Key Considerations To Ensure A Successful Drug Substance Transfer

Scaling up to large-scale manufacture of biopharmaceutical products represents a critical stage in a life science company’s growth. However, large-scale technology transfers often present significant technical and operational challenges – challenges that many companies simply aren’t prepared to address. It is often assumed that small scale, early clinical phase manufacturing processes are robust and process steps are scalable. But manufacturing at scale requires adherence to established process parameters that are scale-dependent, as well as close examination of product characteristics and quality attributes. Limited knowledge, expertise and understanding of key and critical process parameters, process robustness, requirements for validation, analytical method transfer and validation, raw material lead times, procurement and management, and other factors associated with technology transfer and scale up can potentially lead to challenging (and expensive) delays.

At Samsung Biologics, which includes the world’s largest single capacity biologics drug substance (DS) facility, we frequently work with clients that are preparing to scale up and transfer their biopharmaceutical processes. Along the way, we’ve identified key considerations that all life science companies should consider when preparing to move their products from small scale to large scale production.

Make Process Development Your First Priority

Successful technology transfer and scale up are entirely contingent on the knowledge and understanding of, as well as the robustness of, the manufacturing processes used. Careful forethought and planning are required to ensure process reproducibility at scale with ability to support clinical and long-term commercial supply. Process development activities should encompass several integrated areas, including:

• DS Upstream Processing: Select and develop your media and cell culture operations considering enhanced development approaches utilizing design of experiment (DOE) studies, then evaluate process dependent parameters and optimize for scalability and robust performance, factoring in specific bioreactor conditions. Plan and develop pilot scale production to support necessary characterization and clinical studies to minimize potential deviations and ensure product quality & safety at manufacturing scale.
• DS Downstream Processes: Undertake process risk assessments early in the development cycle to evaluate equipment, materials and processing conditions for all process steps. Consider using resin screening to optimize chromatography and filtration processes for scalability and targeted performance, saving time (and costs) down the line. Also consider design of experiment (DOE) during development of unit operations and evaluate process robustness at representative scale to support clinical manufacturing. Minimize process changes at commercial scale between engineering runs and process performance Qualification (PPQ) to better avoid potential issues and batch inconsistencies.
• DS Formulation Development: Undertake studies to support a robust final formulation step, including concentration, diafiltration, excipient addition and mixing steps. Also undertake requisite protein characterization as well as buffer and excipient screening (factoring in stabilizers, solubilizers, surfactants, etc.). Where possible, plan to develop three to five formulation candidates by means of stability studies.
• Analytical Method Development: Method qualification and validation is an essential component of your long-term manufacturing strategy. Undertake a robust characterization of product, both in-process and for finished product. Additionally, consider time needed to validate more time consuming, biological methods such as potency or other cell-based assays, which evaluate critical quality attributes that cannot be typically evaluated using in-vitro methods.

By investing time and resources in these areas early on, you can improve batch-to-batch consistency and product quality, maximizing the probability of success prior to process performance qualification (PPQ). Properly designed engineering runs ideally manufactured to current good manufacturing practices (cGMP) should reduce the compliance risk of using specific raw materials, such as chromatography resins for non-human use batches and ensure product quality and patient safety.

If you require aseptic drug product (DP) filling services, ensure your supply chain and lead times are appropriately managed and operating with minimal or no interruption. Consider a state-of-the-art aseptic filling facility with a proven track record of GMP manufacture, ideally using facilities approved by several regulatory authorities with a successful audit and compliance history. Additionally, ensure your aseptic manufacturing team is staffed with highly experienced and educated personnel capable of supporting all aspects of your DP filling needs, from development through final commercial operations.

Then, Understand and Mitigate Key Operational Risks

Beyond taking appropriate steps to ensure your large-scale manufacturing processes are robust, scalable, and optimized, you should undertake risk mitigation as a core part of planning and execution at all stages of product development.

Ensuring your manufacturing facility adheres to cGMP practices is an important first step, as cGMP compliance is a requirement to ensure long-term product quality and safety. For clinical production, consider using a facility that can quickly and flexibly deliver changing production volumes. When you reach the point of commercial production, look for an adequately equipped facility with chromatography skids, virus filtration skids, and Class A bulk filling capacity, as well as product pool vessel capacities for your specific volume requirements.

In addition, you should also undertake a robust facility fit exercise, evaluating process equipment, facilities and utilities, process characterization and verification, including:

• Facility Fit Evaluation: Assess your processes and equipment to ensure process parameters developed at small scale are appropriate and will be operational at large scale, determine equipment comparability and identify any gaps that may require process changes of other mitigation.
• Data Integrity: Ensure data integrity and continued compliance with U.S. 21 CFR Part 11 and Eudralex Volume 4, Annex 11.
• Streamlined Sample Management: Develop comprehensive sample plans and leverage an appropriate laboratory information management system (LIMS) within the QC laboratories to automate workflows and integrate instruments to reduce errors and improve efficiency.

Work with a quality control (QC) team that co-ordinates with manufacturing, compliance, and analytical development teams to ensure successful, sustained cGMP manufacturing operations. If you partner with a CDMO, additional service offerings to provide comprehensive biosafety testing services (BTS) is another potential advantage. Robust biosafety testing includes established assays to ensure cell banks and material produced for human use are evaluated for bacteria, fungi, yeasts, mycoplasma, adventitious viruses, and any other potential contaminants to ensure consistent product quality and patient safety.

Samsung Biologics – A True CDMO Partner

Transferring your process technology to clinical or commercial scale requires careful planning in order to most efficiently invest your time and resources. As companies increasingly turn to CDMOs for biologics development and manufacturing, securing a succession of excellence in every stage of the process is essential for not only ensuring seamless operations, but also long-term success. That’s why over 30 pharma/biotech firms have trusted Samsung Biologics, the world’s largest and most forward-thinking CDMO, with 620 successful product batches and 47 regulatory approvals since 2011, representing a >98% batch success rate.

Samsung’s world-class Manufacturing, Science and Technology (MSAT) teams have extensive experience undertaking comprehensive process & facility fit and gap assessments throughout your company’s tech transfer process, from ideation to successful execution. We evaluate the manufacturing process, equipment, and facility fit and determine mitigation strategies to improve efficiency and minimize risk. Our manufacturing teams also have proven experience supporting traditional batch manufacturing, as well as capability to support innovative and advanced technologies such as N-1 perfusion processing.

CASE STUDY

Turning Process Innovation into Increased Productivity

A Closer Look at N-1 Bioreactor Perfusion

Samsung Biologics strives to develop and implement process innovations that provide value. We are currently leveraging N-1 Perfusion Processing, a process generally implemented in small-scale bioprocessing, for large-scale commercial applications. Perfusion processing utilizes a continuous bioreactor production mode that allows for fresh growth medium to be supplied to the mammalian cell culture while removing waste medium and metabolites.

By installing a bioreactor capable of alternating tangential flow (ATF) perfusion, we enable process intensification capable of achieving high cell culture densities (up to 10-fold) and product titers during bioprocessing. Recently, we successfully performed N-1 (3,000-L) perfusion with ATF to supply a client’s 15,000-L commercial production process. ATF perfusion reduced production time by up to 30%.

Our state-of-the-art facilities in Incheon, South Korea offer our life science partners:

• Cost Competitiveness: We provide clinical and commercial supply of biologics at globally competitive rates.
• Regulatory Compliance: We are routinely inspected and compliant with FDA, EMA, PDMA, and MFDS.
• Segregated Inoculation Suites: We reduce risk of cross contamination and ensure minimal changeover time.
• Optimal Scalability: We operate multiple plants with a broad range of scalable production, ensuring we can deliver product to any specification.
• Cutting-Edge Equipment: Our bioreactors and chromatography skids utilize the latest technologies and automation, and our analytical capabilities for both in-process monitoring and product release are among the most sophisticated in the world.
• Product Safety & Robust Supply: We have extensive experience undertaking critical process steps at large scale associated with viral reduction, inactivation, and filtration, delivering peace of mind.

At Samsung Biologics, we have the expertise to undertake robust process characterization studies, determine operating ranges for all critical process parameters and support process optimization early in the tech transfer process. We minimize potential delays associated with scale up and large-scale manufacturing of biologics, ensuring you can focus on what matters most: innovating for the benefit of patients.

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technology transfer efficient, effective, and risk mitigated.

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About Samsung Biologics

Founded in 2011, Samsung Biologics is a world-class CDMO committed to making a difference in global healthcare. We achieve our mission by providing quality-driven development and manufacturing of biopharmaceutical products. Our advanced cGMP facilities provide clinical and commercial products through cGMP-compliant practices that meet the regulatory requirements of the U.S. FDA, EMA, and local authorities. Our customer-oriented business model supports both collaborative novel drug development and high-quality, fast-turnaround contract manufacturing partnerships.