In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate.

A deep and detailed understanding of drug-dendrimer conjugates key properties is needed to define the critical quality attributes that affect drug product performance. The characterization must be executed both in the formulation media and in biological matrices. This, nevertheless, is challenging on account of a very limited number of suitable, established methods for characterizing the physicochemical properties, stability, and interaction with biological environment of complex drug-dendrimer conjugates. In order to fully characterize AZD0466, a drug-dendrimer conjugate currently under clinical development by AstraZeneca, a collaboration was initiated with the European Nanomedicine Characterisation Laboratory to deploy a state-of-the-art multi-step approach to measure physicochemical properties. An incremental complexity characterization approach was applied to two batches of AZD0466 and the corresponding dendrimer not carrying any drug, SPL-8984. Thus, the aim of this work is to guide in depth characterization efforts in the analysis of drug-dendrimer conjugates. Additionally, it serves to highlight the importance of using the adequate complementary techniques to measure physical and chemical stability in both simple and biological media, to drive a complex drug-dendrimer conjugate product from discovery to clinical development.

Considerations for the Terminal Sterilization of Oligonucleotide Drug Products.

A primary function of the parenteral drug product manufacturing process is to ensure sterility of the final product. The two most common methods for sterilizing parenteral drug products are terminal sterilization (TS), whereby the drug product is sterilized in the final container following filling and finish, and membrane sterilization, whereby the product stream is sterilized by membrane filtration and filled into presterilized containers in an aseptic processing environment. Although TS provides greater sterility assurance than membrane sterilization and aseptic processing, not all drug products are amenable to TS processes, which typically involve heat treatment or exposure to ionizing radiation. Oligonucleotides represent an emerging class of therapeutics with great potential for treating a broad range of indications, including previously undruggable targets. Owing to their size, structural complexity, and relative lack of governing regulations, several challenges in drug development are unique to oligonucleotides. This exceptionality justifies a focused assessment of traditional chemistry, manufacturing, and control strategies before their adoption. In this article, we review the current state of sterile oligonucleotide drug product processing, highlight the key aspects to consider when assessing options for product sterilization, and provide recommendations to aid in the successful evaluation and development of TS processes. We also explore current regulatory expectations and provide our interpretation as it pertains to oligonucleotide drug products.

The Global Characterisation of a Drug-Dendrimer Conjugate - PEGylated poly-lysine Dendrimer.

The recent emergence of drug-dendrimer conjugates within pharmaceutical industry research and development introduces a range of challenges for analytical and measurement science. These molecules are very high molecular weight (100-200kDa) with a significant degree of structural complexity. The characteristics and quality attributes that require understanding and definition, and impact efficacy and safety, are diverse. They relate to the intact conjugate, the various building blocks of these complex systems and the level of the free and bound active pharmaceutical ingredient (API). From an analytical and measurement science perspective, this necessitates the measurement of the molecular weight, impurity characterisation, the quantitation of the number of conjugated versus free API molecules, the determination of the impurity profiles of the building blocks, primary structure and both particle size and morphology. Here we report the first example of a global characterisation of a drug-dendrimer conjugate - PEGylated poly-lysine dendrimer currently under development (AZD0466). The impact of the wide variety of analytical and measurement techniques on the overall understanding of this complex molecular entity is discussed, with the relative capabilities of the various approaches compared. The results of this study are an essential platform for the research and development of the future generations of related dendrimer-based medicines.

Strategies for Identity Testing of Therapeutic Oligonucleotide Drug Substances and Drug Products.

A risk-based approach for routine identity testing of therapeutic oligonucleotide drug substances and drug products is described. Risk analysis of solid-phase oligonucleotide synthesis indicates that intact mass measurement is a powerful technique for confirming synthesis of the intended oligonucleotide. Further risk assessment suggests that the addition of a second, sequence-sensitive identity test, which relies on a comparison of some property of the sample to a reference standard of proven identity, results in a sufficient test of identity for most oligonucleotide drug substances and products. Alternative strategies for drug product identity testing are presented. The analysis creates a common way to communicate risk and should result in a harmonized approach to identity testing that avoids the unnecessary analytical burden associated with routine de novo sequencing, without compromising quality or patient safety.

Evaluation of Particle Size Techniques to Support the Development of Manufacturing Scale Nanoparticles for Application in Pharmaceuticals.

The measurement of nanoparticle size, and size distribution, is important to the development of pharmaceutical nanoparticle products and their manufacturing processes. In this work we report on the use of 4 widely-used liquid-phase techniques, dynamic light scattering, differential centrifugal sedimentation, particle tracking analysis, and tuneable resistive pulse sensing to measure 4 different batches of AZD2811NPs. The techniques rely on different physical principles to measure nanoparticle size. The batches cover a range of different manufacturing scales and different sites of manufacture, and were made to support toxicity, clinical, and engineering studies. The results from the different techniques and different batches are compared in terms of the average size, and size distribution, measured. In addition, we discuss the suitability of techniques for different applications, for example, QC and process understanding.

European Pharma Oligonucleotide Consortium: A Move to Consolidate Oligonucleotide Knowledge and Share Experience Within the Community.

A consortium of seven pharma companies has been formed with the aim of sharing knowledge on and harmonizing approaches to oligonucleotide development. This letter aims to raise awareness of this new group and to set expectations for future publications.

Impurities in Oligonucleotide Drug Substances and Drug Products.

This white paper, which is the 10th in a series intended to address issues associated with the development of therapeutic oligonucleotides, examines the subject of product-related impurities. The authors consider chemistry and safety aspects and advance arguments in favor of platform approaches to impurity identification and qualification. Reporting, identification, and qualification thresholds suitable for product-related impurities of therapeutic oligonucleotides are proposed.