Bench-Scale Characterization of Cleaning Process Design Space for Biopharmaceuticals

A method to evaluate the relative cleanability of new products.
Mar 01, 2009
Volume 22, Issue 3


The characterization and validation of equipment cleanliness are key requirements for biopharmaceutical facilities to assure that the cleaning process can meet predetermined cleanability criteria consistently and reproducibly. For a multi-product facility, the cost of performing such process characterization at large-scale could be substantial. This article describes how a robust bench-scale model can be used to characterize the key operating parameters of the cleaning process. A scale-down model that evaluates the cleanability of various protein drug products on stainless steel coupons was used to explore the process performance over a wide design space. The bench-scale cleaning model is also a useful tool for comparing the cleanability of various products and for developing new cleaning cycles.

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The design space concept as introduced by the International Committee on Harmonization (ICH) for a unit operation can be defined as the linkage between the input variables or process parameters and critical quality attributes.1 Characterizing the design space involves understanding these linkages and identifying variables and ranges within which consistent quality can be achieved. For the cleaning process, the design space can be considered the interactions among various operating parameters (e.g., temperature, soilant, cleaning agent concentration, dirty hold time) and their effect on performance parameters such as residual soil levels at the end of the cleaning process.

Drug product processing involves various process parameters that can affect the safety, quality, efficacy, and purity of the final dosage form.2 Cleaning processes also can have a direct effect on the critical quality attributes of a product by means of contaminant carryover through product contact equipment surfaces. Regulatory expectations call for biopharmaceutical companies to have a sound, documented cleaning validation approach that uses effective and consistent cleaning and keeps the carryover below the acceptable limits.3–5 Such an approach warrants a cleanability assessment before the introduction of a new product into the manufacturing equipment. Bench-scale cleaning studies are a useful model to evaluate the relative cleanability of new products with very low material requirements, well in advance of technology transfer to the manufacturing facility.6–9 Bench-scale models also provide the benefit of performing cleaning evaluations under controlled simulated conditions, thereby offering a useful tool to characterize the process design space.

There are several elements of cleaning process characterization, control, and validation including, but not limited to, cleaning cycle, equipment, sampling techniques, analytical assays, and acceptance criteria.5,7,10 This article focuses on the characterization of the cleaning process with respect to process parameters. A bench-scale model is used to evaluate four different protein drug product formulations over a wide range of operating conditions. Both single parameter and cross interaction among different operating conditions are studied to fully characterize the design space associated with the cleaning process. Results show that temperature and cleaning agent concentration are strongly coupled, and different protein products behave differently with respect to their cleanability because the process conditions are varied. The work also provides useful insights into the development of an optimized cleaning cycle for biopharmaceuticals.


In a typical cleaning process, cleaning agents such as alkaline and acidic reagents are used at elevated temperatures in combination with mechanical action to achieve removal of protein soilants from equipment surfaces. A combination of water and caustic acid rinses is used to achieve the desired level of cleanability needed to ensure minimal product carryover to the next product lot. A hot alkaline wash is considered the critical cleaning step in which conditions of high pH and high temperature are used to remove the protein by degrading it into smaller fragments, and to solubilize any hydrophobic residues.

A cleaning cycle relies on two pathways for soilant removal from equipment surfaces.9,11 The first pathway is the physical removal commonly achieved through mechanical action resulting from the convective action of the fluid flow. The efficacy of this mechanism is governed by the soil–surface interactions and the extent of adhesion. The second mechanism uses chemical interaction between the cleaning agents and the protein soils such as protein degradation, solubilization, wetting, and emulsification to remove the soilant from the surface.11 There are various inputs to the cleaning process that affect these cleaning mechanisms and thereby the overall performance of the cleaning cycle. These key operating parameters include the temperature of the cleaning solution, the concentration of the cleaning agent, the strength of the mechanical action, and contact time with the cleaning agent. In addition, other factors such as soil type, dirty hold time (i.e., how long the soiled equipment is held before cleaning), material of construction (stainless steel, glass, Teflon), and surface finish also affect the cleanability of the equipment.

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