Nucleic acid (NA)-based therapeutics hold immense promise in treating a wide range of diseases, from genetic disorders to infectious diseases and cancer. The interplay between formulation and biological performance is more complex in NA-based therapies compared to conventional small molecule drug development and demands a range of expertise and methods of analysis. This white paper is the result of a partnership between MDC and Seda with the primary aim of showcasing their respective but complementary laboratory capability in elucidating this formulation/efficacy relationship.

In this study, siRNA-loaded liposomes (termed lipoplexes) and lipid nanoparticles (LNPs) were chosen as representative systems to investigate the influence of the manufacturing process of the lipid-based formulation on intracellular delivery. The design and manufacture, including process optimisation and physical characterisation, of both nanoparticle (NP) formulation types were performed by Seda. The biological performance of the NPs was assessed by MDC. Advanced microscopy techniques were used to demonstrate the kinetics of uptake, visualise intracellular trafficking and cytoplasmic delivery of siRNA by lipoplexes and LNPs.

From a complex parenteral medicines perspective, Seda offers robust capability for supporting a range of advanced drug delivery technologies, including liposomes, dendrimers, polymeric nanoparticles, micelles, inorganic and LNPs, and is experienced in navigating challenges regarding formulation stability, characterisation, manufacturing (process understanding and scale-up), and the associated regulatory pathways for clinical trials approval and marketing authorisation.

Partnering with us gives you access not only to our formulation design and manufacturing services but also to our network of internationally recognised collaborators for assessing the performance of nanoparticulate delivery systems.

Medicines Discovery Catapult offers a comprehensive complex medicine analytical platform, incorporating in vitro characterization (cell-specific binding, uptake and cellular delivery), in vivo biodistribution and efficacy, and ex vivo tissue analysis to measure tissue accumulation, penetration and target engagement.

Medicines Discovery Catapult (MDC) is an independent, not-for-profit innovation centre for drug discovery and part of the Catapult Network established by Innovate UK.

Seda is a member of MDC’s CRO Network and part of its Virtual R&D offering. Seda Pharmaceutical Development Services | Medicines Discovery Catapult

Read more about the capabilities of the Seda consultants, modellers and laboratory scientists in the field of complex medicines here Complex Medicines | Seda (sedapds.com)

Contact claire.patterson@sedapds.com today to learn more about how Seda’s Complex Medicines Services can propel your complex medicine development programme.

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The Zetasizer Ultra is a combined Dynamic and Electrophoretic Light Scattering system for the measurement of particle and molecular size, particle charge and particle concentration. Key features include:

• Multi-Angle Dynamic Light Scattering (MADLS) for high sensitivity particle and molecular size and size distribution measurements, in the range 0.3 nm to 15 µm. An extension to MADLS on the Zetasizer Ultra Red Label enables direct analysis of nanoparticle concentration.
• Electrophoretic Light Scattering (ELS) which measures the zeta potential of particles and molecules, indicating sample stability and/or propensity to aggregate and in vivo fate.
• Capillary sizing cells enabling non-destructive, low volume (down to 3 µL) sample analysis.

Thus, in our new R&D HQ and lab complex in Cheadle near Manchester, Seda can perform physicochemical characterisation and formulation prototyping for a growing range of complex drug delivery systems. Using techniques such as nanoprecipitation, dialysis, HPLC and UV-vis spectrometry, differential scanning calorimetry and of course the new Zetasizer, and with access to more complex microscopy and imaging techniques via our network of collaborators, we can offer a comprehensive programme of practical support.

Seda’s established consultancy expertise can provide further insight and support if required, with real world project experience in a range of nanotechnology types from discovery through to clinical phases. Illustrative examples include surface-functionalized inorganic nanoparticles, liposomes, polymeric or peptidic nanoparticles and dendrimers, for the delivery of small molecules, peptides and nucleic acids. These have covered a range of intra- and extracellular targets across various clinical indications such as cancer, pain, and infectious disease. Our role can flex according to the client’s needs and stage of development, but could include consultancy support to a range of activities including technical due diligence, the generation of Quality Target Product Profiles (QTPP), CMC development planning, product design and characterisation studies and development/scalability risk assessments with additional support for vendor selection and management of third party CROs/CDMOs involved in the clinical supply chain. In addition to our technical expertise, we are also well placed to support interactions with global regulatory agencies including the authoring and review of the CMC technical elements of regulatory dossiers.

Please contact one of our complex medicines experts with any enquiries.

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The publication, Conference Report Developing Clinically Relevant Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar Series was published earlier this month in Pharmaceutics as a collaborative effort between an eminent group of authors from across industry, academia, and regulatory bodies. The report is the output from a webinar series that was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics focus group in 2021.  The six-webinar series focused on the challenges of developing CRDSs for oral drug products, with discussions on progress in the field, emerging trends, and areas for continued collaboration and harmonisation.

A CRDS is a specification that takes into consideration the clinical effect of variations in dissolution ensuring a consistent safety and efficacy profile. Physiologically based biopharmaceutics modelling (PBBM)  can be used to develop/support a CRDS. The aim of a PBBM is to achieve a mechanistic model that describes the drug substance, drug product, and physiological properties and processes involved from the point of administration of the drug, (with particular consideration here to solid, oral dosage forms) to absorption and subsequent distribution, metabolism, and excretion.

The report found that continued progress is being made in the field of CRDSs, and the successful application of physiologically based biopharmaceutics modelling (PBBM) is on the rise. However, there remains a clear need to continue the momentum and dialogue between the industry and regulators. Five key areas were identified which require further discussion and harmonisation.

These key areas are:

1. PBBM modelling approaches and their utility, including model verification and validation. Further dialogue is required to clearly understand requirements and manage expectations both for the industry and regulators;
2. Role of dissolution data (QC or more biorelevant media) as appropriate input into PBBM models;
3. Clinical study design to support the setting of clinically relevant dissolution specifications;
4. Regulators and the industry should develop a CRDS roadmap and framework for implementing CRDSs;
5. Opportunity to engage and set up an EMA – Industry workgroup on CRDSs and PBBM in pharmaceutical applications.

Under Paul’s direction, Seda are recognised leaders in the field of clinically relevant dissolution and this knowledge along with biorelevant dissolution data (which can be generated in Seda’s laboratory) allows screening and development of formulations that are most likely to produce the required exposure and optimal pharmacokinetic profiles in patients. In later phases of development and the post launch setting, clinically relevant dissolution ensures consistent clinical performance between different batches of drug product and is a critical regulatory expectation.

For a number of years Paul and other Seda staff have been active proponents of dissolution tests that are linked to clinical performance with their landmark 2008 paper Dickinson, Lee, Stott et al. 2008 coining the term ‘clinical relevance”.

Paul Dickinson shares some personal reflections on Clinically Relevant Specifications below:

Different parts of society have subtly different expectations for medicines and how this relates to meaningful / clinically relevant specification (unambiguous test specification) (Table 1).

Some Clinically Relevant Specifications are uncontroversial and well accepted such as:

• Identity (Safety and Efficacy)
• Assay (Safety and Efficacy)
• Related Substances/Degradants (Safety)

For these unambiguous specifications and methods can be developed that can accurately measure these attributes and different methods (such as a different HPLC column and gradient) will give the ‘same’ result if suitably developed. For example, related substances meet ICH limits or have been qualified in toxicology / safety studies.

Against this background clinically relevant specification appear uncontroversial so why is dissolution testing so challenging?

This is related to two different expectations for dissolution testing as noted in significant regulatory guidances:

Dissolution testing as an important surrogate of clinical performance: “Drug absorption from a solid dosage form after oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract. Because of the critical nature of the first two of these steps, in vitro dissolution may be relevant to the prediction of in vivo performance. Based on this general consideration, in vitro dissolution tests for immediate release solid oral dosage forms, such as tablets and capsules, are used to (1) assess the lot-to-lot quality of a drug product; (2) guide development of new formulations; and (3) ensure continuing product quality and performance after certain changes, such as changes in the formulation, the manufacturing process, the site of manufacture, and the scale-up of the manufacturing process”.

Routine test of product quality: “A dissolution procedure intended to be used as a routine control test for immediate release drug products should be robust, reproducible and discriminatory in order to assure a consistent product quality and to detect product quality attributes, which, if altered, may affect the in vivo performance”.

This mixed role (in vivo performance and quality testing) leads to the challenges experienced in defining / accepting a clinically relevant dissolution specification.  Particularly when considering quality aspects, the dissolution test is seen as a ‘global’ test that may be able to monitor both product attributes and variability in many aspects of the input materials and manufacturing process such as:

• Formulation Composition (Product attributes)
• Solubility of Drug Particles (Product attributes)
• Erosion / Disintegration of the dosage form (Product attributes)
• Granule Porosity (Process linked product attributes)
• Granule Density (Process linked product attributes)
• Tablet Hardness (Process linked product attributes)
• Granule Surface Area (Process linked product attributes)
• Drug Form & Particle Size (Process linked product attributes)

Based on these demands the dissolution test then has a number of desired capabilities (See Column 1, Table 2) and unlike an appropriately validated assay and related substance method it is possible that different dissolution methods can meet the individual method capability requirements differently (Table 1). Depending on the background of the individual considering the dissolution method they may also weight the method capabilities differently and therefore which method is most appropriate. This is a key challenge for CRDS. Although the focus of CRDS is generally on oral drug products these concepts apply equally drug products where there is a release or dissolution step.

When first considering CRDS superficially it can seem to be all about clinical studies on drug product variants with different dissolution profiles and the dissolution test. However, CRDS should be viewed as the end product of efforts to build a knowledge base which allows the understanding of clinical performance to be developed and to then allow the level of risk associated with the test and control of clinical quality to be described such that the performance (quality) of product delivered to the patient is acceptable and thus involves many disciplines.

Thus, at Seda, we believe that a systems approach to developing the understanding required to underpin CRDS was required and that good biopharmaceutics risk understanding / ability to describe clinical performance is required. This requires that this is thought about right from the start of clinical development (CRDS is usually seen as a later phase activity).  It was suggested that BioRAM is a useful framework to implement systems thinking throughout development and highlights the concept of an early QTPP. BioRAM is focused on answering critical questions and moving quickly to decision point to ensures that patient centric drug products are developed and the necessary knowledge and data exists to ensure appropriate drug product quality can be maintained in pivotal studies and on and after launch. The focus of BioRAM is patient centric product design and the roadmap including early QTPP plus scoring grid facilitate this process and will result in CRDS.

Pharmaceutics is a peer-reviewed, open access journal on the science and technology of pharmaceutics and biopharmaceutics, and is published monthly online by MDPI.

For a list of other publications by Seda authors please visit Publications | SEDA (sedapds.com).

The full text, open access report can be accessed here: https://doi.org/10.3390/pharmaceutics14051010

References:

1. P.A Dickinson, W.W. Lee, P.W. Stott, A.I. Townsend, J.P. Smart, P. Ghahramani, T. Hammett, L. Billett, S. Behn, R.C. Gibb and B. Abrahamsson (2008) Clinical Relevance of Dissolution Testing in Quality by Design. AAPS J. 10:380-390, http://dx.doi.org/10.1208/s12248-008-9034-7
2. Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms, 1997; U.S. Department of Health and Human Services Food and Drug Administration (CDER)
3. Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action, EMA/CHMP/CVMP/QWP/336031/2017
4. A. Selen, P.A. Dickinson, A. Müllertz, J.R. Crison, H.B. Mistry, M.T. Cruañes, M.N. Martinez, H. Lennernäs, T.L. Wigal, D.C. Swinney, J.E. Polli, A.T.M. Serajuddin, J.A. Cook, J.B. Dressman (2014) The Biopharmaceutics Risk Assessment Roadmap for Optimizing Clinical Drug Product Performance. J. Pharm Sci. 103: 3377–3397. http://dx.doi.org/10.1002/jps.24162
5. P.A. Dickinson, F. Kesisoglou, T. Flanagan, M.N. Martinez, H.B. Mistry, J.R. Crison, J.E. Polli, M.T. Cruañes, A.T.M. Serajuddin, A. Müllertz, J.A. Cook and A. Selen (2016) Optimizing Clinical Drug Product Performance: Applying Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid. J. Pharm. Sci. 105: 3243-3255. http://dx.doi.org/10.1016/j.xphs.2016.07.024
6. A. Selen, A. Müllertz, F. Kesisoglou, R.J.Y. Ho, J.A. Cook, P.A. Dickinson and T. Flanagan (2020) Integrated Multi-stakeholder Systems Thinking Strategy: Decision-making with Biopharmaceutics Risk Assessment Roadmap (BioRAM) to Optimize Clinical Performance of Drug Products. AAPS J 22: 97- 117. https://doi.org/10.1208/s12248-020-00470-z

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Recently published (Jan 2022) in the Journal of Medicinal Chemistry from scientists at Cancer Research UK is this informative review on this important class of drugs.

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis (acs.org)

Seda scientists are proud to have been involved in the successful multidisciplinary teams behind the development and approval of at least 5 of these life-changing medications. This has included input to pharmaceutical development, clinical pharmacology and regulatory aspects such as:

• Clinical pharmacology package including first in human protocol, DDI and selection of dose using the ‘optimal biological dose’ approach rather than MTD, predating FDA’s Project Optimus initiative (osimertinib and gefitinib).
• Understanding of complex drug absorption characteristics (gefitinib)
• Rapid pharmaceutical development, product introduction and bridging (gefitinib, osimertinib and selumetinib).
• Shaping the regulatory perceptions on Quality by Design with a focus on clinically relevant dissolution specifications (CRDS) (vandetinib, included in FDA QbD pilot program).
• Development of preclinical formulations (osimertinib and selumetinib).
• Partnering between a biotech and big pharma to facilitate a successful approval, launch and commercialisation (acalabrutinib).
• Development of a novel salt form in combination with an enabled formulation to deliver an innovative paediatric product (selumetinib).

FDA-approved small molecule kinase inhibitors from 1999 to 2020 for the treatment of cancer (orange), noncancerous indications (blue), or both (orange-blue lines). Image reproduced without modification from J. Med. Chem. 2022, 65, 2, 1047-1131 under creative commons 4.0

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