Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Chris Spivey

In our March issue, I wrote about the unmet need for faster, more powerful and complete analytics on pharmaceutical development and manufacturing,
which ended with a pledge to discuss new contributions from readers (1). We’ve had some feedback, and I would like to highlight a perspective that came out of a recent article on the insecticide Fipronil. “Almost universally, spectroscopist state Raman and IR [infrared] techniques are complimentary, except virtually everyone uses that statement to say they are equally valuable (i.e., they contain the same information). What if in fact the difference in the IR and Raman spectra itself is a unique fingerprint?” says Walter Schmidt, Research Chemist at USDA-ARS, in conversation about novel analystics.

This kind of insight, borrowing from two well-established workhorse techniques, can lead to fruitful new analyses, in this case particularly for troublesome or difficult-to-resolve structural analogs and in enantiomers (when not present as racemates), which can crop up in the least opportune of situations and times. While this proposed set of “dual modality measurements” may require lengthy time progression to make correct assignments “to discern exactly which vibrational modes are symmetrical and which are asymmetrical (or anti-symmetrical) in a given set of vibrational spectroscopy data … This in turn [in principle] could be a highly specific fingerprint for a particular compound in an otherwise rather complex undifferentiated background spectral signal of ‘noise’,” contends Schmidt. So the importance of a novel technique able to discriminate wavenumber markers for a compound (low in Raman, high in IR, and/or high in Raman, low in IR) in otherwise very difficult to unscramble mixtures of overlapping vibrational modes, could already be at hand.

I’ll let Walter conclude in his own words, “I therefore see gradient temperature Raman spectroscopy [GTRS] as potentially highly valuable in investigating
polymorphism in pharmaceuticals. Normally, such studies require an hour
calibration at each individual temperature, so in a day the maximum number
of unique temperature data sets is 25. In GTRS, applying a weak temperature
gradient of about 1 °C/minute, collecting any range of 100 temperature steps
required only 100 minutes. Data [are] collected not as a function of time, but
when two thermocouples confirm the temperature has increased (e.g., 0.2 °C).
No contest which is more efficient. We typically collect several Mbytes of data
in only one run. The data itself confirms the precise temperature in which a
phase or gel transition is occurring and also collect data just before and just
after that transition. The rest of the time nothing unusual is occurring during
the experiment and the spectra verify that as well. The temperature gradient
is too weak to impact the observed Raman vibrational modes unless phase
or gel transitions are occurring. Spectral vibrational mode assignments are
indistinguishable from those which can be obtained from steady state Raman
experiments taken at individual temperatures.”

I am glad to have sparked a conversation pushing forward a novel approach, hiding in plain sight—unseen until now.


1. C. Spivey, “Characterizing the Unseen Drama of Analytics,” Pharm Tech
46 (3) (2022)

Chris Spivey is the Editorial Director of 

When referring to this article, please cite it as C. Spivey, “Dual Modality and New Analyses,” 

Articles

Fresh insight is instrumental in the discussion of novel analytics.

Dual Modality and New Analyses

Pandemic shortage of test animals increased focus on alternatives, with renewed attention on approaches that had reliable supply infrastructure, could find failures sooner, and markedly reduced timelines and overall costs, while revealing fresh aspects of biology. So, what’s the holdup to widescale industrial adoption to 3D cell cultures? Other than being simply unproven, initial costs are much higher; learning or creating processes take more time, skill, and expertise; there exist no commonly agreed upon standards; and there is a lack of reproducibility. Additionally, for some applications, there were technical stumbling blocks. Efforts directed toward actual organoid replacements for heart, liver, or kidney necessarily required artificial vascularization to support tissue functions for processes such as cell feeding, oxygenation, and waste elimination. Without vascularization, those kinds of biological operations could only be performed through the very poor relative to vascularization, diffusion.

However, for other applications, a lack of vascularization actually more closely mimics the 

 state of many cancer cells and tumor microenvironments. Furthermore, studies have also shown a difference in gene, protein, and cell receptor expression. These differences deliver more realistic responses to such key cell interrogations, and better elucidate roles and requirements for proliferation, angiogenesis, and chemosensitivity (1). Most impressively, only 3D cell cultures reflect the hierarchical structure and cellular heterogeneity that mirror in vivo cell morphology, cell-cell interactions, and diffusion barrier activities (2). The kinds of information most sought after, anyway.

What I would like to draw attention to is a small Israeli company called Tissue Dynamics LTS, who estimates (in a dramatic claim) that the company could cut drug development costs by 40–80%, and time required by 30–50% overall (3). Their approach is to ab initio embed sensors into the organoid while its being grown, which allows AI-driven computation to directly interrogate biology every step along the development process. “This allows the robot to start screening drugs against different models of disease. It can perform, by itself, safety assessments in the microtissues and identify the drug that works best and causes the least damage to human organs, and it does this extremely fast. We can do it in 19,000 tissue samples at once. It is the equivalent of [testing on] 5000 patients,” said Yaakov Nahmias, founder and chief scientific officer of Tissue Dynamics LTS (3).

2. A.W. Daus, P.G. Layer, C. Thielemann, S

3. Debbie Mohnblatt/The Media Line, “Israeli Biotech Company Says It Can Revolutionize Drug Development,” 

Chris Spivey is the Editorial Director for 

When referring to this article, please cite it as C. Spivey, “The Kinds of Information Most Sought After,” 

3D cell cultures could provide key avenues to unlocking critical information.

Next Level Interrogation

 under the unassuming title “Filling the Gaps”, researchers from the Telomere-to-Telomere (T2T) Consortium have reported an advance that may prove instrumental in scientific understanding of human evolution. While the first full human DNA assembly is not yet completed, researchers disentangled most of the remaining 8% of the human genome by making sense of complex repeat sections of the telomeres and centromeres, including the “short arms” of the five chromosomes where centromeres are skewed toward one end.

Historically, these short arms have frustrated biologists – they were believed to operate genes encoding ribosomes, the protein plants of our cells, but a comprehensive understanding eluded them. According to Adam Phillippy, a bioinformatician at the National Human Genome Research Institute, T2T researchers now believe that short arms are likely hotspots for gene evolution. Because gene copies are “parked” there, they can mutate and take on new functions.

This catalog of duplications could be used to gain information on neurological and developmental disorders that are linked to variations in the number of copies of specific sequences. Additionally, Phillippy states that chemical modifications to DNA in the complex repetitive areas are likely to play a role in disease.

This role in disease centers around immunology and drug absorption could have wide ranging implications for drug targeting, delivery, and pharmacokinetics. Here we have the kind of dogged persistence, quietly executed in comparative isolation, that often is looked back upon as ground-breaking. Making sense out of what appears to most as random repetition is a common scientific undertaking. Finding out what lies beneath is of huge biomedical value and well worth pausing for a moment to celebrate.

Researchers from the Telomere-to-Telomere Consortium have discovered new properties about junk DNA that could have wide-reaching implications.

Research Shows that Junk DNA Encodes Essential Immune and Metabolism Instructions

As someone who helped invent and patent several types of biomedical instrument, I feel a traitor for writing the following: our market has unmet need for fast, accurate analytic tools. While I can certainly see why some will resist or equivocate in response, this is absolutely an opportunity and not censure.

It’s not just that messenger RNA (mRNA) needs to be rid of genetic impurities like truncated transcripts or incorrect DNA template, or that wrapping it in lipid nanoparticle formulation for delivery creates more complex analytic challenges. Other recently created, small-molecule less celebrated drug formulations also had a need for new or more powerful analytic tools. Plazomicin (marketed as Zemdri), a novel aminoglycoside effective against gram negative bacteria, required novel modes for development and manufacturing, but it also benefited from a specialized analytic tool, the QMS plazomicin immunoassay (1), for measuring quantities in human plasma while treating complicated urinary tract infections, for which it was FDA approved.

As written elsewhere, there is now also an overarching business imperative to deliver products by continually breaking previous speed record barriers. Once the rewards for increasing patent lifetimes by being earlier to market became tangible, this has provided sustained business impetus to accelerate every aspect that could potentially slow deployment and delivery, hence parallel and redundant capacities and the investment in buildings, manufacturing equipment, and now analytic tools.

When married to increased drug novelty and rising complexity, requirement to have actionable data this hour, not this week, month, or quarter, further deepens this unmet need. In pharmaceutical analytics, this might well be just what the doctor ordered. Don’t get me wrong, I am delighted capillary electrophoresis has made a reappearance, and we’ve imported various stripes of particle size analysis from material sciences. But I keep a weather eye for novel approaches, most especially those incorporating audacious physical determinations. When readers send descriptions about good methods they’ve personally used, we’ll find a way to incorporate them in our coverage. That really should add intensity and drama to analytics, and a dash of new character!

1. C. H. Lias, Letter to Microgenics Corporation, 

When referring to this article, please cite it as C. Spivey, “Characterizing the Unseen Drama of Analytics,” Pharmaceutical Technology, 46 (3) 2022.

Chris Spivey is the editorial director of 

Borrowing is good, but invention is best.

Characterizing the Unseen Drama of Analytics

Supply chain fragility and geopolitical instability discussed as background to in-shoring pharmaceutical manufacturing by Dr. Fernando Muzzio, distinguished professor of chemical and biochemical engineering, Rutgers University and Frederic Kahn, VP Sales, Wavelength Pharmaceuticals. This discussion covers reforming regulations and economics, while introducing novel flow chemistries, robotics, digitalization, and a heightened agility for investment in education, national strategy and communications.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Podcasts

In this episode of the Drug Solutions Podcast, Chris Spivey, Editorial Director talks about the economic and geopolitical benefits of controlling pharmaceutical manufacturing through reshoring, with Dr. Fernando Muzzio, distinguished professor of chemical and biochemical engineering, Rutgers University and Frederic Kahn, VP Sales, Wavelength Pharmaceuticals

Drug Solutions Podcast: Securing Manufacturing Independence Through Re-shoring Facilities to USA

In this episode of the Drug Solutions Podcast, Chris Spivey, editorial director, and Meg Rivers, senior editor, interview Sean Tucker, PhD, chief scientific officer of Vaxart, on developing oral recombinant vaccines, including developing this type of vaccine and how it differs from injectable vaccines, an inside look into the manufacture for clinical trials, what pathogens oral recombinant vaccines may be a better treatment option for, longevity of protection, and how this type of vaccine could impact the pharmaceutical industry.

In this episode of the Drug Solutions Podcast, Chris Spivey, editorial director, and Meg Rivers, senior editor, interview Sean Tucker, PhD, chief scientific officer of Vaxart, on developing oral recombinant vaccines.