supporting multiple clinical studies. With~10,000 GBM cases a year combined with aggressive disease, brain cancer clinical programs often require longer time to complete enrollment.

These adaptive clinical trial programs will hopefully provide more meaningful outcome for clinical trial participants and more rapid approval for needed treatment options.

References:

http://ispy2.org

Target Oncology (targetdonc.com)

Teaming up to Develop Life-Enhancing Medicines

ABC provides IND-enabling, registration, and post-commercialization support for the development, quality control, and lifecycle of innovative therapies and generic medicines. Through development know-how, cross-disciplinary technical expertise, and applied experience with evolving global regulatory frameworks, we help efficiently advance and manage programs for large and small molecule drugs, medical devices, and combination products. Better insight. Better outcomes. Ask ABC.

ABC Laboratories: Pharmaceutical Development Expertise

Over our more than two decades’ experience with drug chemistries, ABC has worked with virtually every class and type of compound, across most indications and all common delivery systems. We have contributed data to and drafted sections of IND, NDA and ANDA submissions for dozens of commercial products. And we’ve helped hundreds of companies like yours answer challenging development questions, respond to regulators and uncover sources of problematic manufacturing issues.

Click here for more on ABC's Pharmaceutical Capabilities.

Analytical Method Development: Beware the Rabbit Hole

By Wayland Rushing, Ph.D.

Senior Scientific Advisor

ABC Laboratories

www.abclabs.com

Developing analytical methods for pharmaceutical analysis can be one of the most time consuming and rewarding experiences in today’s analytical lab. I fondly recall the days (from many years ago) of sitting in front of the HPLC anxiously awaiting the data from the latest run for evaluation.  Either hours/days of hard work were about to be vindicated or hopes dashed and it was back to the drawing boards.  This scenario is still occurs on a daily basis throughout our industry. Unfortunately there is a potential dark side to the developmental process.  It can be very easy for the method developer to get lost in the task, ever trying to develop the “perfect” analytical method.  I have watched many analytical chemists get caught in this web of ever trying to catch this unicorn.  There is never a perfect method, it can always be improved, accuracy tweaked, precision optimized, etc.  So how do we know when enough is enough?

Let’s take the development of an impurities method as an example. The impurity is present at 0.15% and has a specification of 0.5%.  We are going to charge our developer with developing a method to quantitate for the impurity and we turn him lose.  After a couple of weeks we touch base with them and are updated the method isn’t ready, so development continues, couple more weeks pass, then another month, then finally a method is delivered.  The method can see the impurity down to 0.005%, has recovery of >99% with <1% RSD at the quantitation level.  And we stand amazed, not only at the performance of the method (quite impressive), but also finally realizing the time and money spent on a developing a method that far exceeds what it needed to do.  Simply put, for an impurity method, this is overkill, this level of method performance simply isn’t needed.

I have watched this play out in the development arena multiple times over again.  With the main drivers of development being time, quality and cost we must learn how to balance all of them to achieve the goals of development.  The mistake made here is that the development of the method wasn’t guided, there were no expectations set on what the intent of the method should be and what level of performance the method should have.  When initiating any analytical development there should be key questions that are asked and answered before any labwork commences:

• What is the intent of the method?
•  How low does the method need to go down to?
• What level of accuracy is needed?
• How precise does the method need to be?
• What is the range of the method?

So lets re-evaluate our development plan for the above example and answer the above questions first:

• What is the intent of the method?
• Answer: to quantitate the impurity in question for release and stability testing.
• How low does the method need to go down to?
• Answer: the method needs to have an Limit of Quantitation of 0.05%
• What level of accuracy is needed?
• Answer: At the specification the method should have an accuracy between 90 – 110%.
• How precise does the method need to be?
• Answer: At the specification the method should have no greater than 10% RSD.
• What is the range of the method?
• Answer: the method should be linear from 0.05% to 0.75%.

If we apply these questions to the above development we not that the method developer had met these conditions within the first two weeks of the development program.  But his level of understanding of what the method needed to do and the actual needs of the method were not aligned and hence spending an additional couple of months in development, wasting time and money.  This is a common occurrence which is easily preventable, set expectations before you start the work.  Ensure that your internal analyst or the CRO you are working with understands the difference between development a perfect method and developing a method which is suitable for its intended use.  This can often be the difference between having an efficient development program and one that suffers from unexpected delays in time and budget excesses.

Don't Gamble on Extractables & Leachables - You've Got a Lot Riding on This

Extractables & Leachables: You’ve Got a Lot Riding on This

Approaching a product submission to the FDA without full confidence in the container closure system is a big gamble. After investing huge sums in development, why risk lengthy delays, millions in lost sales – or worse yet – a costly, embarrassing recall?

These perils are real. A 2011 survey of parenteral drug development experts found 45% have had marketing applications delayed due to issues with extractables and leachables (E&L), and 24% have had product recalls. More than half the sponsors lack confidence in the clarity of FDA documents and other guidance on container systems. It takes an E&L expert to understand the unique risks of your product and packaging combination.

With so much at stake, it pays to bring in a ringer.

ABC Laboratories offers true expertise in the specialized science of extractables and leachables. We dedicate some of our most talented problem solvers to a special team called the ABC TASC Force (Trace Analysis and Structural Chemistry), representing 200-plus years of experience in polymer chemistry, mass spectrometry, trace analysis and E&L qualification studies…. and we back them with a full house of state-of-the-art instrumentation. Through skilled use of Quality by Design principles, ABC approaches every E&L program with a well-defined scope and a focus on the quality of data each study will produce.

ABC has conducted container closure studies on essentially every form of product and drug delivery device, including higher-risk compounds such as inhalation products and parenterals. What’s more, we understand the regulatory landscape for container closure systems. So, when you choose ABC, you get more than reliable E&L data. You get a development partner who can help optimize your container closure selection. You get the technical horsepower to anticipate and proactively address potential E&L issues before they become concerns. And, you get confidence that your investment will provide the type and depth of data required for a successful submission.

Are You Really Ready?

By Jon Rhodes, M.S.
Senior Scientific Advisor
ABC Laboratories

www.abclabs.com

It’s very easy to build an argument that investing time and other resources in developing and nurturing a relationship between your organization and a new CRO development partner is essential to the success of both organizations. It’s very hard to actually identify and implement the steps necessary to make that success a reality. The landscape is littered with examples of less than successful attempts at building fully functioning, collaborative and engaged partnerships that stand the test of time.

Most organizations, whether they like to admit it or not, are very reluctant to loosen their grip on knowledge, skills, and experience and freely share and disseminate such things in a transparent manner. That’s why it’s essential to create a crystal clear vision about what success looks like, how it can be achieved, and what the rewards will be. It’s about creating a culture of enthusiasm and anticipation. The right processes and the right people are essential to creating this culture of success and this should come first, before actual knowledge and technology is transferred.

Marrying the best discovery engine and product pipeline with the best applied science and registration support isn’t strictly science – communication, collaboration, and transparency are everything.

Metabolite Profiling: More Than Just Detective Work

By Jim Schmidt
Sr. Scientific Advisor
ABC Laboratories
www.abclabs.com

Time flies!  It’s been just over a year since my first posts on this blog. One of my early posts, back in September 2014, concerned a chapter on metabolite profiling I was writing for a forthcoming book of invited essays.  I submitted the chapter in late spring of this year and the book - New Horizons in Predictive Drug Metabolism and Pharmacokinetics (published by the Royal Society of Chemistry), with about two dozen contributors – is set to be released in just a few weeks.

I performed metabolite profiling of one kind or another for most of my nearly thirty-year career at the bench; even though I’m not in the lab, presently, it’s still a passion and interest, and with good reason: metabolite profiling is a very intellectually satisfying exercise, owing in no small part to its interdisciplinary nature. The “detective work” of metabolite profiling contributes to medicinal chemistry, enzymology, pharmacology, toxicology, mechanistic chemistry, analytical chemistry, and many other fields. Among the more satisfying and exciting results of metabolite profiling is the discovery of novel and/or unexpected metabolites.

Apart from the satisfying “detective work,” there are some other very important and practical reasons for performing metabolite profiling early and often, including but not limited to:

Drug Attrition - The most practical reason for pursuing metabolite profiling efforts as early and as diligently as possible is to mitigate attrition in the drug discovery process. Owing in no small part to an increased focus on metabolite profiling in drug design, attrition attributed to poor pharmacokinetic  (PK) behavior decreased from 40% in the early 1990s to <10% in 2000 (in one recent study, poor PK behavior represented as little as 3% of drug failures in preclinical evaluation). In fact, metabolite profiling can support troubleshooting of other aspects of drug attrition and should not be limited simply to improving PK behavior.

The Law - The aphorism applied to highway speed limits and (cheekily) applied to gravity—“It’s Not Just a Good Idea. It’s the Law”—can also be applied to metabolite profiling. Guidance documents, including—but not limited to—those from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)/ICH, have formalized the regulatory framework and decision-making of metabolite profiling.

Due Diligence - Another important rationale is the due diligence process that is associated with the process of acquisition of intellectual property and/or drug portfolios. While limited funding may result in a temptation to delay or minimize metabolite profiling efforts, that temptation should be ignored: scientific due diligence is every bit as essential as financial analysis and important questions about metabolites and pathways help minimize poor choices in investment decisions; likewise, groups should be prepared to answer these questions to improve chances for desired investment.

Stay tuned to this blog for more thoughts on metabolite profiling.

What are you doing to pay more (and earlier) attention to metabolites in the drug discovery and development process?

Download ABC's 3 Presentations from AAPS 2015

Below are recent presentations by ABC at this year's AAPS in October.

Don’t Leave Method Transfers to Chance

When planning your development strategy, you probably didn’t give much thought to method transfers. But when an analytical method doesn’t perform as expected, it can take precious days of investigative work to find the problem, and even more to resolve it. Learn about common pitfalls that cause method transfer failures, how to decide what type of method transfer makes sense for your study, and how to implement a fail-safe communication plan that will help put your outsourcing relationship on the right course.

To download this presentation, click here.

 

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 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.

To download this presentation, click here.

Are Extractables & 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, many drug sponsors have been required to address E&L questions as early as phase I/II. It isn’t just CTM containers causing concern; questions often involve the equipment used in manufacturing and dosing devices. Phase-appropriate E&L program design can help you avoid related clinical holds and unplanned expense.

To download this presentation, click here.

AAPS National Meeting- ABC Laboratories' Presentations

By Glenn Petrie, Ph.D.
Senior Scientific Advisor
ABC Laboratories
www.abclabs.com

I always look forward to the AAPS National meeting. It is the one time of year in which I can re-connect with old colleagues, clients and other friends in the industry. It never ceases to amaze me the inter-connectedness of the industry and shows that it is truly a small world. The conference presents multiple opportunities to hear about the latest developments in the field, but also to present our own data. I have the privilege of participating in a number ABC laboratory presentations.

On Tuesday, October 27, Exhibitor Seminar Room 4

·       Analytical Method Transfer: Practice and Pitfalls

Dr. Wayland Rushing and Dr. Glenn Petrie

This seminar will outline how to plan and execute a successful method transfer. This process is oft times not given proper attention and is seen as a “check box” activity. However, there are multiple hazards arising from this attitude that can result in a tremendous loss in time and money. Dr. Rushing and I will discuss method appropriate best practices, as well as several case studies.

·       The Critical Role of CMC in Your IND Submission

Dr. Glenn Petrie and Dr. Wayland Rushing

Submitting an IND is a tremendous task, particularly the CMC section. This seminar will cover various aspects of CMC including:

o   General requirements

o   Minimal requirements and safety

o   The CMC continuum

o   Risk and Reward: Analytical, formulation and Stability

The goal is to provide information to optimize your CMC section in terms of time and money, resulting in a successful IND submission.

On Thursday, October 29, 10:30-11:30 AM, Exhibit Hall WA3

I will be presenting Poster R6208 “Development and Validation of a Polysorbate 20 Assay in a Therapeutic Antibody Formulation by RP-HPLC and Charged Aerosol Detector (CAD).

o   Polysorbate 20 is a key excipient utilized in biotherapeutic formulations. This poster examines the validation data for an accurate and precise method for assay of Polysorbate 20 in the presence of a high concentration of monoclonal antibody.

Be sure to stop by ABC Laboratories at Booth #1825!