Where’s Your CRO Relationship Headed?

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

For many in the pharmaceutical, agrichemical, chemical and consumer product, and biotechnology industries, outsourcing of laboratory, clinical and field-based product development and support activities is fast becoming an essential element of business success.  Many business organizations in these industries are shifting their internal focus to discovery and lead optimization along with management of regulatory and product support activities and timelines.  Laboratory, clinical and field-based research activities, along with the deep product knowledge that results from those activities is shifting to external Partners.

Outsourcing strategies are continually evolving and run the gamut from limited scope and intermittent use of a variety of individual CRO’s to extensive and continuous engagement of a limited set of CRO’s. Limited and intermittent relationships are typically based on fee for service or time and materials arrangements on a per-project basis.  The activities typically consist of single projects or a few small projects.  Companies that employ this strategy typically have a relatively narrow regulatory path to follow.  Continuous relationships are more often based on leveraging the scientific knowledge, skills, and experience of the CRO with the intellectual property, discovery activities, and regulatory drivers of the developing Company.  Outsourced activities typically revolve around the application of a broad range of scientific disciplines and cross multiple development programs.  Companies that are developing and supporting multiple products with global applicability and who are dealing with multiple regulatory authorities would benefit from this strategy.

Relationships with Contract Research Organizations (CRO’s) can be unpredictable and complicated affairs fraught with difficulty and uncertainty.  Regardless of the strategy currently being used any organization must continually evaluate the state of their relationships with CRO’s.  A successful relationship results in CRO Partners becoming a seamless extension of your product development team.  With quality science and meeting challenging timelines on the line, investing time in developing, nurturing, and growing relationships between your organization and a CRO Partner is essential to product development success.

A Biotech Scientist Answers the Question: "Is JURASSIC WORLD Possible?"

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

As a boy I was fascinated with dinosaurs. But while most children grew out of this by 7 or 8, I remained engrossed in all things “saurus”. As I started my career in biotechnology, I was particularly interested in Michael Crichton’s book Jurassic Park. I read it in a single sitting and went to the first showing when the movie was released. Now that JURASSIC WORLD is a worldwide phenomenon, interest in reviving extinct species, or de-extinction, has been brought to the forefront. But could JURASSIC WORLD actually be possible? The short answer is no. DNA is the key to any attempts at de-extinction, but while stable, it is not stable for millions of years. Therefore, since dinosaurs went extinct 65 million years ago, there is no viable DNA

However, DNA can survive tens of thousands of years in the right environment, particularly frozen. There are numerous articles in both the scientific and popular literature regarding bringing Wooly Mammoths back to life. Frozen carcasses discovered in Russia have yielded partially intact DNA. JURASSIC WORLD scientists use the bottom-up technique, i.e. start with a fairly complete genome and plug the gaps with that of similar species. In reality the top-down approach is more likely since only partial DNA genomes have been recovered. Scientists are attempting to modify elephant DNA with some of the mammoth’s. The goal is to obtain a hybrid, an elephant with some mammoth traits. With the explosion in biotechnology, one could envision a Pleistocene Park. Rather than dinosaurs it would be populated with animals from the Pleistocene era, ~10,000 years ago. Among the possible exhibits could be Wooly Mammoths, Saber Tooth Cats, Wooly Rhinoceros, Giant Ground Sloths and the Giant Short-faced Bear. Think of the La Brea Tar Pits brought to life.

Even if this is possible, should it be attempted (“But John, if Pirates of the Caribbean breaks down, the pirates don’t eat the tourists.”)? While no one is seriously proposing de-extinction as a theme park, many are interested in using this technology to increase biodiversity and bring back species that humans destroyed, e.g. passenger pigeon, Steller seal, Tasmanian tiger and the dodo. Since there are numerous specimens of these species throughout the museums of the world, there is a reasonable chance of success. However, many ecologists see this as a zero sum game. They believe that any money spent on de-extinction represents less money for efforts to save endangered species; protection, habitat, etc. There may be a middle ground in which de-extinction methods could be used with endangered species to increase genomic diversity and increase the chances for a healthy population.

I look forward to following the latest developments in this exciting field and will provide an update with the release of JURASSIC WORLD 2.

Visit www.abclabs.com for more on Biotech, Biopharmaceuticals and ABC Laboratories' other services.

Upcoming ABC Webinar: "Analytical Method Transfers: Practice and Pitfalls" (July 23, 1pm CST)

Delays not part of your game plan?

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.

“Analytical Method Transfers: Practice and Pitfalls”

July 23, 2015 @ 2PM EST

RegisterNow

Webinar produced with and hosted by Contract Pharma

Of Scientists and New "Toys"

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

Several years ago I had the great privilege of writing an article¹ for the magazine Today’s Chemist at Work about the history of chemistry sets.  Part of the fun in the writing was canvassing chemists for reminiscences of having a chemistry set in their youth and how it was much more than just a "toy"; it actually inspired and influenced their career choice.

As professional analytical chemists and experimental scientists, the anticipation of adding new instruments – and it is no coincidence that we often refer to them as “toys” - to the lab maintains a good amount of the excitement of younger days.

Indeed, just last week, a colleague here at ABC Labs – recently returned from the annual meeting of the American Society for Mass Spectrometry – eagerly shared news about some new tools and techniques well suited for the work that he and his team perform.

There are many reasons to invest in new instruments – faster sample throughput, better sensitivity, improved quality of results, reduced environmental waste, easier use, smaller footprints, lower maintenance costs, and anticipation of future needs.

There is another (perhaps) under-appreciated, yet very important, justification that gets to both the practical and the personal aspect of those investments; as one science writer put it:

“Keeping the lab furnished with modern, technologically advanced equipment not only keeps laboratory operations competitive by increasing productivity; it also provides such intangible benefits as staff pride in the workplace and enhanced stature with customers.”²

To that end, the addition of new instruments and technologies in our labs is news that we happily and eagerly share.  As an example, see the recent post by Glenn Petrie, PhD, on how the ProteinSimple® Wes™ system is being used in our laboratories.

Keep an eye on this blog for more updates on new instruments and technologies being employed by our expert scientists; even better, subscribe to the blog using the notification tools on the top right so you don’t miss another post!

What new “toy” are you looking forward to adding to your laboratory?

References

1.    Schmidt, J. M., “Yesterday’s Toy Becomes Tomorrow’s Trade,” Today’s Chemist at Work, December 2004, pp. 34-37.

2.    Collins, W., “Managing Obsolescence,” Laboratory Manager, May 2010, pp. 56-60

ABC Webinar Archive: "Evolving CMC Analytical Techniques for Biopharmaceuticals: Obsolete methods have you feeling on the hook?"

Presented by Glenn Petrie, Ph.D.
Senior Scientific Advisor
ABC Laboratories

Originally produced in association with Contract Pharma
on Thursday, May 28th, 2 pm EST

Regulatory expectations for understanding product impurities and degradants in biopharmaceuticals continue to increase, and many biopharmaceutical developers are finding their “current” CMC methods are quickly becoming obsolete. New, highly sensitive and specific technologies are now emerging from R&D into the QC lab and are becoming the “new normal.” But how do you address heightened regulatory expectations while managing the risk associated with mid-course changes to methods?

To view an archive of the webinar on ABC Laboratories' website, click here.

Pay now or Later? Early Method Development and Phase-Appropriate Validation-Considerations and Issues for Pharmaceutical Drug Development

By Harley Everett Wilcox, MBA

Senior Scientific Advisor

ABC Laboratories
www.abclabs.com

I do not know an explicit percentage, but I would guess roughly 30% - 50% of early purity methods for drug products have issues prior to phase II clinical.  The issue often observed include:

• New chromatographic peaks showing up in the drug product during stability

• Peaks migrating, or moving around over time

• System Suitability issues over time

Often, minimal efforts are put into early HPLC methods as the drug product may change and extra efforts would appear to be not useful and down-right costly.  In addition, time-lines are often tight. Additional method development efforts suggested for methods supporting phase one studies should be in concert with the established specifications and thus the issue.  Drug product specifications are required for release and stability monitoring and typical determined as the IND nears. If little is known about a new formulation, degradation profiles, and purity of lab/engineering, batches how does one determine purity specifications? Often, ICH guidelines or drug substance data are referenced for total impurities of NMT 2% and no unknown impurity greater than 0.2% represent typical specifications. OK, now we have specifications and we validate the early development methods as phase appropriate conducting minimal accuracy, linearity, precisions, stability of solution, LOD and LOQ.  We stay away from robustness, intermediate precisions, and complete specificity which would could be completed probably in a few weeks. Why do phase appropriate? Again, as things may change the cost would be sunk.

Often and unfortunately, either at release or during stability the analyst will encounter an investigation as the product does not meet specification because of:

• New peaks > unknowns specification

• New peaks, or higher than expected impurities from early manufacturing

Drug developers will exclaim ‘those unknowns are very likely excipient or excipients related’ and thus not a real OOS, or ‘I thought the method was validated’.  However, as the unknown peaks move around from run to run, and often have insufficient resolution from known active impurities, more work is necessary to confirm the unknowns as excipients or not. Typically, this requires evaluating placebo, placebo on stability, stressed excipients and possible some excipient drug compatibility studies. Gains made from the savings for early development/phase appropriateness are lost and unless more efforts are applied to understand the method, we may revisit costly investigations in the future.  The message—it is most cost effective to insure that methods and specifications are compatible and or conduct appropriate studies during method development to understand degradents and representative impurity levels.

Radiolabeled CTMs in Early Phase Development under GLP

By Wayland Rushing, Ph.D.

Senior Scientific Advisor

ABC Laboratories

www.abclabs.com

Radiolabeled products are used extensively during pre-clinical studies in BA/DMPK studies. The material used for these studies is typically research grade material released under Good Laboratory Practices (GLP’s). However radiolabeled drugs are also used during ADME and bio-availability studies. Since the products are now intended for use in human studies, they now must comply with CGMP regulations in terms of its manufacture and release testing.

While the processes by which CGMP’s are applied to the synthesis, control and testing of non-labeled materials is well understood, we have found there is a fair amount of confusion in terms of the regulatory requirement and how to apply those to radiolabeled products.  Here I want to address one specific aspect of this: Analytical Methods and Testing.

Typically during the point in development that CGMP radiolabeled materials are needed, significant work has been performed on the unlabeled material.  This normally means that analytical methods and testing specifications have already been developed and validated accordingly.  There are two issues which may occur in implementing these analytical methods for testing of the labeled material:

·       Impurity profiles: The impurity profile of the radiolabeled material may be significantly different than the un-labeled material.  This may be the result of the synthetic route having to be altered to prepare the labeled material and/or  radio-induced degradation which can lead to new impurities being formed.  This requires evaluation of the existing methods to ensure that they still properly work for determination of the chemical purity without interferences.

·       Radio-purity determination: One of the key specifications of the labeled material is the radio-purity of the final material.  The existing analytical methods are not able to determine this as it requires the use of a radio-detector (typically in-line with HPLC).

Since the testing of the final material is required to be CGMP compliant then the methods used are required to be developed and phase-appropriately validated for their intended use.  As a result the analytical testing for radio-labeled materials can be a complex process requiring: method transfer (of existing methods), method development and phase appropriate method validation.  Hence it is critical that at the initiation of a CGMP radiolabeling program a thorough plan is designed and implemented to ensure that not only is the material synthesis accordingly to meet the regulatory needs, but also that the analytical methods are also appropriate for use for the testing and release of the final product.

I will expand on this topic at the 12^th International Symposium on the Synthesis and Application of Isotopically Labelled Compounds on the campus of Princeton University June 7-11.  Join me at 10:30 AM June 11 for a podium presentation titled, “CGMP Radiosynthesis for Early Clinical Trials: A Unique Challenge.”