Formulated oligonucleotide APIs: Regulatory aspects

Formulated oligonucleotide APIs: Regulatory aspects
\nAuthors
\nChristian Wetter (Roche), Chris Chorley (Biogen), Corrine Curtis, (Janssen), Nicole del Canto (Biogen), Gair Ford (AstraZeneca), Jenny Franklin (Ionis), Cinzia Gazziola (Roche), Michael T. Jones (Pfizer), Judy Lee (Novartis), Arnold McAuley (Amgen), Floor Saraber (Janssen), Audrey Scott (GSK), Janine Tom (Amgen)
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\nThe European Pharma Oligonucleotide Consortium (EPOC) [1] is a collaboration between multiple pharma companies with the aim of sharing chemistry, manufacturing, and control (CMC) knowledge as well as strategies to enable harmonization of oligonucleotide development and commercialization. The objective of the consortium is to publish science-based recommendations for the development of oligonucleotide therapeutics in a series of technical and regulatory white papers, drawing on its collective subject matter expertise and complementing that in the literature and guidelines. This public body of prior knowledge endeavors to serve as a reference for industry practice and help establish development principles for oligonucleotides. The consortium aims at being proactive and inclusive, and it anticipates initiating wider discussion on oligonucleotide CMC practice and policy, thus expediting access to these potentially life changing medicines.
\nIntroduction
\nThe concept of formulated APIs (also called API mixes by EMA) for oligonucleotides was described by Muslehiddinoglu et al in 2020 [2]. The publication discusses technical aspects related to formulated oligonucleotide APIs, such as their stability, manufacture, microbial control, packaging and storage. Various criteria such as supply chain, scale, dosage strengths, etc., may influence the best choice of the API form – resulting in use of either a solid API, an API in water, or a formulated API. The formulated API may be ready-to-fill, or may require further dilution or addition of excipients. Muslehiddinoglu et al left regulatory aspects out of scope of the published article; therefore, the present communication aims to complement the first manuscript and discuss relevant regulatory and GMP aspects of a formulated API. In addition, this article aims to initiate interaction and discussion with regulators to promote the use of the formulated API approach in oligonucleotide drug manufacture. The authors hope to contribute to EMA’s initiative ‘Regulatory Science to 2025 – Strategic Reflection’, in “developing expertise in novel manufacturing technologies”, “identifying bottlenecks”, and “addressing regulatory challenges” that could be overcome by “modernizing relevant regulations and guidelines”. The authors would like to propose solutions for “promoting a flexible and fit-for-purpose approach in application of GMP”, and “supporting the development of greener manufacturing technologies in line with EU’s ‘Strategic Approach to Pharmaceuticals in the Environment’” [3].
\nProblem statement 
\nOligonucleotides are typically synthetically derived and can be isolated as a solid, in water or as formulated APIs. While available guidelines generally provide flexibility with respect to the designation of a formulated API as an API, EMA and Health Canada have set a more restrictive framework in which API-excipient mixtures can be designated as APIs in exceptional cases only. Typically API-excipient mixtures have to be designated as drug product intermediates. A guideline review is provided below.
\nWhen designating a formulated API as a drug product intermediate, the manufacturers have to fulfill drug product GMP standards for the manufacturing steps converting the API into a formulated API. The requirements for clean areas as defined in ISO 14644-1 [43] and the EU guideline to GMP, Annex 1 [5] apply. This is typically not possible in facilities designed for manufacture of oligonucleotide APIs. 
\nFurther, the designation of a formulated API as a drug product intermediate poses challenges around the shelf-life definition of the oligonucleotide drug product. Per standard requirements for chemical products, the shelf-life is defined by the start of the drug product manufacturing process, i.e., the mixing of the API with other product ingredients [6]. Storage of the formulated API for a prolonged period before further manufacture and/or filling would thereby shorten the shelf-life of the finished product upon release for market distribution.
\nSimilar challenges have been identified when using co-processed APIs [7].
\nCurrent regulatory landscape
\nICH
\nIn the ICH Q7 [8] glossary, an API is defined as “any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product (...)”. As per ICH Q7 Q&A [9], “when a mixture is classified in the regulatory filing as an API in a region or country in which it is used in a drug product, ICH Q7 should be applied to the manufacturing of these mixtures [ICH Q7, Section 1.2, 20 – see Glossary for definition of ‘API’]”. 
\nAs per ICH Q6B [10], for biological products, the drug substance (bulk material) “may also contain excipients including other components such as buffers”.
\nWHO
\nThe WHO Annex 3 on ‘Pharmaceutical development of multisource (generic) finished pharmaceutical products – points to consider’ from 2012 [11] defines an API as “Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form”. 
\nEMA
\nIn their Q&A document [12] the CHMP quality working party (QWP) defines an API mix as a “mixture of an API with one or more excipients”, and “the manufacture of an API mix is considered to be the first step of the manufacture of a finished product”. Further, “in certain circumstances, i.e. stability or safety reasons, the applicant can submit data on such a mixture under part 3.2.S (...).” However, “In case of an API mix prepared due to workability purposes or reasons other than safety and stability, the manufacturing steps from the addition of the excipient to the API should be described in the appropriate part of CTD 3.2.P. In addition the steps following addition of the excipient must be conducted in accordance with GMP Part I and an appropriate manufacturing authorisation”. Moreover, “a justification based only on workability reasons, e.g. to ease handling when processed into final dosage form, is not acceptable. Toxicological considerations (e.g. very potent drugs) fall under workability reasons and are not accepted as justifications.”
\nCanada
\nIn their quality (chemistry and manufacturing) guidance, Health Canada states the following related to the start of drug product manufacture and possible exceptions based on safety and stability reasons [13]. The expectations are aligned with the QWP Q&A discussed above, and Health Canada encourages a discussion with their pre-market approval bureau/office.
\nThat first processing step of the drug substance in the presence of any other substance would be considered a drug product manufacturing activity, subject to Part C, Division 2 of the Food and Drug Regulations, and would define the date from which the expiry date for the drug product would be established. (…) Sponsors having situations that might be an alternative to the above interpretation (e.g. inability to isolate the drug substance in a pure and stable form or mixing with excipients for safety or stability purposes, e.g. nitroglycerin, cholecalciferol) should discuss their case and scientific justification in advance with the pre-market approval bureau/office.”
\nProposed path forward
\nThe authors recognize that two elements need to be addressed to enable the designation of formulated APIs as APIs: First, designation of an API-excipient mixture as an API should not be justified solely by the benefits from a usability perspective [12], [13]. Second, applicants should address concerns related to the GMP standards of API manufacturing facilities [4], [5]. The following proposed path forward is intended to address these two hurdles.
\nFor biological products, the use of formulated APIs is a generally accepted common practice, originally mandated by the stability behavior of the proteins. Oligonucleotides are generally stable in formulation; however, certain factors can impact stability. For example, the pH of the formulation strongly influences oligonucleotide degradation [14] and the addition of buffers to an oligonucleotide API can have a stability benefit. For example, Poecheim et al. showed in 2018 that buffered solutions of a model oligonucleotide API show superior stability behavior compared to the aqueous solution [15]. Furthermore, while a solid API is typically stable when stored at -20°C, the use of a buffered solution may allow storage and shipment at 2°C to 8°C or even at room temperature, which is of high relevance for oligonucleotides manufactured at a larger scale. The stability promoting properties conferred by a buffered formulation support use of formulated oligonucleotide APIs as a meaningful option.
\nIn order to address the requirements defined in the QWP Q&A, stability data should be generated for both the API (in solid state or in water) and the formulated API under ICH long-term conditions for up to 6 months. If it can be demonstrated that the formulated API provides superior or equivalent stability behavior, the use of formulated API should be permissible. In case the stability behavior is equivalent, the authors propose that additional aspects can be considered for justification, as detailed below. 
\nIf the API is isolated as a solid, the solid API can be used for the stability comparison with the formulated API. If the API is processed further as an aqueous solution, without isolation, the API in water can be used for comparison wi

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