The drug development landscape is constantly evolving, with science and technology advancing hand-in-hand to improve the essential steps of determining drug concentration profiles and the characterization of drug transformation products. The ultimate goal is to better understand drug distribution, metabolism, and pharmacokinetic characteristics, and to present regulatory bodies with a complete and comprehensive submission package driven by current guidelines.

To this end, liquid chromatography (LC) coupled with mass spectrometry (MS) via an atmospheric pressure ionization (API) interface is a well-established analytical approach to support each phase of drug development, from early discovery through to clinical studies.

In Issue 30 of The Altascientist, we explore the numerous benefits of incorporating a stable isotope labelled internal standard for quantitative LC-MS, and detail recent advances in MS technology, including: 
•    stable isotope labelled internal standards (SLIS) for LC-MS quantitation
•    Dried blood microsampling
•    anti-epileptic drug panel
•    COVID-19 neutralizing monoclonal antibodies
•    differential mobility spectrometry
•    bioequivalence 
•    large molecule bioanalysis
•    oligonucleotides

Also included are several case studies, which exemplify novel bioanalytical workflows that are required to meet the challenges faced in both nonclinical and clinical development, across a variety of drug classes.

What is Liquid Chromatography-Mass Spectrometry?

The mainstream adoption of the LC-MS approach for the support of drug development initiatives originated in the early 1990s, pioneered by the triple-stage quadrupole (QqQ) platform. To this day, the QqQ architecture remains the gold standard for drug quantitation in biological fluids due to the unique nature by which MS/MS is performed.

Specifically, ionized precursor ions with a targeted mass-to-charge ratio (m/z) are transmitted through the first resolving quadrupole (Q1) and axially accelerated into a collision cell (q) containing an inert gas (N2 or Ar). The resulting collision-induced fragmentation leads to the production of progeny ions whose profile represents a fingerprint unique to that of the selected precursor. Progeny ions of a specific m/z can then be transmitted from the collision cell through the third resolving quadrupole (Q3) for detection. The scan function representing precursor ion selection with subsequent collision-induced dissociation and detection of a specific progeny ion is often referred to as multiple (or selected) reaction monitoring (MRM or SRM, respectively), and is single-handedly responsible for the mainstream adoption of the QqQ platform for quantitative mass spectrometry.

Over the years, advancements in LC-MS technology have been required to meet the ever-increasing complexities of assay demands. And the ubiquitous leveraging of LC-MS may largely be attributed to the following characteristics:
•    high sensitivity with broad dynamic range and selectivity from interferences, particularly when incorporating a tandem mass spectrometric (i.e., MS/MS) approach;
•    a near-universal and thermodynamically favorable electrospray ionization process that facilitates the transport of analyte ions from the condensed state of LC into the gas phase for MS detection; and
•    the ability to support multiplexing capabilities due to rapid MS/MS scanning and chromatographic separation. 

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Ophthalmic medications have a particular set of challenges that can impact their speedy and successful path to market. From prototype formulation through preclinical testing, early-phase clinical and manufacturing and development, ophthalmic drug development presents with specific and unique complexities. It is best to entrust drug development to a partner with regulatory knowledge, technical expertise, and a thorough understanding of the market in this growing therapeutic area. From current reality to future trends, being at the forefront of ophthalmic drug development delivers tangible benefits to sponsors.

In Issue 27 of The Altascientist, we dive into all areas of ophthalmic drug development, including: 
•    Prototype development, formulation, and manufacturing 
•    Preparing for first-in-human studies 
•    Species and strain selection parameters 
•    Routes of administration 
•    Specialized ocular assessments and equipment 
•    bioanalysis
•    Phase I clinical research
•    Phase II to commercialization

Three case studies are also included!

Navigating the Complexities of Ophthalmic Drug Development

The global market for ophthalmic drugs was valued at USD 36.7 billion in 2020, according to Grandview Research. The compound annual growth rate (CAGR) is expected to be 6.4% from 2021 to 2028. The acceleration in market growth is influenced by increasing awareness of eye-related diseases and advancements in related technology. The aging of the population, as well as the impact of COVID-19 ocular involvement, are also contributing factors. Certain ocular diseases are quite rare, whereas others, such as cataracts, age-related macular degeneration (AMD), and glaucoma, are very common, especially in the aging population.

Drug development in the ocular space has specific challenges. The eye is a multi-faceted organism and has many barriers to drug delivery. Formulation and delivery options must be expertly planned and developed to overcome those barriers and ensure that the maximum bioavailability is achieved without negatively impacting vision or the physical structure of the eye. Planning of preclinical studies must consider the appropriate animal species for the route of administration and therapeutic area of the investigational drug. Some species are more appropriate for certain routes of administration, while others have relevant retinal mutations that can be leveraged in ocular development.

Clinical trials need to be carefully designed by knowledgeable specialists with significant ophthalmic experience. The delicate nature of the eye and the importance of subject safety are key considerations. Just as importantly, the bioanalysis of trial samples necessitates the use of bioanalytical techniques created especially for the often uncommon and frequently fragile matrices involved. Finally, understanding the regulatory environment and related guidances, as well as proactive and appropriate discussions with relevant agencies when warranted, are critical components of the pathway and can help ensure a seamless experience.

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