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18 Pharmaceutical Technology ® Innovations in mRNA eBook April 2024 PharmTech.com Regul ations The reg ulator y f ramework for advanced therapy me- d ici na l produc t s (AT M Ps) i ncludes bot h gene t herapy med ici na l products (GTMPs) a nd somat ic cel l t herapy medicinal products (sCTMPs). mRNA-based products may be classified under either categor y, depending on their intended use. To help navigate the regulator y complexity in Europe, t he Com m it tee for Adva nced T herapies, a n adv i sor y committee that reports into EMA, provides non-binding opinions including classifications of ATMPs. This legal status is critical to understand as it can have implications for different controls and other specificities that are in- tended to limit risks for different product types. Navigating a region's regulations can be challenging and sometimes cause for confusion. Guidance documents ser ve an impor tant role in providing industr y with the health authority's interpretation of policy on a regulatory issue while not being legally enforceable. Naturally, guid- ance documents become an important part of the region's regulatory framework. The process for the development and issuance of g uidelines is based on polic y itself, in- volves public consultation, and can be quite lengthy. As of March 2024, neither FDA nor EM A have issued specific guidelines related to chemistry, manufacturing, and control (CMC) considerations for mRNA-based prod- ucts. Past g uidance documents issued by FDA, such as the 2018 FDA final guidance document on liposome drug products and the 2022 final guidance document on drug biological products containing nanomaterials, offer some regulatory insight to mRNA developers that employ lipo- some delivery strategies, but these guidelines are written broadly and are not specific to mRNA (1,2). T he i nteg rat ion of m R NA-ba sed vacci nes i nto cl i n i- cal and market settings during the COVID-19 pandemic highlighted the need for a collaborative approach to stan- dardize quality expectations, facilitating their successful development. Early efforts are focused on vaccines for in- fectious disease, but undoubtably there will be principles and considerations that will be relevant to other mRNA therapies. In June 2023, t he Biologics Work i ng Pa r t y, who pro- vides qualit y and safet y recommendations to EMA's sci- entif ic committees, issued a concept paper to industr y for the development of guidelines on qualit y aspects of mRNA vaccines (3). The concept paper acknowledged the novel nat ure of m RNA vaccines for in fectious disease, which do not fully align with existing general guidance for human vaccines. Specific qualit y considerations for f ut ure g uidel i nes w i l l add ress topics such as sta r t i ng materia l def inition and controls, potenc y testing, and formulation strategies. T he Un ited St ates Ph a r m acopeia (USP), t he not-for- prof it organization involved wit h establishing qua lit y standards for dr ugs, issued t heir Analytical P rocedures for mR NA Vaccine Qualit y (Draf t Guidelines)–2nd Edition in April 2023 (4). A key objective of the USP initiative is to create a shared understanding of mRNA quality attri- butes through the development of a set of methods for mRNA quality to enable accelerated product development. While these efforts have focused on regulatory expec- tations for mRNA-based vaccines, significant work is still needed to clarify requirements for other mRNA products, which may vary greatly by treatment type in terms of dos- ing, route of administration, and clinical targets. These variations point to the need for the consideration of dif- ferent or more stringent quality control elements. As reg u lators cont i nue to ref i ne a nd develop g uide- lines, developers should engage with these initiatives by actively par ticipating in consultation activities, provid- ing their input, and joining industr y groups involved in regulator y development within their target markets for ef fective collaboration and compliance. Importance of early and frequent engagement with regulators Engaging with regulators for product-specific guidance is an important strategic element of a drug development program, especially for novel products and where guide- l i nes a re lack i ng. Seek i ng a scient i f ic adv ice meet i ng early in the development process serves as an initial step toward building a strong working relationship. It helps t he rev iew d iv ision become acqua i nted w it h bot h t he product and the process, and it also offers a chance to mit- igate risks associated with development strategies. How- ever, t he success of such meetings h inges on t he spon- sor's preparedness. The information package presented to regulators must be thorough, with questions framed precisely to solicit constr uctive feedback. The most ef- fective meetings occur when sponsors are well-prepared, willing to discuss their development strateg y in detail, and ready to tackle tough questions. As product development progresses to meet new clini- cal milestones, additional check-ins with the regulator are often critical to ensure that the CMC remains on track with regulatory expectations. Meeting with FDA to discuss de- velopment topics can occur at a milestone meeting (end of phase) or planning an ad hoc technical meeting (type C or D). A schematic of meeting engagement opportunities with FDA during clinical development is presented in Figure 1. Engaging with regulators for product- specific guidance is an important strategic element of a drug development program ...