Abstract
Manufacture of oligonucleotide active pharmaceutical ingredients (APIs) typically consists of solid-phase synthesis, deprotection and cleavage, purification and filtration, and isolation from aqueous solutions through lyophilization. In the first step of drug product manufacture, the API is dissolved in water again and excipients are added. While isolation of oligonucleotide APIs can be meaningful in many cases, there may be cases where keeping the API in solution provides benefit, and multiple technical aspects must be taken into account and balanced when determining the appropriate API form. A significant factor is whether an API in solution will contain additional components. While APIs in solution containing additional components (so-called formulated APIs) are well established for biological products, there are regulatory guidelines in place that represent hurdles for industry to using a formulated API approach for oligonucleotide drugs. The present communication outlines conditions where a formulated API approach can be chosen in compliance with existing guidelines. Relevant aspects pertaining to risk management, GMP standards, facility design, control strategies, and regulatory submission content are discussed. In addition, the authors propose that existing guidelines be modernized to enable the use of a formulated API approach for additional reasons than the ones described in the existing regulatory framework. The manuscript aims to promote a dialog with regulators in this field.
Highlights
Muslehiddinoglu et al described the concept of active pharmaceutical ingredients (APIs) in solution for oligonucleotides [1]
Content Re-test period and storage conditions will be assigned to the formulated API, justified by stability data of the formulated API Composition of the drug product should be provided including excipients used in the drug product manufacture, as well as processing salts and components added when manufacturing the formulated API
The use of formulated APIs is generally accepted for biologics products
Summary
Muslehiddinoglu et al described the concept of active pharmaceutical ingredients (APIs) in solution for oligonucleotides [1]. The publication discusses technical aspects related to solution oligonucleotide APIs, such as their stability, manufacture, microbial control, packaging, and storage. The authors propose that existing guidelines are modernized and allow the designation of formulated oligonucleotide APIs as APIs for additional reasons, such as benefits related to (greener) manufacturing, supply security, quality, and other science-based reasons [2]. It will be the responsibility of the applicant to evaluate the various aspects discussed by Muslehiddinoglu et al [1] and to use the aspects discussed in this paper for justification of the selected approach and the proposed API designation. The current article focuses on oligonucleotides, but the considerations provided could be applied to other smallmolecule modalities administered via a parenteral route, such as peptides
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