Transitioning from Using RUO to CGMP Chemicals for Clinical Trials

Global biologics pipeline analysis The global biologics market is expected to grow at a CAGR of 8.7% and reach $664.7 billion by 2030.1 However, the regulatory demands, time and costs of bringing a new drug to market are also growing, with one study reporting a 27% increase in the number of endpoints for typical Phase II and Phase III trials since 2009. For new and emerging biopharma companies who want to be first to market with their molecule, the pressure of balancing budgetary and regulatory requirements while accelerating the pace from lab to clinic can be challenging. Common biopharma challenges going into preclinical and early phase trials Thousands of compounds are screened, tested and optimized in the search for new drug candidates. As the drug development journey progresses, fewer and fewer compounds advance. Only a small fraction is granted FDA approval. The entire process, from discovery to market, requires an estimated 10 to 15 years and can cost over $2.6 billion, while FDA approval will be granted to around 12% of the compounds that enter clinical trials.2 Mitigating risks and avoiding delays related to raw material sourcing and supply chain management can help new and emerging biopharma companies maintain a competitive edge. Common material risks In biopharmaceutical manufacturing, sourcing and applying regulatory guidance confidently and correctly to raw materials and products is not always straightforward. A thorough understanding of the material, including its role in the overall process, quality level and risks regarding safety and performance is fundamental. For example, source or starting materials that will become an essential part of the active substance will require different assessments and controls than other raw materials used during the manufacturing process. Additionally, the quality requirements of all materials and processes escalate upon entering human clinical trials. The global biologics market is expected to grow at a CAGR of 8.7% and reach $664.7 billion by 2030.1 TRANSITIONING FROM USING RUO TO cGMP CHEMICALS FOR CLINICAL TRIALS 2 JANUARY 2023 PRESENTED BY: PUBLISHED BY:Navigating the unknown: What to expect when transitioning from RUO to cGMP What is cGMP Current Good Manufacturing Practices (cGMP) are globally recognized guidelines for ensuring the safety, quality and traceability of manufactured products. The guidance emphasizes the continual improvement of industry best practices. The methods for maintaining compliance are integrated throughout the organization by way of quality systems, policies, procedures, material choices and training. In biopharma, adhering to these guidelines helps assure the safety, quality and consistency of drugs and other therapeutics manufactured for use in humans. Regulatory guidance, though broadly similar on a worldwide level, do vary by country or region. The formation of global organizations, such as the International Council for Harmonisation (ICH) and the International Organization for Standardization (ISO), helps reconcile diverse guidelines to maintain compatibility across regulatory bodies and streamline the compliance requirements for multi-regional projects. In global manufacturing, companies must comply with both general ICH and regional cGMP guidelines. Why is cGMP important? cGMP manufacturing is intended to produce safe, high-quality products that consistently meet regulatory and patient expectations. Integrating robust quality controls and monitoring throughout the manufacturing process can reduce non-conformances caused by human error, equipment malfunction and other failures, thereby minimizing the production of non-compliant products and the risks of causing serious harm to consumers. By providing a set of foundational standards for organizations to build and improve upon, companies from diverse regions can create products that meet the same final safety and quality specifications today and in the future. RUO vs. cGMP starting materials From sourcing raw materials to implementing quality systems, cGMP demands a greater organizational commitment than the research use only (RUO) approach; however, both have a role in the drug discovery process, as well as preclinical and clinical trials, respectively. Companies with limited manufacturing experience may expect that determining raw material quality is a straightforward task rather than a multi-layered endeavor that will affect all stages of bringing a biologic to clinic and to market. cGMP manufacturing is intended to produce safe, high-quality products that consistently meet regulatory and patient expectations. TRANSITIONING FROM USING RUO TO cGMP CHEMICALS FOR CLINICAL TRIALS 3 JANUARY 2023 PRESENTED BY: PUBLISHED BY:Upstream and downstream considerations RUO materials are not produced to the same quality standards as their cGMP counterparts and are not intended for manufacturing products for use in humans; however, due to their lower costs and wider availability, RUO materials are generally used in the research and discovery phases of the process. GMP-quality materials are required once the project transitions to clinical trials and the focus becomes testing in humans for safety, dose range and efficacy. While timing the introduction of cGMP materials and processes will vary in response to an organization’s risk sensitivity, cost, and the specific needs of the project, adopting cGMP materials as early as possible may actually save valuable time and resources by reducing inevitable manufacturing process adjustments and retraining when additional controls, systems and documentation are integrated. Typically, biopharmaceutical companies developing a therapeutic or vaccine should transition from RUO to cGMP materials no later than Phase I clinical trials. Producing cGMP-compliant biologics Manufacturing reliable cGMP-compliant biologics, like monoclonal antibody therapies, requires expertise, advanced technology and diligence. In addition to the general cGMP guidelines, products derived from biological sources require additional controls and must adhere to specific regulations due to the inherent variability of source materials. These biological sources, as defined by the World Health Organization (WHO) include: • Non-transgenic animal or plant sources • Transgenic animal, plant, or bacterial sources • Virus or bacterial cell cultures • Human sources3 The tech transfer: Working with suppliers and partners when transitioning processes Developing strong relationships with suppliers is essential to effectively transition from RUO to cGMP-compliant materials. Trusted suppliers will add their expertise to the planning and management of the RUO to cGMP transition. Identifying and effectively collaborating with reliable suppliers will make the transition shorter and simpler, thus reducing the potential for significant delays. Early cGMP compliance lays the groundwork for a simpler and more comprehensive tech transfer that can save valuable time and resources. The additional level of preparation offers potential advantages that include effective planning and project management, the ability to share robust information and analytical methods, allowing you to smoothly conduct pre-GMP engineering runs and GMP runs. Developing strong relationships with suppliers is essential to effectively transition from RUO to cGMPcompliant materials. TRANSITIONING FROM USING RUO TO cGMP CHEMICALS FOR CLINICAL TRIALS 4 JANUARY 2023 PRESENTED BY: PUBLISHED BY:Mitigating risks: The importance of quality In the first quarter of 2021, non-conformances affected 4.5% of chemicals received by the Thermo Fisher Scientific Production Chemicals and Services team.4 These errors consisted of mixed or incorrect lot numbers (27%), damaged materials (20%) and shipments not meeting customer specifications (19%).4 Figure 1 shows the most prevalent errors Thermo Fisher observed from cGMP chemical vendors in a three-month timeframe. Partnering with a quality-conscious distribution and service provider can help protect organizations from the complications and costs of poor quality (COPQ) resulting from supply and material errors. Monitoring disruptions in supply chain availability and intercepting and resolving shipment errors before the items reach the client go a long way to avoiding production slow-downs due to a lack of supplies or the inadvertent use of an out-of-spec material in the manufacturing process. FIGURE 1 Raw material errors from cGMP chemical vendors 5 JANUARY 2023 TRANSITIONING FROM USING RUO TO cGMP CHEMICALS FOR CLINICAL TRIALS Partnering with a quality-conscious distribution and service provider can help protect organizations from the complications and costs of poor quality (COPQ) resulting from supply and material errors. PRESENTED BY: PUBLISHED BY:Access to chemical documentation and dossiers Identifying reliable supply chain partners is based on quality management essentials that include: • QMS system: A QMS (quality management system) identifies, monitors and manages processes and resources to ensure that customer needs and requirements are met. • Order and supply chain management: Effective order and supply chain management helps ensure compliance with customer requirements at every turn, from order and storage through delivery. • Material receipt: A documented, multistep material inspection is needed to verify the condition and compliance of materials upon receipt. If non-conformances are identified, documentation and resolution steps are taken in collaboration with the vendor before nonconforming material is delivered to the customer. • Handling and storage: Raw materials are stored according to product and customer requirements in a cGMP warehouse under controlled conditions to prevent commingling with non-conforming or chemically incompatible products. • Picking and shipping: A documented process using state-of-the-art scanning technology ensures picking accuracy and compliance with customer requirements. Secondary sourcing and supplier selection Multiple suppliers as back-ups Supply chain disruptions can create chaos for biopharma manufacturers, especially when budgets and timelines are tight. Disruptions caused by supply shortages or spikes in demand dramatically increase manufacturing and sourcing costs and affect the ability to meet milestones. Identifying and maintaining multiple trusted suppliers along with employing a primary and secondary sourcing strategy creates a resilient supply chain by providing the depth needed to successfully weather fluctuations in the availability of supplies. Case study A recent experience by a CDMO client of Thermo Fisher emphasizes the importance of a comprehensive supply chain strategy that includes secondary sourcing, communication and transparency. The CDMO was facing a possible facility shutdown due to the supply disruption of a highvolume raw material. The upsurge in global demand increased the lead Disruptions caused by supply shortages or spikes in demand dramatically increase manufacturing and sourcing costs and affect the ability to meet milestones. TRANSITIONING FROM USING RUO TO cGMP CHEMICALS FOR CLINICAL TRIALS 6 JANUARY 2023 PRESENTED BY: PUBLISHED BY:time from three to 24 weeks and made predictable sourcing problematic. The CDMO’s only stop-gap was to hold excessive safety stock in their warehouse; however, this had additional drawbacks and was not a permanent solution. The Thermo Fisher team worked with the CDMO’s Directors of Materials Management and Operations to evaluate the extent of the supply disruption and its impact on the company. The results identified several key areas for improvement, including supply chain planning and transparency, supplier communication, a lack of multiple qualified material sources, and inadequate warehouse capacity due to the reliance on excessive safety stock. Through the expertise and access to a global network of qualified suppliers from Thermo Fisher, the CDMO was connected with an alternate provider within days and a stronger sourcing strategy based on contingent suppliers was developed and implemented. This second sourcing strategy allowed the CDMO to avoid $3M in lost revenue by maintaining their original production schedule.5 Additionally, the CDMO now enjoys $30K in annual savings and an 87% reduction in lead time due to improved raw material sourcing with an alternate supplier, as shown in Figure 2.5 FIGURE 2 Reduction in lead time by sourcing from an alternate supplier Resource allocation and planning Careful resource allocation and planning are critical to the success of small and medium biomanufacturers. Pool of qualified staff Manufacturing biopharmaceutical products is complex and highly regulated, requiring specialized systems, equipment, materials, technology and staff. Any adjustments made to the manufacturing process will require some level of technology transfer that wil