Perspectives on the Designation of Oligonucleotide Starting Materials

The understanding, control, and removal of nonoligonucleotide process-related impurities (PRI) are of key importance for the manufacturing of therapeutic oligonucleotides as their presence in the final product is both a quality and safety concern. Regulatory agencies require manufacturers to demonstrate that PRI are under control or adequately purged during the manufacturing process. Purging depends on the physicochemical properties of the impurities and the unit operations of the manufacturing process but should be independent of oligonucleotide size or type. The purging power of unit operations relevant to oligonucleotide manufacturing (synthesis, cleavage and deprotection, chromatography, ultrafiltration/diafiltration) was measured using representative solvents and other small molecules typical for oligonucleotide synthesis. The results show that each unit operation has significant purging capability (synthesis >1000; cleavage and deprotection >100 (reactivity, when applicable); chromatography >1000; ultrafiltration/diafiltration >10) and that large overall purge factors can be obtained (≥1 × 107). Experimentally determined purge values are aligned with theoretical purge values; thus, the use of purge arguments in oligonucleotide control strategies is a sound scientific approach. Guidance on reasonable purge values for oligonucleotide unit operations is presented. Additionally, the data demonstrate that solvents and reagents typically used in oligonucleotide synthesis are robustly cleared by the process and should not require testing in the final product.

Section: Introductionmentioning

confidence: 99%

Determination of Purge Factors for Use in Oligonucleotide Control Strategies

Fillon

Akhtar

Andrews

et al. 2022

“…For small-molecule DS, regulatory guidelines, 11 industry benchmarking and position papers, 12 and risk assessment tools 13 are now publicly available to inform SM selection (albeit this topic continues to inspire much discussion). 14 Although ADCs are not formally within the scope of this framework, general principles can nonetheless be extended to drug-linkers. However, a significant difference is that, unlike a small-molecule DS, drug-linkers are intermediates that undergo further processing (Scheme 1b).…”

Section: ■ Introductionmentioning

confidence: 99%

Drug-Linkers in Antibody–Drug Conjugates: Perspective on Current Industry Practices

Bulger,

Conlon,

Cink

et al. 2023

Antibody–drug conjugates (ADCs) are becoming increasingly established as a mainstream therapeutic modality for oncology, with more than a dozen compounds already approved for marketing and hundreds of clinical trials ongoing. ADCs are a hybrid construct combining, via chemical conjugation, biologic (monoclonal antibody) and small-molecule (drug-linker) moieties into a single drug substance. They also present significant technical and strategic challenges for chemistry, manufacturing, and controls (CMC). Within the IQ Consortium, a Working Group (WG) on Small Molecule Considerations for ADC Development has been established to assess current biopharmaceutical industry practices specific to the drug-linker moiety and to provide recommendations for future development. This paper presents results and analysis from a survey of IQ member companies covering a variety of drug-linker topics, including control of small-molecule impurities, starting material (SM) designation, considerations for clinical versus commercial stages, and interactions with regulatory agencies. Survey data, perspectives, and forward-looking proposals from the WG are provided. Additionally, this work provides the foundation for a subsequent series of papers from the WG, which will go into more depth on (1) post-conjugation purification operations, (2) a proposal for alignment on SM selection, and (3) post-approval synthesis changes and comparability. The overall goals are to offer visibility and insight into the current state of drug-linker development for ADCs and to provide tools to facilitate discussions between companies and regulatory agencies on future directions.

“…Position papers 12 and risk assessment methodologies 13 have been published by industry companies as tools to facilitate SM designation for small molecule DS. 14 However, none of these documents provide specific guidance for ADCs. This manuscript serves to address this gap.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The ICH Q11 guideline, along with its accompanying Questions and Answers document, outlines regulatory expectations for designating SMs in a manufacturing process. Position papers and risk assessment methodologies have been published by industry companies as tools to facilitate SM designation for small molecule DS . However, none of these documents provide specific guidance for ADCs.…”

Section: Introductionmentioning

confidence: 99%

Considerations for Starting Material Designation for Drug-Linkers in Antibody–Drug Conjugates

Jones,

Dirat,

Conlon

et al. 2023

By combining the unique targeting ability of monoclonal antibodies with the cancer-killing ability of cytotoxins, antibody−drug conjugates (ADCs) exhibit unique properties that preclude them from being viewed strictly as either a biologic or a small molecule. Instead, they are more accurately considered as hybrid compounds with unique attributes. In the absence of a formal regulatory guidance for Chemistry, Manufacturing, and Controls (CMC) development specific to ADCs, biopharmaceutical industry companies and regulatory agencies follow existing regulatory guidelines for small molecule drugs and monoclonal antibodies. Conventional regulatory strategies involve the need to understand material attributes and their potential impact to downstream quality. Control strategies for both small and large molecule development should consider the origin and significance of impurities as they relate to the final ADC drug substance. This understanding is also used to help designate a starting material (SM) for CMC regulatory filings. While historically regulatory authorities have treated the drug-linker as a drug substance, it is in fact an intermediate in the ADC process. This paper discusses how the principles of ICH Q11 for SM designation for drug substance (e.g., the ADC) can be applied to the drug-linker moiety to support identification of suitable SMs for ADCs. It also highlights key ADC factors, including the structure of the hybrid conjugate and specific manufacturing steps such as the post-conjugation purification by ultrafiltration/diafiltration, that should be incorporated into the SM designation process and the overall control strategy for small molecule impurities.