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.

21st Century Cures Act – Is It Truly Progress?

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

Dr. Francis Collins, Director of NIH, has stated that it takes “around 14 years and $2 billion or more “to develop a new drug. Based on statements like these, Congress has come to the conclusion that the drug approval process is too onerous and lengthy and is the primary impediment to the discovery and approval of new drugs. In response they have passed the 21^st Century Cures Act with nearly unanimous, bipartisan approval. But is this a fallacious assumption? Some argue that the FDA review and approval process is the fastest and most streamlined in the world and that accelerating the approval process may impact patient safety.

In an editorial in the New England Journal of Medicine, Dr. Jerry Arvon states ”The bill would also encourage the FDA to rely more on biomarkers and other surrogate measures rather than actual clinical end points in assessing the efficacy of both drugs and devices.” While surrogates have previously been utilized as endpoints by the FDA to support accelerated approvals, this was only for drugs intended to treat life threatening illnesses.  Dr. Arvon goes on to state that biomarkers “may not always predict the drug’s capacity to improve patient outcomes “. The literature has many examples of cancer drugs approved utilizing these criteria that not only do not extend life, but have side effects.

While the argument regarding expedited drug approval continues, one aspect of the new law has unanimous support; an additional $8.75 billion in funding for NIH over the next 5 years.  According to a study published in Health Affairs, federal funding of basic research played a major role in the origin of transformative drugs approved between 1984 and 2009.

ABC Laboratories: Addressing the Growing Needs of the Biotech Crop Industry

ABC combines more than 45 years' experience analyzing chemical compounds in plant and environmental matrices with expertise in protein analysis to address the growing needs of the biotechnology crop industry. We offer a wide range of techniques required to fully characterize expressed proteins, as well as the various studies required to confirm the food, feed and environmental safety of products that represent the trait.

Some of ABC's Biotech Crop Services include:

• Protein expression analysis


• Feeding and exposure studies


• Ecotoxicological testing


• Environmental Fate Studies


• Compositional Equivalence


• Sample Processing

All work is performed in well managed, modern laboratories equipped to handle most any analytical methodology. And all of our capabilities are wrapped in a stellar regulatory record—a testament to strong quality systems, rigorous GLP compliance and ABC's deeply ingrained culture of continuous improvement.

See the full description of the Biotech Crop services ABC offers here:

http://www.abclabs.com/agriculture_ag-biotech.html

Dynamic Duo Coming Soon? (FDA and EPA Talk About Teaming Up and Sharing Info)

John Bucksath

President and CEO

ABC Laboratories, Inc.

The U.S. Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) have recently communicated they will be teaming up to improve effectiveness by sharing information between the two agencies. This agreement was announced when a Memorandum of Understanding was completed and released to the public announcing the EPA will share data on pesticides and toxic substances with the FDA. It was noted that this information will better inform their assessments of risks to the public and the environment.

FDA is responsible for protecting and promoting the public health by ensuring the safety of food (including animal food and feed), human drugs, animal drugs, and cosmetics by enforcing the Food, Drug, and Cosmetic Act, and several related public health laws. EPA is responsible for managing the pesticides and toxic substances programs under the Federal Insecticide, Fungicide, and Rodenticide Act, the FD&C Act, and the Toxic Substances Control Act. Arguably, both FDA and EPA are the world's most respected regulatory authorities. 

Industry has long known these independent agencies and the ever increasing scrutiny they apply in their respective areas of responsibility to protect the public. Industry realizes that FDA and EPA have complementary roles in their regulatory authority for some substances incorporated into food (including animal food and feed), animal drugs, and cosmetics. However, it is probably safe to assume the general public would find the complexity of this process a bit daunting. The responsibilities of these agencies  are becoming increasing complex as new product development technology is increasingly pushing new limits almost daily.

In today's "information at your fingertips society," the agencies may appear to be teaming up to take advantage of the wealth of information accumulated over decades of regulatory development and finding new ways to share information. More importantly, I believe there is a sense of urgency in finding new ways to communicate information in a way that their collective stakeholders (the public, industry, government, etc.) can understand. After all, isn't the real measure of communication the recipients' ability to apply what has been received and use responsibly? 

As most in industry know, both FDA and EPA have been under tremendous pressure to continually improve the efficiency in the way they perform their work. The rapidly expanding global market, increased number of products being developed and imported into the U.S. and a relative shrinking budget has challenged both agencies to innovate at a blistering pace. Yes, I said it, the EPA and FDA are innovating at a blistering pace. Does the future hold even more teamwork between the two agencies? Will the halls of history echo such dynamic duos as Batman and Robin, Thelma and Louise and FDA and EPA?  Stay tuned...

For technical information contact: Colby Lintner, Regulatory Coordinator, Environmental Assistance Division (7408M), Office of Pollution Prevention and Toxics, Environmental Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; telephone number: (202) 564-1404; email address: lintner.colby@epa.gov.

Additional information on this activity can be obtained from: Scott M. Sherlock, Attorney Advisor, Office of Pollution Prevention and Toxics (OPPT), Office of Chemical Safety, Pesticides and Prevention (OCSPP), Environmental Protection Agency, 1200 Pennsylvania Ave., Washington, DC 20460-0001; telephone number (202) 564-8257; email address: sherlock.scott@epa.gov.

For general information contact: The TSCA-Hotline, ABVI-Goodwill, 422 South Clinton Ave., Rochester, NY 14620; telephone number: (202) 554-1404; email address: TSCA-Hotline@epa.gov