Battling Zika: A Biotechnological Approach

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

www.abclabs.com

Zika is a disease caused by the Zika virus which is spread to humans primarily through the bite of an infected Aedes species mosquito. The disease can also be by transmitted through sex with an infected partner. The symptoms of Zika are fever, rash, joint pain, and conjunctivitis. The illness is usually mild with symptoms lasting for several days to a week and rarely requires hospitalization. There is no vaccine or specific treatment for Zika virus infection. Treatment is symptomatic and supportive, including rest and the use of acetaminophen to relieve fever.

Federal health officials recently confirmed that the Zika virus causes a rare birth defect and other severe fetal abnormalities, typically, abnormally small heads and severe brain defects. There is also limited evidence of Guillian-Barre’ syndrome and multiple sclerosis being related to Zika infection. The greatest risk is to pregnant women; however the Center for Disease control has recommended that men and women should wait a minimum of 8 weeks after possible exposure before trying to conceive. This period may increase based on the latest findings regarding the latency of the virus.

In a recent article in The New England Journal of Medicine it was noted that Zika is the fourth mosquito-borne illness to infiltrate the Western Hemisphere over the past 20 years, following dengue, West Nile, and chikungunya. There is currently no available vaccines for any of these diseases. According to the World Health Organization (WHO), more than 60 research institutes and companies are working on products to combat the spread of the Zika virus, but a vaccine is likely to take years to develop.

The disease can alternatively be attacked by control of the vector, Aedes aegypti. WHO states that traditional insecticide spraying methods have had no significant impact in decreasing the spread of dengue, implying that these classical methods for battling mosquito borne disease may be equally ineffective for Zika.

There is another possibility for eradicating the Aedes species mosquito over large areas. This involves modification of the mosquitos themselves. This approach has been used successfully in the past for eradication of the screwworm, an insect that was a major cause for livestock deaths in the mid- 20^th century. The screwworms were irradiated, sterilizing the male flies. Only the male flies were released, typically sprayed from small planes. The sterile males could not produce progeny, gradually eradicating the species. The technique was an unmitigated success.  The last cases of screwworm in the United States were reported in 1982, followed by eradication in Mexico and Central America.

Now, the world is focused not only on the Zika virus, but dengue, chikungunya and yellow fever, all transmitted by Aedes aegypti .  A British company, Oxitec, has approached the problem utilizing genetic engineering and inserting a gene that kills the insect. Male mosquitoes containing the gene are released to mate with wild females. The released male mosquitoes have no effect on people because males don’t bite. Offspring die before they reach adulthood, in that way suppressing the population of wild mosquitoes. Small-scale tests conducted in the Cayman Islands, Panama and Brazil since 2009 reduced local mosquito populations by as much as 99 percent.

Last month the federal government tentatively approved a field test (Florida Keys) of genetically engineered mosquitoes that might help slow the spread of the Zika virus. A final approval for the trial will not be made until the FDA receives and assesses comments from the public, which is likely to take months and the plan has faced fierce opposition from some residents in the state.

Information for this article was obtained from The Washington Post, The New York Times, The New England Journal of Medicine, CDC website and WHO website.

Biosimilars: They May Look the Same, but One is a Real Stinker

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.

Choosing the Right Analytical Partner May Be the Most Economically Important Decision You Make

FDA guidance calls for a “complete and thorough” CMC section that begins with extensive comparative characterization of the biosimilar and... click here for more.

Enantiomers: Exactly the Same… Only, Different!

By Jim Schmidt

Senior Scientific Advisor
ABC Laboratories

www.abclabs.com

In chemistry, enantiomers are stereoisomers that are non-superimposable mirror images of each other - much like your left and right hands are the same except for being reversed along one axis.

*Image courtesy of Wikimedia Commons

Indeed, the study of enantiomers – chirality – comes from the Greek word, “Χειρ = Cheir =  Hand”!

Enantiomers have identical chemical and physical properties except for their ability to rotate plane-polarized light by equal amounts but in opposite directions.

However, in biological systems, they can have very different behavior.  Some of the most interesting – and important – differences are in drug metabolism.

For the better part of a century, the consideration of enantiomers in drug metabolism was limited to academic study and/or to natural products, owing in no small part to the limits of separations chemistry.

However, for many reasons (including improvements in analytical chemistry), chirality has been earning ever-greater importance in drug discovery and development, such that many new drugs reaching the market in the first decades of the 21st century are single enantiomers, rather than the racemic mixtures (or achiral drugs) that dominated the latter half of the 20th century.

Indeed, in the recent report, “The Year in New Drugs” (C&E News, February 1, 2016, pp. 12-17), it can be seen that more than half of the newly-approved small-molecule drugs in 2015 had specific stereochemistry (and often with more than one chiral center).

Examples of enantio-selective biotransformations include:

• Prochiral to Chiral 
• Chiral to Chiral 
• Chiral to Achiral 
• Chiral to Diastereoisomer 
• Chiral Inversion

These metabolism pathways can have significant effects on pharmacology and drug safety. While the movement towards single enantiomers as drug candidates, noted above, mitigates safety problems that might  be associated with racemic mixtures, they do not necessarily alleviate the need to consider and study achiral-to-chiral, chiral-to-chiral, and/or chiral-to-diastereomer transformations.

Adapted from my chapter – “Metabolite Profiling” – in New Horizons in Predictive Drug Metabolism and Pharmacokinetics (edited by Alan G. E. Wilson; Royal Society of Chemistry, 2015).

Well Characterized Biopharmaceuticals Meeting - 2016

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

The 20th annual Well Characterized Biopharmaceuticals (WBCP) meeting will take place in Washington, D.C. the week of January 24th. I attended the inaugural meeting and have only missed one in the last 20 years. This is always an excellent meeting covering both the scientific and regulatory aspects of biopharmaceutical development in equal measure. I am particularly excited about this year’s topics including Higher Order Structure, Combo Products, Biosimilars and Pre-clinical development. I am looking forward to seeing you at the ABC Labs booth to discuss some of our exciting studies. These include:

• · Utilizing the WES system to quantitate both intact and degraded protein DP in fecal matter
• · Supported two successful IND submissions for Antibody Drug Conjugates in 2015 with a third in progress. This included full characterization, method development, qualification, release and stability studies. These submissions had NO comments regarding the chemistry section of CMC.
• · Supported our clients during difficult times
• During a Phase II trial, reagent changes caused bioanalytical ELISA results to be “offset” from the previous results. We were able to troubleshoot and solve the client’s problem.
• When a client suddenly severed a relationship with its CRO we were able to transfer, qualify and release methods in support of GMP DS and DP while meeting deadlines.

We hope to speak to you about your biopharmaceutical analytical needs during the breaks, as well as at the Exhibitor Reception, Wednesday, from 5:30-7:00 PM.

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.

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!