Best Practices For Biopharmaceutical Technology Transfer: Facility Fit And Process Gap Assessments
During a long, complex journey of drug discovery with many specialized activities involved, technology transfer is an intrinsic part of the successful development, manufacturing, and commercialization of a product. Biopharmaceutical technology transfer requires careful planning and evaluation to meet project timelines for scale up and GMP manufacture.
Technology transfers inherently involve a number of technical, as well as logistical challenges as manufacturing processes that have been developed at small scale must be transferred and manufactured compliantly to GMP standards with commercial scale in mind. Even with the application of a platform manufacturing process and standardized procedures, facility and equipment capabilities at the intended GMP manufacturing site must be carefully considered together with a structured approach to technology transfer including risk assessment for phase appropriate manufacturing.
Furthermore, accelerated technology transfer timelines required to manufacture biologics to address specific unmet medical needs, such as the development of neutralizing antibody therapies for the treatment of COVID-19, may require an expedited assessment of facility and process fit. Alternate raw materials or equipment may need to be considered as soon as possible depending on the impact of supply shortages and lead times. An expedited technology transfer program may reduce the time needed to manufacture products at commercial scale, but as a result traditional process development timelines may not be possible.
The Importance of Facility Fit and Gap Analysis
One initial requisite for technology transfer is a detailed facility fit assessment and gap analysis, which considers the receiving site manufacturing capabilities, process controls, analytical requirements, material selection and facility design. The facility fit assessment requires a thorough understanding of the transferred process and product characteristics such that the process controls influencing quality attributes are known and their relationships characterized if appropriate for the required manufacturing phase. A close partnership with transparent communication of risks between sending and receiving sites is essential for a successful facility fit assessment.
In addition to sharing information and aligning expectations between the sending and receiving site teams, the primary purpose of the facility fit assessment is to identify the gaps between the existing process design and associated controls with the intended manufacturing site capabilities. The timing of this assessment is critical and will determine the overall project time required to complete technology transfer. For example, if additional equipment is required, the time taken to specify, procure and qualify new equipment often becomes the bottleneck for timely technology transfer completion. Large scale bioprocess equipment such as chromatography columns, bioprocess skids, UF/DF systems typically have long lead times. In cases where equipment cannot be purchased from a supplier without impacting timelines, the required equipment may be transferred from another plant or facility. Its historical use, including cleaning and sanitization, would need to be evaluated and fully documented to ensure no product quality risk from potential carry over or contamination.
The selection of materials, process aids, consumables and their associated testing requirements may also be time constraints and their availability for use on site is heavily influenced by vendor lead times. For example, customized single-use parts, such as filter or tubing assemblies, custom media formulations, specialized chemicals and chromatography resins, typically require long lead times, which are further extended with the ongoing COVID-19 pandemic. Considerations for material grade, specifications, and testing need to be identified as early as possible. Mitigation may extend to the utilization of qualified suppliers, common materials, compendial testing and alternate sourcing.
Facility fit and gap assessments usually start with an evaluation of the manufacturing process description from the sending site to determine whether the receiving site’s production and analytical equipment is capable of meeting the process parameter control ranges and required process outputs, including quality attributes. In addition to the operational control parameters, other factors also need to be considered. In order to assess process fit, a full mass balance is required to determine scale dependent quantities and volumes. For example, the expected cell culture titer and step yields provide an indication of the required process volumes that may result in liquid handling issues based on available chromatography systems or tank capacity. The accurate estimation of minimum and maximum volumes may also impact sampling location and cleaning effectiveness. Expected volumes may also not be optimal to ensure adequate mixing required for a product adjustment step such as dilution or titration. In addition, an understanding of the inherent process variability and/or influence of scale dependent parameters is important to accurately “book end” the process such that the mass balance represents the intended manufacturing process at the receiving site. The use of empirical and mechanistic modelling can also aid process fit with respect to this assessment.
Facility considerations include expected equipment flow rates and pressure limits, as the available bioprocess equipment may not be capable to operate at the required controls such that the flow rate may be below the operational capacity of available pumps to ensure consistent flow. The batch cadence (run rate) and operational safety are other factors influenced by flow rates and throughput that require consideration. For a cost efficient manufacturing facility, batch cadence and facility utilization are of primary importance. An in-depth understanding of operational durations, including equipment set up, process, changeover and cleaning times, as well as analytical requirements, such as in-process controls is fundamental. For example, an increased number of cycles with smaller chromatography columns will require additional process time that may not be supported at the time of technology transfer with the required intermediate stability or resin lifetime data. Another example may extend to the requirement for off-line analytical measurements as forward-process controls may result in batch interruption until the required testing result is available. Real- or near-time analytics may help resolve this bottleneck such as the application of SoloVPE for protein concentration measurement on the shop floor.
Recognizing Potential Bottlenecks or Pitfalls
Facility fit and gap assessments for early clinical phase products may be challenging because of limited historical manufacturing data. Process characterization is unlikely to have been completed and the process description and development information, such as process parameter ranges determined from small scale studies, may be insufficient. For early clinical stage products, process control capabilities to meet parameter set points or narrow operating ranges need to be evaluated. This may be based on existing process knowledge and understanding of similar platform processes, or by considering historical manufacturing data generated with similar products at the sending site.
This gap can be mitigated by partnering with and leveraging an experienced CMO’s manufacturing know-how to guide clients with respect to bioprocess control capabilities, platform approaches, standardized procedures and best known methods. Consideration of phase appropriate manufacturing is also important to determine the receiving site’s flexibility to make changes during technology transfer with respect to the quality systems and manufacturing procedures.
Another challenge may be encountered when undertaking facility fit for a legacy product that is being transferred with process improvements or modifications as part of a second generation product or under a continuous improvement paradigm. Whilst this may present additional risks, process changes to an existing commercial process are typically considered to improve manufacturing consistency or robustness, to replace older technology or improve yields. Specific changes to unit operations and process controls are usually supported with laboratory and manufacturing scale data. The output of the facility fit assessment is a comprehensive list of potential gaps identified that is evaluated and agreed by the technology transfer teams at both the sending and receiving sites. All intended process changes to products must be evaluated with respect to product and process comparability and the prior validated state as applicable.
Conducting a Thorough Risk Assessment
The second step of a facility fit assessment is to evaluate potential risks and challenges associated with technology transfer and identify remediation actions that may be required to ensure the process will consistently produce product of the required quality. Any gaps identified are evaluated using risk analysis or failure mode tools (FMEA), such as scoring potential gaps based on severity (impact on product quality) and occurrence (failure rate based on evaluation of historical manufacturing data) are quantified, and ranked as low, medium or high risk. Raw materials and consumables are also typically evaluated in a gap assessment. In addition to understanding the material attributes with potential impact to process performance or product quality, consideration must also be given to material preparation, storage, disposal, safe handling and any supply constraints.
Any risk assessment requires the appropriate technical knowledge and understanding of the process, analytical testing, and equipment required at manufacturing scale to produce the product. The risk assessment should be undertaken by a team of subject matter experts from technical (MSAT), Manufacturing, Quality Control, Quality Assurance, and Supply Chain representatives as applicable, with input from both the sending and receiving sites. Effective teamwork and knowledge sharing between technical and manufacturing teams is essential to ensure all gaps are identified and evaluated.
For medium and high scoring risks, a risk mitigation strategy is developed and the rationale and justification for the risk evaluation and any remediation actions must be scientifically sound and documented. Additional actions may be recommended for medium risks to reduce the risk to the lowest practical level. Risk mitigation strategies are generally proportional to the potential risk to product quality or process performance. In cases where high risks gaps cannot be easily mitigated, additional controls are considered. For example, if a mixing study at the receiving site does not represent worst case mixing conditions, additional sampling and testing (visual inspection, pH and conductivity) may be implemented to ensure sufficient mixing with additional mixing studies considered during subsequent manufacturing batches. If any gaps are identified, risk ratings and mitigation actions are determined, and recommendations for process or facility modifications are proposed to address any gaps. An assessment of risk pre- and post-remediation is recommended to document the impact of proposed changes to address the specific gaps identified.
Finally, an assessment of the regulatory CMC impact of the facility fit and gap assessment should be considered based on the intended countries and licensing strategy for product distribution from the new manufacturing site. If the intention is to add a second site of commercial manufacture to an existing regulatory filing, the impact of process changes on product comparability will need to be evaluated, combined with an assessment of the risk of meeting validation acceptance criteria when undertaking process performance qualification (PPQ). Additionally, any environmental or health and safety risks should be evaluated to ensure that there are no potential issues that could impact scale-up and large scale manufacture. For example, storage and handling of large volumes of solvents, including alcohols within a GMP production facility, may present health and safety risks that may need to be considered.
The availability and use of chemicals for biopharmaceutical manufacturing may also be impacted by government legislation (1). The recent inclusion of octylphenol ethoxylates, including Triton X, into the EU REACH legislation (Annex XIV) is a recent example of this. Triton X is used for some manufacturing processes for viral inactivation. Starting January 2021, Triton X may not be used unless authorization is granted by the authorities or the intended use is exempted from authorization. This has implications on the availability of these substances for European biopharmaceutical manufacturers and also non-European production facilities intending to export their products into Europe. The global sourcing of raw materials may also be impacted by other events, such as the current COVID-19 pandemic that may require an evaluation of existing supply chains.
A successful and seamless technology transfer requires extensive experience and know how. Undertaking a comprehensive facility fit and gap assessment as part of the technology transfer permits timely evaluation of any equipment or process gaps and reduces last minute surprises that may result in costly delays to biopharmaceutical development programs. It’s imperative to initiate the facility fit as a priority when initiating technology transfer to avoid unexpected delays and additional cost later that could impact the manufacturing schedule.
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.
Samsung’s highly qualified Manufacturing, Science and Technology (MSAT) teams have extensive experience undertaking comprehensive process and facility fit and gap assessments, from ideation to successful execution. We evaluate the manufacturing process, equipment, and facility fit and determine mitigation strategies to improve efficiency and minimize risk. Samsung Biologics’ manufacturing teams also have proven experience supporting traditional fed-batch manufacturing, as well as the capability to support innovative and advanced technologies such as N-1 perfusion processing. Our extensive track record entails not only successful technology transfers, but are also backed by appropriate risk mitigation plans and thorough evaluations, which we consider mandatory to prevent significant process changes that could be critical to your overall project timeline.
Contact us for further inquiry at sbio.bd@samsung.com
About Samsung Biologics Co., Ltd.
Samsung Biologics (KRX: 207940.KS) is a fully integrated, contract service provider offering development, manufacturing, and testing services, all from a single location. We provide highly tailored solutions to clients, while meeting the evolving needs of the global healthcare industry.
With proven regulatory approvals, Samsung Biologics is a trusted CDMO partner of choice, and is uniquely able to provide seamless offerings from cell line development to final fill/finish as well as laboratory testing services at every stage for biopharmaceutical products.
To maximize our operational efficiency and expand capabilities in response to growing biomanufacturing demands, Samsung Biologics is constructing a fourth plant, which will further advance the company’s standing as the world’s largest manufacturing facility at a single site — holding a 604KL total capacity upon completion. Our facilities are all cGMP compliant with bioreactors ranging from small to large scales. We continue to upgrade our capabilities to accommodate our clients by investing in single-use technology and additional aseptic filling capacity. Samsung Biologics has also opened a new R&D Center in South San Francisco to further expand our global presence and commitment to offering faster and better services to our clients. We are committed to an on-time, in-full delivery of the products we manufacture with our flexible manufacturing solutions, operational excellence, and proven expertise.
References:
- Substances fulfilling one or more of the criteria defined in Article 57 of the EU REACH Regulation can be identified as substances of very high concern (SVHC). REACH Authorization List 2020, Annex XIV
https://www.echa.europa.eu/authorisation-list