A Few Good Questions From Last Week's 'Genotoxic Impurities' Webinar

By Harley Everett Wilcox, MBA
www.abclabs.com

I recently conducted a webinar on Genotoxic Impurities and during the course of the webinar, there were a number of good questions that I had the opportunity to answer. Here are a few of them…

“Describe the earliest – in terms of development phase – that you have seen potential Genotoxic issues. What were the options explored for solving those issues?”

The earliest I recall – referring back to an introduced Genotoxin  - was in the second step of five step synthesis. In terms of how it was handled - certainly, you could do the fate Analysis to see “what happens” to this particular entity. Within this process, we have purification steps and we’re going to monitor this throughout the entire synthesis so that it would hopefully be virtually non-existent in the last stages of the API. From an earliest-step scenario, we’re able to tell if we have a know structure of concern.

“What is the best way to determine initial indications that Genotoxicity might be an issue that needs to be explored?”

The best way to discover issues is to anticipate them by establishing a solid plan early on. You get your team together and say “let’s do a risk assessment”. It may be that you have a solvent that may be a problem, or a reagent that may cause issues. It’s during these early planning sessions that you would determine different levels of risk assessment as you proceed forward through the development of the drug. This level of early-stage planning becomes increasingly more important, because risk mitigation gets more resource dependent as you go along.

“Are there any differences in how regulations are applied to semi-synthetic (i.e., complex profile APIs) vs typical APIs?”

Once you move beyond the actual natural product (for instance, an extraction from the bark of a yew tree – where it has not been modified from the original natural product) to the place where you have modified a product with a synthetic step, I believe the agencies would look at that particular modified product as a new chemical entity, meaning that their standard set of assessments would be applicable. But if your compound is an oncology compound that is known to interact with DNA, then the whole Genotoxic argument becomes less relevant.

For more questions and answers from last week’s ABC webinar, please visit ABC’s website to view the entire presentation which can be streamed from their Resources page here:

http://www.abclabs.com/resources_webinars_2015-01_GenotoxinsInPharma-HowLowShouldYouGo.html

ABC's Webinar on "Genotoxins in Pharmaceuticals" now ARCHIVED...

Did you miss ABC's latest webinar "Genotoxins in Pharmaceuticals: How Low Should You Go? Analytical Characterization of Mutagenic Impurities" (produced with Contract Pharma)?

Then you'll be happy to know that we've posted an archive of the video for you here:

http://www.abclabs.com/resources_webinars_2015-01_GenotoxinsInPharma-HowLowShouldYouGo.html

ABC White Paper: "Determination of N-Glycan Sialylation in a Therapeutic Antibody"

By Rowel Tobias, William Hanshaw, Alan Leslie, Paul Lightner, Glenn Petrie, and Mike Whalon

Analytical Bio-Chemistry Laboratories 

Sialylation of N-glycans in monoclonal antibody is an important quality attribute that could impact safety and ecacy of antibody therapeutics. The two most common N-linked Sialic acids in monoclonal antibodies are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Neu5Gc could potentially elicit immunogenic response in mammalian system. A quantitative method for determining the amount of sialic acid was developed for characterization of a therapeutic monoclonal antibody. Analysis typically involves the hydrolysis of sialic acids from the antibody molecule and subsequent derivatization with a uorescent probe. Quantitation is based on calibration curve using commercially available standards. The current study describes the development and partial qualication of the sialic acid assay for antibody therapeutics.

Click here to download this ABC White Paper

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...

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Analytical Method Transfers: Effective Communication of Information is Crucial

By Wayland Rushing, Ph.D.

Senior Scientific Advisor

ABC Laboratories

www.abclabs.com

Analytical method transfers are a very common occurrence in our industry.  The range from simple to complex in nature and can be a source of regulatory headaches resulting in 483’s.  As a result it is still surprising the number of times the procedure is approached almost as an afterthought or check-box exercises without the proper thought and planning put into them.  One of the most common issues which I have observed is a failure to communicate critical information.  During the initial steps it is the originating lab’s responsibility to gather and effectively communicate the appropriate information the receiving lab will need to successfully complete the transfer.  This includes not only the analytical method but also may include QC, validation reports, internal SOPs and any other critical information required for the performance of the method.

The following are just a few of the comments encountered during failure investigations performed on method transfers which demonstrate the importance of effective communication between sites during the performance of a method transfer.

“Those specific instrument settings are set by SOP, so we didn’t list them in the method, did you need them?”

“Our internal SOP allows for variance of the method conditions as long as system suitability is met”

“The chromatograms in the method really are not representative of what we commonly see, attached are more common examples”

In each of the above instances, the originating lab failed to communicate critical information in the transfer package to the receiving lab. As a result, the method transfers failed during the initial executions resulting in delays and increased expense.

Prior to initiating the transfer here are just some procedures/questions that could be used to ensure the proper information is communicated:

·      • Get feedback from the lab personal who normally run the method

·      • Is the representative data being communicated really representative?

·      • Is there any information critical to the method contained in other documents, i.e. SOP’s?

·      • What are the common issues encountered internally with the method?

·      • Gather the make/model of instruments used on the method.

·      • Gather the validation report, any other transfer reports or addendums which have been

         performed

By not properly preparing and communicating you can inadvertently doom the transfer to failure ever before it gets into the lab.

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

Wait For It... (Frank Lautenberg Chemical Safety for the 21st Century Act)

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

Wait for it...... Waaiitt forrr ittttt...

That’s the phrase I use with my dog while I hold a treat three inches from the end of her nose.  Her eyes are locked on target and there are long tendrils of drool streaming from her lips in anticipation of something so fantastically tasty that she’s willing to postpone immediate gratification.

Last Tuesday’s announcement that the Frank Lautenberg Chemical Safety for the 21^st Century Act was being introduced in the U.S. Senate triggered memories of anticipation, related to previous efforts to reform the nearly 40-year old Toxic Substances Control Act (TSCA).  Wasn’t it the Chemical Safety Improvement Act (CSIA) in 2013?

The Frank Lautenberg Chemical Safety for the 21^st Century Act appears to be an improved version of the CSIA and addresses preemption by states – a major sticking point and provides a funding mechanism via user fees.  It mandates chemical safety decisions that are based solely on risk to public health and the environment and eliminates cost and benefits as considerations in the evaluation of chemicals.  Interestingly, it appears to enjoy broader bi-partisan support. 
Bi-partisan support?

Waaiitt forrr ittttt...

Environmental Assessment for Pharmaceuticals: Don't Let it Become a Regulatory Bottleneck

Environmental Assessment Solutions from the Drug Development Experts at ABC

A quality Environmental Assessment (EA) package is a critical component of many drug product submissions. Not having the right data—or not starting EA investigations soon enough—can become a regulatory bottleneck that's tough to push through. 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.

Who better to predict potential environmental effects of your drug than the CRO that helped you develop it?

While rarely a focus of development strategy, evaluating a drug's potential environmental impact requires diverse and highly specialized expertise. ABC Laboratories has nearly... (for more click here.)

Biosimilars Arrive - First Biosimilar Drug Approved in the U.S. (Zarxio)

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

On Friday, Sandoz’s Zarxio became the first biosimilar drug approved in the U.S.

Zarxio is approved for the same indications as Amgen’s Neupogen however, Zarxio was approved as a biosimilar, not an interchangeable. This means that it cannot be substituted without the approval of the physician who originally prescribed the originator drug. While Zarxio is the first biosimilar approved in the U.S., Apotex is poised to get approval of its own Neupogen biosimilar. This is indicative of the anticipated flood of biosimilars expected in the next few years. This includes Humira, Enbrel, Remicade and Lautus.

Due to their complexity, it is considerably more difficult to demonstrate the structural identity of biopharmaceuticals versus that for traditional generics. That is why the terminology is biosimilar. In addition to animal and clinical studies, structural characterization was critical to Zarxio’s approval. While Zarxio is a relatively simple molecule (18.8 kD) it still required complete analysis of its sequence, secondary and tertiary structure. The barrier to structural characterization of monoclonal antibodies is much greater. These biopharmaceuticals are large (150 kD), have multiple subunits and disulfide linkages and are glycosylated. Biosimilar developers will need to employ sophisticated analytical techniques including QToF MS, CD, peptide maps and SPR in order to show biosimilarity with the innovator’s product.

Upcoming ABC Webinar: "Genotoxicity: Analytical Evaluation of Mutagenic Impurities"

Upcoming ABC Webinar:
Analytical Evaluation of Mutagenic Impurities
March 26, 12p CST
Presenter: Harley Everett Wilcox
Senior Scientific Advisor, ABC Laboratories

Impurity evaluations can take on a whole new level of specificity when mutagenic risk is present. Whether an evaluation is in support of clinical development, a marketing application, or post-commercial manufacturing changes, acceptance criteria often require parts-per-billion detection. On the other hand, “As Low as Reasonable Practicable” rules may not always apply. Misguided analytical strategies waste time and money. Many have left many promising development programs in limbo.

This webinar will address recent ICH M7 and other relevant guidelines that address genotoxic and carcinogenic potential. It also will discuss various genotoxic sources, including synthetic processes and impurities/degradation products, as well as relevant analytical testing methodologies.

Sign up now.

From Legislation to Lab Bench

I'm just a bill.

Yes, I'm only a bill.

And I'm sitting here on Capitol Hill

-Schoolhouse Rock (1975)

A few weeks ago I had the great privilege and pleasure of speaking to a group of students in the Biochemistry Department in historic Schweitzer Hall at the University of Missouri, here in Columbia.

The students are prospective interns for a successful and growing program here at ABC Labs, taking preparatory coursework before they begin their internship in earnest in the summer months.

My presentation was a “Regulatory Agency Overview.”

Minimally, I wanted to give the students a sense of the many agencies – local, state, federal, and global – under whose auspices our scientific work is regulated.  It’s a veritable “alphabet soup”: EPA, FDA, USDA, MDNR, EMA, OECD, and many more.

But that was just a start – Using relevant examples, I took them on a journey from public policy to legislation to regulation and rulemaking to guidelines to guidance.  I made the point that what starts out as evening news may well end up affecting activities at the laboratory bench, and that as scientists it behooves us to not only be aware of policy changes but also policy debates.

The students asked terrific questions, among the most important of which was how one keeps up-to-date with a dizzying array of changes.

It’s a great question in our business of providing contract research services to help our clients satisfy regulatory requirements for product development.

As interesting: they skipped the question of “Why stay up-to-date?” It’s intuitive that the costs of non-compliance – in time and money – are great.

The question of “How?” gets to the heart of one of our missions as subject matter experts – professional Reading, active participation in industry associations, travel to conferences, collaboration with consultants, and interaction with our clients, all in order to remain attuned to regulatory changes is part of the job.

But it’s not all soaking in information – we also endeavor to be the educators via webinars, whitepapers, this blog, and other venues. (As an example, I recently gave a webinar on new EPA guidance on “Strategies for Bound and Non-Extractable Residues in Laboratory Environmental Fate Studies").

How do you stay aware of regulatory changes? What can we do to help? Let us know!