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PharmTech.com Trends in Manufacturing eBook May 2024 Pharmaceutical Technology ® 17 MultiModal • Grade B—cell therapy • Grade C—gene therapy, LNPs • Grade D—plasmids, mRNA, oligonucleotides. Operational integrity With different modalities, there will be operational issues that should be reviewed and addressed, includ- ing uni-directional or bidirectional f lows to support operational and segregation strategy; manufacturing operations hazard analysis; waste handling; and con- tainment strategy for biosafety. For example, LNP production involves water-mis- cible solvents such as ethanol, methanol, or acetone. The use of these solvents requires special consider- ations for storage and handling, dependent on the volumes being used in the process. Current building/ safety codes mandate that facility design attributes take these requirements into consideration. Process closure and the validation approach A k e y s uccess at t r ibute i n mu lt i mod a l f ac i l it y design must focus on a validated, closed process as previously mentioned. It is essential to tailor the va l idat ion approach to t he speci f ic produc t a nd process in question. Validation requirements may vary based on the complexity and criticality of the product, the potential risks involved, and applicable regulatory guidelines. To en s u re a comprehen sive, robu s t va l id ated approach, it's imperative to consider the following key points: • Risk assessment. Perform a comprehensive risk assessment to identify potential process closure failure modes. This assessment involves assess- ing the process steps, equipment, materials, and personnel involved in the manufacturing pro- cess unit operations. The goal is to identify any potential risks that could compromise product quality, safety, or efficacy. • Failure mode and effects analysis (FMEA). Conduct an FMEA to prioritize and evaluate the identified failure modes based on their severity, occurrence, and detectability. This analysis helps in understanding the most critical failure modes within the facility that would require attention. • D e s i g n a n d c o n t r o l s t r a te g i e s . D e ve lo p appropriate design and control strategies to mitigate the identified risks. This may involve modif ying equipment or process parameters, as well as potentially implementing additional controls and monitoring systems based on the process attributes. • Process validation. Conduct process validation studies to demonstrate that the implemented design and control strategies are effective in preventing or minimizing process closure fail- ure modes. Process validation typically includes these three stages: process design, process qual- ification, and continued process verification. • Process monitoring and control. Implement ro- bust monitoring and control systems to continu- ously monitor critical process parameters (CPP) and performance indicators. This would include the use of process analytical technologies (PAT) and real-time process monitoring to promptly detect any deviations. • Quality management system (QMS). Establish a comprehensive QMS to ensure adherence to standard operating procedures (SOPs), good manufacturing practices (GMPs), and other rel- evant quality standards. • Training and personnel qualification. Ensure that all personnel involved in the manufactur- ing process are adequately trained and qualified to perform their tasks effectively and in com- pliance with the required quality standards for each defined modality. • Change control. Implement a rigorous change cont rol s ys tem to a ssess t he i mpac t of a ny process ch a nges on process closu re fa i lu re modes. Changes to the process should undergo t horoug h eva luat ion a nd va l id at ion before implementation. • Regulatory compliance. Ensure that the valida- tion activities and documentation comply with relevant regulatory requirements, such as FDA in the United States or the European Medicines Agency (EMA) in Europe. A multimodal design approach A multimoda l manufact uring faci lit y refers to a ma nu fac t u r i ng a sset t hat ca n add ress d i f ferent manufacturing processes/platforms as elaborated upon previously. For organizations such as contract manufacturing organizations (CMOs), the decision to establish a multimodal manufacturing facilit y should be based on a thorough assessment of their strategic goals, market dynamics, and their techno- logical competencies. Considerations underpinning such a decision are described as follows: • Speed to market. Dif ferent ma nufact ur ing modes ca n of fer va r y i ng le vel s of s peed to market for some products. By having a multi- modal facility, a manufacturing organization can choose the most suitable approach for each product platform, accelerating product delivery. • Cost efficiency. Depending on the specific prod- uct and production requirements, different man- ufacturing modes can offer cost advantages. A multimodal facility empowers a CMO to choose the most cost-effective manufacturing method for each product, optimizing operational expenses.