Technology transfer and scale down model development strategy for biotherapeutics produced in mammalian cells
© Kochanowski and Malphettes; licensee BioMed Central Ltd. 2013
Published: 4 December 2013
The goal of manufacturing process development for drug substance and drug product is to establish a commercial process capable of consistently producing drug substance/drug product of the intended quality. Based on regulatory requirements, the manufacturing process has to be characterized prior to process validation. Since performing the characterization study at the manufacturing scale is not practically feasible, development of a scale down model that represents the performance of the commercial process is essential to achieve reliable process characterization. The developed scale down model could also be applied for cell line selection, process and medium development, raw material evaluation, limit of cell age studies, process parameter excursions, etc. Process development and commercial production should not be on the critical path to market despite the compressed time-to-market expectations. That is why Technology Transfer (TT) is a vulnerable time for companies. According to World Health Organization, Transfer of technology is defined as "a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacture sites". In the pharmaceutical industry, Technology Transfer refers to the processes that are needed for successful progress from drug discovery to product development to clinical trials to full-scale commercialization or it is the process by which a developer of technology makes its technology available to commercial partner that will exploit the technology. This article describes the strategies and activities required to develop a scale down model. It also sketches a Technology Transfer approach for bioprocesses by focusing on the upstream part of a cell culture based process.
Scale down model development strategy
"Small-scale models can be developed and used to support process development studies. The development of a model should account for scale effects and be representative of the proposed commercial process. A scientifically justified model can enable a prediction of quality, and can be used to support the extrapolation of operating conditions across multiple scales and equipment . The key elements for designing a scale down model are inputs (raw materials and components, cell source, environmental conditions) and outputs (performance and product quality metrics, sample handling/storage, analytical methods). A scale down model can be equivalent for some outputs but not for all and still be a representative model. It should reproduce at small scale the effect/impact seen at large scale. The acceptability of an observed offset has to be statistically evaluated and scientifically understood.
Technology Transfer strategy
Technology transfer documentation
Bill of materials
List of all components and their step of use (Supplier, grade)
Research and Development reports
Historical data of pharmaceutical development of new drug substances and drug products at stage from early development to final application of approval - Quality profiles of manufacturing batches (including stability data) - Specifications and test methods of drug substances, intermediates, drug products, raw materials and components, and their rationale - Change histories of important processes and control parameters
Process flow charts - Scale up - Equipment changes - Media and feed preparation
Product information - Process step flow diagram - Cell culture steps description (cell line/ inoculum/expansion/production bioreactor - Media and feed preparation - Harvest description - Raw materials/equipment)
Technology transfer file
Introduction - Manufacturing process description, process parameters - Equipment - Raw materials - Analyses - Safety, environment - Stability (conditions, results) - Packaging (cold chain requirements, etc...) - Cleaning - Shipment characteristics and proper validation if needed - Historical data available
Technology transfer protocol
Technology transfer description - Scope - Objective - Responsibilities - Process Description - Equipment list (receiving unit) - Raw material list - Reference of Master batch record/number of repetitions and status of batches/acceptance criteria/relevant specifications/description of coaching
Manufacturing and testing description of the process
Product information - Process step flow diagram - Cell culture steps description (cell line/inoculum/cell expansion/production bioreactor) - Media and feed preparation - Harvest description (holding time/storage conditions) - Raw materials - Equipments
Routine and non-sampling plans
List of all the samplings that should be taken and kept in addition to the in-process control samples listed in the manufacturing description
Data recording list
Online and offline data to be monitored and recorded during the process
Description in details of the deviations and reporting of the impact on the product titer and quality
Technology transfer report
Technology transfer description - Objective - Scope - List of deviations and discussion - Process results and comparison to acceptance criteria -, Conclusions
A scale down models is a tool for developing and characterizing the process and should be designed and demonstrated as appropriate representations of the manufacturing process. The transfer of technology from R&D to the commercial production site is a critical process in the development and launch of a biotherapeutical product. The three primary considerations to be addressed during an effective technology transfer are the project plan, the people involved and the process.
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